A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion

Lustig, Robert H.; Greenway, FL; Velasquez-Mieyer, Pedro; Heimburger, Douglas C.; Schumacher, Donald; Smith, Diane K.; Smith, William B.; Soler, Norman G.; Warsi, Ghulam; Berg, William J.; Maloney, Jennifer; Benedetto, Jean-Pierre; Zhu, Wenwen; Hohneker, John

doi:10.1038/sj.ijo.0803074

Cited by 98 publications

(71 citation statements)

References 39 publications

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“…Moreover, across multiple models, we found that obesity and lipid homeostasis are more sensitive to small changes in circulating insulin levels than glucose homeostasis. Collectively, these experiments also fit well with clinical and pre-clinical studies demonstrating that therapy with long-acting insulin analogues leads to weight gain, and with small trials showing weight loss with drugs that reduce insulin secretion (Alemzadeh et al 1998, Lustig et al 2005, ORIGIN Trial Investigators et al 2012, Skovso et al 2015. For example, a recent investigation reported that chronic insulin infusion via mini-osmotic pump leads to WAT expansion in mice (Rajan et al 2016).…”

Section: :3supporting

confidence: 55%

“…Although our published studies have demonstrated that preventing hyperinsulinemia can prevent obesity in euglycemic conditions, we have not yet shown that obesity can be treated by reducing insulin secretion in mice that have already gained weight or demonstrated that hyperinsulinemia has a similar role in a more typical scenario that includes dysglycemia. Clinical evidence to support reducing insulin as a therapy for obesity has been presented (Lunetta et al 1996, Alemzadeh et al 1998, Lustig et al 2005, but conflicting data on specific patient populations have also been published (Brauner et al 2016). Therefore, a focus on hyperinsulinemia as a target for obesity has not yet been widely adopted.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, clinical and experimental evidence indicates that hyperinsulinemia can precede and promote both obesity (Genuth et al 1971, Odeleye et al 1997, Corkey 2012, Mehran et al 2012 and insulin resistance or dysglycemia (Cusin et al 1990, Le Stunff & Bougnères 1994, Dankner et al 2009). Moreover, drugs that alleviate or prevent hyperinsulinemia can lead to weight loss (Alemzadeh et al 1996, Lustig et al 2005 and can enhance insulin-stimulated glucose uptake (Alemzadeh et al 1996, Gray et al 2010. Measured baseline insulin levels within healthy human and mouse populations are subject to wide variance (McAuley et al 2001, Li et al 2006, Berglund et al 2008, and diet intervention studies have indicated that obese individuals with the highest insulin secretion respond best to diets that reduce postprandial glycemia and insulinemia, whereas obese subjects with relatively lower insulin levels experience equivalent weight loss on low-fat diets (Pittas et al 2005, Ebbeling et al 2007.…”

Section: Hyperinsulinemia In the Etiology Of Insulin Resistance And Tmentioning

confidence: 99%

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A causal role for hyperinsulinemia in obesity

Templeman

Skovsø

Page

et al. 2017

Journal of Endocrinology

134

116

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Insulin modulates the biochemical pathways controlling lipid uptake, lipolysis and lipogenesis at multiple levels. Elevated insulin levels are associated with obesity, and conversely, dietary and pharmacological manipulations that reduce insulin have occasionally been reported to cause weight loss. However, the causal role of insulin hypersecretion in the development of mammalian obesity remained controversial in the absence of direct loss-of-function experiments. Here, we discuss theoretical considerations around the causal role of excess insulin for obesity, as well as recent studies employing mice that are genetically incapable of the rapid and sustained hyperinsulinemia that normally accompanies a high-fat diet. We also discuss new evidence demonstrating that modest reductions in circulating insulin prevent weight gain, with sustained effects that can persist after insulin levels normalize. Importantly, evidence from long-term studies reveals that a modest reduction in circulating insulin is not associated with impaired glucose homeostasis, meaning that body weight and lipid homeostasis are actually more sensitive to small changes in circulating insulin than glucose homeostasis in these models. Collectively, the evidence from new studies on genetic loss-of-function models forces a re-evaluation of current paradigms related to obesity, insulin resistance and diabetes. The potential for translation of these findings to humans is briefly discussed.

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Section: :3supporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Hyperinsulinemia In the Etiology Of Insulin Resistance And Tmentioning

confidence: 99%

See 1 more Smart Citation

A causal role for hyperinsulinemia in obesity

Templeman

Skovsø

Page

et al. 2017

Journal of Endocrinology

134

116

View full text Add to dashboard Cite

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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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A multicenter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion

Cited by 98 publications

References 39 publications

A causal role for hyperinsulinemia in obesity

A causal role for hyperinsulinemia in 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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