Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats

Abstract

Leptin has been shown to reduce hyperglycemia in rodent models of type 1 diabetes. We investigated the effects of leptin administration in University of California, Davis, type 2 diabetes mellitus (UCD-T2DM) rats, which develop adult-onset polygenic obesity and type 2 diabetes. Animals that had been diabetic for 2 mo were treated with s.c. injections of saline (control) or murine leptin (0.5 mg/kg) twice daily for 1 mo. Control rats were pair-fed to leptintreated animals. Treatment with leptin normalized fasting plasma glucose and was accompanied by lowered HbA1c, plasma glucagon, and triglyceride concentrations and expression of hepatic gluconeogenic enzymes compared with vehicle (P < 0.05), independent of any effects on body weight and food intake. In addition, leptin-treated animals exhibited marked improvement of insulin sensitivity and glucose homeostasis compared with controls, whereas pancreatic insulin content was 50% higher in leptin-treated animals (P < 0.05). These effects coincided with activation of leptin and insulin signaling pathways and down-regulation of the PKR-like endoplasmic reticulum (ER) kinase/eukaryotic translation inhibition factor 2α (PERK-eIF2α) arm of ER stress in liver, skeletal muscle, and adipose tissue as well as increased proopiomelanocortin and decreased agouti-related peptide in the hypothalamus. In contrast, several markers of inflammation/immune function were elevated with leptin treatment in the same tissues (P < 0.05), suggesting that the leptin-mediated increase of insulin sensitivity was not attributable to decreased inflammation. Thus, leptin administration improves insulin sensitivity and normalizes fasting plasma glucose in diabetic UCD-T2DM rats, independent of energy intake, via peripheral and possibly centrally mediated actions, in part by decreasing circulating glucagon and ER stress.glucagon reduction | lipid lowering

The role of leptin in diabetes: metabolic effects

“…However, while the therapeutic potential of leptin for the treatment of obesity remains limited [60], as leptin plays a key role in glycaemic control, independent of its effects on energy balance, it might be useful as a therapy for other conditions. Leptin therapy has already been approved for the treatment of lipodystrophy and has glucose-lowering effects in rodent models of type 1 and type 2 diabetes [61]. This raises the possibility that leptin may be a potentially useful adjunct to insulin treatment in the management of diabetes.…”

Protein Tyrosine Phosphatase 1B Regulates Pyruvate Kinase M2 Tyrosine Phosphorylation

“…Firstly, we used UCD-T2DM diabetic rats, which exhibit adult onset polygenic obesity and insulin resistance and subsequently develop type 2 diabetes (37). Leptin administration to diabetic UCD-T2DM rats normalizes fasting plasma glucose concentrations and markedly improves insulin sensitivity independently of food intake (38). Diabetic UCD-T2DM rats received leptin (murine recombinant, 0.5 mg/kg) or saline injections (control).…”

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“…8 The observed significant increases in leptin and C-peptide levels in patients who received FPSCT versus no significant increases in these parameters in control group patients in our study may indicate the effectiveness of FPSCT. 3 In our study, leptin levels increased significantly within 3 months after FPSCT in patients with type 2 DM. Thus, increased levels of leptin, as well as C-peptide, after FPSCT may serve as a confirmation of the effectiveness of this procedure in patients with type 2 DM.…”

“…1,2 Centrally mediated actions of leptin on tissues conclude in activating leptin-responsive relays initiating in the hypothalamus that mediate leptin action on the endocrine pancreas and insulin-sensitive tissues through sympathetic and parasympathetic nervous systems. [1][2][3] Both leptin deficiency and leptin resistance profoundly affect glucose metabolism in rodents and humans. 3 One of the potentially effective therapeutic approaches to regenerating islet cells is fetal pancreatic stem cell transplant (FPSCT).…”

“…[1][2][3] Both leptin deficiency and leptin resistance profoundly affect glucose metabolism in rodents and humans. 3 One of the potentially effective therapeutic approaches to regenerating islet cells is fetal pancreatic stem cell transplant (FPSCT). 4 This procedure may be of clinical importance in the treatment of hyperglycemia, especially in leptin deficiency and in leptin resistance, such as in DM.…”