Pparg-P465L mutation worsens hyperglycemia in Ins2-Akita female mice via adipose-specific insulin resistance and storage dysfunction.

Published

Journal Article

The dominant-negative P467L mutation in peroxisome proliferator activated receptor-γ (PPARγ) was identified in insulin-resistant patients with hyperglycemia and lipodystrophy. In contrast, mice carrying the corresponding Pparg-P465L mutation have normal insulin sensitivity, with mild hyperinsulinemia. We hypothesized that murine Pparg-P465L mutation leads to covert insulin resistance, which is masked by hyperinsulinemia and increased pancreatic islet mass, to retain normal plasma glucose.We introduced in Pparg(P465L/+) mice an Ins2-Akita mutation that causes improper protein folding and islet apoptosis to lower plasma insulin.Unlike Ins2(Akita/+) littermates, male Pparg(P465L/+)Ins2(Akita/+) mice have drastically reduced life span with enhanced type 1 diabetes. Hyperglycemia in Ins2(Akita/+) females is mild. However, Pparg(P465L/+)Ins2(Akita/+) females have aggravated hyperglycemia, smaller islets, and reduced plasma insulin. In an insulin tolerance test, they showed smaller reduction in plasma glucose, indicating impaired insulin sensitivity. Although gluconeogenesis is enhanced in Pparg(P465L/+)Ins2(Akita/+) mice compared with Ins2(Akita/+), exogenous insulin equally suppressed gluconeogenesis in hepatocytes, suggesting that Pparg(P465L/+)Ins2(Akita/+) livers are insulin sensitive. Expression of genes regulating insulin sensitivity and glycogen and triglyceride contents suggest that skeletal muscles are equally insulin sensitive. In contrast, adipose tissue and isolated adipocytes from Pparg(P465L/+)Ins2(Akita/+) mice have impaired glucose uptake in response to exogenous insulin. Pparg(P465L/+)Ins2(Akita/+) mice have smaller fat depots composed of larger adipocytes, suggesting impaired lipid storage with subsequent hepatomegaly and hypertriglyceridemia.PPARg-P465L mutation worsens hyperglycemia in Ins2(Akita/+) mice primarily because of adipose-specific insulin resistance and altered storage function. This underscores the important interplay between insulin and PPARγ in adipose tissues in diabetes.

Full Text

Duke Authors

Cited Authors

  • Pendse, AA; Johnson, LA; Tsai, Y-S; Maeda, N

Published Date

  • November 2010

Published In

Volume / Issue

  • 59 / 11

Start / End Page

  • 2890 - 2897

PubMed ID

  • 20724579

Pubmed Central ID

  • 20724579

Electronic International Standard Serial Number (EISSN)

  • 1939-327X

International Standard Serial Number (ISSN)

  • 0012-1797

Digital Object Identifier (DOI)

  • 10.2337/db10-0673

Language

  • eng