LA CONSULTA SEMANAL

 

 

 

 

 

Glucotoxicidad y lipotoxicidad en la diabetes tipo 2

 

1: Metabolism 2002 Feb;51(2):163-8

Effects of biotin on glucotoxicity or lipotoxicity in rat pancreatic islets.

Yoshikawa H, Tajiri Y, Sako Y, Hashimoto T, Umeda F, Nawata H.

Department of Medicine and Bioregulatory Science, Graduated School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Biotin (vitamin H) plays an important role as a cofactor in glucose or lipid metabolism. We showed that biotin potentiated glucose-induced insulin release in isolated rat islets, while biotin alone did not affect insulin release. Coculture with biotin in islets for 48 hours significantly enhanced glucose-induced insulin release or islet insulin content. Similarly, preproinsulin or pancreatic/duodenal homeobox-1 (PDX-1) mRNA was also enhanced in islets cultured with biotin for 48 hours. Furthermore, we measured effects of biotin on beta-cell function under glucotoxic or lipotoxic states. In islets cultured with high glucose or palmitate for 48 hours, glucose-induced insulin release or islet insulin content deteriorated. Coculture with biotin significantly restored glucose-induced insulin release or islet insulin content together with the restoration of preproinsulin or PDX-1 mRNA. We conclude that biotin exerts its beneficial effects on beta-cell dysfunction induced by glucose or free fatty acids probably through the enhancement of insulin biosíntesis.

 

2: Endocrinology 2002 Feb;143(2):339-42

Minireview: Secondary beta-cell failure in type 2 diabetes--a convergence of glucotoxicity and lipotoxicity.

Poitout V, Robertson RP.

Pacific Northwest Research Institute, Seattle, Washington 98122, USA. vpoitout@pnri.org

Chronic hyperglycemia and hyperlipidemia can exert deleterious effects on beta-cell function, respectively referred to as glucotoxicity and lipotoxicity. Over time, both contribute to the progressive deterioration of glucose homeostasis characteristic of type 2 diabetes. The mechanisms of glucotoxicity involve several transcription factors and are, at least in part, mediated by generation of chronic oxidative stress. Lipotoxicity is probably mediated by accumulation of a cytosolic signal derived from the fatty acid esterification pathway. Our view that hyperglycemia is a prerequisite for lipotoxicity is supported by several recent studies performed in our laboratories. First, prolonged in vitro exposure of isolated islets to fatty acids decreases insulin gene expression in the presence of high glucose concentrations only, and glucose is rate-limiting for the incorporation of fatty acids into neutral lipids. Second, normalization of blood glucose in Zucker diabetic fatty rats prevents accumulation of triglycerides and impairment of insulin gene expression in islets, whereas normalization of plasma lipid levels is without effect. Third, high-fat feeding in Goto-Kakizaki rats significantly impairs glucose-induced insulin secretion in vitro, whereas a similar diet has no effect in normoglycemic animals. We propose that chronic hyperglycemia, independent of hyperlipidemia, is toxic for beta-cell function, whereas chronic hyperlipidemia is deleterious only in the context of concomitant hyperglycemia.

Publication Types: Review

   

3: Rev Med Chil 2001 Jun;129(6):671-9

Glucotoxicity and lipotoxicity: factors in the pathogenesis and evolution of type 2 diabetes [Article in Spanish]

Durruty P, Garcia de los Rios M. Unidad de Diabetes y Nutricion, Facultad de Medicina Occidente Universidad de Chile.

Glucose toxicity refers to the structural and functional damage in the beta cells and target tissues of insulin, caused by chronic hyperglycemia. These alterations cause a lower hormonal secretion and action (insulin resistance). Lipid toxicity refers to the damage caused by persistently high free fatty acid levels, as a consequence of triacylglycerol catabolism. Since elevated glucose and lipid levels cause a similar damage and interact, the term glucose and lipid toxicity refers to their additive effects. This toxicity can be implicated in the pathogenesis of type II diabetes and in the secondary failure of oral hypoglycemic drugs, leading to the requirement of insulin treatment. Insulin resistance with normal glucose levels, glucose intolerance and clinical diabetes are the three recognized stages in the development of type 2 diabetes. Considering that the first two stages are reversible, a good metabolic control to avoid glucose and lipid toxicity could revert or avoid the development of clinical diabetes.

Publication Types: Review

   

4: Postgrad Med 2001 Apr;109(4):55-9, 63-4  [Texto completo]

Lipotoxicity and glucotoxicity in type 2 diabetes. Effects on development and progression.

Sivitz WI.

Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Iowa College of Medicine, Iowa City, USA. william-sivitz@uiowa.edu

Excess fat, excess glucose, or both act on diverse cells and tissues to counteract insulin-mediated glucose uptake, hepatic regulation of glucose output, and insulin secretion. These effects are labeled lipotoxicity and glucotoxicity because, when severe enough, each may contribute to the diabetic state. Lifestyle modifications and certain new pharmacologic agents may be effective in modulating these effects and could prove useful in primary prevention of type 2 diabetes.

Publication Types: Review

 

5: Rev Med Liege 1999 Jun;54(6):535-8

Glucotoxicity and lipotoxicity, two implicated accomplices in the vicious circle of type 2 diabetes. [Article in French]

Scheen AJ, Paquot N, Lefebvre PJ.

Departement de Medecine, CHU Sart Tilman, Liege.

Type 2 diabetes mellitus is a dynamic disease whose natural history is characterized by a progressive aggravation leading to a progressively severe hyperglycaemia, which generally requires a more complex therapy as time progresses. Such an evolution results from a vicious circle where both glucotoxicity and lipotoxicity contribute to reduce insulin secretion and the action of insulin on cell glucose metabolism. These new concepts are able to modify the strategies of prevention and treatment of type 2 diabetes.

Publication Types: Review

 

6: Clin Geriatr Med 1999 May;15(2):255

Glucotoxicity: potential mechanisms.

Mooradian AD, Thurman JE.

Division of Endocrinology, Diabetes, and Metabolism, Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.

Plasma concentration of glucose is found within a relatively narrow range of values for most animal species, yet it has little correlation with maximum lifespan; however, hyperglycemia in most animals is associated with premature death. This article presents evidence for hyperglycemia-induced tissue toxicity and discusses potential mechanisms of glucotoxicity and implications for the aging organism.

Publication Types: Review

 

7: Diabetes 1998 Dec;47(12):1889-93

Shared biochemical properties of glucotoxicity and lipotoxicity in islets decrease citrate synthase activity and increase phosphofructokinase activity.

Liu YQ, Tornheim K, Leahy JL.

Division of Endocrinology, Diabetes and Metabolism, University of Vermont, Burlington, USA.

Diabetic states are characterized by a raised serum/islet level of triglycerides and a lowered EC50 (concentration at half-maximal stimulation) for glucose-induced insulin secretion. Culturing islets with long-chain fatty acids (FAs) replicates the basal insulin hypersecretion. In a previous study, we showed that the mechanism involved deinhibition of hexokinase by a 60% decrease in glucose-6-phosphate (G-6-P). The key event was proposed to be an increased phosphofructokinase (PFK) Vmax secondary to an upregulatory effect of the FA metabolite, long-chain acyl-coenzyme A (LC-CoA). We now show another contributory factor, a lowered content of the PFK inhibitor citrate. Citrate synthase Vmax and citrate levels were lowered 45% in rat islets cultured with 250 micromol/l oleate for 24 h. Both effects were reversed by triacsin C, an inhibitor of fatty acyl-CoA synthetase, the enzyme that generates LC-CoA. Culturing islets with high doses of glucose (16.7 mmol/l) for 48 h should also raise cytosolic LC-CoA. As predicted, citrate synthase Vmax was lowered and PFK Vmax was increased, both in a triacsin C-reversible fashion. These results show shared selected functional and biochemical properties in beta-cells of so-called glucotoxicity and lipotoxicity.

 

 

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