Daily Endocrinology Research Analysis

AIMS/HYPOTHESIS: The aim of this study was to identify shared and distinct metabolite profiles prospectively associated with nephropathy, retinopathy and neuropathy at 15 years' follow-up among 1947 participants in the Diabetes Prevention Program Outcomes Study, the long-term follow-up of the Diabetes Prevention Program (DPP). METHODS: We applied bootstrapped LASSO to 353 annotated metabolites to identify metabolites associated with one or more complication. For these metabolite hits, we tested for an interaction with DPP treatment arm, and ran multivariable models for the pooled sample or within treatment group as appropriate. RESULTS: At follow-up, 572 participants had one or more complication (n=277 nephropathy, n=194 retinopathy, n=212 neuropathy). Of 105 metabolites that predicted any complication, 74 predicted one, 27 predicted two, and four predicted all three. In a pooled analysis of 69 metabolites without treatment arm interactions, histidine predicted lower odds of nephropathy (OR 0.75; 95% CI 0.69, 0.88), and serine predicted lower odds of nephropathy (OR 0.69; 95% CI 0.58, 0.82) and neuropathy (OR 0.68; 95% CI 0.56, 0.84). Of 36 metabolites that interacted with treatment arm, higher N-carbamoyl-β-alanine predicted greater odds of nephropathy (OR 1.99; 95% CI 1.38, 2.99) and C22:0-sphingomyelin predicted lower odds of neuropathy (OR 0.54; 95% CI 0.37, 0.77) in the metformin arm. In the lifestyle intervention arm, quinolinic acid predicted greater odds of neuropathy (OR 1.64; 95% CI 1.24, 2.19). These estimates accounted for sex, race, baseline age, BMI and smoking, and time elapsed during follow-up. Further adjustment for HbA CONCLUSIONS/INTERPRETATION: The existence of distinct metabolite profiles associated with single microvascular complications highlights the importance of characterising pathophysiological mechanisms specific to each complication, in addition to studying shared mechanisms across multiple complications.

Obesity is the principal driver of insulin resistance, and lipodystrophy is also linked with insulin resistance, emphasizing the vital role of adipose tissue in glucose homeostasis. The quality of adipose tissue expansion is a critical determinant of insulin resistance predisposition, with individuals suffering from metabolic unhealthy adipose expansion exhibiting greater risk. Adipocytes are pivotal in orchestrating metabolic adjustments in response to nutrient intake and cell intrinsic factors that positively regulate these adjustments are key to prevent Type-2 diabetes. Employing unique genetic mouse models, we established the critical involvement of heparan sulfate (HS), a fundamental element of the adipocyte glycocalyx, in upholding glucose homeostasis during dietary stress. Genetic models that compromise adipocyte HS accelerate the development of high-fat diet-induced hyperglycemia and insulin resistance, independent of weight gain. Mechanistically, we show that perturbations in adipocyte HS disrupts endogenous FGF1 signaling, a key nutrient-sensitive effector. Furthermore, compromising adipocyte HS composition detrimentally impacts FGF1-FGFR1-mediated endocrinization, with no significant improvement observed in glucose homeostasis. Our data establish adipocyte HS composition as a determinant of Type 2 diabetes susceptibility and the critical dependency of the endogenous adipocyte FGF1 metabolic pathway on HS.

BACKGROUND & AIMS: Alcohol consumption has been inversely associated with type 2 diabetes (T2D), but its influence on autoimmune diabetes is unclear. We investigated the risk of latent autoimmune diabetes in adults (LADA) and T2D in relation to alcohol intake and assessed if potential associations were modified by genetic susceptibility to diabetes. METHODS: We used data from a case-control study with incident diabetes cases (n = 695 LADA and n = 2679 T2D) and matched controls (n = 2752), and a prospective cohort study with 59,710 participants and incident diabetes cases (n = 221 LADA and n = 3335 T2D). Pooled relative risks (RR) with 95 % confidence intervals (CI) were estimated in relation to self-reported alcohol consumption. Analyses were stratified according to human leukocyte antigen (HLA) genotypes and polygenic score (PGS) for T2D (T2D-PGS). RESULTS: Moderate alcohol consumption (10-14.9 g/day) compared to low consumption (0.1-4.9 g/day) was associated with a reduced risk of LADA (RR: 0.74, CI: 0.56, 0.98) and T2D (RR: 0.81, CI: 0.69, 0.94). No further risk reduction was observed for the highest intake category (≥15 g/day). Stratification by T2D-PGS revealed an inverse association with LADA in those with high T2D-PGS (≥10 g/day vs. 0.1-4.9 g/day; RR: 0.38, CI: 0.23, 0.64), but not low/intermediate T2D-PGS (RR: 0.89, CI: 0.54, 1.46). The corresponding RRs for high- and low/intermediate-risk HLA carriers were 0.64 (CI: 0.35, 1.17) and 0.48 (CI: 0.31, 0.74). For T2D, RRs were 0.70 (95 % CI: 0.53, 0.93) in individuals with low/intermediate T2D-PGS and 0.85 (95 % CI: 0.64, 1.14) in those with high T2D-PGS. CONCLUSION: Moderate alcohol intake was linked to reduced LADA risk, particularly in individuals with high T2D-PGS and low/intermediate-risk HLA genotypes, indicating that the association is primarily present for T2D-like LADA. The extent to which genetic predisposition influences the association between alcohol and T2D remains less clear.