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Objective: Consumption of high-fat diet exerts adverse effects on learning and memory formation, which is linked to impaired hippocampal function. Activation of glucagon-like peptide-1 (GLP-1) signalling ameliorates detrimental effects of obesity-diabetes on cognitive function; however, mechanisms underlying these beneficial actions remain unclear. This study examined effects of daily subcutaneous treatment with GLP-1 mimetic, Liraglutide, on synaptic plasticity, hippocampal gene expression and metabolic control in adult obese diabetic ( ob/ob ) mice. Results: Long-term potentiation (LTP) induced by area CA1 was completely abolished in ob/ob mice compared with lean controls. Deleterious effects on LTP were rescued ( P <0.001) with Liraglutide. Indeed, Liraglutide-treated mice exhibited superior LTP profile compared with lean controls ( P <0.01). Expression of hippocampal brain-derived neurotropic factor and neurotrophic tyrosine kinase receptor-type 2 were not significantly different, but synaptophysin and Mash1 were decreased in ob/ob mice. Treatment with Liraglutide over 21 days increased expression of Mash1 in ob/ob mice (2.0-fold; P <0.01). These changes were associated with significantly reduced plasma glucose (21% reduction; P <0.05) and markedly improved plasma insulin concentrations (2.1- to 3.3-fold; P <0.05 to P <0.01). Liraglutide also significantly reduced the glycaemic excursion following an intraperitonal glucose load (area under curve (AUC) values: 22%; P <0.05) and markedly enhanced the insulin response to glucose (AUC values: 1.6-fold; P <0.05). O 2 consumption, CO 2 production, respiratory exchange ratio and energy expenditure were not altered by Liraglutide therapy. On day 21, accumulated food intake (32% reduction; P <0.05) and number of feeding bouts (32% reduction; P <0.05) were significantly reduced but simple energy restriction was not responsible for the beneficial actions of Liraglutide. Conclusion: Liraglutide elicits beneficial effects on metabolic control and synaptic plasticity in mice with severe obesity and insulin resistance mediated in part through increased expression of Mash1 believed to improve hippocampal neurogenesis and cell survival.

High-calorie diet has been shown to impair learning ability and hippocampal synaptic plasticity in rodents. This study examined effects of daily treatment with the glucagon-like peptide-1 mimetic, exendin-4, on cognitive function and hippocampal synaptic plasticity in a model of diet-induced obesity, which exhibits compromised cognitive performance. Mice fed a high-fat diet were treated with exendin-4 (25 nmol kg−1 bodyweight; twice daily) or saline vehicle (0.9% (w/v) NaCl) over 21 days. In addition to improving metabolic control, exendin-4-treated mice exhibited a marked increase in recognition index highlighting improved learning and memory. High-fat diet resulted in the elimination of in vivo electrophysiological long-term potentiation, which was rescued following exendin-4 treatment. This study shows that exendin-4 therapy improves cognitive function and ameliorates impaired hippocampal synaptic plasticity in dietary-induced obesity.

OBJECTIVE: Compromise of gastric inhibitory polypeptide (GIP) receptor action and activation of cholecystokinin (CCK) receptors represent mechanistically different approaches to the possible treatment of obesity-related diabetes. In the present study, we have compared the individual and combined effects of (Pro 3 )GIP[mPEG] and (pGlu-Gln)-CCK-8 as an enzymatically stable GIP receptor antagonist and CCK receptor agonist molecule, respectively. RESULTS: Twice-daily injections of (pGlu-Gln)-CCK-8 alone and in combination with (Pro 3 )GIP[mPEG] in high-fat-fed mice for 34 days significantly decreased the energy intake throughout the entire study ( P <0.05 to P <0.01). Body weights were significantly depressed ( P <0.05 to P <0.01) in all treatment groups from day 18 onwards. Administration of (pGlu-Gln)-CCK-8, (Pro 3 )GIP[mPEG] or a combination of both peptides significantly ( P <0.01 to P <0.001) decreased the overall glycaemic excursion in response to both oral and intraperitoneal glucose challenge when compared with the controls. Furthermore, oral glucose tolerance returned to lean control levels in all treatment groups. The beneficial effects on glucose homeostasis were not associated with altered insulin levels in any of the treatment groups. In keeping with this, the estimated insulin sensitivity was restored to control levels by twice-daily treatment with (pGlu-Gln)-CCK-8, (Pro 3 )GIP[mPEG] or a combination of both peptides. The blood lipid profile on day 34 was not significantly different between the high-fat controls and all treated mice. CONCLUSION: These studies highlight the potential of (pGlu-Gln)-CCK-8 and (Pro 3 )GIP[mPEG] in the treatment of obesity-related diabetes, but there was no evidence of a synergistic effect of the combined treatment.

Parenteral delivery of long-acting glucagon-like peptide-1 (GLP-1) mimetics has received much attention as a therapeutic option for diabetes. However, cell therapy-based GLP-1 treatments may provide a more physiological regulation of blood glucose. The present study assessed the effects of chronic GLP-1 delivery by cell therapy, using the GLP-1-secreting GLUTag cell line, in normoglycemic and streptozotocin-induced diabetic mice. GLUTag cell aggregates were transplanted into the subscapular region of mice. Over 30 days, cellular transplantation gave rise to encapsulated and well-vascularized growths, which contained immunoreactive GLP-1. Cell implantation was well tolerated and had no appreciable metabolic effects in normal mice. However, transplantation significantly ( P <0.001) countered excessive food and fluid intake in diabetic mice and maintained normal body weight. Circulating glucose ( P <0.01) and glucagon ( P <0.05) were significantly reduced and plasma insulin and GLP-1 dramatically increased. This was associated with significantly ( P <0.01) improved glucose tolerance in diabetic mice. Histological examination of the pancreata of these mice revealed elevations ( P <0.001) in islet and β-cell area, with reduced ( P <0.001) α-cell area. Increased β-cell mass reflected the enhanced proliferation relative to apoptosis. These studies emphasize the potential of chronic GLP-1 delivery by cell therapy as a potential therapeutic option for diabetes.

Trigonella foenum-graecum (fenugreek) seeds have been documented as a traditional plant treatment for diabetes. In the present study, the antidiabetic properties of a soluble dietary fibre (SDF) fraction of T. foenum-graecum were evaluated. Administration of SDF fraction (0·5 g/kg body weight) to normal, type 1 or type 2 diabetic rats significantly improved oral glucose tolerance. Total remaining unabsorbed sucrose in the gastrointestinal tract of non-diabetic and type 2 diabetic rats, following oral sucrose loading (2·5 g/kg body weight) was significantly increased by T. foenum-graecum (0·5 g/kg body weight). The SDF fraction suppressed the elevation of blood glucose after oral sucrose ingestion in both non-diabetic and type 2 diabetic rats. Intestinal disaccharidase activity and glucose absorption were decreased and gastrointestinal motility increased by the SDF fraction. Daily oral administration of SDF to type 2 diabetic rats for 28 d decreased serum glucose, increased liver glycogen content and enhanced total antioxidant status. Serum insulin and insulin secretion were not affected by the SDF fraction. Glucose transport in 3T3-L1 adipocytes and insulin action were increased by T. foenum-graecum. The present findings indicate that the SDF fraction of T. foenum-graecum seeds exerts antidiabetic effects mediated through inhibition of carbohydrate digestion and absorption, and enhancement of peripheral insulin action.

Plantago ovata has been reported to reduce postprandial glucose concentrations in diabetic patients. In the present study, the efficacy and possible modes of action of hot-water extracts of husk of P. ovata were evaluated. The administration of P. ovata (0·5g/kg body weight) significantly improved glucose tolerance in normal, type 1 and type 2 diabetic rat models. When the extract was administered orally with sucrose solution, it suppressed postprandial blood glucose and retarded small intestinal absorption without inducing the influx of sucrose into the large intestine. The extract significantly reduced glucose absorption in the gut during in situ perfusion of small intestine in non-diabetic rats. In 28d chronic feeding studies in type 2 diabetic rat models, the extract reduced serum atherogenic lipids and NEFA but had no effect on plasma insulin and total antioxidant status. No effect of the extract was evident on intestinal disaccharidase activity. Furthermore, the extract did not stimulate insulin secretion in perfused rat pancreas, isolated rat islets or clonal β cells. Neither did the extract affect glucose transport in 3T3 adipocytes. In conclusion, aqueous extracts of P. ovata reduce hyperglycaemia in diabetes via inhibition of intestinal glucose absorption and enhancement of motility. These attributes indicate that P. ovata may be a useful source of active components to provide new opportunities for diabetes therapy.

Diabetes mellitus is a complex metabolic disease characterised by glucose overproduction and under-utilisation. As the incidence of diabetes expands rapidly across the globe there is an urgent need to expand the range of effective treatments. Higher plants such as Asparagus adscendens provide therapeutic opportunities and a rich source of potential antidiabetic agents. In the present study an aqueous extract of Asparagus adscendens was shown to induce a significant non-toxic 19–248% increase in glucose-dependent insulinotropic actions (P<0·001) in the clonal pancreatic β cell line, BRIN-BD11. In addition, the extract produced an 81% (P<0·0001) increase in glucose uptake in 3T3-L1 adipocytes. Asparagus adscendens also produced a 21% (P<0·001) decrease in starch digestion in vitro. The present study has revealed the presence of insulinotropic, insulin-enhancing activity and inhibitory effects on starch digestion in Asparagus adscendens. The former actions are dependent on the active principle(s) in the plant being absorbed intact. Future work assessing its use as a dietary adjunct or as a source of active components may provide new opportunities for the treatment of diabetes

Male weanling rats were fed diets containing either adequate (6.2 mg/kg) or deficient (0.82 mg/kg) quantities of copper for 35 days. Six rats from each group (n = 12) were then injected with streptozotocin to induce diabetes. Rats were killed after a further 16 days and tissues removed for the analysis of the copper level and antioxidant enzyme activities. Diabetes resulted in increased cardiac catalase, glutathione S-transferase (GST), copper-zinc Superoxide dismutase and manganese superoxide dismutase activities. Renal catalase levels were decreased in diabetes, while glucose-6-phosphate dehydrogenase activity (G6PDH) was increased. Diabetes significantly decreased the activities of hepatic GST and G6PDH. The combination of diabetes and copper deficiency resulted in increased levels of hepatic GST, glutathione peroxidase and glutathione reductase. Hepatic and renal tissue copper levels were also increased in diabetes, apparently improving copper status in the copper-deficient rats. Alterations of antioxidant enzyme activities in diabetes were suggestive of increased oxidant stress, especially in cardiac tissue.