Evaluation of the Antidiabetic and Insulin Releasing Effects of A. squamosa, Including Isolation and Characterization of Active Phytochemicals

Annona squamosa is generally referred to as a ‘custard apple’. Antidiabetic actions of hot water extract of Annona squamosa (HWAS) leaves together with isolation of active insulinotropic compounds were studied. Insulin release, membrane potential and intracellular Ca2+ were determined using BRIN-BD11 cells and isolated mouse islets. 3T3L1 adipocytes and in vitro models were used to determine cellular glucose uptake, insulin action, starch digestion, glucose diffusion, DPP-IV activity and glycation. Glucose intolerant high-fat fed rats were used for in vivo studies. Active compounds were isolated and characterized by HPLC, LCMS and NMR. HWAS stimulated insulin release from clonal β-cells and mouse islets. Using fluorescent indicator dyes and modulators of insulin secretion, effects could be attributed to depolarization of β-cells and influx of Ca2+. Secretion was stimulated by isobutylmethylxanthine (IBMX), tolbutamide or 30 mM KCl, indicating additional non-KATP dependent pathways. Extract stimulated cellular glucose uptake and insulin action and inhibited starch digestion, protein glycation, DPP-IV enzyme activity and glucose diffusion. Oral HWAS improved glucose tolerance and plasma insulin in high-fat fed obese rats. Treatment for 9 days with HWAS (250 mg/5 mL/kg), partially normalised energy intake, body weight, pancreatic insulin content, and both islet size and beta cell mass. This was associated with improved oral glucose tolerance, increased plasma insulin and inhibition of plasma DPP-IV activity. Isolated insulinotropic compounds, including rutin (C27H30O16), recapitulated the positive actions of HWAS on beta cells and in vivo glucose tolerance and plasma insulin responses. Annona squamosa is attractive as a dietary adjunct in treatment of T2DM and as a source of potential antidiabetic agents including rutin.

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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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Anti-hyperglycaemic and insulin releasing effects of Camellia sinensis leaves and isolation and characterization of active compounds

British Journal Of Nutrition ◽

10.1017/s0007114520005085 ◽

2020 ◽

pp. 1-35

Author(s):

Prawej Ansari ◽

Peter R. Flatt ◽

Patrick Harriott ◽

Yasser H.A. Abdel-Wahab

Keyword(s):

Glucose Tolerance ◽

Glucose Uptake ◽

Insulin Release ◽

Camellia Sinensis ◽

Insulin Action ◽

Hot Water ◽

Protein Glycation ◽

Starch Digestion ◽

Dpp Iv ◽

Glucose Diffusion

Abstract Antidiabetic actions of Camellia sinensis leaves, used traditionally for type 2 diabetes (T2DM) treatment, have been determined. Insulin release, membrane potential and intracellular calcium ([Ca2+]i) were studied using the pancreatic beta-cell line, BRIN-BD11, and primary mouse pancreatic islets. Cellular glucose-uptake/insulin action by 3T3-L1 adipocytes, starch digestion, glucose diffusion, DPP-IV activity and glycation were determined together with in vivo studies assessing glucose homeostasis in high fat fed (HFF) rats. Active phytoconstituents with insulinotropic activity were isolated using RP-HPLC, LCMS and NMR. Hot water extract of Camellia sinensis, increased insulin secretion in concentration dependent manner. Insulinotropic effects were significantly reduced by diazoxide, verapamil and under calcium-free conditions, being associated with membrane depolarization and increased intracellular Ca2+. Insulin releasing effects were observed in presence of KCl, tolbutamide and IBMX, indicating actions beyond K+ and Ca2+channels. Extract also increased glucose uptake/insulin action in 3T3L1 adipocyte cells and inhibited protein glycation, DPP-IV enzyme activity, starch digestion and glucose diffusion. Oral administration of extract enhanced glucose tolerance and insulin release in HFF rats. Extended treatment (250mg/5ml/kg orally) for 9 days, led to improvements of body weight, energy intake, plasma and pancreatic insulin, and corrections of both islet size and β-cell mass. These effects were accompanied by lower glycaemia and significant reduction of plasma DPP-IV activity. Compounds isolated by HPLC/LCMS, isoquercitrin and rutin (464.2 Da & 610.3 Da), stimulated insulin release and improved glucose tolerance. These data indicate that Camellia sinensis leaves warrant further evaluation as an effective adjunctive therapy for T2DM and source of bioactive compounds.

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Dietary (-)-epicatechin mitigates high fat-induced apoptosis, oxidative and endoplasmic reticulum stress in pancreatic β-cells both in vivo and in vitro

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2020.12.383 ◽

2021 ◽

Vol 165 ◽

pp. 44

Author(s):

Eleonora Cremonini ◽

Maëlys Rouget ◽

Solenne Arredi ◽

Charlotte Devulder-Mercier ◽

Robin Cellier ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

High Fat ◽

Β Cells ◽

Pancreatic Β Cells ◽

Induced Apoptosis

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Antecedent protein restriction exacerbates development of impaired insulin action after high-fat feeding

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.1.e85 ◽

1999 ◽

Vol 276 (1) ◽

pp. E85-E93 ◽

Cited By ~ 18

Author(s):

Mark J. Holness ◽

Mary C. Sugden

Keyword(s):

Insulin Secretion ◽

Glucose Tolerance ◽

Insulin Action ◽

Protein Restriction ◽

Protein Diet ◽

Glucose Disposal ◽

High Fat ◽

Impaired Insulin ◽

Impaired Insulin Action ◽

Fat Feeding

The study investigated whether a persistent impairment of insulin secretion resulting from mild protein restriction predisposes to loss of glucoregulatory control and impaired insulin action after the subsequent imposition of the diabetogenic challenge of high-fat feeding. Offspring of dams provided with either control (20% protein) diet (C) or an isocaloric restricted (8%) protein diet (PR) were weaned onto the maintenance diet with which their mothers had been provided. At 20 wk of age, protein restriction enhanced glucose tolerance despite impaired insulin secretion and an augmented and sensitized lipolytic response to norepinephrine in adipocytes. C and PR rats were then transferred to a high-fat diet (HF, 19% protein, 22% lipid, 34% carbohydrate) and sampled after 8 wk. These groups are termed C-HF and PR-HF. Glucose tolerance was impaired in PR-HF, but not C-HF, rats. Insulin-stimulated glucose disposal rates were significantly lower (by 30%; P < 0.01) in the PR-HF group than in the C-HF group, and a specific impairment of antilipolytic response of insulin was unmasked in adipocytes from PR-HF, but not C-HF, rats. The study demonstrates that antecedent protein restriction accelerates and augments the development of impaired glucoregulation and insulin resistance after high-fat feeding.

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Suppression of Peroxisome Proliferator-Activated Receptor γ-Coactivator-1α Normalizes the Glucolipotoxicity-Induced Decreased BETA2/NeuroD Gene Transcription and Improved Glucose Tolerance in Diabetic Rats

Endocrinology ◽

10.1210/en.2009-0241 ◽

2009 ◽

Vol 150 (9) ◽

pp. 4074-4083 ◽

Cited By ~ 10

Author(s):

Ji-Won Kim ◽

Young-Hye You ◽

Dong-Sik Ham ◽

Jae-Hyoung Cho ◽

Seung-Hyun Ko ◽

...

Keyword(s):

Glucose Tolerance ◽

Receptor Site ◽

Diabetic Rats ◽

Peroxisome Proliferator ◽

Β Cells ◽

Β Cell ◽

Peroxisome Proliferator Activated Receptor ◽

Cell Dysfunction

Abstract Peroxisome proliferator-activated receptor γ-coactivator-1α (PGC-1α) is significantly elevated in the islets of animal models of diabetes. However, the molecular mechanism has not been clarified. We investigated whether the suppression of PGC-1α expression protects against β-cell dysfunction in vivo and determined the mechanism of action of PGC-1α in β-cells. The studies were performed in glucolipotixicity-induced primary rat islets and INS-1 cells. In vitro and in vivo approaches using adenoviruses were used to evaluate the role of PGC-1α in glucolipotoxicity-associated β-cell dysfunction. The expression of PGC-1α in cultured β-cells increased gradually with glucolipotoxicity. The overexpression of PGC-1α also suppressed the expression of the insulin and β-cell E-box transcription factor (BETA2/NeuroD) genes, which was reversed by PGC-1α small interfering RNA (siRNA). BETA2/NeuroD, p300-enhanced BETA2/NeuroD, and insulin transcriptional activities were significantly suppressed by Ad-PGC-1α but were rescued by Ad-siPGC-1α. PGC-1α binding at the glucocorticoid receptor site on the BETA2/NeuroD promoter increased in the presence of PGC-1α. Ad-siPGC-1α injection through the celiac arteries of 90% pancreatectomized diabetic rats improved their glucose tolerance and maintained their fasting insulin levels. The suppression of PGC-1α expression protects the glucolipotoxicity-induced β-cell dysfunction in vivo and in vitro. A better understanding of the functions of molecules such as PGC-1α, which play key roles in intracellular fuel regulation, could herald a new era of the treatment of patients with type 2 diabetes mellitus by providing protection from glucolipotoxicity, which is an important cause of the development and progression of the disease.

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Effect of early dietary restriction on insulin action and secretion in the GK rat, a spontaneous model of NIDDM

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2000.278.6.e1097 ◽

2000 ◽

Vol 278 (6) ◽

pp. E1097-E1103 ◽

Cited By ~ 3

Author(s):

Carmen Alvarez ◽

Danielle Bailbe ◽

Françoise Picarel-Blanchot ◽

Eric Bertin ◽

Ana-Maria Pascual-Leone ◽

...

Keyword(s):

Insulin Secretion ◽

Weight Gain ◽

Glucose Tolerance ◽

Glucose Uptake ◽

Insulin Action ◽

Food Restriction ◽

Plasma Insulin ◽

Insulin Level ◽

Gk Rat ◽

Basal Plasma

The availability of the Goto-Kakisaki (GK) rat model of non-insulin-dependent diabetes mellitus prompted us to test the effect of a limited period of undernutrition in previously diabetic young rats on their insulin secretion and insulin action during adult age. Four-week-old female GK rats were either food restricted (35% restriction, 15% protein diet) or protein and energy restricted (35% restriction, 5% protein diet) for 4 wk. Food restriction in the young GK rat lowered weight gain but did not aggravate basal hyperglycemia or glucose intolerance, despite a decrease in basal plasma insulin level. Furthermore, the insulin-mediated glucose uptake by peripheral tissues in the GK rat was clearly improved. We also found that food restriction, when it is coupled to overt protein deficiency in the young GK rat, altered weight gain more severely and slightly decreased basal hyperglycemia but conversely aggravated glucose tolerance. Improvement of basal hyperglycemia was related to repression of basal hepatic glucose hyperproduction, despite profound attenuation of basal plasma insulin level. Deterioration of tolerance to glucose was related to severe blunting of the residual glucose-induced insulin secretion. It is, however, likely that the important enhancement of the insulin-mediated glucose uptake helped to limit the deterioration of glucose tolerance.

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Pannexin-2-deficiency sensitizes pancreatic β-cells to cytokine-induced apoptosis in vitro and impairs glucose tolerance in vivo

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2017.04.001 ◽

2017 ◽

Vol 448 ◽

pp. 108-121 ◽

Cited By ~ 3

Author(s):

Lukas A. Berchtold ◽

Michela Miani ◽

Thi A. Diep ◽

Andreas N. Madsen ◽

Valentina Cigliola ◽

...

Keyword(s):

Glucose Tolerance ◽

Β Cells ◽

Pancreatic Β Cells ◽

Induced Apoptosis

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METABOLIC PHENOTYPING GUIDELINES: Assessing glucose homeostasis in rodent models

Journal of Endocrinology ◽

10.1530/joe-14-0182 ◽

2014 ◽

Vol 222 (3) ◽

pp. G13-G25 ◽

Cited By ~ 102

Author(s):

James E Bowe ◽

Zara J Franklin ◽

Astrid C Hauge-Evans ◽

Aileen J King ◽

Shanta J Persaud ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glucose Tolerance ◽

Glucose Homeostasis ◽

Β Cells ◽

Advantages And Disadvantages ◽

Autoimmune Destruction ◽

Normal Glucose

The pathophysiology of diabetes as a disease is characterised by an inability to maintain normal glucose homeostasis. In type 1 diabetes, this is due to autoimmune destruction of the pancreatic β-cells and subsequent lack of insulin production, and in type 2 diabetes it is due to a combination of both insulin resistance and an inability of the β-cells to compensate adequately with increased insulin release. Animal models, in particular genetically modified mice, are increasingly being used to elucidate the mechanisms underlying both type 1 and type 2 diabetes, and as such the ability to study glucose homeostasisin vivohas become an essential tool. Several techniques exist for measuring different aspects of glucose tolerance and each of these methods has distinct advantages and disadvantages. Thus the appropriate methodology may vary from study to study depending on the desired end-points, the animal model, and other practical considerations. This review outlines the most commonly used techniques for assessing glucose tolerance in rodents and details the factors that should be taken into account in their use. Representative scenarios illustrating some of the practical considerations of designingin vivoexperiments for the measurement of glucose homeostasis are also discussed.

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