Goodarzi, M. O. | Search bioRxiv

bioRxiv2018

Adiposity-Independent Effects of Aging on Insulin Sensitivity and Clearance in Humans and Mice

Aims/hypothesisAging is associated with impaired insulin sensitivity and increased prevalence of type 2 diabetes. However, it remains unclear whether aging-related insulin resistance is due to age per se, or increased adiposity associated with advanced age. In the present study, we investigate the impact of aging on insulin sensitivity independent of changes in body composition.\n\nMethodsCohorts of C57BL/6J male mice at 4-8 months of age ( young) and 18-27 mo ( aged) exhibiting similar body composition were characterized with static (plasma glucose and insulin levels) and dynamic (glucose and insulin tolerance tests) measures of glucose metabolism on chow and high-fat diets. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analysis. The relationship between aging and insulin resistance in humans was investigated in 1,250 non-diabetic Mexican-American individuals who underwent hyperinsulinemic-euglycemic clamps.\n\nResultsIn mice with similar body composition, age had no detrimental effect on plasma glucose and insulin levels. However, aged mice demonstrated mildly, but reproducibly, improved glucose tolerance on both chow and high-fat diets due to increased glucose-stimulated insulin secretion. Moreover, hyperinsulinemic-euglycemic clamps revealed impaired insulin sensitivity and reduced insulin clearance in aged mice on both diets. Consistent with results in the mouse, age remained an independent determinant of insulin resistance after adjustment for body composition in Mexican-Americn males. Advanced age was also associated with diminished insulin clearance, but this effect was dependent on increased BMI.\n\nConclusions/interpretationThis study demonstrates for the first time that aging per se impairs insulin sensitivity independent of adiposity in mice and humans. These results raise the possibility that the pathogenetic mechanisms of age-related and obesity-associated insulin resistance are distinct.\n\nAbbreviations

physiology↗

bioRxiv2018

Large-Scale Genome-Wide Meta Analysis of Polycystic Ovary Syndrome Suggests Shared Genetic Architecture for Different Diagnosis Criteria.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed with different criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease indicate shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. Only one locus differed in its association by diagnostic criteria, otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or Rotterdam criteria across common variants at 13 loci.

genetics↗