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

Bethany P. Cummings, Ahmed Bettaieb, James L. Graham, Kimber Stanhope, Riva Dill, Gregory J. Morton, Fawaz Haj, Peter J Havel

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)14670-14675
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number35
DOIs
StatePublished - Aug 30 2011

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Leptin
Type 2 Diabetes Mellitus
Fasting
Glucose
Insulin Resistance
Endoplasmic Reticulum Stress
Glucagon
Insulin
Inflammation
Pro-Opiomelanocortin
Liver
Energy Intake
Type 1 Diabetes Mellitus
Hyperglycemia
Endoplasmic Reticulum
Hypothalamus
Adipose Tissue
Rodentia
Skeletal Muscle
Triglycerides

Keywords

  • Glucagon reduction
  • Lipid lowering

ASJC Scopus subject areas

  • General

Cite this

Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats. / Cummings, Bethany P.; Bettaieb, Ahmed; Graham, James L.; Stanhope, Kimber; Dill, Riva; Morton, Gregory J.; Haj, Fawaz; Havel, Peter J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 35, 30.08.2011, p. 14670-14675.

Research output: Contribution to journalArticle

Cummings, Bethany P. ; Bettaieb, Ahmed ; Graham, James L. ; Stanhope, Kimber ; Dill, Riva ; Morton, Gregory J. ; Haj, Fawaz ; Havel, Peter J. / Subcutaneous administration of leptin normalizes fasting plasma glucose in obese type 2 diabetic UCD-T2DM rats. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 35. pp. 14670-14675.
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AB - 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.

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