Phloridzin Improves Hyperglycemia But Not Hepatic Insulin Resistance in a Transgenic Mouse Model of Type 2 Diabetes

Abstract

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.

Insulin resistance causes increased beta-cell mass but defective glucose-stimulated insulin secretion in a murine model of type 2 diabetes

“…The lack of obesity was not due to decreased food intake, which was increased in HFSD-fed MKR mice (Table 1). An increase in caloric intake in association with decreased body weight was also observed in MKR mice on a normal diet (Table 1), consistent with previous findings [26]. The precise mechanisms responsible for these findings are unclear, although factors including increased metabolic and physical activity may contribute [20].…”

“…Improving lipid metabolism by activation of peroxisome proliferator-activated receptor alpha in MKR mice normalised hyperglycaemia and insulin secretion, suggesting that lipotoxicity or glucolipotoxicity is responsible for the beta cell dysfunction in this model [24]. Alternatively, the involvement of insulin signalling in beta cell function suggests hyperinsulinaemia may contribute to MKR beta cell dysfunction because circulating insulin levels remained elevated and IGT persists in phloridzin-treated MKR mice [9,26,[36][37][38].…”

“…The precise mechanisms responsible for these findings are unclear, although factors including increased metabolic and physical activity may contribute [20]. The lower body weight in MKR mice is due to a reduction in lean body mass, and changes in adipose tissue mass, ranging from a slight increase to nonsignificant change, have been reported [26,27].…”

Pck1 Gene Silencing in the Liver Improves Glycemia Control, Insulin Sensitivity, and Dyslipidemia in db/db Mice

“…Lower insulin levels could be secondary to reduced glycemia; however, phloridzin treatment, which inhibits intestinal glucose uptake and renal reabsorption, has been shown to reduce glycemia with no effects on insulin sensitivity in a type 2 diabetes mouse model (22). Moreover, an ameliorated intraperitoneal insulin tolerance test (IPITT) and higher insulin-stimulated AKT phosphorylation in muscle and adipose tissue strongly support the hypothesis of an insulin-sensitizing effect.…”

Impaired Adipogenesis Caused by a Mutated Thyroid Hormone α1 Receptor

“…2A, lane 1), and its PV/ϩ mice. Food consumed by mice in 2 days was measured, and the food intake was normalized to the body weight of each mouse and expressed as g/g body weight Ϫ0.75 (24,50). Each circle represents an individual mouse, and the horizontal bars represent the mean values.…”