Biochemical adaptations of mammalian hibernation: exploring squirrels as a perspective model for naturally induced reversible insulin resistance

Abstract

An important disease among human metabolic disorders is type 2 diabetes mellitus. This disorder involves multiple physiological defects that result from high blood glucose content and eventually lead to the onset of insulin resistance. The combination of insulin resistance, increased glucose production, and decreased insulin secretion creates a diabetic metabolic environment that leads to a lifetime of management. Appropriate models are critical for the success of research. As such, a unique model providing insight into the mechanisms of reversible insulin resistance is mammalian hibernation. Hibernators, such as ground squirrels and bats, are excellent examples of animals exhibiting reversible insulin resistance, for which a rapid increase in body weight is required prior to entry into dormancy. Hibernator studies have shown differential regulation of specific molecular pathways involved in reversible resistance to insulin. The present review focuses on this growing area of research and the molecular mechanisms that regulate glucose homeostasis, and explores the roles of the Akt signaling pathway during hibernation. Here, we propose a link between hibernation, a well-documented response to periods of environmental stress, and reversible insulin resistance, potentially facilitated by key alterations in the Akt signaling network, PPAR-γ/PGC-1α regulation, and non-coding RNA expression. Coincidentally, many of the same pathways are frequently found to be dysregulated during insulin resistance in human type 2 diabetes. Hence, the molecular networks that may regulate reversible insulin resistance in hibernating mammals represent a novel approach by providing insight into medical treatment of insulin resistance in humans.

Tropical heterothermy is “cool”: The expression of daily torpor and hibernation in primates

“…There is also prospective benefit to a larger portion of the human population. The possible links between hibernation and reversible insulin resistance that is generally involved in type II diabetes is a rapidly growing research area, and one that could potentially impact hundreds of thousands of diabetics . Hibernators, particularly the dwarf lemurs, which can almost double their body mass in a couple of months, convert large amounts of high‐sugar food items into lipid deposits prior to hibernation without any ill effects.…”

Characterization of the SIRT family of NAD+-dependent protein deacetylases in the context of a mammalian model of hibernation, the thirteen-lined ground squirrel

“…cellular inactivity, low temperatures), hibernators avoid damage to their tissues by actively employing protective strategies to mitigate the harm that would otherwise occur under such circumstances in non-hibernating species [6,40]. Because of this capacity to circumvent the potentially harmful repercussions of the torpid state, and due to their remarkable ability to rapidly and effectively modulate their metabolic processes and energy requirements, hibernators have become a very interesting model for studies of metabolic disorders and stress-related cellular damage and are proving to be useful models for conditions such as diabetes, obesity, and aging [47].…”

Identification of a novel dehydration responsive gene, drp10, from the African clawed frog, Xenopus laevis

“…The most well‐known of these adaptive strategies is the use of hypometabolism (also known as metabolic rate depression) to decrease cellular energetic demands until the stress is removed (Storey and Storey, ; Storey, ). To date, the use of hypometabolism as an adaptive strategy during periods of environmental stress is most well‐known in animals and stresses found within the Northern hemisphere, including: hibernation (i.e., bats and squirrels), freezing (i.e., invertebrates, frogs, and hatchling turtles), and anoxia (i.e., invertebrates, frogs, and adult turtles) (Storey and Storey, ; Roufayel et al, ; Biggar et al, ; Wu et al, ; Zhang et al, ; Biggar and Storey, ; Wu et al, ). Although these stresses are commonly associated with low‐temperature adaptation, high temperatures during the summer (or during the dry season) can also impose similar habitat restrictions to those seen in the above stresses; namely, a characteristic reduction in water and nutrient availability that can easily threaten organism survival.…”