In vitro and in vivo effects of new insulin releasing agents

Nguyen, Quynh-Anh; Antoine, Marie-Hélène; Ouedraogo, R.; Hermann, Marcel; Sergooris, Jacqueline; Pirotte, Bernard; Masereel, Bernard; Lebrun, Philippe

doi:10.1016/s0006-2952(01)00880-2

Cited by 6 publications

(3 citation statements)

References 21 publications

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“…The dramatic consequence is that although blood glucose levels are initially lowered and glucose tolerance is enhanced (Figures 1 and 3), within a few days the phenotype crosses over to hyperglycemia and glucose intolerance that is strikingly similar to the adult phenotype of K ATP KO mice for all except the very lowest-dose pellets. Earlier studies of “long-term” treatment of animals with sulfonylureas have generally not gone beyond a few days [46], presumably due to the practical difficulties of injection regimens. Importantly, young mice injected daily with glibenclamide showed a degranulation effect in their β-cells, which might explain the reduced secretory capacity, although this effect was apparently not present in older mice [47].…”

Section: Discussionmentioning

confidence: 99%

Chronic Antidiabetic Sulfonylureas In Vivo: Reversible Effects on Mouse Pancreatic β-Cells

Remedi

Nichols

2008

PLoS Med

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BackgroundPancreatic β-cell ATP-sensitive potassium (KATP) channels are critical links between nutrient metabolism and insulin secretion. In humans, reduced or absent β-cell KATP channel activity resulting from loss-of-function KATP mutations induces insulin hypersecretion. Mice with reduced KATP channel activity also demonstrate hyperinsulinism, but mice with complete loss of KATP channels (KATP knockout mice) show an unexpected insulin undersecretory phenotype. Therefore we have proposed an “inverse U” hypothesis to explain the response to enhanced excitability, in which excessive hyperexcitability drives β-cells to insulin secretory failure without cell death. Many patients with type 2 diabetes treated with antidiabetic sulfonylureas (which inhibit KATP activity and thereby enhance insulin secretion) show long-term insulin secretory failure, which we further suggest might reflect a similar progression.Methods and FindingsTo test the above hypotheses, and to mechanistically investigate the consequences of prolonged hyperexcitability in vivo, we used a novel approach of implanting mice with slow-release sulfonylurea (glibenclamide) pellets, to chronically inhibit β-cell KATP channels. Glibenclamide-implanted wild-type mice became progressively and consistently diabetic, with significantly (p < 0.05) reduced insulin secretion in response to glucose. After 1 wk of treatment, these mice were as glucose intolerant as adult KATP knockout mice, and reduction of secretory capacity in freshly isolated islets from implanted animals was as significant (p < 0.05) as those from KATP knockout animals. However, secretory capacity was fully restored in islets from sulfonylurea-treated mice within hours of drug washout and in vivo within 1 mo after glibenclamide treatment was terminated. Pancreatic immunostaining showed normal islet size and α-/β-cell distribution within the islet, and TUNEL staining showed no evidence of apoptosis.ConclusionsThese results demonstrate that chronic glibenclamide treatment in vivo causes loss of insulin secretory capacity due to β-cell hyperexcitability, but also reveal rapid reversibility of this secretory failure, arguing against β-cell apoptosis or other cell death induced by sulfonylureas. These in vivo studies may help to explain why patients with type 2 diabetes can show long-term secondary failure to secrete insulin in response to sulfonylureas, but experience restoration of insulin secretion after a drug resting period, without permanent damage to β-cells. This finding suggests that novel treatment regimens may succeed in prolonging pharmacological therapies in susceptible individuals.

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Section: Discussionmentioning

confidence: 99%

Chronic Antidiabetic Sulfonylureas In Vivo: Reversible Effects on Mouse Pancreatic β-Cells

Remedi

Nichols

2008

PLoS Med

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“…␤-Cell-selective potassium channel openers (KCOs) such as diazoxide, BPDZ 154, BPDZ 73, NNC 55-0118, and other less selective KCOs (e.g., levcromakalim, pinacidil, nicorandil, etc. ), bind to SUR1 and activate K ATP channels in a nucleotide-dependent manner (16,21,46,50,68,163,164,216). The differential sensitivity of the heterogeneous family of K ATP channels to these compounds is explained by the location of the binding sites for KCOs on SUR1 and SUR2.…”

Section: Pharmacology Of K Atp Channelsmentioning

confidence: 99%

Hyperinsulinism in Infancy: From Basic Science to Clinical Disease

Dunne

Cosgrove²,

Shepherd³

et al. 2004

Physiological Reviews

263

277

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Dunne, Mark J., Karen E. Cosgrove, Ruth M. Shepherd, Albert Aynsley-Green, and Keith J. Lindley. Hyperinsulinism in Infancy: From Basic Science to Clinical Disease. Physiol Rev 84: 239–275, 2004; 10.1152/physrev.00022.2003.—Ion channelopathies have now been described in many well-characterized cell types including neurons, myocytes, epithelial cells, and endocrine cells. However, in only a few cases has the relationship between altered ion channel function, cell biology, and clinical disease been defined. Hyperinsulinism in infancy (HI) is a rare, potentially lethal condition of the newborn and early childhood. The causes of HI are varied and numerous, but in almost all cases they share a common target protein, the ATP-sensitive K+ channel. From gene defects in ion channel subunits to defects in β-cell metabolism and anaplerosis, this review describes the relationship between pathogenesis and clinical medicine. Until recently, HI was generally considered an orphan disease, but as parallel defects in ion channels, enzymes, and metabolic pathways also give rise to diabetes and impaired insulin release, the HI paradigm has wider implications for more common disorders of the endocrine pancreas and the molecular physiology of ion transport.

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“…levcromakalim, pinacidil, nicorandil, etc.) bind to SUR1 and activate K ATP channels in a nucleotide-dependent manner [52][53][54][55][56][57][58][59]. The differential sensitivity of the heterogeneous family of K ATP channels to these compounds is explained by the location of the binding sites for KCOs on SUR1 and SUR2.…”

Section: Pharmacology Of K Atp Channelsmentioning

confidence: 99%

Genetics and Pathophysiology of Hyperinsulinism in Infancy

et al. 2004

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Hyperinsulinism in infancy (HI) is a condition of neonates and early childhood. For many years the pathophysiology of this potentially lethal disorder was unknown. Advances in the genetics, histopathology and molecular physiology of this disease have now provided insights into the causes of β-cell dysfunction and revealed levels of diversity far in excess of our previous knowledge. These include defects in ion channel subunit genes and mutations in several enzymes associated with β-cell metabolism and anaplerosis. In most cases, β-cell pathophysiology leads to an alteration in the function of ATP-sensitive K⁺ channels. This can manifest as ‘channelopathies’ of K_ATP channels through gene defects in ABCC8 and KCNJ11 (Ch.11p15); or as a result of ‘metabolopathies’ through defects in the genes encoding glucokinase (GCK, Ch.7p15–p13), glutamate dehydrogenase (GLUD1, Ch.10q23.3) and short-chain L-3-hydroxyacyl-CoA dehydrogenase (HADHSC, Ch.4q22–q26). This review focuses upon the relationship between the causes of HI and therapeutic options.

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In vitro and in vivo effects of new insulin releasing agents

Cited by 6 publications

References 21 publications

Chronic Antidiabetic Sulfonylureas In Vivo: Reversible Effects on Mouse Pancreatic β-Cells

Chronic Antidiabetic Sulfonylureas In Vivo: Reversible Effects on Mouse Pancreatic β-Cells

Hyperinsulinism in Infancy: From Basic Science to Clinical Disease

Genetics and Pathophysiology of Hyperinsulinism in Infancy

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