Weight loss in obese men by caloric restriction and high‐dose diazoxide–mediated insulin suppression

Boekel, Gerben A.J. van; Loves, Sandra; Sorge, Adriaan van; Ruinemans-Koerts, Janneke; Rijnders, Ton Ajm; Boer, H. de

doi:10.1111/j.1463-1326.2008.00878.x

Cited by 27 publications

(26 citation statements)

References 31 publications

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“…Short term treatments showed contradictory results with either no change in body weight (45) or anti-obesity effect in hyperinsulinemic obese adults (46). A 6-month diazoxide treatment of obese hyperinsulinemic men, combined with moderate caloric restriction, resulted in lower fasting insulin levels associated with significant weight loss, in particular of the fat mass (23). Diazoxide induces hyperglycemia, which is not observed in ␤Glud1 Ϫ/Ϫ mice possibly because, to some extent, their ␤-cells remained sensitive to glucose.…”

Section: Discussionmentioning

confidence: 99%

“…Obese patients who received octreotide for 6 months lost weight compared with placebo (22). In a pilot study conducted on obese subjects, high dose diazoxide treatment over a 6-month period reduced their fasting insulin and fat mass (23). Thus, on a background of obesity and hyperinsulinemia, reducing the ␤-cell efficiency could favorably impact on body weight.…”

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confidence: 99%

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The Amplifying Pathway of the β-Cell Contributes to Diet-induced Obesity

Vetterli¹,

Carobbio²,

Frigerio³

et al. 2016

Journal of Biological Chemistry

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Efficient energy storage in adipose tissues requires optimal function of the insulin-producing ␤-cell, whereas its dysfunction promotes diabetes. The associated paradox related to ␤-cell efficiency is that excessive accumulation of fat in adipose tissue predisposes for type 2 diabetes. Insulin exocytosis is regulated by intracellular metabolic signal transduction, with glutamate dehydrogenase playing a key role in the amplification of the secretory response. Here, we used mice with ␤-cell-selective glutamate dehydrogenase deletion (␤Glud1 ؊/؊ ), lacking an amplifying pathway of insulin secretion. As opposed to control mice, ␤Glud1 ؊/؊ animals fed a high calorie diet maintained glucose tolerance and did not develop diet-induced obesity. Islets of ␤Glud1 ؊/؊ mice did not increase their secretory response upon high calorie feeding, as did islets of control mice. Inhibited adipose tissue expansion observed in knock-out mice correlated with lower expression of genes responsible for adipogenesis. Rather than being efficiently stored, lipids were consumed at a higher rate in ␤Glud1 ؊/؊ mice compared with controls, in particular during food intake periods. These results show that reduced ␤-cell function prior to high calorie feeding prevented diet-induced obesity.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Amplifying Pathway of the β-Cell Contributes to Diet-induced Obesity

Vetterli¹,

Carobbio²,

Frigerio³

et al. 2016

Journal of Biological Chemistry

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“…However, ß-cell-targeted genetic intervention in mice protects against obesity, either by the reduction of insulin gene dosage (Mehran et al, 2012) or by the ablation of the amplifying pathway of glucose-stimulated insulin secretion (Vetterli et al, 2016a). Clinical data have shown that pharmacological inhibition of insulin secretion in obese subjects can promote weight loss (Lustig et al, 2006;van Boekel et al, 2008), although drugs used in these studies are associated with undesired side effects, such as hyperglycemia. Weight control by lifestyle modification has a low success rate, therefore calling for alternative therapy.…”

Section: Introductionmentioning

confidence: 99%

Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?

Pournourmohammadi

Grimaldi

Stridh

et al. 2017

The International Journal of Biochemistry & Cell Biology

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a b s t r a c tGlucose homeostasis is determined by insulin secretion from the ß-cells in pancreatic islets and by glucose uptake in skeletal muscle and other insulin target tissues. While glutamate dehydrogenase (GDH) senses mitochondrial energy supply and regulates insulin secretion, its role in the muscle has not been elucidated. Here we investigated the possible interplay between GDH and the cytosolic energy sensing enzyme 5 -AMP kinase (AMPK), in both isolated islets and myotubes from mice and humans. The green tea polyphenol epigallocatechin-3-gallate (EGCG) was used to inhibit GDH. Insulin secretion was reduced by EGCG upon glucose stimulation and blocked in response to glutamine combined with the allosteric GDH activator BCH (2-aminobicyclo-[2,2,1] heptane-2-carboxylic acid). Insulin secretion was similarly decreased in islets of mice with ß-cell-targeted deletion of GDH (ßGlud1 −/− ). EGCG did not further reduce insulin secretion in the mutant islets, validating its specificity. In human islets, EGCG attenuated both basal and nutrient-stimulated insulin secretion. Glutamine/BCH-induced lowering of AMPK phosphorylation did not operate in ßGlud1 −/− islets and was similarly prevented by EGCG in control islets, while high glucose systematically inactivated AMPK. In mouse C2C12 myotubes, like in islets, the inhibition of AMPK following GDH activation with glutamine/BCH was reversed by EGCG. Stimulation of GDH in primary human myotubes caused lowering of insulin-induced 2-deoxy-glucose uptake, partially counteracted by EGCG. Thus, mitochondrial energy provision through anaplerotic input via GDH influences the activity of the cytosolic energy sensor AMPK. EGCG may be useful in obesity by resensitizing insulin-resistant muscle while blunting hypersecretion of insulin in hypermetabolic states.

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“…Some available clinical data do support such observations made in rodents. Indeed, pharmacological inhibition of insulin secretion in obese subjects is accompanied by weight loss [20,21], although such a treatment may be associated with undesired side effects, for example hyperglycemia. Restricting the inhibition of insulin secretion to the only amplifying pathway of the b-cell might potentially prevent such side effects, as demonstrated using a genetic approach [18].…”

Section: Preventing Obesity By the Limitation Of Insulin Secretionmentioning

confidence: 99%

Glutamate pathways of the beta-cell and the control of insulin secretion

Maechler

2017

Diabetes Research and Clinical Practice

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InsulinGlucose Glutamate A B S T R A C T Pancreatic beta-cells secrete insulin in response to circulating glucose, thereby maintaining euglycemia. Inside the beta-cell, glucose is transformed into intracellular signals stimulating exocytosis. While calcium is an obligatory messenger, this ion is not sufficient to promote the full secretory response. Accordingly, glucose metabolism produces the additive factor glutamate that participates to an amplifying pathway of the calcium signal.Although intracellular glutamate potentiates insulin secretion, extracellular glutamate may activate ionotropic receptors. As a consequence of such activation, insulin exocytosis is slowed down. Therefore, for the beta-cell glutamate is a double-edged sword, an amplifying pathway and a negative feedback, illustrating the principle of homeostasis.

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Weight loss in obese men by caloric restriction and high‐dose diazoxide–mediated insulin suppression

Cited by 27 publications

References 31 publications

The Amplifying Pathway of the β-Cell Contributes to Diet-induced Obesity

The Amplifying Pathway of the β-Cell Contributes to Diet-induced Obesity

Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?

Glutamate pathways of the beta-cell and the control of insulin secretion

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