Aim: To cluster adults with diabetes using variables from real-world clinical care at manifestation. Materials and Methods:We applied hierarchical clustering using Ward's method to 56 869 adults documented in the prospective Diabetes Follow-up Registry (DPV).Clustering variables included age, sex, body mass index (BMI), HbA1c, diabetic ketoacidosis (DKA), components of the metabolic syndrome (hypertension/dyslipidaemia/ hyperuricaemia) and beta-cell antibody status. Time until use of oral antidiabetic drugs (OADs), use of insulin, chronic kidney disease (CKD), cardiovascular disease (CVD), retinopathy or neuropathy were assessed using Kaplan-Meier analysis and Cox regression models.Results: We identified eight clusters: four clusters comprised early diabetes onset (median age 40-50 years) but differed with regard to BMI, HbA1c, DKA and antibody positivity. Two clusters included adults with diabetes onset aged in their early 60s who met target HbA1c, but differed in BMI and sex distribution. Two clusters were † Julia M. Grimsmann and Sascha R. Tittel contributed equally to this study.

Central insulin is critically involved in the regulation of hedonic feeding. Insulin resistance in overweight has recently been shown to reduce the inhibitory function of insulin in the human brain, but how this relates to effective weight management is unclear, especially in the elderly, who are highly vulnerable to hyperinsulinemia and in whom neural target systems of insulin action undergo age-related changes. Here, fifty overweight, pre-diabetic elderly participated in a double-blind, placebo-controlled pharmacological longitudinal fMRI study before and after randomization to a 3-month caloric restriction or active waiting group. Our data show that treatment outcome in dieters can be predicted by baseline measures of individual intranasal insulin (INI) inhibition of value signals in the ventral tegmental area related to sweet food liking as well as, independently, by peripheral insulin sensitivity. At follow-up, both INI inhibition of hedonic value signals in the nucleus accumbens and whole-body insulin sensitivity improved with weight loss. These data highlight the critical role of central insulin function in mesolimbic systems for weight management in humans and directly demonstrate that neural insulin function can be improved by weight loss even in older age, which may be essential for preventing metabolic disorders in later life.