Simultaneous Measurement of Insulin Sensitivity, Insulin Secretion, and the Disposition Index in Conscious Unhandled Mice

Abstract

Of the parameters that determine glucose disposal and progression to diabetes in humans: first-phase insulin secretion, glucose effectiveness, insulin sensitivity, and the disposition index, only insulin sensitivity can be reliably measured in conscious mice. To determine the importance of the other parameters in murine glucose homeostasis in lean and obese states, we developed the frequently sampled intravenous glucose tolerance test (FSIVGTT) for use in unhandled mice. We validated the conscious FSIVGTT against the euglycemic clamp for measuring insulin sensitivity in lean and obese mice. Insulin resistant mice had increased first-phase insulin secretion, decreased glucose effectiveness and a reduced disposition index, qualitatively similar to humans. Intriguingly, while insulin secretion explained most of the variation in glucose disposal in lean mice, glucose effectiveness and the disposition index more strongly predicted glucose disposal in obese mice. Disposition index curves identified individual diet-induced obese mice as having compensated or decompensated insulin secretion. Conscious FSIVGTT opens the door to apply mouse genetics to the determinants of in vivo insulin secretion, glucose effectiveness and disposition index, and further validates the mouse as a model of metabolic disease.

FGF19 action in the brain induces insulin-independent glucose lowering

“…While fasting blood glucose levels were similar in i.c.v. vehicle-treated ob/ob and WT mice, basal plasma insulin levels were markedly elevated in the former group, consistent with previous evidence of severe insulin resistance in these animals (2). Similarly, glucose tolerance was markedly impaired in i.c.v.…”

“…We therefore turned our attention to its effects on the two other determinants of glucose tolerance, Si and insulin-independent glucose disposal. As expected (2), minimal model analysis of glucose and insulin data from the FSIGT revealed the Si index to be markedly reduced in i.c.v. vehicle-treated ob/ob mice relative to that in WT controls ( Figure 3E).…”

“…infusion of leptin completely normalizes glycemia in rats with streptozotocin-induced diabetes (22)(23)(24)(25) suggests that the brain has the capacity to potently lower glucose levels via mechanisms that are insulin independent. To investigate the hypothesis that FGF19 has the capacity to lower blood glucose by mechanisms that are insulin independent, we used minimal model analysis of glucose and insulin data from a FSIGT, an approach developed in humans and recently validated for use in mice (2). We found that, in ob/ob mice, a single i.c.v.…”

“…In leptin-deficient ob/ob mice, for example, GE was shown recently to be reduced by approximately 70%, based on minimal model analysis of data obtained from a frequently sampled i.v. glucose tolerance test (FSIGT) (2). Based on its importance to glucose homeostasis, we hypothesized that any intervention capable of normalizing glucose tolerance in these mice should do so, at least in part, by increasing GE.…”

Leptin enhances hypothalamic lactate dehydrogenase A (LDHA)–dependent glucose sensing to lower glucose production in high-fat–fed rats

“…Indeed, a reduction in glucose responsiveness was associated with impaired glucose tolerance in obese individuals (4). As seen in humans, obese and diabetic rodents such as the leptin deficient ob/ob mice also display a loss of glucose sensing (5). Thus, the ability of glucose sensing per se to regulate its own metabolism is highly relevant in obesity and diabetes.…”