Obesity and metabolic syndrome; from double diabetes to atherosclerotic risk

Abstract

Obesity is increasingly common among people with type 1 diabetes mellitus (DM1), challenging the traditional paradigm of a disease defined exclusively by insulin deficiency. The term “double diabetes” describes the coexistence of autoimmune DM1 with insulin resistance and features of type 2 diabetes mellitus, including central adiposity, hypertension, hypertriglyceridemia, and low HDL cholesterol. Although no universal definition exists, this phenotype is associated with a higher risk of cardiovascular complications independently of glycemic control¹.

Its pathophysiology is multifactorial. Genetic susceptibility, an obesogenic environment, visceral adiposity, and treatment-related factors interact. Insulin resistance increases insulin requirements, whereas treatment intensification and eating to prevent or correct hypoglycemia may promote weight gain and perpetuate this cycle. Insulin resistance also promotes atherogenic dyslipidemia, characterized by hypertriglyceridemia, low HDL cholesterol, increased remnant lipoproteins, and a predominance of small dense LDL particles. Together with low-grade inflammation and endothelial dysfunction, this profile accelerates atherosclerosis even when LDL cholesterol is not markedly elevated^1,2.

Atherosclerotic risk in DM1 cannot be interpreted solely from glycated hemoglobin. Glycemic variability, weight gain, insulin resistance, and abnormalities in glucagon, amylin, and incretin pathways contribute to residual cardiometabolic risk. Furthermore, subcutaneous insulin administration produces a nonphysiological distribution, with relative hepatic hypoinsulinemia and peripheral hyperinsulinemia, which may disrupt the growth hormone/IGF-1 axis, increase free fatty acids, and promote endothelial dysfunction, arterial stiffness, and coronary calcification. Insulin remains essential but does not address all these mechanisms by itself².

Management should combine optimized insulin therapy, nutrition, physical activity, and intensive treatment of conventional risk factors with strategies specifically targeting obesity. A recent consensus recommends considering GLP-1 receptor agonists and dual GLP-1/GIP receptor agonists in adults with DM1 and overweight or obesity, together with careful insulin titration, continuous glucose monitoring, ketone surveillance, and structured education³. In a propensity-matched cohort including 4,088 individuals per group, these therapies were associated with lower risks of mortality, heart failure, and cardiovascular events without increased diabetic ketoacidosis. Because this evidence is observational, the findings require confirmation in randomized trials⁴. Recognizing double diabetes ultimately means moving beyond a glucocentric approach toward comprehensive and personalized cardiometabolic prevention.