GLUT4, an insulin-sensitive glucose transporter, plays a major role of postprandial glucose disposal. We previously reported that human GLUT4 promoter-driven insulin receptor knockout (GIRKO) mice have reduced insulin signaling in central and peripheral tissues and develop hyperglycemia, albeit at a lower rate in an age-dependent manner on normal chow diet. Long-term high fat diet (HFD) feeding is well established for causing adiposity gain, increased inflammation, and insulin resistance. We hypothesized that HFD feeding will exacerbate the insulin resistance and result in rapid progression to overt diabetes in GIRKO mice. To test this, we examined the physiological response of euglycemic GIRKO mice to HFD in a time course study. We used indirect calorimetry analysis and found that GIRKO mice showed differences in energy partitioning shortly after HFD feeding started. The majority of GIRKO mice cohorts had 5-fold higher circulating insulin and 1.5-fold elevated blood glucose after 1 month of HFD feeding. In addition to the hyperglycemia and hyperinsulinemia, GIRKO mice also exhibited impaired glucose tolerance and islet hyperplasia, suggesting extreme insulin resistance exceeded the compensatory increase of insulin production. After 3 months on HFD, GIRKO mice had increased relative liver size, elevated hepatic triglycerides, and reduced hepatic glycogen, demonstrating impaired hepatic insulin signaling to stimulate glycogen synthesis and inhibit gluconeogenesis. We also confirmed the increase of key hepatic gluconeogenic gene expression, which likely contributed to hyperglycemia. The rapid progression of metabolic defects of GIRKO mice on HFD is not due to excessive weight or adiposity gain.

In conclusion, our studies of HFD-fed GIRKO mouse will offer insights in the role of the dietary contribution to diabetes disease progression without the confounding factor of increased adiposity.


A. Reilly: None. S. Yan: None. A.J. Loncharich: None. H. Ren: None.


Indiana University Diabetes and Obesity Research Training Program (T32DK064466); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK120772, R00DK098294); Indiana Diabetes Center (P30DK097512); Indiana Clinical and Translational Sciences Institute (UL1TR002529)

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