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The low risk group of patients includes NB patients without MYCN amplification with or without life threatening symptoms in the following clinical situations: . Autoři: Bousquet J; University Hospital, Montpellier, Stockholm and Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

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Karolinska universitetssjukhuset kontakt torrent

Опубликовано в Mpc tutorial books torrent | Октябрь 2nd, 2012

karolinska universitetssjukhuset kontakt torrent

Astrid Lindgrens Barnsjukhus, Karolinska Universitetssjukhuset metabolism och diabetes, Karolinska Universitetssjukhuset. Network building with clinicians at Karolinska University Hospital to discuss and design follow-up strategies. MGI-bild. Field Application Scientist. MGI. sep. Astrid Lindgrens Barnsjukhus, Karolinska Universitetssjukhuset metabolism och diabetes, Karolinska Universitetssjukhuset. NAVIGACIJOS ZEMELAPIAI NEMOKAMI TORENTAI The sandbox is A powerful uninstaller software that you When you define control remote computers. Chris is a I started getting repeated login errors. 30 days of above is for v1 because it with features such were later available.

In the Coronary Artery Calcification in Type 1 diabetes CACTI study, elevated fasting levels of triglycerides were independently associated with increased coronary artery calcification progression []. Whereas it is generally agreed that the utility of lowering LDL-cholesterol levels in type 2 diabetes patients nowadays is undisputed [], controversy lingers as to whether this is also the case in type 1 diabetes. However, treatment, chiefly by statins, indicates that LDL-lowering can be beneficial in reducing CVD incidence also in patients with type 1 diabetes [, ].

Hypertension is a common and over-represented co-morbidity among both type 1 and type 2 diabetes patients [29, ], compared to the general population, and is a strong predictor of CVD events []. It is particularly important to strive for rigorous blood pressure control if the type 1 diabetes patient also has albuminuria.

Increased risk for diabetes-related vascular complications is associated with components of the metabolic syndrome, in which insulin resistance is an important factor. This has been conclusively shown particularly in type 2 diabetes individuals [73, ]. This gives some clues, or at least hints, that insulin resistance per se may be an important risk factor for diabetic angiopathy not only in type 2 diabetes but also in type 1 diabetes [].

The quantitative impact of insulin resistance on CVD is not easy to dissect out, since it is co-incident with several other traditional CVD risk factors, e. Nonetheless, some epidemiologic studies lend support to the notion that insulin resistance is pathogenically important for CVD development also in type 1 diabetes. In the Pittsburgh EDC study, the hazard ratio of CHD was increased for those with a family history of type 2 diabetes, even after adjustments for known confounding factors in the insulin resistance syndrome [].

Excessive weight gain, not infrequently occurring as a direct consequence of intensified insulin treatment, has been considered as a cause for concern of contributing to CVD events in type 1 diabetes []. This was addressed among adult DCCT patients where it was found that the quartiles who gained most weight in both treatment groups also had the highest blood pressure and lipid levels []. Diabetes nephropathy is strongly associated to CVD.

Macroalbuminuria renders the diabetes patients susceptible to developing CVD. In the FinnDiane study, as well as in the Pittsburgh EDC study, both micro- and macroalbuminuria and ESRD correlated significantly with increasing mortality risk for each stage of renal compromise [71, 74]. Conversely, it is important to keep in mind that an improvement in glycemic control reduces the incidence of microalbuminuria.

Management approaches for dyslipidemia are the same between the organizations, i. Similar approaches apply for the treatment of hypertension, i. Hypertension is quite common in children and adolescents with type 1 diabetes [], in whom obesity, hyperglycemia and diabetic nephropathy aggravate this situation [].

These and other studies make it clear that elevated traditional CVD risk factors, such as high levels of HbA 1c , blood pressure and cholesterol, not only are all quite common during childhood and adolescence of patients with type 1 diabetes [], but also that surprisingly few of the patients receive antihypertensive or lipid-lowering medications, in spite of current guidelines from both the ADA, EASD and ISPAD.

Hemodynamic changes evoked by hypoglycemia include increased heart rate, widening of pulse pressure, due to reduced central blood pressure and peripheral artery resistance, as well as increased peripheral blood pressure []. Hypoglycemia is also assumed to cause malignant arrhythmias by prolonging the QT interval and cardiac repolarization, thereby increasing the risk of sudden death. In one autopsy study, it was demonstrated that sudden death was four times more common in type 1 diabetics compared to non-diabetic persons [].

Type 1 diabetes individuals are at great risk of iatrogenic hypoglycemia, not least due to the fact that insulin resistance is much less of a problem in type 1 diabetes as most of these patients are non-obese. Both in the DCCT and the SDIS studies, an increased incidence of severe hypoglycemia in the intensively insulin-treated groups was demonstrated [43, 44]. Notwithstanding this, none of these studies was designed to address long-term CVD consequences of severe hypoglycemia.

In a Swedish registry study, 1, type 1 diabetes subjects with CVD complications were investigated. Further a dose-response relationship between the numbers of previous hypoglycemia and survival after CVD, as well as CVD mortality, was demonstrated []. The present thesis project has its focus on macrovascular complications of diabetes.

On the other hand, study II has a combined micro- and macrovascular approach with chronic foot ulcers as the primary outcome measure. The development of diabetic foot ulcers usually starts with neuropathy, but is also closely related to the development of PAD. Over the years of follow-up, the level of glycemia -- both at baseline and at the follow-up study years -- was closely related to the progression of retinopathy []. A strong association between chronic hyperglycemia and microvascular complications has been conclusively demonstrated in several large epidemiological studies [95, 96, ].

As mentioned above, the SDIS and -- slightly later -- the DCCT trials were both pioneering and groundbreaking studies demonstrating that intensified insulin treatment halts microvascular complications in type 1 diabetes due to improved glycemic control [43, 44]. This treatment had also long-term beneficial effects on the macrovascular complications [99]. Whether microvascular dysfunction precedes the development of macrovascular complications remains a controversial and elusive issue.

However, microvascular complications in type 1 diabetes, such as peripheral neuropathy [], nephropathy [] and retinopathy [], are all independent risk factors for macrovascular disease. The DCCT and SDIS trials both found an undisputable effect on diminishing microvascular complications by means of intensive insulin treatment and thereby improved glycemic control [43, 44]. Self-monitoring of blood glucose levels did not exist; urinary glucose excretion was sometimes monitored.

Sometimes short-acting insulin was introduced as well. This, in conjunction with the establishment of HbA 1c measurements and blood glucose self-monitoring, made it possible to improve glycemic control more easily. The DCCT was launched in , eventually enrolling 1, patients with type 1 diabetes. They were randomly assigned to receive either intensified anti-hyperglycemic treatment or standard treatment with a mean follow-up of 6. Patients in the intensively treated group were introduced to three or more insulin injections per day -- or insulin pump treatment -- in contrast to the conventional treatment group which had one or two daily insulin injections.

Glycemic goal was to achieve blood glucose levels as close to normal as possible. These very impressive improvements were, however and perhaps not so surprisingly , accompanied by an increased risk of severe hypoglycemia in the intensive treatment group 62 vs. In this sub-study with adolescent patients, the risk of severe hypoglycemia was three times higher in the intensive insulin therapy group. Another report showed that levels of HbA 1c , both at study entry and during DCCT completion, were positively correlated to the risk of retinopathy progression [].

The first evaluation of macrovascular events demonstrated no statistically significant differences, although the absolute numbers were higher in the conventional treatment group []. Risk factors for CVD, such as dyslipidemia were improved in the intensive treatment group, but -- as expected -- weight gain was also significantly greater. After DCCT was ended, all patients were offered the intensive treatment regimen.

After 6 years, the cIMT was significantly greater among study subjects compared to age- and sex-matched non-diabetics; also the progression in cIMT was greater for those with conventional insulin treatment compared to the group receiving intensive insulin treatment during DCCT. On the other hand, the year follow-up analysis showed no difference in cIMT progression between the two DCCT groups from years 6 to 12 [].

These salutary effects on macrovascular complications in the intensively insulin-treated group were suggested not to be driven by differences in levels of HbA 1c , blood lipids, blood pressure or pharmacological treatment although more patients in the conventional group had beta blockers. Authors speculated that the earlier 6. Now, nearly 30 years after DCCT commenced, 1, of the original study subjects have been followed up, demonstrating a modest, although statistically significant, difference in all-cause mortality rate in favor of those previously randomized to initial intensive insulin replacement therapy compared with conventional glycemic treatment [22].

The treatment effects were, by any standard, very impressive. Per Reichard in in order to investigate whether intensive insulin therapy could reduce the incidence of microvascular complications in type 1 diabetes patients in Sweden [44].

One hundred and two patients were randomly assigned to receive either intensified conventional treatment ICT or standard treatment ST for a period of 7. Inclusion criteria were type 1 diabetes diagnosed before the age of 31, and requiring insulin treatment within one year , no or non-proliferative retinopathy, and normal urinary albumin excretion rate and glomerular filtration rate.

The treatment regimen in the ICT group consisted of four daily injections of insulin while the majority in the ST group received two daily injections of insulin. Patients were evaluated regarding microvascular complications after approximately 18 months [], 3 and 5 years of study start [, ], and at the end of the study [44]. A year follow-up was also made with respect to mortality and treatment side effects [44, ]. During the SDIS, four patients died in the intensive treatment group and three in the conventional treatment group and -- as in the DCCT -- a three-fold higher incidence of serious hypoglycemia was noted in the intensive treatment group, and a borderline significant weight gain [].

In the year follow-up of SDIS, the glycemic control was still significantly better in the intensive treatment group despite the fact that the randomization had ceased and treatments were individualized. However, even at this late time point, the microvascular complications were even more prevalent in the conventionally treated group [44, ].

Although the number of participants in SDIS was relatively few and the study primarily was designed and statistically powered to study microvascular complications, some sub-studies after 7. Fifty nine of the subjects were tested for risk markers of CVD such as flow mediated vasodilatation in the brachial artery an established surrogate marker for endothelial dysfunction , cIMT, arterial wall stiffness calculated and the carotid arteries scanned for plaques [].

The results showed a better outcome for the previously intensively treated group with thinner cIMT and less stiff arteries. Moreover, among all participants, patients with lower levels of HbA 1c had less stiff arteries and a better endothelial function [].

Although the mean HbA 1c converged between the two treatment groups in DCCT soon after study end, the effect of the diverging treatment intensity during the trial continued to cause more complications in the previously conventionally treated group [99, , ].

This phenomenon was later on described as a glycemic memory. One suggested mechanism behind the purported glycemic memory is epigenetic alterations, i. Epigenetic modifications can also be caused by alterations in the environment [] and by exercise. Experimental models have demonstrated that a high-glucose environment causes alterations in epigenetic post-translational histone modification affecting inflammation and vascular complications [, ]. Established CHD is a strong risk factor for recurrent events, especially if combined with diabetes [].

Coronary artery bypass grafting CABG is, together with percutaneous coronary intervention PCI , currently the methods of choice for interventional coronary revascularization therapy in CHD. This figure is even further increased if subjects with pre-diabetes i. Revascularization surgery for patients with multivessel CHD is a common procedure. Patients with diabetes and established CHD often have more disseminated and aggressive atherosclerosis and are at much higher risk of developing major adverse CVD events and death than those without diabetes [].

The outcomes of most studies have favored CABG over PCI as the preferred type of intervention, not least in diabetic subjects since they as mentioned above often have multi-vessel disease []. A recent meta-analysis, based on eight studies including some , subjects, also found outcome in favor of CABG compared to PCI []. However, in a sub-analysis of diabetic patients not specified by the protocol , the five-year survival rate was significantly increased in patients randomized to CABG [].

The five year event rates of all-cause mortality, non-fatal myocardial infarction and non-fatal stroke were all significantly lower in the CABG group compared to PCI []. The stroke frequency, on the other hand, was higher in the CABG group, being consistent with many other studies and demonstrated in a recent meta-analysis of 19 RCTs with 10, subjects []. The higher rate of stroke has been suggested to be caused by more extensive coronary artery disease, perhaps being typical for diabetes patients.

In this thesis, the following hypothesises were tested. First Study I , we hypothesized that young type 1 diabetes individuals have more signs of atherosclerotic development, measured by means of cIMT as a surrogate marker, and that they are more insulin resistant compared to subjects of a matched healthy control group.

Moreover, we also hypothesized that glycemic memory, or rather the earlier intensive insulin therapy, may explain the putative differences in outcomes between those groups. Since numerous studies have demonstrated a shorter longevity and an increased risk of CVD related mortality in type 1 diabetes, as compared to non-diabetic subjects, we hypothesized Study IV an increased risk of death in type 1 diabetes individuals, vs.

Briefly, these projects focus on macrovascular complications in individuals with type 1 diabetes in different settings. The last project was aiming at exploring the outcome of macrovascular complications in type 1 diabetes patients undergoing CABG and to compare the incidence of such complications with type 2 diabetes patients and non-diabetics. Twenty healthy peers aged years were also invited by means of visiting schools in the same area as our patients and constituted a matched control group.

The participants were followed for 7. These 72 individuals constitute the study population in Study II Figure 1. SDIS randomization ended after mean 7. Six patients participated only partially. The study population consisted of all persons, in total 39, patients, who underwent primary isolated non-emergency CABG in Sweden between and This was a cross-sectional study.

After a 12 hours overnight fast, blood test were drawn for analyses of blood lipids, creatinine and HbA 1c. BMI, waist circumference, and blood pressure were also measured. Thereafter a hyperinsulinemic euglycemic clamp was performed to measure insulin sensitivity. After the clamp procedure, cIMT was measured with high-resolution ultrasonography. Patients in the ICT group received extra education, including how to use self blood glucose tests several times daily.

They had continuous tutoring by telephone and scheduled visits to the diabetology outpatient clinic every 2 nd month. The ST patients were instructed how to use self blood glucose tests. They received no extra education and only discussed the treatment at regular visits to the outpatient clinic every four months. Glycemic control was measured by means of HbA 1c levels every four months for all participants.

Seven and a half years after the first inclusion into the SDIS, the randomization ceased and both the ICT and ST patients continued visiting the attending diabetologist according to the standard diabetes care at the time. The ST patients were now given advice on how to further improve their insulin replacement therapy in order to improve their HbA 1c levels.

Study II was a prospective follow-up study Figure 2. Seventy two patients from the original SDIS cohort were evaluated regarding skin microcirculation with iontophoresis topically applied with the following vasoactive stimuli: acetylcholine ACh [endothelial-dependent vasodilatation], sodium nitroprusside SNP [endothelial-independent vasodilatation], and capsaicin [C-nociceptive-dependent vasodilatation].

HbA 1c levels were prospectively collected from and tested for association with skin microcirculation. The cohort was then followed up as described in study III until the 31 st of December and primary outcome was defined as the first recorded hospitalization for ischemic foot ulcer. Study III was a longitudinal and observational study Figure 2.

Primary outcome was all-cause mortality, mortality in stroke, myocardial infarction and kidney failure and secondary outcomes were morbidity in myocardial infarction, stroke and ESRD. HbA 1c , lipid profile, blood pressure, microalbuminuria, smoking habits and use of acetyl salicylic medications, antihypertensive and lipid lowering agents were collected and the latest available data was recorded. Mean HbA 1c levels were also analyzed for the entire period from Study IV was an observational, nation-wide population-based cohort study.

The type of diabetes was obtained from NDR. The definition of type 1 diabetes was onset of diabetes before the age of 30 years and treatment with insulin only. Type 2 diabetes was defined as diabetes treated with diet or oral hypoglycemic agents alone, or age 40 years or older at onset and treated with insulin alone or in combination with oral hypoglycemic agents. All persons not included in the NDR were defined as non-diabetic.

The data were censored at the time of death or at the end of the follow-up period March 24, , whichever occurred first. Primary endpoint was defined as mean group difference in cIMT and its association to insulin sensitivity measured by glucose infusion rate obtained from the clamp.

Secondary outcomes were to explore changes in skin microvascular circulation, measured by laser Doppler flowmetry, after topical administration of ACh, SNP and capsaicin, by means of iontophoresis technique and its association to which group study participants were randomized to in the original SDIS study. The primary outcome was all-cause mortality and a composite mortality from myocardial infarction, stroke and ESRD. The secondary outcomes were morbidity disease-free survival from CVD complications, i.

The primary outcome was all-cause mortality. All the tests were drawn in the morning before the clamp. Serum insulin and C-peptide levels were analyzed locally by an immunometric method with monoclonal antibodies Modular E , Roche Diagnostics Scandinavia, Stockholm, Sweden. In SDIS, HbA 1c levels were measured in both groups at study entry, after 6 months and then approximately at every 4 months.

Mean HbA 1c levels were calculated for the whole 7. In our follow-up period from study II-III , analyses of HbA 1c and total cholesterol levels were performed by the local clinical chemistry laboratory whenever each participant had their routine visits. The hyperinsulinemic euglycemic clamp is considered to be the gold standard method for determining insulin sensitivity [].

The aim of the clamp is to increase the plasma insulin concentration level and maintain this until steady-state usually minutes. To avoid hypoglycemia, and to keep the blood glucose concentration at a constant level, a variable glucose infusion is given. In summary, one intravenous needle was inserted into the antecubital vein on the left arm and a second one, in a retrograde fashion, on the back of the right hand.

The hand was kept warm with an electric device for intermittent sampling of arterialized venous blood. Blood glucose samples were taken from the right hand vein catheter every 5 minutes and the rate of dextrose infusion was adjusted to achieve a blood glucose level of 5.

This calculation is assumed to correct for differences in prevailing, individual glucose and insulin concentrations. Measurement of cIMT is a well-accepted method used in estimating atherosclerotic changes in large vessel walls []. It has been used in both adult, childhood and adolescent populations [] and to assess impact from various chronic illnesses [, ].

The subjects head was tilted in order to get the common carotid artery CCA just proximal to the bulb placed horizontally across the screen. Magnified pictures were frozen incidentally with the R wave on the electrocardiogram. The cIMT was defined as the distance between the leading edge of the lumen-intima echo and the leading edge of the media-adventitia echo in the far wall Figure 4.

Lumen diameter was defined as the distance between the leading edge of the intima-lumen echo of the near wall and the leading edge of the lumen-intima echo of the far wall. The computer system calculated the average intima-media thickness and lumen diameter of the analyzed section. All measurements were performed by one operator, blinded to all other data, using an automated computerized analyzing system. The computer system calculated the average cIMT and lumen diameter of the analyzed section.

As cIMT of multiple measurements is most widely used, it was chosen as our primary end point measurement. Figure 5 cIMT measurement of the common carotid artery intima media layer, area indicated by square. Glucose in the blood binds irreversibly to the hemoglobin in the erythrocytes, thus creating glycated hemoglobin, i.

HbA 1c. HbA 1c is firmly established as a tool for evaluating both clinical interventions and scientific investigations. During the eighties and nineties, different countries had different HbA 1c standardization programs, i. Generally, the Mono S method readouts are 1. Hence, this method of measuring HbA 1c is used by the laboratories in Sweden since During the time of our follow-up , IFCC have introduced a change in reference method for calibration of HbA 1c [].

To estimate glomerular filtration rate, as a measure of kidney function, eGFR based on measurements of creatinine levels is a valid and widely used method. Iontophoresis is an established method by which a small applied electrical field is used to facilitate the rate of penetration of drugs into accessible tissues, such as skin Figure 6. In combination with laser Doppler flowmetry, the technique enables access to the microvascular bed and, by applying vasoactive substances, makes measurements of changes in cutaneous blood flow amenable.

A probe holder for combined single-point iontophoresis and blood flow measurement was fixed on the dorsum of the right foot. Skin blood flow at a depth of approximately 1 mm was registered by laser Doppler flowmetry technique Periflux, Perimed, Stockholm, Sweden. Basal flow was calculated as an average of flow for 10 seconds during the last minute before the start of iontophoresis. Blood flow after administration of drugs was defined as the average blood flow for the 10 seconds with the maximal flow following the stimulation.

Results are given as the change in blood flow for each of the vasoactive substances used, calculated as a ratio between the maximum blood flow after stimulation and basal flow, and presented as arbitrary perfusion units PU. Iontophoresis was performed with a 0. For the ACh we used an anodal current, while for the SNP and the capsaicin we used a cathodal current. The investigator and the interpreter of the results were blinded to the former allocation of the individual patient.

It became mandatory for all county councils to report to the register from and attained national coverage in From , the register also includes outpatient visits from specialized private and public caregivers.

A drawback is that, as of today, primary care is not covered in the IPR. On the other hand, people with type 1 diabetes are routinely followed in special care units at the hospitals in Sweden. A quality control of the data reported to the IPR is routinely performed.

The control includes ascertainment that compulsory variables, i. The validity of all variables is tested and if the data is obviously incorrect it is corrected and is sent back to the liable unit for approval. Today, virtually all type 1 diabetes patients are included in the register []. The Swedish Renal Register is a national health data registry for patients on maintenance for renal replacement therapy []. Every patient with chronic renal insufficiency starting dialysis treatment or receiving a kidney transplant should be reported to the register, and all dialysis and transplant units in Sweden report to the register.

Test of normality was conducted with Kolmogorov-Smirnov and Shapiro Wilks test. Spearman test was used for the correlation data. All risk factors were included and successively excluded in a stepwise order, starting with S i. Associations were determined with linear univariable and multiple regression analysis. The measurements of skin microcirculation for each of the vasoactive substances used ACh, SNP and capsaicin were log transformed in order to achieve normality and then studied in the regression analyses for predefined factors collected at the time of the iontophoresis: age, duration of diabetes, HbA 1c , smoking, sBP, and severe microvascular complications i.

Time to first hospitalization for ischemic foot ulcer was analyzed using the Kaplan—Meier method, and differences between ICT and ST groups tested with the logrank test. Time to death for all-cause mortality and mortality in myocardial infarction and stroke composite outcome , as well as time to first hospitalization for cardiovascular events, i. Patient characteristics were described using frequencies and percentages for categorical variables, and means and standard deviations for continuous variables.

Cox regression was used to estimate the risk of all-cause mortality or a combined end point all-cause mortality or hospital stay for myocardial infarction, heart failure, stroke, or repeat revascularization in patients with type 1 and type 2 diabetes in a comparison with reference patients without diabetes. All four study protocols are in full agreement with the declaration of Helsinki.

In study I, all participating adolescents and young adults, as well as the parents of those below18 years of age, gave written informed consent before inclusion. In study II, all participants in the iontophoresis study gave their written informed consent before inclusion. Seven of the type 1 diabetes individuals were treated with insulin pump and 13 with multiple daily injections, having a mean insulin dose of 0.

There was no difference in HbA 1c between those treated with insulin pump and those with insulin injections 68 vs. As expected, glucose homeostasis differed between the study groups; however, there were no significant differences in BMI, waist circumference, blood pressure or in lipid profile between groups. Mild retinopathy was found in seven diabetes individuals and moderate in one. There was no difference in carotid lumen diameter between the study groups.

Type 1 diabetes individuals were significantly more insulin resistant, demonstrated by a significantly lower GIR 5. Also, the glucose clamp-derived index of insulin sensitivity S i index; adjusting for insulin concentration during clamp was correspondingly lower in the diabetes group compared to the non-diabetic group Figure 7 Association between cIMT and insulin sensitivity in diabetes individuals and controls. No such correlations were observed for the other risk factors of atherosclerosis, i.

When introducing all the atherosclerotic risk factors in a multivariate regression model, with cIMT dependent and group explanatory , S i abolished the significant association between cIMT and group, with no such effects for the other factors. Whenever the S i factor was excluded -- but including one or more of the other risk factors in multivariate analyses -- the association between cIMT and group was, again, statistically significant.

Seventy-two patients participated in the iontophoresis study, 35 from the former ICT group and 37 from the former ST group. All 72 were followed up until the end of our follow-up in Group characteristics for the ICT and ST groups revealed no statistically significant differences, except for a more frequent use of anti-hypertensive treatment in the ST group Table 2. The incidences of nephropathy and retinopathy were significantly lower in the ICT group at the time of iontophoresis; this is in accordance with the previously published results from the SDIS [44].

During the 20 year follow-up from to and in , HbA 1c levels were similar between the groups. There were no significant differences in total cholesterol levels at any point during our follow-up period from to Cholesterol was not measured in the original SDIS study. During the median 28 years of follow-up, 13 patients developed ischemic foot ulcer. Figure 8 Ischemic foot ulcer disease-free survival. At time of the iontophoresis, the basal skin microcirculation blood flow rates did not differ between groups ICT 4.

During the iontophoresis, skin microcirculation blood flow was higher in the ICT group compared with the ST group for all three vasoactive substances applied: ACh 8. The differences between groups were already evident during the shortest stimulation time 15 s when ACh or SNP were applied, and with the second shortest stimulation time 30 s during iontophoresis with capsaicin-induced vasodilatation.

By using the other two time points, i. At the end of the present follow-up, observational study group characteristics showed no statistically significant differences, except for a significantly higher use of anti-hypertensive treatment in the ST group Table 3.

There were no study subjects lost to follow-up, nor were there any missing data at year Three persons died from cancer, i. For the predefined cause-specific mortality composite endpoint, i. The diabetes duration for the person in the ICT group before dialysis was 33 years.

All people who developed ESRD died during the follow-up. Patients with type 1 diabetes were more likely to be younger, female, and have diabetes nephropathy, PAD or heart failure in comparison with patients with no diabetes or type 2 diabetes. The mean follow-up time was 5. Figure 10 The crude incidence rate of death in patients with no diabetes, type. When analyzing death and MACE as a composite outcome, the associations found were similar to those for death alone, with nearly a doubling of risk in patients with type 1 diabetes and only a small increase in risk in patients with type 2 diabetes Figure In When HbA 1c levels and duration of disease were added to the multivariable model, the risk for all-cause mortality in type 1 diabetes compared with type 2 diabetes was slightly attenuated HR 1.

The patients with type 1 diabetes had a longer duration of disease mean The adjusted risk of death was similar among men and women with type 1 diabetes: HR 1. After adjustment for confounders, the relative risks for death and MACE were similar for both men and women with type 2 diabetes. The main findings of this thesis are that throughout life, and in different populations and concepts, type 1 diabetes renders the affected person a significantly increased risk of macrovascular complications.

Adolescents and young adults with type 1 diabetes have signs of early atherosclerotic development, as reflected by increased thickening of the intima-media layer of the carotid artery walls concomitant with insulin resistance. Long term follow-up of intervention with earlier intensive insulin treatment, improving glycemic control, seems to exert a favorable impact on the outcome in future macrovascular complications, as well as for diabetes nephropathy. Also, type 1 diabetes individuals have a dire outcome after CABG interventions compared to type 2 diabetes and non-diabetes individuals in the same situation.

Insulin resistance and markers of atherosclerosis cIMT. There are other studies that have examined the influence of insulin sensitivity on cIMT, of which some [], but not all [], have found an association. Not only insulin resistance, but clustering of metabolic factors such as hyperglycemia, hypertension and dyslipidemia have all been demonstrated as risk factors involved in the progression of cIMT [, ].

Progression of cIMT was associated with age, blood pressure, smoking, blood lipids, microalbumiuria and levels of HbA 1c []. Also the progression of cIMT was greater for those with conventional insulin treatment, compared to the group with earlier intensive treatment during DCCT []. The discrepancy between our study and others, in terms of lack of association between glycemic control and cIMT, may possibly be explained by cohort size, age and diabetes duration [, ].

SDIS and DCCT clearly demonstrated that intensified insulin treatment and improved glycemic control retards microvascular complications in type 1 diabetic patients [43, 44]. The two trials share many features regarding population and study protocol, as well as the timing. We found in our SDIS follow-up study that the previously intensified insulin-treated individuals had significantly fewer ischemic foot ulcers and ESRD events.

One can argue that these findings might purely be by chance. SDIS was a small cohort and therefore underpowered and never designed to study macrovascular outcome. On the other hand, previous reports from the SDIS cohort have demonstrated that markers of atherosclerosis can be halted by intensified insulin treatment []. The long-term perspective of nearly three decades in SDIS also strengthens our findings. Even though the rates of diabetes-related complications have substantially declined over the last decades, there is still a large burden of the disease [15] and in fact higher for type 1 diabetes individuals compared to type 2 [].

One explanation for this might simply be owing to the duration of the disease. An average duration of 45 years, as observed in SDIS, substantially increases the risk of complications. The same goes for the findings after CABG intervention where the type 1 diabetes patients had more than 30 year longer diabetes duration compared to their type 2 diabetes counterparts. Here the type 1 diabetes individuals had twice the mortality risk compared to type 2 diabetics [].

The former were also more likely to have diabetic nephropathy, PAD and heart failure, thus having more advanced macrovascular co-morbidity. Only levels of HbA 1c were associated with endothelial-dependent ACh-induced and C-nociceptive-dependent capsaisin-induced skin microvascular blood flow, but not with non-endothelial dependent SNP -nduced.

C-nociceptive-nerve fibers stimulate the release of vasoactive substances, e. Development of foot ulcers in patients with diabetes is common with serious implications, including leg amputations []. The majority of leg amputations are caused by PAD in combination with skin infection [66]. Still, microvascular disturbances and progressive neuropathy most often precede the development of foot ulcers []. Glycemic control and diabetes nephropathy. We found that intensive insulin treatment for an average of 7.

Since there were multiple secondary outcomes and no correction was made for multiplicity, this result should be interpreted with some caution. Impairment of GFR is the unified common pathway for renal failure, i. Diabetic nephropathy, including ESRD, clearly adversely impacts the mortality rate [24, 25], which was also observed in the SDIS follow-up study where patients had a mean survival rate of only 28 months after the start of dialysis.

These findings are hopeful and provide impetus for continuous efforts in early improvement in glycemic control and treatment of albuminuria and hypertension [, ]. There is a relationship between hypoglycemia and CVD mortality in type 1 diabetes []. In our studies, we did not investigate hypoglycemic events in association to macrovascular complications.

Earlier follow-up studies from these trials have not shown any differences in cognitive function [, ]. In contrast to this, cross-sectional studies have demonstrated some detrimental impact of severe hypoglycemia on cognitive function in type 1 diabetes individuals [, ]. Others have expressed concerns regarding weight gain as a result of intensified insulin treatment []. Glycemic memory. The long-term outcomes from the SDIS, may suggest a role for glucose memory, in which the 7.

Also, an increasing number of experimental studies where a high glucose environment can cause alterations in epigenetic post-translational modifications -- for example affecting inflammation and vascular complications [, ] -- offer mechanistic insights into this phenomenon. It was also recently suggested that levels of HbA 1c , very early from the onset of type 1 diabetes, i.

Throughout the work with the thesis, the over-arching goal has been to describe diabetes complications as a continuum gradually developing in a life-time perspective. We have found in our studies on type 1 diabetes that:. Study I was an explorative study with no power analysis conducted. Also, since this study was cross-sectional no conclusions can be made regarding causal relationship between cIMT and insulin resistance.

The SDIS cohort was small and was not primarily designed for analyses of macrovascular complications. In study III, no correction was made for multiple comparisons. On the other hand, CABG is today considered the treatment of choice in patients with diabetes. I believe there is a need to explore treatment regimens for handling unsatisfactory glycemic control and weight gain, and to further explore the role of adjuvant type 1 diabetes treatment that traditionally has been traditionally been targeting type 2 diabetes, metformin [], incretin-based therapy [].

Also, sodium glucose transporter-2 SGLT2 inhibitors has gained interest [], but in the light of recent reports on development of ketoacidosis during treatment in type 1 diabetes patients the safety needs to be better evaluated []. Some of these anti-diabetic agents may even have beneficial effects on the vasculature beyond glucose control []. In conjunction with this, the impact of insulin resistance and possible gender differences in development of long-term CVD complications in type 1 diabetes individuals would be interesting to investigate.

A recent publication by Steineck et al. Here the adjusted hazard ratio for fatal CHD and CVD were significantly lower in the group using insulin pump treatment compared to patients using multiple injections. Another aspect worth considering might be the influence of treatment mode on blood glucose variability and its effect on endothelial function and repair.

Continuous glucose monitoring systems offer more sophisticated control of diabetes management, especially if used in combination with insulin pump therapy, i. In Sweden the use is common in children and adolescents with diabetes but less so in adults, although increasing. Internationally, recommendations slowly change towards more active use of these techniques in adults as well []. As the use of continuous glucose monitoring systems and insulin pump therapy are more expensive, compared to self-monitoring of glucose and treatment with multiple daily injections, there is a need for studies evaluating effects on treatment satisfaction and long term complication development [, ].

Since type 1 diabetes individuals have an increased risk of adverse outcomes after CABG [] , one obvious issue to address is whether preoperative treatments could predict CVD events or death after such a procedure. It would also be of great interest to investigate whether hypoglycemia or glucose variability, or variability of glycemic control may predict CVD events or death after CABG in type 1 diabetes individuals.

They instead found an association between high levels of HbA 1c and mild cognitive dysfunction. Microvascular complications, smoking, hypertension and increased levels of HbA 1c are all risk factors affecting cognition and psychomotor function []. These issues need to be further studied. En person i den intensivbehandlade gruppen och sju i standardbehandlingsgruppen insjuknade i terminal njursvikt.

I have learned a great many things from our many discussions through the years. I owe special thanks to Thomas, my main supervisor. Your expertise in research in general and diabetes in particular have been invaluable. You have firmly guided me through this project with your constructiveness and great enthusiasm.

I am filled with admiration of your generosity towards me and of your compassion. No one could ask for a better teacher. To Svante, for your constant encouraging and willingness to assist and for sharing insights in your scientific knowledge. The free fatty acids are waiting for us.

I also want to thank Kerstin for sharing your great expertise with me and for, calmly, pointing me in the right directions. I also want to thank my co-writers for all their efforts during this project. My warmest thanks to Gunnar Lilja, my mentor, for being encouraging and helpful and for putting my research in perspective. Anna Wennberg, my dearest friend, for watching over me and supporting me at all times. Our walks and endless discussions have been invigorating.

Please, keep on LOL. To Anna Lindholm Olinder for inspiring me to continue with this project and for valuable input. I am also grateful to Monica, Margareta, Lotta and Katarina and the rest of the diabetes team for covering for me and for giving me space to finish this project.

I owe you one. Finally, I owe many thanks my family. To my parents Solveig och Per for their never ending love and support. To my sister, Maria, and to Lena and Pelle for your constant support. To my dear wife Charlotte. Without you this would not have been possible. I love you very much. To you and to Paula, my daughter, for being the two most important persons in my life.

I am also grateful for receiving grants from the Childhood Diabetes Foundation, The Samariten Foundation and Svenska diabetesstiftelsen. Bluestone, J. Herold, and G. Eisenbarth, Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature, Harjutsalo, V.

Sjoberg, and J. Tuomilehto, Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study. Lancet, Maahs, D. Endocrinol Metab Clin North Am, Dabelea, D. Berhan, Y. Diabetes, Craig, M. Pediatr Diabetes, American Diabetes, A. Diabetes Care, Imagawa, A. N Engl J Med, Alberti, K. Zimmet, Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation.

Diabet Med, Shaw, J. Sicree, and P. Zimmet, Global estimates of the prevalence of diabetes for and Diabetes Res Clin Pract, Kannel, W. McGee, Diabetes and cardiovascular risk factors: the Framingham study. Circulation, Muller-Nordhorn, J. Eur Heart J, Berg, J. BMC Cardiovasc Disord, Gregg, E. Soedamah-Muthu, S. Laing, S. Miller, R. Secrest, A. Livingstone, S. JAMA, Lind, M. Lusis, A. Ross, R. Hansson, G. Stary, H. Krantz, J. J Pediatr, Andersen, A.

Diabetologia, Prevalence of hypertension in newly presenting type 2 diabetic patients and the association with risk factors for cardiovascular and diabetic complications. J Hypertens, Petitti, D. Arch Pediatr Adolesc Med, Dawber, T. Meadors, and F. Moore, Jr. The Framingham offspring study. Am J Epidemiol, Garcia, M. Sixteen year follow-up study. McGee, Diabetes and cardiovascular disease.

The Framingham study. Orchard, T. Koivisto, V. Kleinman, J. Lloyd, C. Gender differences in risk factors but not risk. Arterioscler Thromb Vasc Biol, Morrish, N. Moss, S. Klein, and B. Klein, Cause-specific mortality in a population-based study of diabetes. Am J Public Health, Huxley, R.

Lancet Diabetes Endocrinol, DCCT and w. Reichard, P. Nilsson, and U. Rosenqvist, The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. Marchant, B. J Am Coll Cardiol, Dorman, J. Mortality results. Green, A. Hougaard, Epidemiological studies of diabetes mellitus in Denmark: 5. Mortality and causes of death among insulin-treated diabetic patients. Klein, B. Arch Intern Med, Skrivarhaug, T.

Simons, L. Heart Lung Circ, Hamer, M. Atherosclerosis, Jauch, E. Stroke, Adams, H. Neurology, Sundquist, K. Li, Type 1 diabetes as a risk factor for stroke in men and women aged a nationwide study from Sweden. Fuller, J. Stevens, and S. Ann Med, Wang, S. The world health organization multinational study of vascular disease in diabetes.

Hagg, S. Diab Vasc Dis Res, ESC, G. Boulton, A. Br J Surg, Kumar, S. Singh, N. Armstrong, and B. Lipsky, Preventing foot ulcers in patients with diabetes. Reiber, G. Jude, E. The 18th Camillo Golgi lecture. Kennon, B. Jorgensen, M. Almdal, and K. Faerch, Reduced incidence of lower-extremity amputations in a Danish diabetes population from to Molitch, M. Rossing, P. Pambianco, G. Costacou, and T. Orchard, The prediction of major outcomes of type 1 diabetes: a year prospective evaluation of three separate definitions of the metabolic syndrome and their components and estimated glucose disposal rate: the Pittsburgh Epidemiology of Diabetes Complications Study experience.

Groop, P. Nordwall, M. Deckert, T. The Steno hypothesis. Raile, K. Ceriello, A. Roy, M. Kidney Int, Genuth, S. Weinrauch, L. J Clin Hypertens Greenwich , Thorn, L. J Am Soc Nephrol, Simpson, M. Cardiovasc Diabetol, Costacou, T. Ferrell, and T. Orchard, Haptoglobin genotype: a determinant of cardiovascular complication risk in type 1 diabetes.

Asleh, R. Circ Res, Eliasson, B. Prog Cardiovasc Dis, Group, A. Writing Committee, and M. Lu, L. Mackay, and J. Pell, Meta-analysis of the association between cigarette smoking and peripheral arterial disease. Heart, Schwab, K. Int J Adolesc Med Health, Brownlee, M. Goh, S. Cooper, Clinical review: The role of advanced glycation end products in progression and complications of diabetes.

J Clin Endocrinol Metab, Dyer, D. J Clin Invest, Klein, R. Lehto, S. Forrest, K. A prospective study. Nathan, D. Selvin, E. Ann Intern Med, Khaw, K. Int J Epidemiol, Prince, C. Inzucchi, S. DCCT and R. Trial experience. Perez, A. Q: Do you think the weight loss is less when lixisenatide is used in combination with insulin vs. A: I would refer you to the LixiLan-O trial, where we saw greater weight loss with lixisenatide alone. Here we have mitigation of the weight gain with insulin glargine.

Q: But the average weight loss seems to be less here than when you add on a GLP-1 agonist without insulin or even separately. A: Part of it might be the final dose, which was 17 mcg of lixisenatide on average. Was the administration of glargine alone done at the same time? A: Glargine could be administered at any time and it was consistent throughout the trial. The combination was injected an hour before breakfast. Do you think the results would be different if it was administered with the largest meal rather than breakfast?

There was a sub-study looking at dosing at the main meal vs. Were the profiles of both components really preserved? It seems like a very weak effect. A: The PK data were consistent with what was seen in the lixisenatide standalone program. I would also state here that we had a greater A1c reduction down to 6.

Would you anticipate different results if you had a more well-controlled group? The 7-point SMPG, reflective of control in the comparator group, showed the control we typically see with titration with insulin glargine postprandial glucose of ss during the day.

This, along with detailed review of titration, superimposable fasting glucoses, and insulin doses all support appropriate titration in the control group. Q: Can you give us an idea on how the insulin was adjusted? A: The basal insulin glargine dose was given according to the classical algorithm used for a patient with basal-only insulin.

It was then titrated by 2 units. Q: You had a baseline A1c of 8. Did you look at those non-responders? A: The patients had an excellence response if you look at the standard deviation. You see that there is minimal variation, suggested that nearly all the patient responded to therapy. The difference between the two groups was highly significant between the two groups.

Q: Dr. Stephano Del Prato: There is something that is not completely clear to me. People in the placebo group required 26 more units of glargine compared to 13 units for dulaglutide, yet there was no difference in the rate of hypoglycemia. What is the explanation? Because one of the things that we have been exposed to is that the combination of insulin plus a GLP-1 agonist often comes with a reduction in hypoglycemia.

Is it because of the titration? A: Yes, I think it is the titration. Stephano Del Prato: Do you have the time course of the hypoglycemic events? A: [Dr. Pozzilli showed the slide with the hypoglycemia data, which is written in an above bullet point]. Min remarked that in the absence of head-to-head comparisons, these results could serve as the best available evidence for selecting oral agents in patients uncontrolled on insulin. Did you include both doses or the maximum dose? A: We included the data from the maximum approved dose.

A: Thank you for your question. We did not stratify the patients by A1c. The study recruited patients with inadequate glycemic control on diet and exercise A1c Twenty-six-week data showed that both ertugliflozin doses provided statistically significantly greater A1c reductions vs. Week Change from baseline to wk Ertugliflozin 5mg. Ertugliflozin 15mg.

Ertugliflozin 5mg vs. Ertugliflozin 15mg vs. Body Weight. SBP mmHg. DBP mmHg. Odds Ratio. Difference in least squares means based on a constrained longitudinal data analysis model. A1c declined a strong 0. More study details below! A1c Results. Usual Care. Time In Range Results.

Hypoglycemia Results. Hyperglycemia Results. Other Results. Study Background and Baseline Characteristics. CGM compliance, said Dr. Wolpert, is all about the tradeoff between benefits and demands — with better technology now accurate, reliable, easier to use , the benefits are starting to outweigh the hassles for more patients. Indeed, Dr. To close his remarks, Dr. Medtronic presented accuracy data from a pivotal study of its fourth-generation sensor Enlite 3 , to be used with the MiniMed G or the Guardian Connect mobile app.

Eight-nine participants took part in the study, each wearing two sensors on the abdomen one paired to the G pump and one paired to Guardian Connect mobile app; we have averaged the data for brevity. Enlite 3 was calibrated once at the start of every hour in-clinic visit, and not again unless the device asked for a smart calibration.

Of the 89 study participants, 26 had type 2 diabetes of whom 16 did not require insulin. At some point, further improvements in accuracy for any company will offer diminishing marginal value, and we continue to believe the future of CGM innovation will be in dramatically cutting cost, reducing calibrations, improving on-body wearability, and offering valuable software that augments the data.

Obviously, it needs to give the data people expect too! Getting the right balance of all these factors is the tricky part, and Dexcom and Medtronic are both talking about multiple product lines with different indications e.

Following its ATTD poster hall debut , a Medtronic poster shared a larger data set on its fifth-generation sensor i. This accuracy study included 37 participants with diabetes who wore up to four sensors on the abdomen or arm for 10 days. Meal challenges were administered at three in-clinic session days 1, 7, 10 , and blood glucose measurements were recorded every 15 minutes for three to four hours with the Bayer Contour Next Link meter. Participants were also asked to take blood glucose measurements daily when at home.

Overall MARD was Sensors lasted a mean of 9. The fifth-gen CGM includes a minute warm up, redundancy via two sensor flexes, a proprietary fusion algorithm to combine the two outputs, and intelligent diagnostics to assist with fault detection and sensor health. Overall, this feasibility data looks encouraging, though the accuracy is behind what Dexcom has said it expects for its ten-day wear, one calibration per day G6 similar to the current MARD of 9.

The OpenAPS design considerations posted here are pretty instructive on the safety front only temp basals, no automatic correction boluses, etc. Our takeaways from this poster and inspiring community are: i automated insulin delivery can make a huge difference, even for well-controlled patients; ii even though the system is burdensome to set up and wear, patients would not do it and use it unless the benefits were worthwhile; iii lots of learning is occurring in the OpenAPS community that could be leveraged for commercial systems; iv OpenAPS could push the FDA and industry to move faster, and that is a good thing; and v the relative risks here seem low, given the setup burden, the solid design for safety, and real-world dangers of insulin therapy.

The single-arm, multicenter investigation enrolled 71 patients with type 1 diabetes, who had two sensors inserted bilaterally into their upper arm Clinical Trials Identifier: NCT At first glance, six-month accuracy was relatively encouraging and consistent with preliminary day data first seen at DTM — overall MARD was We look forward to seeing how initial commercialization goes this year in Europe, and what Senseonics can get in its label with this updated long-term data e.

Steven Russell summarized a paper he co-authored with Dr. Roy Beck, soon to be published in Diabetes Care. David Maahs also summarized a soon-to-be-published Diabetes Care paper focused on standardizing a short set of basic, easily interpreted outcomes in artificial pancreas studies. The paper has 24 authors, many of whom are considered leading thinkers in the field. The goal is to facilitate interpretation and basic comparison between studies, and more importantly, to accelerate adoption of artificial pancreas technologies via regulators, HCPs, payers, and patients.

As an aside, Dr. Maahs has accepted a position to join Stanford pediatric endocrinology team — congratulations to Dr. Bruce Buckingham — again!! Mean CGM glucose. Standard Deviation. Coefficient of Variation. TDD of insulin. TDD of glucagon or other hormones.

Other considerations:. Study design and stratification into relevant subgroups. ITT analysis. Report medians quartiles instead of mean if not normally distributed. Ascensia has come to ADA with a bang! Additional EU launches are planned for later in The Contour Next One system is still being reviewed by FDA and the company anticipate clearance before the end of The purpose of the soft launch is to gather feedback from early users to inform the subsequent full-scale rollout.

Back to the booth, the infusion set itself was not on display as BD — per usual — focused its exhibit on injection counseling technique. The demo allowed us to experience an injection technique counseling session as a patient with type 2 diabetes who had just been instructed to go on insulin, with one video documenting common mistakes physicians make and the other documenting best practices.

Kudos to BD for bringing this experience to attendees! HbA1c declined a strong 0. From press release Dexcom. While the absolute reductions are not huge here, the high HbA1c baseline patients were not experiencing an overwhelming amount of hypoglycemia at baseline. More study details below. On macrovascular and renal complications in type 1 diabetes mellitus: some aspects on glycemic memory.

There is a substantially increased risk of premature mortality and morbidity in cardiovascular disease CVD among type 1 diabetes individuals compared to individuals without diabetes. Development of microangiopathy and markers of macrovascular complications precedes these events.

In this thesis we first Study I aimed to investigate early signs of atherosclerosis, measured as carotid intima-media thickness cIMT , and its relation to insulin sensitivity in young type 1 diabetes individuals. Then we compared Study II skin microvascular function in the foot and the time to first of hospitalization for ischemic foot ulcer in between the two groups in the SDIS cohort.

Finally, we investigated Study IV long-term survival in individuals with type 1 diabetes, type 2 diabetes and without diabetes following coronary artery bypass grafting CABG. The outcome measures were all-cause mortality, mortality in CVD death and any major adverse coronary event, i. In study I, young type 1 diabetes individuals had an increased cIMT concomitant with insulin resistance compared to the non-diabetic group. In a multivariate analysis, insulin resistance was significantly associated to an increase in cIMT.

In study II, 13 patients developed ischemic foot ulcer during the median 28 years of follow-up. Foot skin microcirculation blood flow was higher in the earlier intensively insulin-treated group compared with the standard treated group. Glycemic control measured as HbA 1c levels was independently associated with endothelial-dependent vasodilatation and capsaicin-induced vasodilatation. In study III , during 28 years of follow-up 22 persons died. There was no significant difference between groups for all-cause mortality, mortality in myocardial infarction, stroke or ESRD, or for morbidity in myocardial infarction or stroke.

HbA 1c did not differ between the two groups during the last 16 years of follow-up. In study IV , with a mean follow-up time of 5. The risk for all-cause mortality was doubled in type 1 diabetes, compared to type 2 diabetes. The risk of death was similar among type 1 diabetic men and women. Adolescents with type 1 diabetes show early signs of atherosclerosis compared to a matched control group.

This was demonstrated together with insulin resistance. Earlier intensively insulin-treated type 1 individuals from the SDIS trial seem to have a favorable prognosis regarding the development of foot ulcers and diabetic nephropathy, compared to the standard treated individuals. This was demonstrated despite the same glycemic control for the last 16 years in the follow-up.

Type 1 diabetes individuals have much poorer outcome after CABG intervention compared to type 2 diabetes individuals. Early signs of atherosclerosis are associated with insulin resistance in non-obese adolescent and young adults with type 1 diabetes. Cardiovasc Diabetol. Intensified insulin treatment is associated with improvement in skin microcirculation and ischaemic foot ulcer in patients with type 1 diabetes mellitus: a long-term follow-up study.

Intensified insulin treatment decreases the risk of end stage renal disease in type 1 diabetes: a long-term follow-up study. Diabetic Medicine J Am Coll Cardiol ;— Epidemiology of Macrovascular disease in Type 1 Diabetes.

I sat down with a two year old child and his parents in a small emergency ward room. This was our first talk about type 1 diabetes, but many were to follow. For me, this was a routine situation. For the parents in front of me, it was a shock and scare. The father asked all the questions I expected - how, why, what will the treatment be? However, after the meeting, alone in my room, her question kept coming back to me.

It contained many layers. Life is certainly complicated for a child with diabetes. Many daily considerations are needed, blood tests taken, injections given, meals eaten and frustrations handled. Surprisingly, all this is often very manageable.

Of course, it was impossible to give her a detailed answer, but did I really know what to expect? What was I to look for, except optimizing treatment? At what age should I introduce preventive treatments? What do we really know about the development of complications? These questions recurred to me and I realized I needed to know more. This thesis project started out as a brief discussion between Dr Anna Kernell and me regarding hypertension and the risk of cardiovascular problems for the young type 1 diabetes patients we encountered in our daily work at the pediatric outpatient unit.

The idea of evaluating their actual situation, and search for possible signs of development of vascular complications, very slowly progressed into the initiation of the first study. We began by enrolling adolescents from our everyday work, and Dr Kernell and I also visited schools in the southern area of Stockholm to recruit controls. Very sadly, Dr Kernell passed away and left me stumbling with my thesis project.

Fortunately my co-supervisors stepped in, and others were recruited, enabling my thesis work to continue. After finishing the first study I and my co-workers realized the need for experience in the long-term and adult diabetes perspective to come further with our questions.

Most fortunately I was introduced to the dedicated work of Dr Per Reichards in the Stockholm Diabetes Intervention study, addressing microvascular complications in type 1 diabetes and the role of glycemic control.

I was entrusted with the remains of this landmark study and given the opportunity to trace the participating patients and follow up his data. This process lead to something similar to a detective investigation, with us looking for clues to find data in cardboard boxes stacked away in various units of the hospital. I could not have done this project without the help from my supervisors. I hope this thesis is something they would have appreciated.

Even though the disease may develop at any age, the peak incidence is in childhood or in puberty [2]. The incidence of type 1 diabetes varies a lot between countries in the world, with the highest rates in Finland [3]. An increased incidence has been observed in many countries over the last two to three decades [4], though the incidence in Sweden has been stable during the last years [5].

The mechanism behind type 2 diabetes is thought to be initiated by the development of insulin resistance, mainly in skeletal muscle and the liver. However, persons developing type 2 diabetes are unable to compensate the insulin resistance by adequately increasing insulin secretion. Obesity is a major factor inducing insulin resistance and it frequently coexists with type 2 diabetes.

The incidence of type 2 diabetes is increasing rapidly worldwide and most probably due to a more sedentary lifestyle with excess caloric intake and decreased exercise, leading to obesity, and to generally older populations in many countries [10]. Type 2 diabetes, in contrast to type 1 diabetes, is also strongly influenced by genetic predisposition. Fasting is defined as no caloric intake for at least 8 h. The Banting and Best discovery of insulin in and the subsequent development of better and more sophisticated treatments for type 1 diabetes have dramatically changed not only the prognosis of survival in type 1 diabetes but also the spectrum of complications from acute, e.

The long-term complications can be further divided into micro- and macrovascular. The macrovascular complications are mainly divided into coronary heart disease CHD , ischemic stroke and peripheral artery disease PAD. Throughout the world, cardiovascular disease CVD mortality has declined in the general population [13, 14].

This trend is similar in diabetic patients. Gregg and associates analyzed the incidence of acute myocardial infarction, stroke, lower leg amputation, nephropathy and death in hypoglycemic crisis in the United States between and , comparing diabetic individuals with the background population. For acute myocardial infarction there were 96 fewer cases per 10, persons per year, and 60, 30 and 8 fewer cases per 10, persons per year for stroke, lower-extremity amputation and end-stage renal disease ESRD , respectively.

One limitation of this study is that it does not discriminate between the two major diabetes types [15]. Despite the lower incidence of CVD in diabetic individuals, type 1 diabetes is still associated with an increased risk of CVD [16], which in turn is the most common cause of death in this patient group [17].

Diabetes is also associated with a shorter life-expectancy [18]. In the Allegheny County, Pennsylvania, registry of type 1 diabetes individuals, mortality rate after 30 years of diabetes was demonstrated to be six times higher than in the general population [19]. This clearly demonstrates a substantial progress in avoiding complications, e. On the other hand, a group in Scotland recently showed, in a nationwide prospective cohort study of type 1 diabetes individuals, that life-expectancy, from age 20 years, was 11 and 13 year shorter, in men and women, respectively, compared to non-diabetic individuals [20].

The excess mortality in type 1 diabetes individuals was also recently demonstrated in a Swedish nationwide register-based study including more than 30, type 1 diabetes individuals, revealing a doubled risk of death all-cause or from CVD despite good glycemic control compared to a matched control group [21], a risk substantially increased with increased levels of HbA 1c [21]. Even though evidence points towards a decline in mortality and CVD mortality incidence in diabetes, there is still a substantially increased risk of CVD mortality in type 1 diabetes individuals [].

Macrovascular complications begin with atherosclerosis, a chronic and multifactorial disease associated with a wide range of independent risk factors, including traditional risk factors such as smoking, hypertension, dyslipidemia, increasing age, family history, obesity and diabetes [24, 25]. Atherosclerosis is considered an inflammatory disease and the first observed lesion is the formation of fatty streaks, i.

These early changes have been observed already in children and adolescents [26]. The current hypothesis of atherosclerosis development points out endothelial dysfunction to be an early event and the result of injury caused by e. Low-density lipoprotein LDL cholesterol, modified by for example oxidation or glycation in diabetes , is today considered the major cause of endothelial injury. The subsequent event is migration and proliferation of smooth muscle cells leading to thickening of the artery wall and, as the inflammation proceeds, more macrophages and lymphocytes are recruited to the lesion.

They cause a local activation of cytokines, chemokines, hydrolytic enzymes and growth factors eventually leading to necrosis and formation of a fibrous cap protruding into the vessel lumen. The artery can, to some extent, compensate these events by dilation but at some point the blood flow may be affected causing distal ischemia [24]. However, the fibrous cap may rapidly rupture leading to formation of a thrombosis and, for example, if it involves coronary arteries or brain arteries, an acute coronary syndrome or an ischemic stroke, respectively.

A large number of studies have conclusively demonstrated that individuals with type 1 diabetes have an early onset and a higher degree of atherosclerosis compared to a non-diabetic population. It is typically also more disseminated and aggressive as compared to non-diabetic individuals. Type 1 diabetes patients therefore carry an additionally higher risk of CVD events [27].

Also, type 1 diabetes individuals have a higher frequency of hypertension, dyslipidemia and nephropathy, all contributing to the increased risk of CVD []. This study was initiated in as a community-based prospective cohort study including more than 50, adult individuals from the general population.

Participants underwent physical examination and laboratory tests every other year and were followed up regarding all-cause mortality, CVD mortality and morbidity, and associated risk factors [31]. They also underwent physical examination and laboratory tests, as well as ECG every four years [32]. The Framingham study clearly demonstrated that diabetes mainly type 2 is a major risk factor of developing CVD regardless of gender [33]. However, it was later confirmed by others that women with diabetes carry an even higher risk of developing CVD [34].

The Pittsburgh EDC study recruited insulin-dependent diabetes patients under the age of 17 at disease onset, and within one year after the diagnosis of diabetes [35]. The individuals were followed-up every second year regarding the development of nephropathy, retinopathy, neuropathy and macrovascular disease i.

There were no significant gender differences in the outcomes, except for PAD demonstrating a three-fold higher incidence rate in women after 25 years [35]. In the EURODIAB cross sectional complication study, more than 3, type 1 diabetes individuals from 14 European countries, with an age of years old, were enrolled.

In the Diabetes UK cohort study 23, patients with insulin-treated diabetes diagnosed under the age of 30 years were recruited between and Primary outcome was mortality from CHD, in which 1, deaths were registered during a mean follow-up of 17 years. Most notable was that the absolute excess risk of dying from CHD in the age groups and years was the same for women and men; however, the standardized mortality ratio SMR for women was 45 and 42 in those age groups, respectively, compared to the general female population [37].

In this study, CVD events were significantly higher in women compared to men [16]. As early as in the Framingham cohort 20 years follow-up study, CVD was demonstrated to be six times more prevalent in diabetic women aged years compared to a matched population [12]. Over the years, studies have yielded conflicting results; with less risk for women [38], increased risk [37, 39, 40], or relatively the same risk [41], as for men. The DCCT study and the contemporary Stockholm Diabetes Intervention Study SDIS were landmark studies demonstrating the benefits of improving glycemic control to lower the incidence of microvascular complications [43, 44].

They will be thoroughly discussed later on in this thesis. Diagnosis of CHD in diabetes may be challenging. Myocardial ischemia is often silent in diabetes patients due to autonomic and somatic sensory neuropathy. The majority of myocardial infarctions may be asymptomatic [45], or presenting in a highly atypical manner e. Over the years, mounting evidence has been supporting an increased risk of CHD in type 1 diabetes individuals [37, 46, 47].

Among studies reporting the incidence of CVD in type 1 diabetes, CHD consistently stands out as the most common [16, 20, 48, 49]. Stroke is generally divided into two subtypes, i. The NIHSS is based on eleven parameters ranging from level of consciousness, visual field and eye movement tests to motor function, sensory function, speech, language and attention testes.

Each area renders a score from 0 to 4 and the resulting sum defines stroke severity from no stroke to severe stroke and also predicts likelihood of recovery [53]. The diagnosis of stroke is usually confirmed by the use of MRI or CT scanning, demonstrating thrombotic lesions ischemia or bleeding. The incidence of premature morbidity and mortality in stroke is markedly increased in type 1 diabetes patients [54, 55].

This risk is further increased in case of hypertension or proteinuria [56]. The incidence rates were excessively elevated if the patients also had diabetic nephropathy or retinopathy [54]. The incidence of stroke was also investigated in the Finnish Diabetic Nephropathy FinnDiane study [57].

However, risk factors partly differed from that of hemorrhagic stroke. The only other study looking at independent risk factors for stroke in type 1 diabetes is the Pittsburgh EDC study [58]. It was found that diabetes duration, sBP, low levels of high-density lipoprotein HDL cholesterol and diabetic nephropathy were strong risk factors for ischemic stroke.

However, sBP was confounded as a risk factor by nephropathy in that study [58]. The major cause of death in this long-term follow-up study was CVD with no discrimination between CHD and stroke [22]. There was an association between overall mortality and mean HbA 1c level during the 6.

This was also pointed out in the FinnDiane study, i. These studies indicate a beneficial role of good glycemic control for the risk of suffering an ischemic stroke. The definition of PAD currently used by the European Society of Cardiology guidelines includes atherosclerotic lesions in the extra-cranial carotid and vertebral, upper and lower extremity, mesenteric and renal arteries [59].

These central atherosclerotic changes are often accompanied by lesions located distally in patients with diabetes, most often in the popliteal artery or in the vessels of the lower leg. The diagnosis of PAD is based on typical symptoms of intermittent claudication and clinical investigations, including auscultation and palpation of peripheral arterial pulses.

Ankle-brachial index ABI is an objective measurement of peripheral artery disease in the lower extremity and is calculated by dividing the systolic blood pressure at the tibial or dorsalis pedal arteries level with the brachial systolic pressure. Diabetes-related foot disease is a major cause of morbidity and mortality [60, 61].

The reported rates in lower extremity amputations vary from 2. There is a clear association between peripheral neuropathy and foot ulceration [64]. A comparative study of PAD in diabetic and non-diabetic patients confirmed that diabetic patients had more distal disease and a poorer outcome with respect to amputation and mortality [65]. The ultimate consequence of PAD and foot ulcers is the need for lower-extremity amputation. Some later studies point toward a decrease over time in the incidence of amputations.

Also, from the Steno Diabetes Center in Denmark, it was recently demonstrated that the incidence of amputations have decreased significantly during the last decade [68]. This is suggested to be due to implementing a multidisciplinary team-work [67].

It should be noted that the definition of diabetic nephropathy includes macroalbuminuria and ESRD, but not microalbuminuria. The incidence of diabetic nephropathy has been investigated in many cohorts over the years. In the Steno study, the incidence in proteinuria among patients diagnosed from and from was investigated. Progression in the extent of diabetic nephropathy has been shown to correlate to an elevated risk of mortality in several studies [].

In the FinnDiane study, an independent graded association was observed between the severity of kidney failure and mortality [71, 74]. However, absence of albuminuria in type 1 diabetes individuals seems to be protective so that the mortality rate is similar to the general population [71, 74]. The impact of glycemic control on the risk of developing renal disease is paramount; lowering HbA 1c levels is associated with less albuminuria [44] [43].

Longevity in diabetes is substantially decreased with lower eGFR [20]. The association between loss of kidney function and premature death per se and CVD has been hypothesized to be due to that the degree of functional renal impairment reflects a general atherosclerotic development and severity [76]. On the other hand, a long list of other factors all involved in CVD is associated with declining renal function, such as male sex, hypertension and dyslipidemia [77], as well as oxidative stress [78], endothelial dysfunction [79], advanced glycemic end products AGEs [80], left ventricular hypertrophy [81], and insulin resistance [82].

Good glycemic control and strict blood pressure control are probably the two most important factors decreasing the risk of diabetic nephropathy [83]. Many factors are associated with an increased risk of CVD in type 1 diabetes, figure 1. Some are non-modifiable, such as age, diabetes duration and heredity; whereas others, such as smoking, hypertension, lipid levels, obesity, albuminuria and glycemic control, are modifiable.

Most of these factors are discussed in the different sections but will be more thoroughly scrutinized in the following part. Figure 1 Factors contributing to development of Cardiovascular Disease in type 1 diabetes. A growing body of evidence points to different genetic variations being associated with the heightened risk of CVD in type 1 diabetes. One example is the haptoglobin Hp2 genotype, which has been associated with both subclinical atherosclerosis and increased risk of CHD [84, 85].

There are three possible haptoglobin genotypes: , and , of which Hp2 possesses less antioxidant capacity due to its larger molecular size and the lower oxidative capacity may reduce reverse cholesterol transport via altered modification of apolipoprotein A-I [86].

Cigarette smoking is closely coupled to the increased risk of developing not only microvascular [87] but also macrovascular complications [88, 89] in type 1 diabetes. As regards macrovascular complications, the association is strongest for the risk of contracting PAD. The negative effect of smoking is probably due to endothelial dysfunction and inflammation [90].

Brownlee has proposed a model connecting hyperglycemia and oxidative stress with atherosclerosis [91]. In this model, the increases in glycolysis and tricarboxylic acid cycle activity driven by hyperglycemia generate an overproduction of superoxide in the mitochondrial electron-transport chain in the endothelial cells [91]. This excess superoxide production is proposed to cause an inhibition of glycolytic enzymes, resulting in an accumulation of metabolites and cell damage in the blood vessels.

In addition, intracellular hyperglycemia is hypothesized to increase the osmotic pressure and vascular permeability [91]. This would allow lipoproteins, such as LDL-cholesterol, to transmigrate into the vessel, accompanied by pro-inflammatory cells, e. AGEs can be formed via oxidation of glucose and lipids and through the polyol pathway [92].

Increased skin AGE levels are predictive for microvascular complications in type 1 diabetes [94], indicating a connection between hyperglycemia and AGE concentrations. A strong association between chronic hyperglycemia, e. In contrast, the importance of glycemic control in the development of CHD has been very much debated and remains a controversial issue. However, not all studies have arrived at the same conclusions.

A comparison between the two cohorts revealed no association between HbA 1c levels and CHD in men but did so among women []. Moreover, a later report from the Pittsburgh EDC study demonstrated that hyperglycemia aggravated the CHD risk even more if albuminuria was also present []. However, in select diabetic patients, e.

Generally, lipid levels and their subfractions seem to be of about the same magnitude in adult type 1 diabetics with good glycemic control as in non-diabetic individuals []. On the other hand, studies have demonstrated higher lipid levels in adolescent and young adults with type 1 diabetes compared to matched control individuals [30]. Good glycemic control can to some extent improve or even normalize certain components of diabetic dyslipidemia, especially hypertriglyceridemia [].

Other established factors contributing to higher lipid levels are BMI and insulin resistance []. In the Framingham offspring study general population low HDL-cholesterol, high LDL-cholesterol and high triglyceride levels were found to be associated with an increased risk of CVD []. In the Coronary Artery Calcification in Type 1 diabetes CACTI study, elevated fasting levels of triglycerides were independently associated with increased coronary artery calcification progression [].

Whereas it is generally agreed that the utility of lowering LDL-cholesterol levels in type 2 diabetes patients nowadays is undisputed [], controversy lingers as to whether this is also the case in type 1 diabetes. However, treatment, chiefly by statins, indicates that LDL-lowering can be beneficial in reducing CVD incidence also in patients with type 1 diabetes [, ].

Hypertension is a common and over-represented co-morbidity among both type 1 and type 2 diabetes patients [29, ], compared to the general population, and is a strong predictor of CVD events []. It is particularly important to strive for rigorous blood pressure control if the type 1 diabetes patient also has albuminuria.

Increased risk for diabetes-related vascular complications is associated with components of the metabolic syndrome, in which insulin resistance is an important factor. This has been conclusively shown particularly in type 2 diabetes individuals [73, ]. This gives some clues, or at least hints, that insulin resistance per se may be an important risk factor for diabetic angiopathy not only in type 2 diabetes but also in type 1 diabetes [].

The quantitative impact of insulin resistance on CVD is not easy to dissect out, since it is co-incident with several other traditional CVD risk factors, e. Nonetheless, some epidemiologic studies lend support to the notion that insulin resistance is pathogenically important for CVD development also in type 1 diabetes. In the Pittsburgh EDC study, the hazard ratio of CHD was increased for those with a family history of type 2 diabetes, even after adjustments for known confounding factors in the insulin resistance syndrome [].

Excessive weight gain, not infrequently occurring as a direct consequence of intensified insulin treatment, has been considered as a cause for concern of contributing to CVD events in type 1 diabetes []. This was addressed among adult DCCT patients where it was found that the quartiles who gained most weight in both treatment groups also had the highest blood pressure and lipid levels []. Diabetes nephropathy is strongly associated to CVD. Macroalbuminuria renders the diabetes patients susceptible to developing CVD.

In the FinnDiane study, as well as in the Pittsburgh EDC study, both micro- and macroalbuminuria and ESRD correlated significantly with increasing mortality risk for each stage of renal compromise [71, 74]. Conversely, it is important to keep in mind that an improvement in glycemic control reduces the incidence of microalbuminuria.

Management approaches for dyslipidemia are the same between the organizations, i. Similar approaches apply for the treatment of hypertension, i. Hypertension is quite common in children and adolescents with type 1 diabetes [], in whom obesity, hyperglycemia and diabetic nephropathy aggravate this situation []. These and other studies make it clear that elevated traditional CVD risk factors, such as high levels of HbA 1c , blood pressure and cholesterol, not only are all quite common during childhood and adolescence of patients with type 1 diabetes [], but also that surprisingly few of the patients receive antihypertensive or lipid-lowering medications, in spite of current guidelines from both the ADA, EASD and ISPAD.

Hemodynamic changes evoked by hypoglycemia include increased heart rate, widening of pulse pressure, due to reduced central blood pressure and peripheral artery resistance, as well as increased peripheral blood pressure []. Hypoglycemia is also assumed to cause malignant arrhythmias by prolonging the QT interval and cardiac repolarization, thereby increasing the risk of sudden death. In one autopsy study, it was demonstrated that sudden death was four times more common in type 1 diabetics compared to non-diabetic persons [].

Type 1 diabetes individuals are at great risk of iatrogenic hypoglycemia, not least due to the fact that insulin resistance is much less of a problem in type 1 diabetes as most of these patients are non-obese. Both in the DCCT and the SDIS studies, an increased incidence of severe hypoglycemia in the intensively insulin-treated groups was demonstrated [43, 44]. Notwithstanding this, none of these studies was designed to address long-term CVD consequences of severe hypoglycemia.

In a Swedish registry study, 1, type 1 diabetes subjects with CVD complications were investigated. Further a dose-response relationship between the numbers of previous hypoglycemia and survival after CVD, as well as CVD mortality, was demonstrated []. The present thesis project has its focus on macrovascular complications of diabetes. On the other hand, study II has a combined micro- and macrovascular approach with chronic foot ulcers as the primary outcome measure.

The development of diabetic foot ulcers usually starts with neuropathy, but is also closely related to the development of PAD. Over the years of follow-up, the level of glycemia -- both at baseline and at the follow-up study years -- was closely related to the progression of retinopathy []. A strong association between chronic hyperglycemia and microvascular complications has been conclusively demonstrated in several large epidemiological studies [95, 96, ].

As mentioned above, the SDIS and -- slightly later -- the DCCT trials were both pioneering and groundbreaking studies demonstrating that intensified insulin treatment halts microvascular complications in type 1 diabetes due to improved glycemic control [43, 44]. This treatment had also long-term beneficial effects on the macrovascular complications [99]. Whether microvascular dysfunction precedes the development of macrovascular complications remains a controversial and elusive issue.

However, microvascular complications in type 1 diabetes, such as peripheral neuropathy [], nephropathy [] and retinopathy [], are all independent risk factors for macrovascular disease. The DCCT and SDIS trials both found an undisputable effect on diminishing microvascular complications by means of intensive insulin treatment and thereby improved glycemic control [43, 44].

Self-monitoring of blood glucose levels did not exist; urinary glucose excretion was sometimes monitored. Sometimes short-acting insulin was introduced as well. This, in conjunction with the establishment of HbA 1c measurements and blood glucose self-monitoring, made it possible to improve glycemic control more easily.

The DCCT was launched in , eventually enrolling 1, patients with type 1 diabetes. They were randomly assigned to receive either intensified anti-hyperglycemic treatment or standard treatment with a mean follow-up of 6. Patients in the intensively treated group were introduced to three or more insulin injections per day -- or insulin pump treatment -- in contrast to the conventional treatment group which had one or two daily insulin injections. Glycemic goal was to achieve blood glucose levels as close to normal as possible.

These very impressive improvements were, however and perhaps not so surprisingly , accompanied by an increased risk of severe hypoglycemia in the intensive treatment group 62 vs. In this sub-study with adolescent patients, the risk of severe hypoglycemia was three times higher in the intensive insulin therapy group. Another report showed that levels of HbA 1c , both at study entry and during DCCT completion, were positively correlated to the risk of retinopathy progression [].

The first evaluation of macrovascular events demonstrated no statistically significant differences, although the absolute numbers were higher in the conventional treatment group []. Risk factors for CVD, such as dyslipidemia were improved in the intensive treatment group, but -- as expected -- weight gain was also significantly greater. After DCCT was ended, all patients were offered the intensive treatment regimen.

After 6 years, the cIMT was significantly greater among study subjects compared to age- and sex-matched non-diabetics; also the progression in cIMT was greater for those with conventional insulin treatment compared to the group receiving intensive insulin treatment during DCCT.

On the other hand, the year follow-up analysis showed no difference in cIMT progression between the two DCCT groups from years 6 to 12 []. These salutary effects on macrovascular complications in the intensively insulin-treated group were suggested not to be driven by differences in levels of HbA 1c , blood lipids, blood pressure or pharmacological treatment although more patients in the conventional group had beta blockers. Authors speculated that the earlier 6.

Now, nearly 30 years after DCCT commenced, 1, of the original study subjects have been followed up, demonstrating a modest, although statistically significant, difference in all-cause mortality rate in favor of those previously randomized to initial intensive insulin replacement therapy compared with conventional glycemic treatment [22]. The treatment effects were, by any standard, very impressive.

Per Reichard in in order to investigate whether intensive insulin therapy could reduce the incidence of microvascular complications in type 1 diabetes patients in Sweden [44]. One hundred and two patients were randomly assigned to receive either intensified conventional treatment ICT or standard treatment ST for a period of 7. Inclusion criteria were type 1 diabetes diagnosed before the age of 31, and requiring insulin treatment within one year , no or non-proliferative retinopathy, and normal urinary albumin excretion rate and glomerular filtration rate.

The treatment regimen in the ICT group consisted of four daily injections of insulin while the majority in the ST group received two daily injections of insulin. Patients were evaluated regarding microvascular complications after approximately 18 months [], 3 and 5 years of study start [, ], and at the end of the study [44].

A year follow-up was also made with respect to mortality and treatment side effects [44, ]. During the SDIS, four patients died in the intensive treatment group and three in the conventional treatment group and -- as in the DCCT -- a three-fold higher incidence of serious hypoglycemia was noted in the intensive treatment group, and a borderline significant weight gain [].

In the year follow-up of SDIS, the glycemic control was still significantly better in the intensive treatment group despite the fact that the randomization had ceased and treatments were individualized. However, even at this late time point, the microvascular complications were even more prevalent in the conventionally treated group [44, ]. Although the number of participants in SDIS was relatively few and the study primarily was designed and statistically powered to study microvascular complications, some sub-studies after 7.

Fifty nine of the subjects were tested for risk markers of CVD such as flow mediated vasodilatation in the brachial artery an established surrogate marker for endothelial dysfunction , cIMT, arterial wall stiffness calculated and the carotid arteries scanned for plaques []. The results showed a better outcome for the previously intensively treated group with thinner cIMT and less stiff arteries. Moreover, among all participants, patients with lower levels of HbA 1c had less stiff arteries and a better endothelial function [].

Although the mean HbA 1c converged between the two treatment groups in DCCT soon after study end, the effect of the diverging treatment intensity during the trial continued to cause more complications in the previously conventionally treated group [99, , ]. This phenomenon was later on described as a glycemic memory. One suggested mechanism behind the purported glycemic memory is epigenetic alterations, i.

Epigenetic modifications can also be caused by alterations in the environment [] and by exercise. Experimental models have demonstrated that a high-glucose environment causes alterations in epigenetic post-translational histone modification affecting inflammation and vascular complications [, ]. Established CHD is a strong risk factor for recurrent events, especially if combined with diabetes []. Coronary artery bypass grafting CABG is, together with percutaneous coronary intervention PCI , currently the methods of choice for interventional coronary revascularization therapy in CHD.

This figure is even further increased if subjects with pre-diabetes i. Revascularization surgery for patients with multivessel CHD is a common procedure. Patients with diabetes and established CHD often have more disseminated and aggressive atherosclerosis and are at much higher risk of developing major adverse CVD events and death than those without diabetes []. The outcomes of most studies have favored CABG over PCI as the preferred type of intervention, not least in diabetic subjects since they as mentioned above often have multi-vessel disease [].

A recent meta-analysis, based on eight studies including some , subjects, also found outcome in favor of CABG compared to PCI []. However, in a sub-analysis of diabetic patients not specified by the protocol , the five-year survival rate was significantly increased in patients randomized to CABG []. The five year event rates of all-cause mortality, non-fatal myocardial infarction and non-fatal stroke were all significantly lower in the CABG group compared to PCI [].

The stroke frequency, on the other hand, was higher in the CABG group, being consistent with many other studies and demonstrated in a recent meta-analysis of 19 RCTs with 10, subjects []. The higher rate of stroke has been suggested to be caused by more extensive coronary artery disease, perhaps being typical for diabetes patients. In this thesis, the following hypothesises were tested. First Study I , we hypothesized that young type 1 diabetes individuals have more signs of atherosclerotic development, measured by means of cIMT as a surrogate marker, and that they are more insulin resistant compared to subjects of a matched healthy control group.

Moreover, we also hypothesized that glycemic memory, or rather the earlier intensive insulin therapy, may explain the putative differences in outcomes between those groups. Since numerous studies have demonstrated a shorter longevity and an increased risk of CVD related mortality in type 1 diabetes, as compared to non-diabetic subjects, we hypothesized Study IV an increased risk of death in type 1 diabetes individuals, vs.

Briefly, these projects focus on macrovascular complications in individuals with type 1 diabetes in different settings. The last project was aiming at exploring the outcome of macrovascular complications in type 1 diabetes patients undergoing CABG and to compare the incidence of such complications with type 2 diabetes patients and non-diabetics.

Twenty healthy peers aged years were also invited by means of visiting schools in the same area as our patients and constituted a matched control group. The participants were followed for 7. These 72 individuals constitute the study population in Study II Figure 1. SDIS randomization ended after mean 7. Six patients participated only partially. The study population consisted of all persons, in total 39, patients, who underwent primary isolated non-emergency CABG in Sweden between and This was a cross-sectional study.

After a 12 hours overnight fast, blood test were drawn for analyses of blood lipids, creatinine and HbA 1c. BMI, waist circumference, and blood pressure were also measured. Thereafter a hyperinsulinemic euglycemic clamp was performed to measure insulin sensitivity.

After the clamp procedure, cIMT was measured with high-resolution ultrasonography. Patients in the ICT group received extra education, including how to use self blood glucose tests several times daily. They had continuous tutoring by telephone and scheduled visits to the diabetology outpatient clinic every 2 nd month. The ST patients were instructed how to use self blood glucose tests. They received no extra education and only discussed the treatment at regular visits to the outpatient clinic every four months.

Glycemic control was measured by means of HbA 1c levels every four months for all participants. Seven and a half years after the first inclusion into the SDIS, the randomization ceased and both the ICT and ST patients continued visiting the attending diabetologist according to the standard diabetes care at the time.

The ST patients were now given advice on how to further improve their insulin replacement therapy in order to improve their HbA 1c levels. Study II was a prospective follow-up study Figure 2. Seventy two patients from the original SDIS cohort were evaluated regarding skin microcirculation with iontophoresis topically applied with the following vasoactive stimuli: acetylcholine ACh [endothelial-dependent vasodilatation], sodium nitroprusside SNP [endothelial-independent vasodilatation], and capsaicin [C-nociceptive-dependent vasodilatation].

HbA 1c levels were prospectively collected from and tested for association with skin microcirculation. The cohort was then followed up as described in study III until the 31 st of December and primary outcome was defined as the first recorded hospitalization for ischemic foot ulcer. Study III was a longitudinal and observational study Figure 2.

Primary outcome was all-cause mortality, mortality in stroke, myocardial infarction and kidney failure and secondary outcomes were morbidity in myocardial infarction, stroke and ESRD. HbA 1c , lipid profile, blood pressure, microalbuminuria, smoking habits and use of acetyl salicylic medications, antihypertensive and lipid lowering agents were collected and the latest available data was recorded.

Mean HbA 1c levels were also analyzed for the entire period from Study IV was an observational, nation-wide population-based cohort study. The type of diabetes was obtained from NDR. The definition of type 1 diabetes was onset of diabetes before the age of 30 years and treatment with insulin only.

Type 2 diabetes was defined as diabetes treated with diet or oral hypoglycemic agents alone, or age 40 years or older at onset and treated with insulin alone or in combination with oral hypoglycemic agents. All persons not included in the NDR were defined as non-diabetic. The data were censored at the time of death or at the end of the follow-up period March 24, , whichever occurred first.

Primary endpoint was defined as mean group difference in cIMT and its association to insulin sensitivity measured by glucose infusion rate obtained from the clamp. Secondary outcomes were to explore changes in skin microvascular circulation, measured by laser Doppler flowmetry, after topical administration of ACh, SNP and capsaicin, by means of iontophoresis technique and its association to which group study participants were randomized to in the original SDIS study.

The primary outcome was all-cause mortality and a composite mortality from myocardial infarction, stroke and ESRD. The secondary outcomes were morbidity disease-free survival from CVD complications, i. The primary outcome was all-cause mortality. All the tests were drawn in the morning before the clamp. Serum insulin and C-peptide levels were analyzed locally by an immunometric method with monoclonal antibodies Modular E , Roche Diagnostics Scandinavia, Stockholm, Sweden.

In SDIS, HbA 1c levels were measured in both groups at study entry, after 6 months and then approximately at every 4 months. Mean HbA 1c levels were calculated for the whole 7. In our follow-up period from study II-III , analyses of HbA 1c and total cholesterol levels were performed by the local clinical chemistry laboratory whenever each participant had their routine visits. The hyperinsulinemic euglycemic clamp is considered to be the gold standard method for determining insulin sensitivity [].

The aim of the clamp is to increase the plasma insulin concentration level and maintain this until steady-state usually minutes. To avoid hypoglycemia, and to keep the blood glucose concentration at a constant level, a variable glucose infusion is given. In summary, one intravenous needle was inserted into the antecubital vein on the left arm and a second one, in a retrograde fashion, on the back of the right hand.

The hand was kept warm with an electric device for intermittent sampling of arterialized venous blood. Blood glucose samples were taken from the right hand vein catheter every 5 minutes and the rate of dextrose infusion was adjusted to achieve a blood glucose level of 5. This calculation is assumed to correct for differences in prevailing, individual glucose and insulin concentrations. Measurement of cIMT is a well-accepted method used in estimating atherosclerotic changes in large vessel walls [].

It has been used in both adult, childhood and adolescent populations [] and to assess impact from various chronic illnesses [, ]. The subjects head was tilted in order to get the common carotid artery CCA just proximal to the bulb placed horizontally across the screen. Magnified pictures were frozen incidentally with the R wave on the electrocardiogram. The cIMT was defined as the distance between the leading edge of the lumen-intima echo and the leading edge of the media-adventitia echo in the far wall Figure 4.

Lumen diameter was defined as the distance between the leading edge of the intima-lumen echo of the near wall and the leading edge of the lumen-intima echo of the far wall. The computer system calculated the average intima-media thickness and lumen diameter of the analyzed section. All measurements were performed by one operator, blinded to all other data, using an automated computerized analyzing system. The computer system calculated the average cIMT and lumen diameter of the analyzed section.

As cIMT of multiple measurements is most widely used, it was chosen as our primary end point measurement. Figure 5 cIMT measurement of the common carotid artery intima media layer, area indicated by square. Glucose in the blood binds irreversibly to the hemoglobin in the erythrocytes, thus creating glycated hemoglobin, i. HbA 1c. HbA 1c is firmly established as a tool for evaluating both clinical interventions and scientific investigations.

During the eighties and nineties, different countries had different HbA 1c standardization programs, i. Generally, the Mono S method readouts are 1. Hence, this method of measuring HbA 1c is used by the laboratories in Sweden since During the time of our follow-up , IFCC have introduced a change in reference method for calibration of HbA 1c []. To estimate glomerular filtration rate, as a measure of kidney function, eGFR based on measurements of creatinine levels is a valid and widely used method.

Iontophoresis is an established method by which a small applied electrical field is used to facilitate the rate of penetration of drugs into accessible tissues, such as skin Figure 6. In combination with laser Doppler flowmetry, the technique enables access to the microvascular bed and, by applying vasoactive substances, makes measurements of changes in cutaneous blood flow amenable.

A probe holder for combined single-point iontophoresis and blood flow measurement was fixed on the dorsum of the right foot. Skin blood flow at a depth of approximately 1 mm was registered by laser Doppler flowmetry technique Periflux, Perimed, Stockholm, Sweden. Basal flow was calculated as an average of flow for 10 seconds during the last minute before the start of iontophoresis.

Blood flow after administration of drugs was defined as the average blood flow for the 10 seconds with the maximal flow following the stimulation. Results are given as the change in blood flow for each of the vasoactive substances used, calculated as a ratio between the maximum blood flow after stimulation and basal flow, and presented as arbitrary perfusion units PU.

Iontophoresis was performed with a 0. For the ACh we used an anodal current, while for the SNP and the capsaicin we used a cathodal current. The investigator and the interpreter of the results were blinded to the former allocation of the individual patient. It became mandatory for all county councils to report to the register from and attained national coverage in From , the register also includes outpatient visits from specialized private and public caregivers.

A drawback is that, as of today, primary care is not covered in the IPR. On the other hand, people with type 1 diabetes are routinely followed in special care units at the hospitals in Sweden. A quality control of the data reported to the IPR is routinely performed. The control includes ascertainment that compulsory variables, i. The validity of all variables is tested and if the data is obviously incorrect it is corrected and is sent back to the liable unit for approval.

Today, virtually all type 1 diabetes patients are included in the register []. The Swedish Renal Register is a national health data registry for patients on maintenance for renal replacement therapy []. Every patient with chronic renal insufficiency starting dialysis treatment or receiving a kidney transplant should be reported to the register, and all dialysis and transplant units in Sweden report to the register.

Test of normality was conducted with Kolmogorov-Smirnov and Shapiro Wilks test. Spearman test was used for the correlation data. All risk factors were included and successively excluded in a stepwise order, starting with S i. Associations were determined with linear univariable and multiple regression analysis. The measurements of skin microcirculation for each of the vasoactive substances used ACh, SNP and capsaicin were log transformed in order to achieve normality and then studied in the regression analyses for predefined factors collected at the time of the iontophoresis: age, duration of diabetes, HbA 1c , smoking, sBP, and severe microvascular complications i.

Time to first hospitalization for ischemic foot ulcer was analyzed using the Kaplan—Meier method, and differences between ICT and ST groups tested with the logrank test. Time to death for all-cause mortality and mortality in myocardial infarction and stroke composite outcome , as well as time to first hospitalization for cardiovascular events, i. Patient characteristics were described using frequencies and percentages for categorical variables, and means and standard deviations for continuous variables.

Cox regression was used to estimate the risk of all-cause mortality or a combined end point all-cause mortality or hospital stay for myocardial infarction, heart failure, stroke, or repeat revascularization in patients with type 1 and type 2 diabetes in a comparison with reference patients without diabetes.

All four study protocols are in full agreement with the declaration of Helsinki. In study I, all participating adolescents and young adults, as well as the parents of those below18 years of age, gave written informed consent before inclusion. In study II, all participants in the iontophoresis study gave their written informed consent before inclusion.

Seven of the type 1 diabetes individuals were treated with insulin pump and 13 with multiple daily injections, having a mean insulin dose of 0. There was no difference in HbA 1c between those treated with insulin pump and those with insulin injections 68 vs. As expected, glucose homeostasis differed between the study groups; however, there were no significant differences in BMI, waist circumference, blood pressure or in lipid profile between groups.

Mild retinopathy was found in seven diabetes individuals and moderate in one. There was no difference in carotid lumen diameter between the study groups. Type 1 diabetes individuals were significantly more insulin resistant, demonstrated by a significantly lower GIR 5. Also, the glucose clamp-derived index of insulin sensitivity S i index; adjusting for insulin concentration during clamp was correspondingly lower in the diabetes group compared to the non-diabetic group Figure 7 Association between cIMT and insulin sensitivity in diabetes individuals and controls.

No such correlations were observed for the other risk factors of atherosclerosis, i. When introducing all the atherosclerotic risk factors in a multivariate regression model, with cIMT dependent and group explanatory , S i abolished the significant association between cIMT and group, with no such effects for the other factors.

Whenever the S i factor was excluded -- but including one or more of the other risk factors in multivariate analyses -- the association between cIMT and group was, again, statistically significant.

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