Human genetic variations appear to be responsible for susceptibility to several common diseases. Among these are type 2 diabetes (T2DM) and the closely related metabolic syndrome, which includes cardiovascular disease, stroke and fatty-liver disease. The primary indicator of T2DM is poor glucose tolerance and elevated blood sugar in the presence of insulin. Although obesity is a primary cause of T2DM and metabolic syndrome, there are millions of cases that are not accompanied by obesity, or where pathological symptoms precede obesity.

A major limitation to laboratory studies of genetic variation and T2DM/metabolic syndrome is that laboratory animals have artificial influences on social behavior and breeding. As a result, they do not experience societal pressures and genetic variations that occur in a natural setting.

This study compares glucose tolerance in two closely related species of native North American field mice (Peromyscus), each with notably different behavioral characteristics, in order to examine the link between non-obese T2DM susceptibility and genetic determinants of behavior. A sham glucose tolerance test, in which glucose was replaced with saline, revealed that males of the BW species experience a handling/stress-induced increase in blood sugar not seen either in males of the calmer and highly monogamous PO species, or in BW or PO females. The elevated blood sugar seen in BW males was eliminated by pharmacological inhibition of glucocorticoid (GC) stress hormone synthesis, suggesting an elevation in blood sugar in response to stress. Additionally, the GC levels of PO males are approximately twice those of BW males and do not alter blood sugar concentrations. Further tests using mice bred to carry a PO Y chromosome on a BW background also demonstrate that Y chromosome-linked genetic variance probably contributes to this sensitive response in BW mice.

This paper reports a natural variation in stress response that results in immediate symptoms characteristic of diabetes. Studying the genetic variation between these closely related species may help identify similar human genetic variations that are related to stress tolerance and cause T2DM predisposition. The authors also propose that the superior glucose and stress tolerance of PO males is related to their monogamy, as previous reports have demonstrated a link between increased GC levels with monogamy in primates. This research illustrates the need to consider gene-environment interactions, as well as social interactions and behavior, when studying biological processes and disease mechanisms.

2008