Reversible insulin sensitivity in grizzly bears (Ursus arctos horribilis): the roles of cell autonomous and exogenous factors in seasonal glucose metabolism

Kimberly Scott Rigano

Grizzly bears (Ursus arctos horribilis) have evolved remarkable metabolic adaptations to extended periods of low food availability including hyperphagia and massive fat accumulation during the fall followed by months of fasting throughout hibernation. Seasonal fluctuations in body mass are accompanied by changes in glucose and lipid metabolism, yet bears do not appear to suffer from the harmful effects associated with obesity in humans, such as type 2 diabetes mellitus (T2DM). To better define the metabolic transitions that occur annually in bears, we performed intravenous insulin tolerance tests (ivITTs) in anesthetized grizzly bears and oral glucose tolerance tests (oGTTs) in unanesthetized animals during the hibernation (January/February), active (May), and hyperphagic (September/October) seasons. To further investigate this system, we derived an in vitro model in which stromal vascular fraction (SVF) cells were isolated from subcutaneous fat biopsies during the three seasons. Cells were differentiated into adipocytes and stimulated with insulin under standard culture conditions and following chronic exposure to seasonal bear serum. Bears exhibited seasonal transitions in insulin sensitivity shifting from a sensitive state in the active and hyperphagic seasons to an insulin resistant state during hibernation. This change was accompanied by glucose intolerance and hyperinsulinemia in hibernating bears although euglycemia was maintained throughout the year. Adipocyte cultures mirrored the metabolic states observed in vivo only when exposed to season-matched bear serum. Hibernation serum suppressed insulin-mediated glucose uptake in all cells while hibernation cells exposed to active serum were highly insulin responsive. Active and hyperphagic serum also elevated expression of insulin receptor (INSR) following insulin administration in active cells with corresponding increases in glucose uptake. Protein kinase B (AKT1) expression was suppressed in hibernation cells with season-matched serum, yet elevated in active cells with hibernation serum at baseline (no insulin). Thus, both serum factors and cell autonomous mechanisms play a role in seasonal insulin sensitivity. Results indicate the importance of serum proteins in regulating glucose metabolism and greatly expand our understanding of bear hibernation physiology. Furthermore, identification of mechanisms responsible for metabolic changes may provide insight into human metabolic disorders.

Reversible insulin sensitivity in grizzly bears (Ursus arctos horribilis): the roles of cell autonomous and exogenous factors in seasonal glucose metabolism

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