Abstract
Prolonged food deprivation increases lipid oxidation and utilization, which may contribute to the onset of the insulin resistance associated with fasting. Because insulin resistance promotes the preservation of glucose and oxidation of fat, it has been suggested to be an adaptive response to food deprivation. However, fasting mammals exhibit hypoinsulinemia, suggesting that the insulin resistance-like conditions they experience may actually result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. To determine whether fasting results in insulin resistance or in pancreatic dysfunction, we infused early- and late-fasted seals (naturally adapted to prolonged fasting) with insulin (0.065 U/kg), and a separate group of late-fasted seals with low (10 pmol/L per kg) or high (100 pmol/L per kg) dosages of glucagon-like peptide-1 (GLP-1) immediately following a glucose bolus (0.5 g/kg), and measured the systemic and cellular responses. Because GLP-1 facilitates glucose-stimulated insulin secretion, these infusions provide a method to assess pancreatic insulin-secreting capacity. Insulin infusions increased the phosphorylation of insulin receptor and Akt in adipose and muscle of early- and late-fasted seals; however, the timing of the signaling response was blunted in adipose of late-fasted seals. Despite the dose-dependent increases in insulin and increased glucose clearance (high dose), both GLP-1 dosages produced increases in plasma cortisol and glucagon, which may have contributed to the glucogenic role of GLP-1. Results suggest that fasting induces adipose-specific insulin resistance in elephant seal pups, while maintaining skeletal muscle insulin sensitivity, and therefore suggests that the onset of insulin resistance in fasting mammals is an evolved response to cope with prolonged food deprivation.
Highlights
Insulin resistance is a common consequence of fasting (van der Crabben et al 2008) and, the exact mechanisms by which it manifests are still unclear, it is thought that its primary cause is the increased utilization of lipids during food deprivation (Koves et al 2005; Samuel et al 2010; Viscarra et al 2012)
Because we have previously suggested that increased lipid utilization contributes to the onset of insulin resistance in late-fasted seals (Viscarra et al 2012), we examined the following lipid handling proteins in adipose to assess the contribution of lipid metabolism to insulin signaling in latefasted elephant seal pups: AMP kinase (AMPk; 65 kDa), adipose triglyceride lipase (ATGL; 55 kDa), fatty acid translocase (CD36; 53 kDa), fatty acid transport protein 1 (FATP1; 63 kDa), fatty acid synthase (FAS; 270 kDa), hormone-sensitive lipase (HSL; 88 kDa), lipoprotein lipase (LPL; 56 kDa), and phosphoenol pyruvate carboxy kinase-c (PEPCK-c; 67 kDa)
Results demonstrate the onset of adipose insulin resistance in late-fasted elephant seal pups and suggest that the phenomenon manifests through the impairment of adipose insulin signaling due to the intracellular accumulation of diacyl glycerol (DAG)
Summary
Insulin resistance is a common consequence of fasting (van der Crabben et al 2008) and, the exact mechanisms by which it manifests are still unclear, it is thought that its primary cause is the increased utilization of lipids during food deprivation (Koves et al 2005; Samuel et al 2010; Viscarra et al 2012). Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
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