Phloridzin improves hyperglycemia but not hepatic insulin resistance in a transgenic mouse model of type 2 diabetes.
The chronic hyperglycemia that occurs in type 2 diabetes may cause deterioration of beta-cell function and insulin resistance in peripheral tissues. Mice that express a dominant-negative IGF-1 receptor, specifically in skeletal muscle (MKR mice), exhibit severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyper-glycemia. To determine the role of hyperglycemia in the worsening of the diabetes state in these animals, MKR mice were treated with phloridzin (PHZ), which inhibits intestinal glucose uptake and renal glucose reabsorption. Blood glucose levels were decreased and urine glucose levels were increased in response to PHZ treatment in MKR mice. PHZ treatment also increased food intake in MKR mice; however, the fat mass was decreased and lean body mass did not change. Serum insulin, fatty acid, and triglyceride levels were not affected by PHZ treatment in MKR mice. Hyperinsulinemic-euglycemic clamp analysis demonstrated that glucose uptake in white adipose tissue was significantly increased in response to PHZ treatment. Despite the reduction in blood glucose following PHZ treatment, there was no improvement in insulin-stimulated whole-body glucose uptake in MKR mice and neither was there suppression of endogenous glucose production by insulin. These results suggest that glucotoxicity plays little or no role in the worsening of insulin resistance that occurs in the MKR mouse model of type 2 diabetes.
Zhao
Hong
H
Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1758, USA.
Yakar
Shoshana
S
Gavrilova
Oksana
O
Sun
Hui
H
Zhang
Yang
Y
Kim
Hyunsook
H
Setser
Jennifer
J
Jou
William
W
LeRoith
Derek
D
D000273:Adipose Tissue / Q000033:anatomy & histology / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001823:Body Composition / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004195:Disease Models, Animal; D002149:Energy Intake; D006943:Hyperglycemia / Q000188:drug therapy*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010695:Phlorhizin / Q000627:therapeutic use*
D001786:Blood Glucose; D010695:Phlorhizin