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Euglycemic Clamp in the FATZO/Pco Mouse: A New Model of Type 2 Diabetes

Obesity and metabolicsyndrome are closely linked to the development of Type 2 diabetes. Recently, a new model of polygenic, non‐leptin mediated, obesity (FATZO/Pco) was developed by crossing C57BL6/Jwith AKR/J mice and selectively bred to select for obesity, insulin resistance, and hyperglycemia. Newly published data suggests that the FATZO mouse responds to various anti‐diabetic agents. To extend these findings, we performed aeuglycemic clamp study in age‐matched FATZO mice with low body weight (LBWV; mean BW=34g+3) and high BW (BW=43g+2) to determine the extent and tissue location of insulin resistance. Subgroups of the high BW group were treated with vehicle (HBWV) or rosiglitazone (HBWR; 30mg/kg, po, qd) for 8 days. A euglycemic‐hyperinsulinemic clamp was performed, using a 40mU/kg insulin bolus and 10mU/kg/min infusion and 3‐3H‐glucoseinfusion to estimate endogenous glucose production (EGP). After an overnight fast, the LBWV group was variably hyperglycemic compared to the HBWV group. However, the basal plasma insulin levels of the HBWV were more than twice as high, suggesting significant insulin resistance. The glucose infusion rate(GIR) was reduced nearly 50% in the HBWV compared to the LBWV group. The GIR of the HBWR group was nearly identical to the LBWV group. There was no difference in basal EGP between LBWV and HBWV groups but basal EGP was reduced in the HBWR group. Insulin‐mediated suppression of EGP was 60% in the LBWV group, 5% in the HBWV group, and 75% in the HBWR group. A bolus of 2‐14C‐Deoxyglucose (2‐DG) was subsequently administered to determine tissue glucose uptake. No significant differences between LBWV and HBWV were detected in the sole us muscle or the epididymal fat pad. However, 2‐DG uptake was significantly reduced in the gastrocnemius and quadriceps muscles in the HBWV group. Administration of rosiglitazone increased 2‐DG uptake in all tissues tested. Suppression of plasma free fatty acids during the clamp period was marginally reduced in the HBWV group. In conclusion, these data demonstrate a marked reduction in whole‐body glucose utilization and profound hepatic insulin resistance in the FATZO mice. In addition, the data reveal evidence of significant insulin resistance in peripheral tissues. The FATZO mouse maybe an ideal, non‐leptin model for diabetes/obesity target evaluation and efficacy determination.