Elimination of the NLRP3-ASC Inflammasome Protects against Chronic Obesity-Induced Pancreatic Damage

Youm, Yun‐Hee; Adijiang, Ayinuer; Vandanmagsar, Bolormaa; Burk, David H.; Ravussin, Anthony; Dixit, Vishwa Deep

doi:10.1210/en.2011-1326

Cited by 157 publications

(130 citation statements)

References 29 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).…”

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confidence: 76%

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: 76%

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

et al. 2014

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“…28 Islet infiltration of ADGRE1 C Mfs in autophagy-competent Atg7 cWTob/ob mice which was significantly higher compared to lean mice, was further augmented in Atg7 cKO-ob/ob mice (P < 0.05) (Fig. S5), suggesting that inflammation in myeloid cell-specific autophagy deficiency occurs in both insulin target tissues and islets producing insulin.…”

Section: Enhanced Adipose Tissue Inflammation Of Atg7 Cko-ob/ob Micementioning

confidence: 95%

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

et al. 2016

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(2016) Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis, Autophagy, 12:8, 1390-1403, DOI: 10.1080/15548627.2016 ABSTRACT Autophagy, which is critical for the proper turnover of organelles such as endoplasmic reticulum and mitochondria, affects diverse aspects of metabolism, and its dysregulation has been incriminated in various metabolic disorders. However, the role of autophagy of myeloid cells in adipose tissue inflammation and type 2 diabetes has not been addressed. We produced mice with myeloid cell-specific deletion of Atg7 (autophagy-related 7), an essential autophagy gene (Atg7 conditional knockout [cKO] mice). While Atg7 cKO mice were metabolically indistinguishable from control mice, they developed diabetes when bred to ob/w mice (Atg7 cKO-ob/ob mice), accompanied by increases in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue. Mfs (macrophages) from Atg7 cKO mice showed significantly higher interleukin 1 b release and inflammasome activation in response to a palmitic acid plus lipopolysaccharide combination. Moreover, a decrease in the NAD C :NADH ratio and increase in intracellular ROS content after treatment with palmitic acid in combination with lipopolysaccharide were more pronounced in Mfs from Atg7 cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient Mfs leads to an increase in lipid-induced inflammasome and metabolic deterioration in Atg7 cKO-ob/ob mice. Atg7 cKO mice were more susceptible to experimental colitis, accompanied by increased colonic cytokine expression, T helper 1 skewing and systemic bacterial invasion. These results suggest that autophagy of Mfs is important for the control of inflammasome activation in response to metabolic or extrinsic stress, and autophagy deficiency in Mfs may contribute to the progression of metabolic syndrome associated with lipid injury and colitis.

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“…In pancreatic islet cells, islet amyloid polypeptide also triggers the NLRP3 inflammasome and generation of mature IL1β, which is reversed by treatment with glyburide 100 . The loss of ASC (Pycard), a critical adaptor required for the assembly of NLRP3, substantially improved insulin action and secretion by ameliorating the production of pancreatic IL1β and β-cell death caused by a long term HFD in mice 101 . The NLRP3 inflammasome, TLR2, and TLR4 are triggers for islet inflammation in T2DM and the activation of macrophages in various tissues is also mediated by activation of the NLRP3 inflammasome 102 .…”

Section: [H3] Nod2mentioning

confidence: 99%

Innate immunity in diabetes and diabetic nephropathy

2015

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Abstract:The innate immune system consists of several classes of pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors (TLRs) and nucleotide-binding domain leucine-rich oligomerization domain (NOD)-like receptors (NLRs).These receptors detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the extracellular and intracellular space. Intracellular NLRs constitute inflammasomes, which activate and release caspase-1, IL1β, and IL18 and thus initiate an inflammatory response. Systemic and local low-grade inflammation and release of proinflammatory cytokines are implicated in the development and progression of diabetes mellitus and diabetic nephropathy. TLR2, TLR4, and the NLRP3 inflammasome are critically involved in the inflammatory responses in pancreatic islets, adipose, liver and kidney tissues. This Review discusses how innate immune system-driven inflammatory processes can lead to apoptosis, tissue fibrosis, and organ dysfunction to cause insulin resistance, impaired insulin secretion, and renal failure. We propose that careful targeting of TLR2, TLR4, and NLRP3 signalling pathways may be beneficial for the treatment of diabetes mellitus and diabetic nephropathy. 2 Key points The innate immune system consists of several classes of pattern recognition receptors, including TLRs and NLRs, which detect pathogen-associated and danger-associated molecular patterns and initiate an inflammatory response  TLR2 and TLR4 are the predominant toll-like receptors expressed on pancreatic β cells that trigger an inflammatory response in insulitis during type 1 diabetes mellitus  TLR2 and TLR4 signaling, and activation of NLRP3 inflammasomes results in production of various proinflammatory cytokines that can induce insulin resistance in type 2 diabetes mellitus (T2DM) and obesity  Innate immune responses in T2DM and obesity are modulated by the status of the gut microbiota, autophagy, and adipokines  TLR2, TLR4, NOD2, and NLRP3 inflammasome-mediated inflammation are involved in the perpetuation of inflammation in diabetic nephropathy  The activation of TLRs and NLRs stimulates the expression of MCP-1, which is associated with the progression of diabetic nephropathy [H1] IntroductionThe prevalence of diabetes mellitus is estimated to be 8.3%, affecting ~387 million people as of 2014. The number of patients living with diabetes mellitus is expected to increase to ~592 million by 2035, as reported by the International Diabetes Federation 1 . The incidence of end-stage renal disease (ESRD) is also rapidly increasing worldwide but varies up to 15-fold by country. In 2012, the number of new diagnoses of ESRD worldwide ranged from 25 to 467 patients per million. The proportion of new cases of ESRD with diabetes mellitus as the primary cause also differs by country, with 66% cases reported in Singapore and 12-16% cases reported in Ukraine, Romania, and the Netherlands 2 . Although intensified multifactorial intervention in patients with type 2 diabete...

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Elimination of the NLRP3-ASC Inflammasome Protects against Chronic Obesity-Induced Pancreatic Damage

Cited by 157 publications

References 29 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

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

Innate immunity in diabetes and diabetic nephropathy

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