Tracking changes of the parameters of glucose-insulin homeostasis during the course of obesity in B6D2F1 mice.

Obesity is one of the primary causes of type 2 diabetes mellitus (T2DM). To better understand how obesity impairs glucose-insulin homeostasis, we tracked fasting blood glucose and insulin levels and the key components of glucose-insulin homeostasis for 7 months in high fat diet (HFD; 45% fat) fed mice (n = 8). Every 2 weeks we measured body weight, fasting blood glucose and insulin levels, and estimated 5 key rate constants of glucose-insulin homeostasis using the methods established previously (Heliyon 3: e00310, 2017). Mice gained weight steadily, more than doubling their weights after 7 months (23.6 ± 0.5 to 52.3 ± 1.4 g). Fasting (basal) insulin levels were elevated (221.3 ± 16.7 to 1043.1 ± 90.5 pmol l-1 ) but fasting blood glucose levels unexpectedly returned to the baseline levels (152.8 ± 7.0 to 152.0 ± 7.2 mg/dl) despite significantly elevated levels (216.8 ± 44.9 mg/dl, average of 3 highest values for 8 mice) during the experimental period. After 7 months of HFD feeding, the rate constants for insulin secretion (k1 ), insulin-independent glucose uptake (k3 ), and insulin concentration where liver switches from glucose uptake to release (Ipi ) were significantly elevated. Insulin-dependent glucose uptake (k2 ) and rate constant of liver glucose transfer (k4 ) were lowered but no statistical significance was reached. The novel and key finding of this study is the wide range of fluctuations of the rate constants during the course of obesity, reflecting the body's compensatory responses against metabolic alterations caused by obesity.