Effects of acute exposure to a high-fat, high-sucrose diet on gestational glucose tolerance and subsequent maternal health in mice.

Gestational diabetes mellitus (GDM) is a common obstetric complication. Half of women who have GDM will go on to develop type 2 diabetes. Understanding the mechanisms by which this occurs requires an animal model of GDM without ongoing diabetes at conception. C57Bl/6J mice react acutely to a high-fat, high-sucrose (HFHS) challenge. Here, we hypothesized that a periconceptional HFHS challenge will induce glucose intolerance during gestation. C57Bl/6J female mice were placed on an HFHS either 1 or 3 weeks prior to mating and throughout pregnancy. Intraperitoneal glucose tolerance tests, insulin measurements, and histological analysis of pancreatic islets were used to assess the impact of acute HFHS. C57Bl/6J females fed HFHS beginning 1 week prior to pregnancy became severely glucose intolerant, with reduced insulin response to glucose, and decreased pancreatic islet expansion during pregnancy compared to control mice. These GDM characteristics did not occur when the HFHS diet was started 3 weeks prior to mating, suggesting the importance of acute metabolic stress. Additionally, HFHS feeding resulted in only mild insulin resistance in nonpregnant females. When the diet was discontinued at parturition, symptoms resolved within 3 weeks. However, mice that experienced glucose intolerance in pregnancy became glucose intolerant more readily in response to a HFHS challenge later in life than congenic females that experienced a normal pregnancy, or that were fed the same diet outside of pregnancy. Thus, acute HFHS challenge in C57Bl/6 mice results in a novel, nonobese, animal model that recapitulates the long-term risk of developing type 2 diabetes following GDM.

Brief high fat high sugar diet results in altered energy and fat metabolism during pregnancy in mice.

During pregnancy several maternal adaptations occur in order to support the growing fetus which are further exacerbated by gestational diabetes mellitus (GDM). Previously we developed a mouse model of GDM, however we did not evaluate alterations to energy and fat metabolism. We have also shown that alterations in lipid metabolism are mediated by adrenomedullin (ADM) in normal and GDM pregnancies. Our objectives were: (1) evaluate energy and fat homeostasis in our GDM mouse model and (2) determine if ADM may play a role in these changes. Female mice were placed on either control (P-CD) or high fat, high sucrose diet (P-HFHS) 1 week prior to and throughout pregnancy. Mice were placed into comprehensive lab animal monitoring system (CLAMS) chambers throughout pregnancy. Visceral adipose tissue (VAT) was collected at d17.5 of pregnancy for analysis. Energy Expenditure was significantly increased (p < 0.05) in P-HFHS dams compared to all other groups. VAT ex-vivo lipolysis was increased (p < 0.05) in P-HFHS compared to P-CD dams. VAT gene expression of ADM receptors Crlr, Ramp2, and Ramp3 was increased (p < 0.05) in P-HFHS dams. ADM dose dependently increased ex vivo lipolysis. This data further validates our animal model of GDM and is usefulness in investigating the pathophysiology of GDM.

Impact of adrenomedullin blockage on lipid metabolism in female mice exposed to high-fat diet.

PURPOSE: Adrenomedullin (ADM) levels are elevated in gestational and type 2 diabetic patients. ADM also stimulates lipolysis in vitro. Disturbed lipid metabolism has been implicated in the pathogenesis of diabetes. Here, we explore whether blockade of ADM is beneficial for metabolic homeostasis in a diabetic mouse model. METHODS: C57BL/6J female mice were placed on either a control or a high fat high sucrose (HFHS) diet for 8 weeks. At week 4, osmotic mini-pumps were implanted for constant infusion of either saline or ADM antagonist, ADM22-52. Glucose tolerance tests were performed prior to infusion and 4 weeks after infusion began. Animals were then sacrificed and visceral adipose tissue collected for further analysis. RESULTS: Mice fed HFHS displayed glucose intolerance, increased mRNA expressions in VAT for Adm and its receptor components, Crlr. HFHS fed mice also had increased basal and isoprenaline-induced glycerol release by VAT explants. ADM22-52 did not significantly affect glucose intolerance. ADM22-52 did suppress basal and isoprenaline-induced glycerol release by VAT explants. This alteration was associated with enhanced mRNA expression of insulin signaling factors Insr and Glut4, and adipogenic factor Pck1. CONCLUSIONS: HFHS diet induces glucose intolerance and enhances ADM and its receptor expressions in VAT in female mice. ADM22-52 treatment did not affect glucose intolerance in HFHS mice, but reduced both basal and isoprenaline-induced lipolysis, which is associated with enhanced expression of genes involved in adipogenesis. These results warrant further research on the effects of ADM blockade in improving lipid homeostasis in diabetic patients.

The Induction of Apoptosis in A375 Malignant Melanoma Cells by Sutherlandia frutescens.

Sutherlandia frutescens is a medicinal plant indigenous to Southern Africa and is commonly known as the "cancer bush." This plant has traditionally been used for the treatment of various ailments, although it is best known for its claims of activity against "internal" cancers. Here we report on its effect on melanoma cells. The aim of this study was to investigate whether an extract of S. frutescens could induce apoptosis in the A375 melanoma cell line and to outline the basic mechanism of action. S. frutescens extract induced apoptosis in A375 cells as evidenced by morphological features of apoptosis, phosphatidylserine exposure, nuclear condensation, caspase activation, and the release of cytochrome c from the mitochondria. Studies in the presence of a pan-caspase inhibitor allude to caspase-independent cell death, which appeared to be mediated by the apoptosis inducing factor. Taken together, the results of this study show that S. frutescens extract is effective in inducing apoptosis in malignant melanoma cells and indicates that further in vivo mechanistic studies may be warranted.