Article

Diabetologia

, Volume 46, Issue 10, pp 1329-1337

First online:

Leptin as an adjunct of insulin therapy in insulin-deficient diabetes

  • F. MiyanagaAffiliated withDepartment of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
  • , Y. OgawaAffiliated withDepartment of Medicine and Clinical Science, Kyoto University Graduate School of MedicineDepartment of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University Email author 
  • , K. EbiharaAffiliated withDepartment of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
  • , S. HidakaAffiliated withDepartment of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
  • , T. TanakaAffiliated withDepartment of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
  • , S. HayashiAffiliated withPharmaceutical Research Laboratories, Takeda Chemical IndustriesNagoya Laboratories, Pfizer Global Research and Development
  • , H. MasuzakiAffiliated withDepartment of Medicine and Clinical Science, Kyoto University Graduate School of Medicine
  • , K. NakaoAffiliated withDepartment of Medicine and Clinical Science, Kyoto University Graduate School of Medicine

Abstract

Aims/hypothesis

The purpose of this study was to assess the therapeutic implication of leptin in insulin-deficient diabetes.

Methods

Insulin-deficient diabetes was induced by streptozotocin (STZ) in transgenic skinny mice overexpressing leptin. Plasma concentrations of glucose, insulin, and leptin were measured. The effects on body weight, food intake, and hypothalamic gene expressions were analyzed. After diabetes was induced, graded doses of insulin ranging from 0.4 to 51.2 mU·g–1·day–1 were injected. Co-administration of leptin and insulin was also carried out using osmotic pumps.

Results

After STZ injection, both transgenic and non-transgenic littermates developed marked hyperglycaemia as a result of severe hypoinsulinaemia [termed diabetic transgenic skinny mice overexpressing leptin (diabetic TGM) and diabetic non-transgenic littermates (diabetic WT) respectively], although diabetic TGM were more sensitive to exogenously administered insulin than diabetic WT. Diabetic WT were hypoleptinaemic and hyperphagic relative to non-diabetic WT, whereas diabetic TGM, which remained hyperleptinaemic, were less hyperphagic than diabetic WT. After STZ injection, hypothalamic expressions of orexigenic and anorexigenic peptide mRNAs were up-regulated and down-regulated, respectively, in diabetic WT, whereas they were unchanged in diabetic TGM. Diabetic TGM became normoglycaemic, when treated with insulin at such doses that did not improve hyperglycaemia in diabetic WT. We found that a sub-threshold dose of insulin that does not affect glucose homeostasis is effective in improving the diabetes in normal mice rendered diabetic by STZ injection, when combined with leptin.

Conclusions/interpretation

This study suggests that leptin could be used as an adjunct of insulin therapy in insulin-deficient diabetes, thereby providing an insight into the therapeutic implication of leptin as an anti-diabetic agent.

Keywords

Leptin transgenic mouse Type 1 diabetes insulin sensitivity streptozotocin neuropeptide Y agouti-related protein proopiomelanocortin