Brevinin-2-related Peptide and its [D4K] Analogue Stimulate Insulin Release In Vitro and Improve Glucose Tolerance in Mice Fed a High Fat Diet

Recent studies suggest that a circulating protein called TRAIL (TNF-related apoptosis inducing ligand) may have an important role in the treatment of type 2 diabetes. It has been shown that TRAIL deficiency worsens diabetes and that TRAIL delivery, when it is given before disease onset, slows down its development. The present study aimed at evaluating whether TRAIL had the potential not only to prevent, but also to treat type 2 diabetes. Thirty male C57BL/6J mice were randomized to a standard or a high-fat diet (HFD). After 4 weeks of HFD, mice were further randomized to receive either placebo or TRAIL, which was delivered weekly for 8 weeks. Body weight, food intake, fasting glucose, and insulin were measured at baseline and every 4 weeks. Tolerance tests were performed before drug randomization and at the end of the study. Tissues were collected for further analyses. Parallel in vitro studies were conducted on HepG2 cells and mouse primary hepatocytes. TRAIL significantly reduced body weight, adipocyte hypertrophy, free fatty acid levels, and inflammation. Moreover, it significantly improved impaired glucose tolerance, and ameliorated non-alcoholic fatty liver disease (NAFLD). TRAIL treatment reduced liver fat content by 47% in vivo as well as by 45% in HepG2 cells and by 39% in primary hepatocytes. This was associated with a significant increase in liver peroxisome proliferator-activated receptor (PPAR) γ (PPARγ) co-activator-1 α (PGC-1α) expression both in vivo and in vitro, pointing to a direct protective effect of TRAIL on the liver. The present study confirms the ability of TRAIL to significantly attenuate diet-induced metabolic abnormalities, and it shows for the first time that TRAIL is effective also when administered after disease onset. In addition, our data shed light on TRAIL therapeutic potential not only against impaired glucose tolerance, but also against NAFLD.

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A low-carbohydrate high-fat diet increases weight gain and does not improve glucose tolerance, insulin secretion or β-cell mass in NZO mice

Nutrition and Diabetes ◽

10.1038/nutd.2016.2 ◽

2016 ◽

Vol 6 (2) ◽

pp. e194-e194 ◽

Cited By ~ 29

Author(s):

B J Lamont ◽

M F Waters ◽

S Andrikopoulos

Keyword(s):

Insulin Secretion ◽

Weight Gain ◽

Glucose Tolerance ◽

High Fat Diet ◽

Cell Mass ◽

High Fat ◽

Β Cell ◽

Nzo Mice ◽

Low Carbohydrate ◽

Improve Glucose Tolerance

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Wholegrain barley β-glucan fermentation does not improve glucose tolerance in rats fed a high-fat diet

Nutrition Research ◽

10.1016/j.nutres.2014.12.006 ◽

2015 ◽

Vol 35 (2) ◽

pp. 162-168 ◽

Cited By ~ 15

Author(s):

Damien P. Belobrajdic ◽

Stephen A. Jobling ◽

Matthew K. Morell ◽

Shin Taketa ◽

Anthony R. Bird

Keyword(s):

Glucose Tolerance ◽

High Fat Diet ◽

High Fat ◽

Improve Glucose Tolerance

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Inhibition of Small Maf Function in Pancreatic β-Cells Improves Glucose Tolerance Through the Enhancement of Insulin Gene Transcription and Insulin Secretion

Endocrinology ◽

10.1210/en.2014-1906 ◽

2015 ◽

Vol 156 (10) ◽

pp. 3570-3580 ◽

Cited By ~ 9

Author(s):

Hiroshi Nomoto ◽

Takuma Kondo ◽

Hideaki Miyoshi ◽

Akinobu Nakamura ◽

Yoko Hida ◽

...

Keyword(s):

Insulin Secretion ◽

Glucose Tolerance ◽

High Fat Diet ◽

Cell Function ◽

High Fat ◽

Β Cells ◽

Β Cell ◽

Β Cell Function

The large-Maf transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) has been found to be crucial for insulin transcription and synthesis and for pancreatic β-cell function and maturation. However, insights about the effects of small Maf factors on β-cells are limited. Our goal was to elucidate the function of small-Maf factors on β-cells using an animal model of endogenous small-Maf dysfunction. Transgenic (Tg) mice with β-cell-specific expression of dominant-negative MafK (DN-MafK) experiments, which can suppress the function of all endogenous small-Mafs, were fed a high-fat diet, and their in vivo phenotypes were evaluated. Phenotypic analysis, glucose tolerance tests, morphologic examination of β-cells, and islet experiments were performed. DN-MafK-expressed MIN6 cells were also used for in vitro analysis. The results showed that DN-MafK expression inhibited endogenous small-Maf binding to insulin promoter while increasing MafA binding. DN-MafK Tg mice under high-fat diet conditions showed improved glucose metabolism compared with control mice via incremental insulin secretion, without causing changes in insulin sensitivity or MafA expression. Moreover, up-regulation of insulin and glucokinase gene expression was observed both in vivo and in vitro under DN-MafK expression. We concluded that endogenous small-Maf factors negatively regulates β-cell function by competing for MafA binding, and thus, the inhibition of small-Maf activity can improve β-cell function.

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Lactiplantibacillus plantarum MG4296 and Lacticaseibacillus paracasei MG5012 Ameliorates Insulin Resistance in Palmitic Acid-Induced HepG2 Cells and High Fat Diet-Induced Mice

Microorganisms ◽

10.3390/microorganisms9061139 ◽

2021 ◽

Vol 9 (6) ◽

pp. 1139

Author(s):

GaYeong Won ◽

Soo-Im Choi ◽

Chang-Ho Kang ◽

Gun-Hee Kim

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Palmitic Acid ◽

High Fat Diet ◽

Hepg2 Cells ◽

Glycogen Content ◽

Histopathological Analysis ◽

Model Assessment ◽

High Fat

The purpose of this study was to evaluate the capacity of Lactiplantibacillus plantarum MG4296 (MG4296) and Lacticaseibacillus paracasei MG5012 (MG5012) on insulin resistance (IR) and diabetes-related metabolic changes in palmitic acid (PA)-induced HepG2 cells and high-fat diet-induced mice. In vitro, cell-free extracts of MG4296 and MG5012 alleviated IR by increasing glucose uptake and glycogen content in PA-induced insulin-resistant HepG2 cells. In vivo, MG4296 and MG5012 supplementation markedly decreased body weight and glucose tolerance. Administration of both strains also improved serum glucose, glycated hemoglobin, insulin, triglyceride, LDL/HDL ratio, and homeostatic model assessment of IR (HOMA-IR). Histopathological analysis of liver tissue demonstrated a significant reduction in lipid accumulation and glycogen content. Moreover, MG4296 and MG5012 treatment enhanced phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) expression in the liver. Overall, MG4296 and MG5012 could prevent HFD-induced glucose tolerance and hyperglycemia by improving IR. Therefore, L. plantarum MG4296 and L. paracasei MG5012 could be useful as new probiotics candidates to improve T2DM.

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Increased insulin secretion and normalization of glucose tolerance by cholinergic agonism in high fat-fed mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.277.1.e93 ◽

1999 ◽

Vol 277 (1) ◽

pp. E93-E102 ◽

Cited By ~ 7

Author(s):

Bo Ahrén ◽

Per Sauerberg ◽

Christian Thomsen

Keyword(s):

Insulin Secretion ◽

Glucose Tolerance ◽

High Fat Diet ◽

Insulin Response ◽

Acute Insulin Response ◽

High Fat ◽

Cholinergic Agonist ◽

Insulin Resistant ◽

Glucose Stimulated Insulin Secretion ◽

Improve Glucose Tolerance

Increased insulinotropic activity by the cholinergic agonist carbachol exists in insulin-resistant high fat-fed C57BL/6J mice. We examined the efficiency and potency of carbachol to potentiate glucose-stimulated insulin secretion and to improve glucose tolerance in these animals. Intravenous administration of carbachol (at 15 and 50 nmol/kg) markedly potentiated glucose (1 g/kg)-stimulated insulin secretion in mice fed both a control and a high-fat diet (for 12 wk), with a higher relative potentiation in high fat-fed mice measured as increased (1–5 min) acute insulin response and area under the 50-min insulin curve. Concomitantly, glucose tolerance was improved by carbachol. In fact, carbachol normalized glucose-stimulated insulin secretion and glucose tolerance in mice subjected to a high-fat diet. Carbachol (>100 nmol/l) also potentiated glucose-stimulated insulin secretion from isolated islets with higher efficiency in high fat-fed mice. In contrast, binding of the muscarinic receptor antagonist [ N- methyl-3H]scopolamine to islet muscarinic receptors and the contractile action of carbachol on ileum muscle strips were not different between the two groups. We conclude that carbachol normalizes glucose tolerance in insulin resistance.

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The effect of maternal protein deficiency during pregnancy and lactation on glucose tolerance and pancreatic islet function in adult rat offspring

Journal of Endocrinology ◽

10.1677/joe.0.1540177 ◽

1997 ◽

Vol 154 (1) ◽

pp. 177-185 ◽

Cited By ~ 57

Author(s):

M R Wilson ◽

S J Hughes

Keyword(s):

Glucose Tolerance ◽

Impaired Glucose Tolerance ◽

Insulin Release ◽

Pancreatic Islet ◽

High Fat Diet ◽

Cell Function ◽

Adult Life ◽

Islet Function ◽

High Fat ◽

Neonatal Nutrition

Abstract To test the hypothesis that poor foetal–neonatal nutrition predisposes adult animals to impaired glucose tolerance or diabetes, pregnant and lactating rats were fed a low (5%) protein diet and glucose tolerance and pancreatic islet function then assessed in the adult offspring. To expose any underlying defects the offspring were allowed access to a sucrose supplement (35%) or fed a high fat diet. Offspring born to low protein-fed females had significantly lower body weights than controls. In islets from previously malnourished rats, insulin release in batch incubations or perifusion was not significantly different to controls. In islets from previously malnourished animals fed sucrose, glucose-stimulated insulin release was reduced in perifusion by 66% (P<0·01) and batch incubations by 26–52% (6–16 mmol/l glucose, (P<0·01). Similarly, impaired secretory responses were found in islets from previously malnourished animals fed a high fat diet. These did not result from a reduced pool of releasable insulin, as arginine-stimulated secretion was not impaired. Rats previously malnourished showed a normal glucose tolerance. Glucose tolerance was impaired, however, in previously malnourished rats fed sucrose (area under the glucose tolerance test curve was increased by 42%, P<0·05) but despite the reduced islet secretory responses was not significantly different to sucrose-fed controls (area increased by 54%, P<0·05). Glucose tolerance was impaired in previously malnourished animals fed high fat diet (area increased by 48%, P<0·05) more so than in high fat fed-controls (28% increase, NS). These data support the hypothesis that poor foetal–neonatal nutrition leads to impaired pancreatic β-cell function which persists into adult life. Alone this is not sufficient to produce diabetes, but an inability to respond to a highly palatable fat diet may tip the balance towards impaired glucose tolerance. Journal of Endocrinology (1997) 154, 177–185

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