On macrovascular and renal complications in type 1 diabetes : 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. The SDIS and subsequent DCCT/EDIC trials conclusively established already in 1993 that early intensified insulin treatment halts microvascular complications. This has also been shown for macrovascular complications in the DCCT/EDIC trial, a finding suggested to be due to glycemic memory.

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. We also investigated (Study III) long-term follow-up complications in the SDIS cohort, comparing incidence in all-cause mortality, mortality in CVD, as well as incidences in CVD events, i.e. myocardial infarction and stroke, and diabetic nephropathy, between patients earlier randomized for 7.5 years to intensive insulin treatment vs. standard treatment. 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). In this study we combined the SWEDEHEART and the Swedish national diabetes registers. The outcome measures were all-cause mortality, mortality in CVD death and any major adverse coronary event, i.e. myocardial infarction, heart failure, stroke or need of revascularization.

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 HbA1c 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. One person in the ICT group compared with seven in the ST group developed ESRD. HbA1c 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 5.9 years, a total of 6,765 out of 39,235 patients died: 17 % of whom had no diabetes, 21 % had type 1 diabetes, and 19 % had type 2 diabetes. 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.

List of scientific papers

I. Rathsman B, Rosfors S, Sjöholm A, Nyström T. Early signs of atherosclerosis are associated with insulin resistance in non-obese adolescent and young adults with type 1 diabetes. Cardiovasc Diabetol. 2012 Nov 27;11:145
https://doi.org/10.1186/1475-2840-11-145

II. Rathsman B, Jensen-Urstad K, Nyström T. 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. Diabetologia. 2014 Aug;57(8):1703-10
https://doi.org/10.1007/s00125-014-3248-2

III. Rathsman B, Donner M, Ursing C, and Nyström T. Intensified insulin treatment decreases the risk of end stage renal disease in type 1 diabetes: a long-term follow-up study. [Submitted]

IV. Holzmann MJ, Rathsman B, Eliasson B, Kuhl J, Svensson AM, Nyström T, Sartipy U. Long-term Prognosis in Patients with Type 1 and Type 2 Diabetes Mellitus After Coronary Artery Bypass Grafting. J Am Coll Cardiol 2015;65:1644–52
https://doi.org/10.1016/j.jacc.2015.02.052