Overexpression of insulin receptor partially improves obese and diabetic phenotypes in <i>db/db</i> mice

Abstract

THERE are 347 million diabetic patients worldwide and 95 % of them are type 2 diabetes mellitus (T2DM), hallmarks of which are impaired secretion and action of insulin [1,2]. Several treatment options for T2DM are in clinical use, including injecting insulin, promoting insulin secretion by insulin secretagogues (such as sulfonylureas and glinides), and improving insulin sensitivity by insulin sensitizers (such as biguanides and thiazolidinediones). However, increasing the amount of insulin receptor in insulin-target tissues has not been explored.Insulin exerts its physiological effects through insulin receptors by binding to the alpha subunit of insulin receptor and stimulating the intrinsic kinase activity of the beta subunit [3][4][5]. However, chronic exposure of cells to insulin leads to down-regulation of insulin signaling through a net loss of insulin receptor from the plasma membrane [6], which is one of the mechanisms involved in insulin resistance. Therefore, increasing the amount of insulin receptor could alleviate insulin resistance. Leptin is an adipokine crucial for the regulation of energy homeostasis [7]. A homozygous loss-of-function mutation in the leptin receptor (the db mutation) causes hyperphagia and obesity, leading to diabetes in mice [8,9]. Since obesity is a major risk factor for impaired insulin sensitivity and T2DM, db/db mice are used as a genetic model of T2DM.

Age-Dependent Onset of Insulin Resistance in Insulin-Resistant Mice

“…33) Over expression of InsR partially improved diabetic phenotypes in db/db mice. 34) Growth hormones (GH) antagonize insulin actions and lead to hyperglycemia, hyperinsulinemia and decreased glucose utilization. 35) Chronic elevations of GH levels in transgenic mice over expressing growth-hormone genes are associated with the development of reduction in InsR number, resulting hyperinsulinemia and insulin resistance.…”

Restoration of insulin receptor improves diabetic phenotype in T2DM mice

“…In the past 2-3 decades, researchers have tried to increase IR level in diabetic animals using genetic approaches to reconstitute insulin action across tissues. However, the results were mixed partially because of challenges with achieving desirable expression in key metabolic tissues and complete glucose normalization or, in the case of transgene animal studies, complication because of concerns over developmental issues (11)(12)(13)(14). In the current study, we applied adeno-associated virus-mediated (AAV-mediated) IR expression in adult mice to restore primarily hepatic IR protein level, which significantly improved diabetic phenotypes in T2DM models without detectable side effects.…”

Whole-Body Vibration Mimics the Metabolic Effects of Exercise in Male Leptin Receptor–Deficient Mice

“…Bone marrow stem cells express receptors for multiple adipokines, including the adipose-derived hormone leptin (9, 10). Data from leptin-deficient rodent models have revealed regionally specific effects on the skeleton, with reports of cortical bone atrophy in weight-bearing long bones like the femur and tibia (11–16). Leptin-deficient (ob/ob) mice also exhibit lower femoral cortical bone mineral density (BMD) and strength compared with wild-type (WT) littermates (13).…”