Leif Groop

Determinants of postabsorptive endogenous glucose output in non-diabetic subjects

Aim/hypothesis. To gain insight into the physiologic determinants of postabsorptive endogenous glucose output (EGO) in humans.¶Methods. We analysed the data of 344 non-diabetic subjects (212 men and 132 women) with a wide range of age (18–85 years) and body mass index (15–55 kg/m2) who participated in the European Group for the Study of Insulin Resistance (EGIR) project. Whole-body endogenous glucose output was measured by tracer ([3H]glucose) dilution at steady-state, peripheral insulin sensitivity (Ñ glucose clearance/Ñ insulin) was measured by the euglycaemic insulin (7 pmol × min–1× kg–1) clamp technique.¶Results. Whole-body endogenous glucose output showed a large variability (mean = 768 ± 202 μmol · min–1, range 209–1512) and was strongly related to lean body mass (r = 0.63, p < 0.0001). This association entirely explained the endogenous glucose output being higher in men than in women (827 ± 189 vs 674 × 187 μmol × min–1, p < 0.0001), its relation to body mass (+ 10 ± 2 per unit of body mass index, p < 0.0001) and its trend to decline with age (–1.1 ± 0.7 μmol · min–1 per year, p = 0.10). Although inversely related to one another (r = –0.41, p < 0.0001), peripheral insulin sensitivity and fasting plasma insulin were both independently associated with endogenous glucose output in an inverse fashion (with partial rs of 0.19 and 0.21, respectively, after adjusting for lean body mass and centre, p < 0.0001 for both).¶Conclusion/interpretation. Among non-diabetic subjects in the postabsorptive condition, total body endogenous glucose output variability is wide and is largely explained by the amount of lean mass; this, in turn, explains differences in total endogenous glucose output due to sex, obesity and age. Independently of the amount of lean mass, peripheral insulin resistance is associated with a higher endogenous glucose output independently of fasting plasma insulin concentration, suggesting coupled regulation of insulin action in peripheral tissues and the liver. [Diabetologia (2000) 43: 1266–1272]

The Genetic Landscape of Renal Complications in Type 1 Diabetes

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10-3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10-5) and the risk of type 2 diabetes (P=6.1×10-4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10-4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10-6), and pentose and glucuronate interconversions (P=3.0×10-6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.