Hepatic noradrenergic innervation acts via CREB/CRTC2 to activate gluconeogenesis during cold.

BACKGROUND AND AIM: Although it is well established that hormones like glucagon stimulates gluconeogenesis via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2, the role of neural signals in the regulation of gluconeogenesis remains uncertain. METHODS AND RESULTS: Here, we characterize the noradrenergic bundle architecture in mouse liver; we show that the sympathoexcitation induced by acute cold exposure promotes hyperglycemia and upregulation of gluconeogenesis via triggering of the CREB/CRTC2 pathway. Following its induction by dephosphorylation, CRTC2 translocates to the nucleus and drives the transcription of key gluconeogenic genes. Rodents submitted to different models of sympathectomy or knockout of CRTC2 do not activate gluconeogenesis in response to cold. Norepinephrine directly acts in hepatocytes mainly through a Ca2+-dependent pathway that stimulates CREB/CRTC2, leading to activation of the gluconeogenic program. CONCLUSION: Our data demonstrate the importance of the CREB/CRTC2 pathway in mediating effects of hepatic sympathetic inputs on glucose homeostasis, providing new insights into the role of norepinephrine in health and disease.

Maternal Vitamin D Deficiency Impairs the Development of ß Cells in Offspring Rats in a Sex-Dependent Manner.

Recent studies have shown that maternal vitamin D deficiency (VDD) causes long-term metabolic changes in offspring. However, little is known about the impact of maternal VDD on offspring endocrine pancreas development and insulin secretion in the adult life of male and female animals. Female rats (Wistar Hannover) were fed either control (1000 IU Vitamin D3/kg), VDD (0 IU Vitamin D3/kg), or a Ca2+-enriched VDD diet (0 IU Vitamin D3/kg + Ca2+ and P/kg) for 6 weeks and during gestation and lactation. At weaning, VDD status was confirmed based on low serum calcidiol levels in dams and pups. Next, male and female offspring were randomly separated and fed a standard diet for up to 90 days. At this age, serum calcidiol levels were restored to normal levels in all groups, but serum insulin levels were decreased in VDD males without affecting glucagon levels, glycemia, or glucose tolerance. Islets isolated from VDD males showed lower insulin secretion in response to different glucose concentrations, but this effect was not observed in VDD females. Furthermore, VDD males, but not females, showed a smaller total pancreatic islet area and lower ß cell mass, an effect that was accompanied by reduced gene expression of Ins1, Ins2, Pdx1, and SLC2A2. The decrease in Pdx1 expression was not related to the methylation profile of the promoter region of this gene. Most of these effects were observed in the male VDD+Ca2+ group, indicating that the effects were not due to alterations in Ca2+ metabolism. These data show that maternal VDD selectively impairs the morphology and function of ß cells in adult male offspring rats and that female offspring are fully protected from these deleterious effects.

Maternal-fetal outcomes of exercise applied in rats with mild hyperglycemia after embryonic implantation.

BACKGROUND: Exercise is commonly recommended to control hyperglycemia, including during pregnancy. We conducted this study to understand the potential benefits and risks of exercise during pregnancy of women with diabetes. Specifically, we evaluated the effects of swimming on a diabetic rat during pregnancy and assayed maternal-fetal parameters. METHODS: Diabetes was induced in the female newborn from Wistar rats by the streptozotocin administration on first postnatal day. At 110 days of life, after confirm mild symptoms of diabetes, the rats were mated and randomly distributed into four experimental groups (minimum of 13 animals/group): Control (C)-nondiabetic animals without swimming; Control and Exercise (CEx)-nondiabetic animals submitted to swimming; Mild Diabetic (MD)-diabetic animals without swimming; Mild Diabetic and Exercise (MDEx)-diabetic animals submitted to swimming. The swimming program was performed from day 7 to 21 of pregnancy. Maternal parameters were evaluated during the pregnancy period. On day 21 of pregnancy, the rats were sacrificed and maternal and fetal parameters analyzed. RESULTS: There are no alterations in body weight, food consumption, water intake, and reproductive outcomes among the groups. The swimming program did not normalize maternal glycemia and other biochemical biomarkers. The diabetes and exercise combination increased organ weight. The fetuses born to these exercising diabetic rats had reduced fetal weight and increased skeletal anomalies (mainly incomplete ossification of sternebra). CONCLUSION: The intense swimming exercise imposed on female rats during pregnancy impaired maternal metabolic repercussions, contributing to intrauterine growth restriction and fetal skeletal anomalies.

The Treatment of Prednisone in Mild Diabetic Rats: Biochemical Parameters and Cell Response.

BACKGROUND: Limited studies have been carried out with prednisone (PRED) in treatment by glucose intolerant individuals, even in this model the animals presented low blood glucose levels at adulthood, by the high regenerative capacity of ß-cell. OBJECTIVE: The aim was to evaluate the effects of the treatment of PRED in mild diabetes on biochemical and immunological biomarkers. METHODS: Rats were randomly divided into four groups: control (C), treated control C+PRED (treatment of 1.25 mg/Kg/day PRED); diabetic DM (mild diabetes) and treated diabetic DM+PRED (treatment with same dose as C+PRED group). Untreated groups received vehicle, adjusted volume to body weight. The treatment lasted 21 days and measured body weight, food and water intake, and glycemia weekly. In the 3rd week, the Oral Glucose Tolerance Test (OGTT) and the Insulin Tolerance Test (ITT) was performed. On the last day, the rats were killed and the blood was collected for biochemical analyzes, leukogram and immunoglobulin G levels. RESULTS: There was a significant decrease in body weight in mild diabetes; however, the treatment in diabetic groups increased food intake, glycemia, and the number of total leukocytes, lymphocytes and neutrophils. On the other hand, it decreased the levels of triglycerides, high-density and very lowdensity lipoproteins. In addition, diabetic groups showed glucose intolerance and mild insulin resistance, confirming that this model induces glucose intolerant in adult life. CONCLUSION: The results showed that the use of prednisone is not recommended for glucose intolerant individuals and should be replaced in order to not to aggravate this condition.