Chronic hyperinsulinemia contributes to insulin resistance under dietary restriction in association with altered lipid metabolism in Zucker diabetic fatty rats

Abstract

Hyperinsulinemia is widely thought to be a compensatory response to insulin resistance, whereas its potentially causal role in the progression of insulin resistance remains to be established. Here, we aimed to examine whether hyperinsulinemia could affect the progression of insulin resistance in Zucker fatty diabetic (ZDF) rats. Male ZDF rats at 8 wk of age were fed a diet ad libitum (AL) or dietary restriction (DR) of either 15 or 30% from AL feeding over 6 wk. Insulin sensitivity was determined by hyperinsulinemic euglycemic clamp. ZDF rats in the AL group progressively developed hyperglycemia and hyperinsulinemia by 10 wk of age, and then plasma insulin rapidly declined to nearly normal levels by 12 wk of age. Compared with AL group, DR groups showed delayed onset of hyperglycemia and persistent hyperinsulinemia, leading to weight gain and raised plasma triglycerides and free fatty acids by 14 wk of age. Notably, insulin sensitivity was significantly reduced in the DR group rather than the AL group and inversely correlated with plasma levels of insulin and triglyceride but not glucose. Moreover, enhanced lipid deposition and upregulation of genes involved in lipogenesis were detected in liver, skeletal muscle, and adipose tissues of the DR group rather than the AL group. Alternatively, continuous hyperinsulinemia induced by insulin pellet implantation produced a decrease in insulin sensitivity in ZDF rats. These results suggest that chronic hyperinsulinemia may lead to the progression of insulin resistance under DR conditions in association with altered lipid metabolism in peripheral tissues in ZDF rats.

Effects of obesity and diabesity on heart rhythm in the Zucker rat

“…The blood glucose levels were also further elevated in ZDF and ZF rats compared to ZL control rats. These differences in 180 minutes blood glucose measured at the start and end of the biotelemetry experiments could be explained by target cell insulin resistance and/or changing levels of insulin, which rise until the age of about 10 weeks and then start to fall 25 . Ageing could also contribute to the differences in blood glucose level observed at the beginning and the end of the experiment.…”

Remodeling of whole-body lipid metabolism and a diabetic-like phenotype caused by loss of CDK1 and hepatocyte division

“…While acute increases in insulin are important for maintaining blood glucose homeostasis, chronic insulin elevation, or chronic hyperinsulinemia, can lead to insulin resistance (44). This can happen by down-regulation of the insulin receptor through miR-27b (93) or by constantly maintaining the insulin receptor in an "insulin refractory state" whereby the insulin receptor has a lower ability to carry out autophosphorylation (94).…”

Pathophysiology of type 2 diabetes and the impact of altered metabolic interorgan crosstalk

“…Using a mouse knockout model for cyclin‐dependent kinase 1 ( Cdk1 cKO; Cdk1 flox/flox Alb‐Cre ), which is defective in hepatocyte proliferation and shows impairments in mitochondrial functions, our group has uncovered impairments in fatty acid oxidation (FAO) and increased lipolysis, promoting high levels of FFAs in the bloodstream, which caused enhanced insulin secretion by β‐cells in young Cdk1 cKO mice [160]. Homeostatic levels of insulin in the blood are essential for sugar metabolism, but at elevated levels, classified as hyperinsulinemia or chronic hyperinsulinemia, insulin resistance develops [161,162]. Hyperinsulinemia was observed in aged Cdk1 cKO mice associated with insulin resistance through reduced INSRB expression as well as the reduction in insulin receptor autophosphorylation, high levels of glucose in the blood, decrease in glucose tolerance, and response to insulin [160].…”