Efficacy of PPARγ therapy on glucose and fatty acid metabolism in muscle, brown adipose tissue, heart, and liver of obese type 2 diabetic rats

Objectives Type 2 Diabetes Mellitus (T2DM) is attributed to systemic disturbances in metabolism characterized by impaired insulin action in peripheral tissues. In the current work, preclinical PET imaging with [¹⁸F]FDG and [¹¹C]Palmitate in conjunction with kinetic modeling was utilized to identify disturbances in glucose and fatty acid (FA) metabolism and to monitor the effect of PPARγ agonist rosiglitazone (RGZ) in liver, heart, muscle, and brown adipose tissue.

Methods Small-animal PET was performed on Lean Zucker (ZL) and Zucker Diabetic Fatty (ZDF) rats assigned to these groups: Controls, age 14wks, no treatment (NT), 1) ZL (N=6), 2) ZDF (N=6); 3) ZDF age 19wks, NT (N=6); and 4) “Treatment group”, ZDF rats treated with 4 mg/kg/day RGZ for 5 weeks (14wks to 19wks) (N=6). A separate group of ZL and ZDF rats (N=4) were used to characterize arterial and portal vein kinetics and to reconstruct liver dual input function. Animals were fasted overnight prior to imaging. The imaging session began with a 20-minute acquisition with [¹¹C]Palmitate followed by a 60-minute [¹⁸F]FDG. In each session, 5-6 arterial whole-blood samples were obtained for substrate levels and metabolite analysis. A two compartment kinetic model was used for [¹⁸F]FDG and [¹¹C]Palmitate in muscle, brown fat and liver, and a four compartment model for [¹¹C]Palmitate was used in the heart.

Results Glucose uptake was impaired in brown fat, muscle, and heart tissues of ZDF rats compared to leans, while RGZ treatment increased glucose uptake compared to untreated ZDF rats. No differences were found in glucose metabolism in the liver. FA uptake decreased, but FA flux increased in brown fat and skeletal muscle of ZDF rats. RGZ treatment resulted in increased uptake of FA in brown fat, but decreased uptake and utilization in liver, muscle and heart.

Conclusions Our data indicate tissue-specific mechanisms for glucose and FA disposal as well as differential action of the insulin-sensitizing RGZ to normalize substrate handling.

Research Support This work was supported by NIDDK Grant 5R01DK085298.