scholarly journals Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice

2017 ◽  
Vol 234 (3) ◽  
pp. 255-267 ◽  
Author(s):  
Paul Millar ◽  
Nupur Pathak ◽  
Vadivel Parthsarathy ◽  
Anthony J Bjourson ◽  
Maurice O’Kane ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Energy Intake ◽  
Diabetic Mice ◽  
Neuroprotective Effects ◽  
Once Daily ◽  
Stratum Pyramidale ◽  
Sodium Glucose Cotransporter ◽  
Neuroprotective Actions

This study assessed the metabolic and neuroprotective actions of the sodium glucose cotransporter-2 inhibitor dapagliflozin in combination with the GLP-1 agonist liraglutide in dietary-induced diabetic mice. Mice administered low-dose streptozotocin (STZ) on a high-fat diet received dapagliflozin, liraglutide, dapagliflozin-plus-liraglutide (DAPA-Lira) or vehicle once-daily over 28 days. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin sensitivity, hormone and biochemical analysis, dual-energy X-ray absorptiometry densitometry, novel object recognition, islet and brain histology were examined. Once-daily administration of DAPA-Lira resulted in significant decreases in body weight, fat mass, glucose and insulin concentrations, despite no change in energy intake. Similar beneficial metabolic improvements were observed regarding glucose tolerance, insulin sensitivity, HOMA-IR, HOMA-β, HbA1c and triglycerides. Plasma glucagon, GLP-1 and IL-6 levels were increased and corticosterone concentrations decreased. DAPA-Lira treatment decreased alpha cell area and increased insulin content compared to dapagliflozin monotherapy. Recognition memory was significantly improved in all treatment groups. Brain histology demonstrated increased staining for doublecortin (number of immature neurons) in dentate gyrus and synaptophysin (synaptic density) in stratum oriens and stratum pyramidale. These data demonstrate that combination therapy of dapagliflozin and liraglutide exerts beneficial metabolic and neuroprotective effects in diet-induced diabetic mice. Our results highlight important personalised approach in utilising liraglutide in combination with dapagliflozin, instead of either agent alone, for further clinical evaluation in treatment of diabetes and associated neurodegenerative disorders.

scholarly journals Daily Consumption of Stevia Drops Effects on Glycemia, Body Weight and Energy Intake: Results from a 12-Week, Open-Label, Randomized Controlled Trial in Healthy Adults

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 663-663
Author(s):  
Nikoleta Stamataki ◽  
Benjamin Crooks ◽  
John McLaughlin
Keyword(s):  
Body Weight ◽  
Glucose Tolerance ◽  
Energy Intake ◽  
Real Life ◽  
Normal Weight ◽  
Control Group ◽  
Oral Glucose ◽  
Daily Consumption ◽  
Glucose Response ◽  
Significant Difference

Abstract Objectives Stevia is a non-nutritive sweetener providing sweet taste with zero calories that could constitute an effective strategy toward sugar reduction. This study tested the effects of daily consumption of stevia drops on glycemia, body weight (BW) and energy intake in healthy normal weight adults, non-habitual consumers of non-nutritive sweeteners. Methods Twenty eight healthy participants were randomly assigned to the stevia group (n = 14, mean age: 25 ± 5.5 y, mean body mass index: 22 ± 1.8 kg/m2) and were required to consume 5 drops of a commercially available stevia extract twice daily along with their habitual drinks, or to the control group (n = 14, 25 ± 4.2 y, 21 ± 1.5 kg/m2) and were instructed not to change anything in their diet for 12 weeks. Both groups were encouraged to maintain their usual diet and physical activity habits. At baseline and week 12, glucose response to an oral glucose tolerance test (OGTT) was measured; BW and energy intake were assessed at baseline, week 6 and week 12. Results There was no significant difference in glucose response to the OGTT over the 12 weeks in any study group. However, there was a significant main effect of participant group on BW change over the 12 weeks (F(1, 26) = 5.56, P = 0.026), showing that stevia consumption prevented weight gain (ΔWeight at week 12 = −0.22 ± 0.32 kg for stevia, +0.89 ± 0.39 kg for the control group). Energy intake was significantly decreased between baseline and week 12 in the stevia group (ΔEnergy at week 12 = −344 ± 80.6 kcal, P = 0.003), however no change in energy intake was found in the control group (ΔEnergy = +13.6 ± 125 kcal, P = 0.973). Conclusions These results suggest that daily consumption of stevia in real-life doses does not affect glycemia in healthy normal-weight individuals, but could aid toward weight maintenance and moderation of energy intake. More research is warranted to explore these promising findings further in individuals with overweight/obesity and/or individuals with impaired glucose tolerance (i.e., pre-diabetes/diabetes). Clinicaltrial.gov identifier: NCT03993418. Funding Sources This project has received a N8 AgriFood Pump Priming Award. Ms Stamataki has a BBSRC DTP Case Studentship.

scholarly journals Tpcn2 knockout mice have improved insulin sensitivity and are protected against high-fat diet-induced weight gain

2018 ◽  
Vol 50 (8) ◽  
pp. 605-614
Author(s):  
Hong He ◽  
Katie Holl ◽  
Sarah DeBehnke ◽  
Chay Teng Yeo ◽  
Polly Hansen ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Wild Type ◽  
High Fat ◽  
Male And Female ◽  
Female Mice

Type 2 diabetes is a complex disorder affected by multiple genes and the environment. Our laboratory has shown that in response to a glucose challenge, two-pore channel 2 ( Tpcn2) knockout mice exhibit a decreased insulin response but normal glucose clearance, suggesting they have improved insulin sensitivity compared with wild-type mice. We tested the hypothesis that improved insulin sensitivity in Tpcn2 knockout mice would protect against the negative effects of a high fat diet. Male and female Tpcn2 knockout (KO), heterozygous (Het), and wild-type (WT) mice were fed a low-fat (LF) or high-fat (HF) diet for 24 wk. HF diet significantly increases body weight in WT mice relative to those on the LF diet; this HF diet-induced increase in body weight is blunted in the Het and KO mice. Despite the protection against diet-induced weight gain, however, Tpcn2 KO mice are not protected against HF-diet-induced changes in glucose or insulin area under the curve during glucose tolerance tests in female mice, while HF diet has no significant effect on glucose tolerance in the male mice, regardless of genotype. Glucose disappearance during an insulin tolerance test is augmented in male KO mice, consistent with our previous findings suggesting enhanced insulin sensitivity in these mice. Male KO mice exhibit increased fasting plasma total cholesterol and triglyceride concentrations relative to WT mice on the LF diet, but this difference disappears in HF diet-fed mice where there is increased cholesterol and triglycerides across all genotypes. These data demonstrate that knockout of Tpcn2 may increase insulin action in male, but not female, mice. In addition, both male and female KO mice are protected against diet-induced weight gain, but this protection is likely independent from glucose tolerance, insulin sensitivity, and plasma lipid levels.

scholarly journals Chickens genetically selected for high or low juvenile body weight display differences in glucose tolerance and insulin sensitivity

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Lindsay Sumners ◽  
Xiaoling Zhao ◽  
Wei Zhang ◽  
Christa Honaker ◽  
Paul Siegel ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Glucose Tolerance

scholarly journals Antidiabetic Potential of Mangifera indica L. cv. Anwar Ratol Leaves: Medicinal Application of Food Wastes

Medicina ◽  
2019 ◽  
Vol 55 (7) ◽  
pp. 353 ◽  
Author(s):  
Mohammad Saleem ◽  
Muiz Tanvir ◽  
Muhammad Furqan Akhtar ◽  
Mazhar Iqbal ◽  
Ammara Saleem
Keyword(s):  
Body Weight ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Leaf Extract ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Diabetic Mice ◽  
Mango Leaves ◽  
Phenolic And Flavonoid ◽  
Phenolic And Flavonoid Compounds

Background and objectives: Anwar Ratol is one of the most famous cultivar of mango in South Asia, especially Pakistan. Mango leaves are left as food waste. This study evaluated the potential of mango (Anwar Ratol) leaves for their use against diabetes mellitus. Material and Methods: In this study, hydro-alcoholic extract of the plant leaves was prepared and evaluated by electrospray ionization mass spectroscopy (ESI-MS) and high-performance liquid chromatography (HPLC) for the presence of phytochemicals. The plant extract was administered to Alloxan induced diabetic mice followed by evaluation through oral glucose tolerance test; determination of postprandial glucose, body weight, lipid profile and histopathological evaluation of pancreas. Results: Chemical evaluation revealed the presence of mangiferin, rhamnetin, catechin, epicatechin, iriflophenone 3-C-β-D-glucoside, gallic acid and other phenolic and flavonoid compounds. The plant extract exhibited a decrease in postprandial blood glucose following seven days therapy in diabetic mice. The extract also prevented the rise in blood glucose level as determined by glucose tolerance test in diabetic mice. Furthermore, therapy of diabetic mice with the extract prevented a decrease in body weight and decline in beta-cell mass associated with alloxan and improved lipid profile. Conclusion: The findings of the study clearly suggested that the leaf extract of the plant might possess anti-diabetic activity possibly due to the presence of mangiferin and other phytochemicals such as phenolic and flavonoid compounds. This study will serve as a basis for the use of mango leaf extract against diabetes. Furthermore, this study will also provide basis for the bioassay-based fractionation and isolation of active principles responsible for the antidiabetic potential of mango leaves.

scholarly journals Chronic Central Leptin Decreases Food Intake and Improves Glucose Tolerance in Diet-Induced Obese Mice Independent of Hypothalamic Malonyl CoA Levels and Skeletal Muscle Insulin Sensitivity

Endocrinology ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 4127-4137 ◽  
Author(s):  
Wendy Keung ◽  
Arivazhagan Palaniyappan ◽  
Gary D. Lopaschuk
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Energy Metabolism ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Tolerance Test ◽  
Acid Oxidation ◽  
Obese Mice ◽  
Malonyl Coa ◽  
Skeletal Muscle Insulin Sensitivity

Although acute leptin administration in the hypothalamus decreases food intake and increases peripheral energy metabolism, the peripheral actions of central chronic leptin administration are less understood. In this study, we investigated what effects chronic (7 d) intracerebroventricular (ICV) administration of leptin has on energy metabolism and insulin sensitivity in diet-induced obese mice. C57/BL mice were fed a low-fat diet (LFD; 10% total calories) or high-fat diet (HFD; 60% total calories) for 8 wk after which leptin was administered ICV for 7 consecutive days. Mice fed a HFD showed signs of insulin resistance, as evidenced by an impaired glucose tolerance test. Chronic leptin treatment resulted in a decrease in food intake and body weight and normalization of glucose clearance but no improvement in insulin sensitivity. Chronic ICV leptin increased hypothalamic signal transducer and activator of transcription-3 and AMP-activated protein kinase phosphorylation but did not change hypothalamic malonyl CoA levels in HFD fed and LFD-fed mice. In the gastrocnemius muscles, the levels of malonyl CoA in both leptin-treated groups were lower than their respective control groups, suggesting an increase in fatty acid oxidation. However, only in the muscles of ICV leptin-treated LFD mice was there a decrease in lipid metabolites including diacylglycerol, triacylglycerol, and ceramide. Our results suggest that chronic ICV leptin decreases food consumption and body weight via a mechanism different from acute ICV leptin administration. Although chronic ICV leptin treatment in HFD mice improves glucose tolerance, this occurs independent of changes in insulin sensitivity in the muscles of HFD mice.

scholarly journals Deficiency in Interferon-γ Results in Reduced Body Weight and Better Glucose Tolerance in Mice

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3690-3699 ◽  
Author(s):  
Nicole Wong ◽  
Barbara C. Fam ◽  
Gitta R. Cempako ◽  
Gregory R. Steinberg ◽  
Ken Walder ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Food Intake ◽  
Glucose Metabolism ◽  
Energy Expenditure ◽  
Glucose Tolerance ◽  
Mrna Expression ◽  
Tolerance Test ◽  
Interferon Γ ◽  
Reduced Body

Obesity is a chronic low-grade inflammatory disease caused by increased energy intake and reduced energy expenditure. Studies using animal models with deletion of inflammatory cytokines have produced conflicting results with some showing increased weight gain and others showing no effect or even reduced body weights. Clearly, more work is necessary to understand the role of cytokines on body weight control. The aim of this study was to determine the effect of interferon-γ deletion (IFNγ−/−) on body weight regulation and glucose metabolism. Male IFNγ−/− and wild-type C57BL/6 mice were fed a low-fat chow diet, and body weight, food intake, and energy expenditure were monitored over 20 wk. At the end of the study, ip glucose tolerance test, insulin tolerance test, basal glucose turnover, and hyperinsulinemic/euglycemic clamps were performed. Expression levels of arcuate nucleus neuropeptide Y, Agouti-related peptide, and proopiomelanocortin mRNA as well as circulating leptin levels were also determined. IFNγ−/− mice had improved glucose tolerance with reduced rate of glucose appearance and increased insulin sensitivity due to greater suppression of endogenous glucose output, which was associated with decreased hepatic glucose-6-phosphatase activity. In addition, we also observed reduced body weight associated with decreased food intake and increased physical activity. Neuropeptide Y and Agouti-related peptide mRNA expression was reduced, whereas proopiomelanocortin mRNA expression was increased, as were plasma leptin levels. Global deletion of IFNγ in mice resulted in reduced body weight associated with negative energy balance, improved glucose tolerance, and hepatic insulin sensitivity. Our findings demonstrate that IFNγ plays a critical role in the regulation of body weight and glucose metabolism.

scholarly journals Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat

2010 ◽  
Vol 299 (3) ◽  
pp. G751-G760 ◽  
Author(s):  
Derek M. Culnan ◽  
Vance Albaugh ◽  
Mingjie Sun ◽  
Christopher J. Lynch ◽  
Charles H. Lang ◽  
...  
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Food Intake ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Zucker Rats ◽  
Ileal Interposition ◽  
Obese Zucker Rat ◽  
Obese Zucker Rats ◽  
Glucagon Like Peptide 1

The hindgut hypothesis posits improvements in Type 2 diabetes after gastric bypass surgery are due to enhanced delivery of undigested nutrients to the ileum, which increase incretin production and insulin sensitivity. The present study investigates the effect of ileal interposition (IT), surgically relocating a segment of distal ileum to the proximal jejunum, on glucose tolerance, insulin sensitivity, and glucose transport in the obese Zucker rat. Two groups of obese Zucker rats were studied: IT and sham surgery ad libitum fed (controls). Changes in food intake, body weight and composition, glucose tolerance, insulin sensitivity and tissue glucose uptake, and insulin signaling as well as plasma concentrations of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide were measured. The IT procedure did not significantly alter food intake, body weight, or composition. Obese Zucker rats demonstrated improved glucose tolerance 3 wk after IT compared with the control group ( P < 0.05). Euglycemic, hyperinsulinemic clamp and 1-[14C]-2-deoxyglucose tracer studies indicate that IT improves whole body glucose disposal, insulin-stimulated glucose uptake, and the ratio of phospho- to total Akt ( P < 0.01 vs. control) in striated muscle. After oral glucose, the plasma concentration of glucagon-like peptide-1 was increased, whereas GIP was decreased following IT. Enhanced nutrient delivery to the ileum after IT improves glucose tolerance, insulin sensitivity and muscle glucose uptake without altering food intake, body weight, or composition. These findings support the concept that anatomic and endocrine alterations in gut function play a role in the improvements in glucose homeostasis after the IT procedure.

scholarly journals Dietary Genistein Could Modulate Hypothalamic Circadian Entrainment, Reduce Body Weight, and Improve Glucose and Lipid Metabolism in Female Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Liyuan Zhou ◽  
Xinhua Xiao ◽  
Qian Zhang ◽  
Jia Zheng ◽  
Ming Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Lipid Metabolism ◽  
Glucose Tolerance ◽  
Energy Intake ◽  
High Fat Diet ◽  
High Fat ◽  
Female Mice ◽  
Reduce Body Weight ◽  
Glucose And Lipid Metabolism

Genistein has beneficial effects on metabolic disorders. However, the specific mechanism is not clearly understood. In light of the significant role of the hypothalamus in energy and metabolic homeostasis, this study was designed to explore whether dietary genistein intake could mitigate the harmful effects of a high-fat diet on glucose and lipid metabolism and whether any alterations caused by dietary genistein were associated with hypothalamic gene expression profiles. C57BL/6 female mice were fed a high-fat diet without genistein (HF), a high-fat diet with genistein (HFG), or a normal control diet (CON) for 8 weeks. Body weight and energy intake were assessed. At the end of the study, glucose tolerance and serum levels of insulin and lipids were analyzed. Hypothalamic tissue was collected for whole transcriptome sequencing and reverse transcription quantitative PCR (RT-qPCR) validation. Energy intake and body weight were significantly reduced in the mice of the HFG group compared with those of the HF group. Mice fed the HFG diet had improved glucose tolerance and decreased serum triacylglycerol, free fatty acids, and low-density lipoprotein cholesterol compared with those fed the HF diet. The HFG diet also modulated gene expression in the hypothalamus; the most abundant genes were enriched in the circadian entrainment pathway. Dietary genistein intake could reduce body weight, improve glucose and lipid metabolism, and regulate hypothalamic circadian entrainment. The ability of genistein intake to influence regulation of the hypothalamic circadian rhythm is important since this could provide a novel target for the treatment of obesity and diabetes.

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