Greb1 Transiently Accelerates Pancreatic β-Cell Proliferation in Diabetic Mice Exposed to Estradiol.

Decrease of pancreatic β cells leads to diabetes. In an inducible cAMP early suppressor (ICER-Iγ) transgenic mouse model of severe type 2 diabetes with reduced insulin production and depleted β cells, supplementation with high concentrations of 17β-estradiol (E2) markedly enhances β-cell proliferation and normalizes glucose levels. The current study explored the underlying mechanisms leading to a dynamic increase of β cells and pathologic changes in diabetic mice exposed to E2.

Differences in long-term effects of standard rodent diets on blood glucose and body weight of offspring.

Standard rodent diets are similar and contain well-balanced components, such as crude protein, fat, fiber, and ash. However, it is not clear whether there are differences in their long-term effects on metabolism. Here, we investigated the effects of long-term feeding of major standard diets, CRF-1, CE-2, and FR-1 to wild-type (WT) C57BL/6 mice on the blood glucose levels and body weight gain of their offspring, which were raised on the same diet and in the same environment as the mothers.

Amelioration of Murine Diabetic Nephropathy with a SGLT2 Inhibitor Is Associated with Suppressing Abnormal Expression of Hypoxia-Inducible Factors.

Diabetic nephropathy (DN), once manifested, is unlikely to completely recover. Factors that influence DN progression were explored by investigating the process of glomerulosclerosis and interstitial fibrosis and chronological changes in glucose, albuminuria, hyperfiltration, and expressions of sodium-glucose cotransporter 2 (SGLT2) and hypoxia-inducible factors (HIFs) up to 50 weeks in inducible cAMP early repressor transgenic mice, a model of severe DN. Long-term intervention with the SGLT2 inhibitor canagliflozin or islet transplantation or heminephrectomy was used.

Effects of 17β-Estradiol and Androgen on Glucose Metabolism in Skeletal Muscle.

Diabetes develops predominantly in males in experimental models, and extensive evidence suggests that 17β-estradiol (E2) modulates progression of diabetes in humans. We previously developed a severely diabetic transgenic (Tg) mouse model by β-cell-specific overexpression of inducible cAMP early repressor (ICER) and found that male ICER-Tg mice exhibit sustained severe hyperglycemia, but female ICER-Tg mice gradually became normoglycemic with aging. This implies that differences in circulating androgen and E2 levels might influence skeletal muscle glucose uptake and glycemic status.

Adjusting the 17β-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy.

Diabetes is manifested predominantly in males in experimental models, and compelling evidence suggests that 17β-estradiol (E2) supplementation improves hyperglycemia in humans. We previously generated a severely diabetic transgenic (Tg) mouse model by β-cell–specific overexpression of inducible cAMP early repressor (ICER) and found that male but not female ICER-Tg mice exhibit sustained hyperglycemia and develop major clinical and pathologic features of human diabetic nephropathy (DN). Thus, we hypothesized that differences in circulating hormone levels have a key role in determining susceptibility to diabetes.

β-cell induction in vivo in severely diabetic male mice by changing the circulating levels and pattern of the ratios of estradiol to androgens.

Previously we have generated transgenic (Tg) mice developing severe diabetes early in life with a profound depletion of β-cells with β-cell-directed expression of inducible cAMP early repressor-Iγ. Only male mice continue to demonstrate hyperglycemia throughout life. To investigate this sexual dimorphism, we treated severely diabetic male Tg mice with orchiectomy (ORX) or 17β-estradiol (E2) pellet implantation alone or in combination with ORX and E2-implantation to change the circulating levels and patterns of the ratio of estradiol to androgens.