Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

Ectopic lipids and defective glucose metabolism: cause or association? (#190)

Clinton Bruce 1
  1. Deakin University, Burwood, VIC, Australia

Accumulation of lipids in non-adipose tissues, particularly liver and skeletal muscle, has been associated with the development of insulin resistance and glucose intolerance. However, it is not entirely clear whether ectopic lipid accumulation plays a causal role in the development of insulin resistance and glucose intolerance or whether this is simply an associative relationship. We have conducted a number of studies to explore this relationship. Firstly, to further understand the role of muscle lipids in mediating insulin action, we generated a muscle-specific knockout of a key enzyme in phospholipid synthesis, CTP:phosphoethanolamine cytidylyltransferase (ECT), which resulted in marked (2-3-fold) increases in both diacylglycerol and triacylglycerol content in muscle (Selathurai et al. 2015). Despite this increase in lipid content, whole body and skeletal muscle insulin sensitivity, as determined by euglycemic hyperinsulinemic clamp, was not altered. These findings demonstrate that lipid accumulation in muscle is not always associated with insulin resistance. To examine the role of hepatic lipids, we performed a study where chronically (8 wk) high-fat, high-sucrose fed (HFSD) mice were switched back to a standard chow diet for 7 days (Kowalski et al. 2016). Upon the switch, energy intake was reduced, resulting in reductions of fat mass and hepatic diacylglycerol and triacylglycerol content. However, these parameters were still elevated compared to chow-fed mice, thus representing an intermediate phenotype. Nonetheless, glucose intolerance and hyperinsulinemia were completely normalized in mice that underwent the 7 day diet switch. This indicates that lipotoxicity per se does not necessarily maintain the glucose intolerant and insulin resistant state in HFSD fed mice. Rather, it appears that persistent over nourishment is likely to be the major factor responsible for causing defects in glucose metabolism. Together, these findings dissociate tissue lipid accumulation from the development of insulin resistance and glucose intolerance.

 

  1. Selathurai A et al. The CDP-Ethanolamine Pathway Regulates Skeletal Muscle Diacylglycerol Content and Mitochondrial Biogenesis without Altering Insulin Sensitivity. Cell Metab 21(5):718-30, 2015.
  2. Kowalski GM et al. Reversing diet-induced metabolic dysregulation by diet switching leads to altered hepatic de novo lipogenesis and glycerolipid synthesis. Sci Rep 6:27541, 2016.