Metabolic alterations and adipose tissue dysfunction in individuals with a family history of type 2 diabetes

Abstract

ABSTRACT Aims The overall aim of this doctoral thesis was to further examine the anthropometric, metabolic and adipose tissue dysfunctions, as well as explore novel metabolites, associated with type 2 diabetes mellitus (T2D), examining individuals both with and without known genetic predisposition to T2D. This thesis is part of the research conducted at Lundberg laboratory for diabetes research, Institute of Medicine, Sahlgrenska Academy, at Gothenburg University.

In study I, we aimed to investigate if markers of adipose tissue dysfunction, as well as anthropometric and biochemical markers of glucose metabolism dysfunction, were present in subjects with a family history of T2D and controls. In study II, we aimed to identify predictive factors of deteriorating glucose tolerance in individuals with known genetic predisposition to T2D, using similar measures as in study I. In study III, we aimed to compare individuals with and without genetic predisposition to T2D. In study IV, we aimed to examine how, in addition to anthropometric and biochemical variables, adipose tissue distribution and morphology and non-targeted serum metabolites predict cardiometabolic profile. In study V, we further examined non-targeted serum metabolites and its associations to markers of glucose and insulin metabolism, as well as to adipose tissue morphology and distribution.

Materials and methods (study I-V) In study I, we examined 17 first-degree relatives (FDR) and compared them to 17 controls without known genetic predisposition using anthropometric data, OGTT data and subcutaneous adipose tissue biopsy data. In study II, we explored predictive factors of deteriorating glucose tolerance in 138 FDR using anthropometric data, OGTT, IVGTT euglycemic clamp data as well as adipose tissue cell size. In study III, we compared 200 FDR to 73 controls in a cross-sectional manner, examining the same variables as described in study II. In study IV and V, we examine 53 male individuals with extensive clinical, biochemical and magnetic resonance imaging phenotyping, as well as targeted and non-targeted serum metabolites. Machine learning methods were used.

Results (study I-V) In study I we found that FDR displayed adipocyte dysfunction and impaired insulin sensitivity, compared to controls. In study II, we found that the FDR that developed IGT and T2D at baseline displayed both markers of impaired insulin sensitivity and impaired insulin secretion, as well as adipose tissue dysfunction. In study III we found differences in several OGTT measurements between groups, indicating that OGTT can be an easy yet effective measure to assess glucose tolerance in high risk individuals. In study IV we found that visceral fat accumulation and age predicted ectopic fat storage in heart and liver, and found metabolites associated with a family history of T2D. In study V, we presented metabolites predicting markers of glucose and insulin metabolism, as well as markers of adipose tissue morphology and distribution.

Conclusion In this doctoral thesis we further characterized the development of T2D in individuals genetically predisposed to the condition, with a focus on adipose tissue dysfunction and the usefulness of the OGTT. We finally explore novel metabolomic markers of T2D.