Cholesterol in islet dysfunction and type 2 diabetes

Brunham, Liam R.; Kruit, Janine K.; Verchere, C. Bruce; Hayden, Michael R.

doi:10.1172/jci33296

Cited by 136 publications

(112 citation statements)

References 84 publications

(95 reference statements)

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…Our data imply that in addition to well-established FAs, cholesterol could be added to the list of lipotoxic agents and that SREBP-2, a key transcription factor for cholesterol synthesis, could be a direct and/or indirect mediator of this new type of lipotoxicity. A recent paper reported, from studies on ABCA-1-null mice, that ABCA-1, a cellular cholesterol transporter, was shown to regulate cholesterol homeostasis and insulin secretion in pancreatic b-cells (40,41). Their data and our current data consistently demonstrate that alterations of islet cholesterol levels through cholesterol efflux and cholesterol synthesis, respectively, could contribute to islet dysfunction and loss of insulin secretion.…”

Section: Discussionsupporting

confidence: 81%

Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity

Ishikawa

Iwasaki

Yatoh

et al. 2008

Journal of Lipid Research

110

View full text Add to dashboard Cite

To determine the role of cholesterol synthesis in pancreatic b-cells, a transgenic model of in vivo activation of sterol-regulatory element binding protein 2 (SREBP-2) specifically in b-cells (TgRIP-SREBP-2) was developed and analyzed. Expression of nuclear human SREBP-2 in b-cells resulted in severe diabetes as evidenced by greater than 5-fold elevations in glycohemoglobin compared with C57BL/6 controls. Diabetes in TgRIP-SREBP-2 mice was primarily due to defects in glucose-and potassium-stimulated insulin secretion as determined by glucose tolerance test. Isolated islets of TgSREBP-2 mice were fewer in number, smaller, deformed, and had decreased insulin content. SREBP-2-expressing islets also contained increased esterified cholesterol and unchanged triglycerides with reduced ATP levels. Consistently, these islets exhibited elevated expression of HMG-CoA synthase and reductase and LDL receptor, with suppression of endogenous SREBPs. Genes involved in b-cell differentiation, such as PDX1 and BETA2, were suppressed, explaining loss of b-cell mass, whereas IRS2 expression was not affected. These phenotypes were dependent on the transgene expression. Taken Sterol-regulatory element binding protein 1c (SREBP-1c) is a membrane-bound transcription factor of the basic HLH (bHLH) leucine zipper family and has been established as a nutritional regulator of lipogenic enzymes in the liver (3, 4). Expression of SREBP-1c is highly upregulated by dietary intake of carbohydrates, sugars, and saturated FAs, whereas PUFAs, such as eicosapentaenoic acid, have been shown to inhibit hepatic SREBP-1c through multiple mechanisms (5, 6). These nutritional regulations of SREBP-1c are also observed in a cultured b-cell line and in isolated islets of mice (7,8). SREBP-1c also plays a role in insulin signaling by inhibiting insulin receptor substrate 2 (IRS-2), the major insulin-signaling mediator in the liver and in b-cells (9, 10).As a model for lipotoxicity by endogenous FAs in pancreatic b-cells, we previously developed transgenic mice overexpressing the active form of SREBP-1c under the insulin promoter expression (10). These mice exhibited impaired glucose tolerance in vivo due to both decreased b-cell mass and impaired insulin secretion estimated in isolated islets, which was enhanced by feeding the mice a high-fat, high-sucrose diet. The SREBP-1c-overexpressing islets had ATP depletion caused by enhanced lipogenesis and increased uncoupling protein 2 (UCP-2). Explaining the loss of b-cell mass, these islets had decreased expression of IRS-2 and PDX1. In addition to inhibition of GSIS,

show abstract

Section: Discussionsupporting

confidence: 81%

Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity

Ishikawa

Iwasaki

Yatoh

et al. 2008

Journal of Lipid Research

110

View full text Add to dashboard Cite

show abstract

“…The pathophysiology of the Tangier disease model has been confirmed in ABCA1 knock-out animals, which exhibited both an increased development of cardiovascular lesions and a progressive impairment of glucose tolerance [45]. The preserved insulin sensitivity demonstrated in these animals suggests that the impaired glucose regulation is exclusively linked to a direct toxic effect of cholesterol on the beta-cell [44]. The experimental data on ABCA1 as a modulator of insulin secretion have been confirmed by clinical observations [49].…”

Section: Dyslipidemia Contributing To Diabetes and Vascular Complicatmentioning

confidence: 79%

“…To this end, various researchers have clearly described specific receptors for LDL-C, namely LRPs, present in pancreatic islets, and they showed that LDL-C particles are incorporated in the metabolic pathway of beta-cells in a highly selective manner [44,45]. However, this increased bioavailability of LDL-C in the pancreatic cell metabolism seems to have a cytotoxic effect, and may cause increased beta-cell apoptosis.…”

Section: Dyslipidemia Contributing To Diabetes and Vascular Complicatmentioning

confidence: 99%

Dyslipidemia and Diabetes: Reciprocal Impact of Impaired Lipid Metabolism and Beta-Cell Dysfunction on Micro- and Macrovascular Complications

Rotella²,

2012

View full text Add to dashboard Cite

■ AbstractPatients with diabetes frequently exhibit the combined occurrence of hyperglycemia and dyslipidemia. Published data on their coexistence are often controversial. Some studies provide evidence for suboptimal lifestyle and exogenous hyperinsulinism at "mild insulin resistance" in adult diabetic patients as main pathogenic factors. In contrast, other studies confirm that visceral adiposity and insulin resistance are the basic features of dyslipidemia in type 2 diabetes (T2D). The consequence is an excess of free fatty acids, which causes hepatic gluconeogenesis to increase, metabolism in muscles to shift from glucose to lipid, beta-cell lipotoxicity, and an appearance of the classical "lipid triad", without real hypercholesterolemia. Recently, it has been proposed that cholesterol homeostasis is important for an adequate insulin secretory performance of beta-cells. The accumulation of cholesterol in beta-cells, caused by defective high-density lipoprotein (HDL) cholesterol with reduced cholesterol efflux, induces hyperglycemia, impaired insulin secretion, and beta-cell apoptosis. Data from animal models and humans, including humans with Tangier disease, who are characterized by very low HDL cholesterol levels, are frequently associated with hyperglycemia and T2D. Thus, there is a reciprocal influence of dyslipidemia on beta-cell function and inversely of beta-cell dysfunction on lipid metabolism and micro-and macrovascular complications. It remains to be clarified how these different but mutually influencing adverse effects act in together to define measures for a more effective prevention and treatment of micro-and macrovascular complications in diabetes patients. While the control of circulating low-density lipoprotein (LDL) cholesterol and the level of HDL cholesterol are determinant targets for the reduction of cardiovascular risk, based on recent data, these targets should also be considered for the prevention of betacell dysfunction and the development of type 2 diabetes. In this review, we analyze consolidated data and recent advances on the relationship between lipid metabolism and diabetes mellitus, with particular attention to the reciprocal effects of the two features of the disease and the development of vascular complications.

show abstract

“…Chez l'homme, les mutations homozygotes de ABCA1 sont reponsables de la maladie de Tangier caractérisée par une incapacité à éliminer le cholestérol cellulaire, des niveaux bas de HDL-cholestérol et un risque accru de maladies coronariennes [31]. La maladie de Tangier est une maladie génétique rare, et aucune donnée n'existe sur un lien possible entre cette maladie, à l'origine de troubles du métabolisme du cholestérol, et le métabolisme glucidique.…”

Section: Revuesunclassified

“…Cette baisse du LDL-cholestérol pourrait empêcher une accumulation du cholestérol dans les cellules , malgré un efflux de cholestérol défaillant, et partiellement masquer un trouble du métabolisme du glucose. Néanmoins, il existe un nombre de polymorphismes de ABCA1 associés au DT2 dans plusieurs groupes ethniques [31]. En particulier, les individus porteurs du variant R230C dans la population mexicaine développent un DT2 précoce [33].…”

Section: Revuesunclassified

Métabolisme du cholestérol et function β-cellulaire

Langhi

Cariou

2010

Med Sci (Paris)

View full text Add to dashboard Cite

L'incidence du diabète de type 2 (DT2) atteint des proportions épidémiques ces dernières années en raison du vieillissement de la population et du développement de l'obésité, elle-même secondaire à l'augmentation de la sédentarité et à une alimentation trop riche en graisses. L'insulinorésistance est un événement précoce dans la physiopathologie du DT2, mais qui demeure relativement stable au cours de l'évolution de la maladie. À l'inverse, la capacité insulinosécrétrice de la cellule  pancréatique diminue au cours du temps et contribue de façon majoritaire à la détérioration progressive de l'équilibre glycémique chez les diabétiques de type 2 [1]. Étant donné que la carence fonctionnelle de la cellule  est potentiellement réversible, il apparaît important de développer des thérapeutiques visant à freiner cette insuffisance [2]. Un des mécanismes moléculaires les mieux étudiés actuellement est la lipotoxicité bêta-pancréatique, qui contribue, via l'accumulation intracellulaire de lipides, à l'altération de l'insulinosécrétion et au développement de l'apoptose [3,4]. Les espèces lipidiques incriminées sont essentiellement les acides gras libres circulants (notamment le palmitate) et les triglycérides, qui favorisent la mort de la cellule  en induisant la production de céramides cytotoxiques [3]. Plus récemment, des données suggè-rent que le cholestérol pourrait également jouer un rôle majeur dans le contrôle de la fonction cellulaire . Nous discuterons en détail ici les différents liens potentiels entre le métabolisme du cholestérol et le contrôle de l'insulinosécrétion. Le cholestérol intracellulaire : un nouvel acteur de l'insulinosécrétionPlusieurs approches expérimentales ont permis d'étu-dier la conséquence des variations de cholestérol intracellulaire sur la sécrétion d'insuline.Rôle de la synthèse de cholestérol intracellulaire SREBP2 (sterol response element binding protein-2) est un facteur de transcription qui régule les concentrations du cholestérol intracellulaire. En réponse à une baisse du cholestérol intracellulaire, SREBP2 stimule la synthèse endogène de cholestérol ainsi que la capture des LDL (low density lipoproteins) en augmentant > Le diabète de type 2 est fréquemment associé à une dyslipidémie mixte, ainsi qu'à une lipotoxicité caractérisée par une augmentation du contenu en triglycérides dans plusieurs types cellulaires. Au niveau de la cellule -pancréatique, cette lipotoxicité conduit à un défaut d'insulinosécrétion et à une apoptose. Plus récemment, de nouvelles données suggèrent l'existence d'un lien entre le métabolisme du cholestérol et la fonction des cellules . Ainsi, l'accumulation de cholestérol dans les îlots pancréatiques altère la sécrétion d'insuline. Sur le plan moléculaire, le transporteur ABCA1 (ATP-binding cassette transporter, member 1) et le récepteur des LDL (low density lipoproteins) apparaissent comme des médiateurs majeurs du métabolisme du cholestérol dans l'îlot. Le cholestérol intracellulaire semble réguler à la fois l'organisation des microdomaines membranai...

show abstract

Cholesterol in islet dysfunction and type 2 diabetes

Cited by 136 publications

References 84 publications

Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity

Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity

Dyslipidemia and Diabetes: Reciprocal Impact of Impaired Lipid Metabolism and Beta-Cell Dysfunction on Micro- and Macrovascular Complications

Métabolisme du cholestérol et function β-cellulaire

Contact Info

Product

Resources

About