Early-stage deficiencies in insulin signaling in an animal model of non-obese type 2 diabetes (T2DM)

Objectives T2DM is generally associated with obesity; however, about 20% of patients are non-obese. The objective of this work was to investigate early-stage deficiencies in insulin signaling in a non-obese T2DM animal model.

Methods We used 9wk-old Goto-Kakizaki (GK) rats, which are non-obese and spontaneously develop T2DM early in life, to investigate early stage deficiencies in insulin signaling. There were 4 groups (n=4-6) of GK rats with corresponding Wistar controls, male and female, insulin or saline injected, used to investigate differences in response to insulin. A subset of rats were injected with [18F]FDG and a 60 min dynamic acquisition obtained. The input function (InF) from the left ventricular blood pool and the arterial InF were generated using published methods. A 2-tissue, 4-parameter model was used to quantify [18F]FDG metabolism in the heart. Myocardial Glucose utilization (MGU) was estimated and the glucose uptake (Ki) obtained using published methods. Hearts were extracted and flash frozen for Western blots and gene expression analyses (using commercial diabetes-associated qPCR gene array plates) of key pivots in insulin signaling.

Results MGU and Ki were significantly higher (P<0.01) in Wistar than GK rats. Insulin treatment increased phosphorylation of both Akt and AS160 in Wistar rats, but not in GK. GLUT4 expression was unchanged. Most genes were down regulated in both genders of GK rats, however, Agt and Fbp1 were upregulated in female GK, but unchanged in males. Gcgr was highly down regulated in males, but unchanged in females.

Conclusions Non-obese T2DM GK rats exhibit early-stage deficiencies in insulin signaling manifested as reduced glucose uptake and utilization, lack of response to insulin stimulation with respect to phosphorylation of proteins involved in glucose metabolism, and reduced gene expression in 19 out of 84 T2DM associated genes examined.