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Apostolopoulou 2018 Thesis

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Apostolopoulou M (2018) Determinants of insulin sensitivity in obesity and recent-onset type 2 diabetes mellitus. PhD Thesis 77.

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Apostolopoulou M (2018) PhD Thesis

Abstract: Insulin resistance, a key feature of type 2 diabetes (T2D), has been associated with inherited and acquired abnormalities of skeletal muscle mitochondrial function. Increased availability of free fatty acids (FFA) is involved in insulin resistance, impairment of mitochondrial function and non-alcoholic fatty liver disease (NAFLD). However, it remains unclear, which factors influence the associations of insulin sensitivity with mitochondrial function in patients with recent-onset, well-controlled T2D and whether specific lipid metabolites contribute to insulin resistance and abnormal mitochondrial function and thereby promote NAFLD.

These questions were addressed by one study in 136 patients with metabolically well-controlled, recent-onset T2D, enrolled in the German Diabetes Study (GDS), and another study in 21 participants (7 lean controls and 14 obese with or without NAFLD) of the Bariatrix study. All volunteers underwent thorough metabolic phenotyping using gold standard methodology, including hyperinsulinemic-euglycemic clamps for measuring insulin sensitivity (M-value). GDS participants also underwent indirect calorimetry and spiroergometry to assess metabolic flexibility (ΔRQ) and maximal oxygen uptake (VO2max), respectively, as measures of whole body energy metabolism. In the Bariatrix study, direct measurement of hepatic oxidative capacity and inflammation was combined with targeted lipidomics to quantify sphingolipid concentrations in various tissues.

The first study revealed that in recent-onset T2D, ΔRQ and VO2max independently associate with the M-value, even upon various adjustments and that only fasting FFA could abolish these relationships. ΔRQ associated positively with FFA, whereas VO2max was lower in the carriers of a polymorphism in the fat and obesity-related (FTO) gene and related negatively with C-reactive protein. The second study found that NAFLD patients feature higher total hepatic ceramide levels. Specific serum ceramide species correlated with peripheral insulin resistance. Particularly, hepatic ceramide 16:0 and lactosylceramides also correlated with increased oxidative stress and inflammation in the liver.

In conclusion, circulating FFA play a central role even in the early course of T2D, affecting muscle mitochondrial function and peripheral insulin sensitivity. In particular, increased serum and hepatic sphingolipid species seem to be important for the development of insulin resistance and hepatic inflammation and the progression of NAFLD.

Bioblast editor: Plangger M

Labels: MiParea: Respiration  Pathology: Diabetes, Obesity 

Organism: Human  Tissue;cell: Liver  Preparation: Homogenate, Isolated mitochondria 

Regulation: Fatty acid  Coupling state: OXPHOS, ET  Pathway: F, N, NS  HRR: Oxygraph-2k 

Labels, 2019-01