Caloric restriction increases hepatic glucose in obese, insulin‐resistant OLETF rats

Abstract

Approximately 40% of adults in the United States are classified as obese. Inappropriately elevated body fat in humans contributes to the impairment of insulin signaling, ultimately resulting in alterations to glucose metabolism associated with insulin resistance (IR) and diabetes, both of which are linked to metabolic syndrome (MetS). MetS typically presents with obesity, as a result of overnutrition and a sedentary lifestyle, and causes adverse effects on metabolism, namely on glucose tolerance and insulin response. Caloric restriction (CR) may improve glucose uptake and cellular metabolism, and consistently increases the responsiveness of insulin, resulting in improved insulin sensitivity. The effects of CR on hepatic glycolytic enzymes are not well defined although it is suggested that CR inhibits hepatic glycolysis. More specifically, the effects of CR on hexokinase are not defined. Hexokinase IV (HK IV) catalyzes the first committed step of glycolysis, which is the phosphorylation of glucose to generate glucose‐6‐phosphate (G6P). To evaluate the effect of CR on glucose metabolism and hepatic HK activity during early onset of type 2 diabetes (T2D), sixteen 12‐week old rats were separated into 4 groups (n=4 per group): (1) control strain, LETO, (2) calorically restricted (30%) LETO, (3) obese insulin‐resistant, OLETF, and (4) calorically restricted OLETF. Prior to dissection, an oral glucose tolerance test (oGTT) was performed, and at dissection livers were harvested for measurements of glucose, G6P, and HK activity. Fasting glucose increased with CR in both LETO (63 ± 3 vs 78 ± 2 mg/dL) and OLETF (86 ± 4 vs 92 ± 4 mg/dL). The area under the curve (AUC) for glucose and insulin concentrations were used to estimate the insulin resistance index (IRI). Mean IRI was higher with CR in OLETF (11.7 ± 1.0 vs 13.7 ± 0.89). Hepatic glucose content increased with CR in OLETF (13.2 ± 3.1 vs 17.1 ± 1.0 nmol/μL). Neither hepatic G6P content nor glucose:G6P ratio were significantly changed with CR. While CR improves systemic glucose tolerance and insulin resistance, it increased hepatic glucose content in insulin resistant OLETF rats suggesting that CR inhibits glycolysis via reduced HK activity. Thus, the robust systemic improvements in glucose tolerance with CR during insulin resistant conditions are likely achieved by enhancing peripheral insulin signaling and glucose metabolism.