Impaired Glucose-Stimulated Insulin Secretion Is Coupled With Exocrine Pancreatic Lesions in the Cohen Diabetic Rat

Weksler-Zangen, Sarah; Lenzen, Sigurd; Jörns, Anne; Ehrenfeld, Shira; Amir, Gail; Oprescu, Andrei I.; Yagil, Yoram; Yagil, Chana; Zangen, David; Kaiser, Nurit

doi:10.2337/db07-0520

Cited by 51 publications

(76 citation statements)

References 53 publications

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“…We have observed previously that the development of hyperglycemia in CDs rats fed HSD is associated with peri-islet infiltration of fat and macrophages ex-pressing IL-1␤ (49). We also showed that copper supplementation to HSD improves GSIS, suggesting the involvement of COX (48).…”

supporting

confidence: 55%

“…The Cohen diabetic rat is a genetic model of nutritionally induced diabetes (49,50) consisting of two contrasting strains, the diabetes-sensitive rat (CDs) that develops hyperglycemia due to impaired GSIS when fed a high-sucrose, low-copper diet (HSD) but maintains normoglycemia on a regular diet and the diabetes-resistant rat (CDr), which maintains normoglycemia on HSD (49). We have observed previously that the development of hyperglycemia in CDs rats fed HSD is associated with peri-islet infiltration of fat and macrophages ex-pressing IL-1␤ (49).…”

mentioning

confidence: 99%

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IL-1β hampers glucose-stimulated insulin secretion in Cohen diabetic rat islets through mitochondrial cytochromecoxidase inhibition by nitric oxide

Weksler-Zangen

Aharon-Hananel

Mantzur

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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induces inhibition of glucose-sensitive rats (CDs) but not Cohen diabetes-resistant rats (CDr). Coppersupplemented HSD increased activity of the copper-dependent mitochondrial respiratory chain enzyme cytochrome c oxidase (COX) and reversed hyperglycemia. This study examined the mechanism by which interleukin-1␤ modulates GSIS and the role of COX in this process. We measured COX activity, ATP content, GSIS, iNOS expression, and nitrite production with and without IL-1␤, N -nitro-L-arginine, copper, or potassium cyanide in isolated islets of CDs and CDr fed different diets. We found reduced COX activity, ATP content, and GSIS in isolated islets of CDs rats fed a regular diet. These were severely reduced following HSD and were restored to regular diet levels on copper-supplemented HSD (P Ͻ 0.01 vs. CDr islets). Potassium cyanide chemically reduced COX activity, decreasing GSIS and thus reinforcing the link between islet COX activity and GSIS. Interleukin-1␤ (2.5 U/ml) reduced GSIS and COX activity in CDs islets. Exposure to 10 U/ml interleukin-1␤ decreased GSIS and COX activity in both CDs and CDr islets, inducing a similar nitrite production. Nevertheless, the effect on GSIS was more marked in CDs islets. A significant iNOS expression was detected in CDs on the HSD diet, which was reduced by copper supplementation. N -nitro-L-arginine and copper prevented the deleterious effect of interleukin-1␤ on COX activity and GSIS. We conclude that reduced islet COX activity renders vulnerability to GSIS inhibition on low-copper HSD through two interrelated pathways: 1) by further reducing the activity of COX that is essential for ␤-cell ATP-production and insulin secretion and 2) by inducing the expression of iNOS and nitric oxide-mediated COX inhibition. We suggest that islet COX activity must be maintained above a critical threshold to sustain adequate GSIS with exposure to low-copper HSD.interleukin-1␤; pancreatic ␤-cell; copper; cytochrome c oxidase; inducible nitrix oxide synthase ELEVATED PLASMA GLUCOSE LEVELS will cause a rise in pancreatic ␤-cell ATP/ADP ratio, triggering insulin secretion by oxidative phosphorylation (OXPHOS), a process elicited by the mitochondrial respiratory chain (20, 51). Therefore, mitochondrial dysfunction could lead to impaired glucose-stimulated insulin secretion (GSIS) and an increased risk of diabetes (25,27). The mitochondrial respiratory chain, situated in the inner mitochondrial membrane, consists of five multisubunit complexes (I-V). Complex IV [cytochrome c oxidase (COX)] is the terminal electron transport chain complex that catalyzes the transfer of electrons from cytochrome c to molecular oxygen. The electrochemical proton gradient formed by complexes I, III, and IV (COX) is utilized by complex V (ATP synthase) to generate ATP (25). COX activity is regulated and inhibited by numerous molecules, including potassium cyanide (KCN) and nitric oxide (NO), which reversibly competes with oxygen at the heme copper active site (8). Studies in diabetic animal models suggest that interleuki...

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supporting

confidence: 55%

mentioning

confidence: 99%

IL-1β hampers glucose-stimulated insulin secretion in Cohen diabetic rat islets through mitochondrial cytochromecoxidase inhibition by nitric oxide

Weksler-Zangen

Aharon-Hananel

Mantzur

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…This islet inflammation could be mediated by CCL2 and CCL13 produced in human beta cells. Islet inflammation was also present in animal models for type 2 diabetes, namely the high-fat-diet-fed and db/db mice [18,36], the Cohen diabetic rat [36] and the Goto-Kakizaki rat [37,38]. The role of these infiltrating macrophages is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…The role of these infiltrating macrophages is unknown. Some propose them to be beneficial to islet function by promoting angiogenesis [39]; others suggest that activated CD68 + cells could cause beta cell dysfunction and death [36,37]. The beta cell inflammatory response was presently reproduced at the RNA and protein level in ND human islets by their in vitro exposure to the saturated NEFA palmitate, and was dependent on the canonical mediator of early inflammation IL-1β.…”

Section: Discussionmentioning

confidence: 99%

Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by beta cells in type 2 diabetes

et al. 2010

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Aims/hypothesis Beta cell failure is a crucial component in the pathogenesis of type 2 diabetes. One of the proposed mechanisms of beta cell failure is local inflammation, but the presence of pancreatic islet inflammation in type 2 diabetes and the mechanisms involved remain under debate.Methods Chemokine and cytokine expression was studied by microarray analysis of laser-capture microdissected islets from pancreases obtained from ten non-diabetic and ten type 2 diabetic donors, and by real-time PCR of human islets exposed to oleate or palmitate at 6 or 28 mmol/l glucose. The cellular source of the chemokines was analysed by immunofluorescence of pancreatic sections from individuals without diabetes and with type 2 diabetes.

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“…4). A similar discrepancy between in vivo and in vitro islet function was observed in other animal models of diabetes displaying islet inflammation (46,47).…”

Section: Discussionmentioning

confidence: 77%

Angiotensin II Induces Interleukin-1β–Mediated Islet Inflammation and β-Cell Dysfunction Independently of Vasoconstrictive Effects

et al. 2014

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Pathological activation of the renin-angiotensin system (RAS) is associated with the metabolic syndrome, and the new onset of type 2 diabetes can be delayed by RAS inhibition. In animal models of type 2 diabetes, inhibition of the RAS improves insulin secretion. However, the direct effects of angiotensin II on islet function and underlying mechanisms independent of changes in blood pressure remain unclear. Here we show that exposure of human and mouse islets to angiotensin II induces interleukin (IL)-1-dependent expression of IL-6 and MCP-1, enhances b-cell apoptosis, and impairs mitochondrial function and insulin secretion. In vivo, mice fed a high-fat diet and treated with angiotensin II and the vasodilator hydralazine to prevent hypertension showed defective glucose-stimulated insulin secretion and deteriorated glucose tolerance. Application of an anti-IL-1b antibody reduced the deleterious effects of angiotensin II on islet inflammation, restored insulin secretion, and improved glycemia. We conclude that angiotensin II leads to islet dysfunction via induction of inflammation and independent of vasoconstriction. Our findings reveal a novel role for the RAS and an additional rationale for the treatment of type 2 diabetic patients with an IL-1b antagonist.Obesity and type 2 diabetes are related to hypertension and to increased activation of the renin-angiotensin system (RAS) (1-3). Multiple trials have shown that RAS blockade reduces the incidence of new-onset type 2 diabetes in high-risk populations (4). On the basis of several meta-analyses, this reduction ranges between 22% and 30% (5,6). In addition, in different animals models of type 2 diabetes, treatment with either angiotensinreceptor blockers or ACE inhibitors improves glucose tolerance and b-cell function (2,7-10). All of this suggests a role for angiotensin II in the development of type 2 diabetes.The RAS is classically known as a systemic hormonal system regulating blood pressure, fluid balance, and electrolyte absorption (11). Finding a local RAS in various tissues and organs such as brain, kidney (12), heart (13), liver, and adipose tissue (14) has expanded its role to diverse physiological functions in addition to its effects on circulation. All key components of the RAS also have been localized to the endocrine pancreas, including the precursor angiotensinogen and the angiotensin II type 1 receptor (15,16). Furthermore, obesity and hyperglycemia increases the expression of the local RAS in pancreatic islets (17), adipose tissue (18), and skeletal muscle.

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Impaired Glucose-Stimulated Insulin Secretion Is Coupled With Exocrine Pancreatic Lesions in the Cohen Diabetic Rat

Abstract: The association of the in vivo insulin secretory defect with lipid accumulation and activated macrophage infiltration in the exocrine pancreas suggests that changes in the islet microenvironment are the culprit in the insulin secretory malfunction observed in vivo.

Cited by 51 publications

References 53 publications

IL-1β hampers glucose-stimulated insulin secretion in Cohen diabetic rat islets through mitochondrial cytochromecoxidase inhibition by nitric oxide

IL-1β hampers glucose-stimulated insulin secretion in Cohen diabetic rat islets through mitochondrial cytochromecoxidase inhibition by nitric oxide

Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by beta cells in type 2 diabetes

Angiotensin II Induces Interleukin-1β–Mediated Islet Inflammation and β-Cell Dysfunction Independently of Vasoconstrictive Effects

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