Islet Inflammation and Fibrosis in a Spontaneous Model of Type 2 Diabetes, the GK Rat

Homo‐Delarche, Françoise; Caldérari, Sophie; Irminger, Jean-Claude; Gangnerau, Marie-Noëlle; Coulaud, Josiane; Rickenbach, Katharina; Dolz, Manuel; Halban, Philippe A.; Portha, Bernard; Serradas, Patricia

doi:10.2337/db05-1526

Cited by 188 publications

(200 citation statements)

References 62 publications

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“…Pancreatic islets from patients with type 2 diabetes are infiltrated with macrophages (7,8), express elevated proinflammatory cytokines (9,10), and express features of fibrosis (11), consistent with reports from animals and primates with this disease (7,(12)(13)(14)(15)(16)(17)(18). The detrimental effects of inflammation on islet b-cell function were recently confirmed, when the interleukin (IL)-1 receptor antagonist reduced hyperglycemia and improved b-cell insulin secretion in patients with type 2 diabetes (1).…”

supporting

confidence: 69%

Glycoprotein 130 Receptor Signaling Mediates α-Cell Dysfunction in a Rodent Model of Type 2 Diabetes

et al. 2014

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Dysregulated glucagon secretion accompanies islet inflammation in type 2 diabetes. We recently discovered that interleukin (IL)-6 stimulates glucagon secretion from human and rodent islets. IL-6 family cytokines require the glycoprotein 130 (gp130) receptor to signal. In this study, we elucidated the effects of a-cell gp130 receptor signaling on glycemic control in type 2 diabetes. IL-6 family cytokines were elevated in islets in rodent models of this disease. gp130 receptor activation increased STAT3 phosphorylation in primary a-cells and stimulated glucagon secretion. Pancreatic a-cell gp130 knockout (agp130KO) mice showed no differences in glycemic control, a-cell function, or a-cell mass. However, when subjected to streptozotocin plus high-fat diet to induce islet inflammation and pathophysiology modeling type 2 diabetes, agp130KO mice had reduced fasting glycemia, improved glucose tolerance, reduced fasting insulin, and improved a-cell function. Hyperinsulinemic-euglycemic clamps revealed no differences in insulin sensitivity. We conclude that in a setting of islet inflammation and pathophysiology modeling type 2 diabetes, activation of a-cell gp130 receptor signaling has deleterious effects on a-cell function, promoting hyperglycemia. Antagonism of a-cell gp130 receptor signaling may be useful for the treatment of type 2 diabetes.Islet inflammation (1,2) and pancreatic a-cell dysfunction (3-6) contribute to hyperglycemia in patients with type 2 diabetes. Pancreatic islets from patients with type 2 diabetes are infiltrated with macrophages (7,8), express elevated proinflammatory cytokines (9,10), and express features of fibrosis (11), consistent with reports from animals and primates with this disease (7,(12)(13)(14)(15)(16)(17)(18). The detrimental effects of inflammation on islet b-cell function were recently confirmed, when the interleukin (IL)-1 receptor antagonist reduced hyperglycemia and improved b-cell insulin secretion in patients with type 2 diabetes (1).Pancreatic a-cell dysfunction is detectable in the early stages of type 2 diabetes, where the inverse relationship between pulsatile insulin and glucagon secretion is lost (19). This dysregulation is associated with relative hyperglucagonemia, which contributes to the development of fasting hyperglycemia associated with frank type 2 diabetes (6). Indeed, inhibition of glucagon action by various means reduces hyperglycemia in rodent models of this disease (5,6).

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confidence: 69%

Glycoprotein 130 Receptor Signaling Mediates α-Cell Dysfunction in a Rodent Model of Type 2 Diabetes

et al. 2014

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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%

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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“…This was supported by Donath and Halban (25). Another explanation was the development of fibrosis secondary to hyperglycemia since the latter was known to stimulate the secretion of fibronectin, collagen I and III by endothelial cells and/or vascular smooth muscle cells (26).…”

Section: -Fold (20)mentioning

confidence: 87%

The Effect of In Vivo Mobilization of Bone Marrow Stem Cells on the Pancreas of Diabetic Albino Rats (A Histological & Immunohistochemical Study)

Ismail¹,

Kamel²,

Yacoub³

et al. 2013

Int J Stem Cells

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Background and Objectives: The rapidly increasing number of diabetic patients across the world drew the attention to develop more effective therapeutic approaches. Recent investigations on newly differentiated insulin producing cells (IPCs) revealed that they could be derived from embryonic, adult mesenchymal and hematopoietic stem cells. This work was planned to evaluate the role of StemEnhance (Aphanizomenon flos-aquae [AFA] plant extract) in mobilizing naturally occurring bone marrow stem cells as well as in improving streptozotocin-induced diabetic rats. Methods and Results: Twenty adult male albino rats were divided into four groups namely the control, the diabetic, the positive control-StemEnhance and the diabetic-StemEnhance groups. After diabetes induction by streptozotocin (STZ), rats received StemEnhance for four weeks. The mean number of blood CD34 immunopositive cells was measured by flowcytometry and random blood sugar was measured weekly. The pancreas was removed from the sacrificed rats and processed for staining with H&E and immunohistochemical staining for CD34+ve and insulin +ve cells. CD34+ve cells increased in the blood after introduction of StemEnhance. CD34+ve cells were observed in the pancreas and the insulin producing cells in the islets of Langerhans were increased from the second to the fourth week of treatment. Blood glucose level improved but it was still higher than the control level after four weeks of StemEnhance treatment. Conclusions: This work points to the significant role of StemEnhance in stem cell mobilization and the improvement of diabetes mellitus.

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Islet Inflammation and Fibrosis in a Spontaneous Model of Type 2 Diabetes, the GK Rat

Cited by 188 publications

References 62 publications

Glycoprotein 130 Receptor Signaling Mediates α-Cell Dysfunction in a Rodent Model of Type 2 Diabetes

Glycoprotein 130 Receptor Signaling Mediates α-Cell Dysfunction in a Rodent Model of Type 2 Diabetes

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

The Effect of In Vivo Mobilization of Bone Marrow Stem Cells on the Pancreas of Diabetic Albino Rats (A Histological & Immunohistochemical Study)

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