Insulin and GLP-1 infusions demonstrate the onset of adipose-specific insulin resistance in a large fasting mammal: potential glucogenic role for GLP-1

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.

Metabolic responses to adrenocorticotropic hormone (ACTH) vary with life-history stage in adult male northern elephant seals

“…It is plausible that elevations in glucose during late breeding might have occurred after the 120-min observation period, but that elevated glucose had not returned to baseline levels by the 48-hour measurement. Prior work in other age classes of elephant seals has demonstrated that the pancreatic release of insulin after a prolonged period of fasting is negligible and that there is an increase in insulin resistance to some tissues [59][60][61]. It is possible that the same trends in the insulin regulation of glucose exist in the adult males subjected to prolonged fasts.…”

Thyroid Hormone Regulation and Insulin Resistance: Insights From Animals Naturally Adapted to Fasting

“…Another endocrine response/consequence of food deprivation is the onset of insulin resistance that spares glucose for glucose-dependent tissues such as the central nervous system (28, 42, 48, 52, 53, 131,133). Fasting in humans is associated with a drop in plasma glucose, a drop that is sustained for up to 33 days of fasting, and decreased plasma insulin; a similar response is seen in rats (23, 46, 62).…”

“…Over the course of their postweaning fast, pups develop adipose-specific insulin resistance associated with an increase in TH production, leading to increased cellular TH-mediated responses (79,82,129,130,132,133). In response to a TSH infusion, both T4 and T3 increased in late-fasted pups.…”

“…Associated with these changes in TH signaling during prolonged fasting were decreases in insulin and adiponectin, which combined would desensitize insulin signaling. The prolonged fast in elephant seal pups is also characterized by relatively high blood glucose levels, increased nonesterfied fatty acid, adipose diacylglycerol (DAG) accumulation, and impaired adipose insulin signaling (130,133). Collectively, the thyroidal status of fasting seals would be considered euthyroid, since the cellular capacity is enhanced with fasting duration despite the presence of tissue-specific insulin resistance, suggesting that the contribution of TH and insulin signaling to the adaptation to prolonged fasting may be unique in these animals.…”

“…Here, we attempt to characterize these phases in animals naturally adapted to protracted periods of food deprivation in contrast to the well established and recognized phases of starvation defined by Cahill and colleagues (22). Given that fasting is also coupled with dynamic changes in endocrine signaling, especially thyroid hormonemediated cellular events that should tightly regulate energy homeostasis (6), prolonged periods of food deprivation can also lead to intermittent insulin resistance (48), which, as a coping mechanism, enables metabolic shifts that spare glucose and lean tissue (129,(131)(132)(133). Most recently, the relationships between changes in thyroidal status and its contribution to, or regulation by, insulin signaling and glucose homeostasis have been well established as detrimental, leading to pathophysiological conditions in humans (59, 123, 134), although the specific mechanisms remain largely elusive.…”