Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus

Westermark, Per; Andersson, Arne; Westermark, Gunilla T.

doi:10.1152/physrev.00042.2009

Cited by 902 publications

(1,249 citation statements)

References 441 publications

(459 reference statements)

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“…Since the oligomer of amyloidogenic human-type IAPP (islet amyloid polypeptide) but not nonamyloidogenic murine IAPP can induce inflammasome activation, 61 the role of inflammasome activation with or without autophagy deficiency may be more prominent in human T2D rather than murine T2D. 61,62 While impairment of b-cell function may not be the primary cause of diabetes in Atg7 cKO-ob/ ob mice, the insulinogenic index was not further increased in Atg7 cKO-ob/ob mice compared to Atg7 cWT-ob/ob mice despite aggravated insulin resistance, suggesting that b-cell response to increased insulin resistance was not adequate in Atg7 cKO-ob/ob mice. More pronounced islet inflammation in Atg7 cKO-ob/ob mice compared to Atg7 cWT-ob/ob mice might be responsible for such an insufficient response to insulin resistance.…”

Section: Figure 7 Systemic Inflammation and Bacterial Invasion Aftermentioning

confidence: 99%

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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Section: Figure 7 Systemic Inflammation and Bacterial Invasion Aftermentioning

confidence: 99%

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

et al. 2016

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“…Amylin is a 37-amino acid hormone, co-secreted with insulin in the pancreatic β-cells (Westermark, Andersson, & Westermark 2011), and its physiological role includes insulin secretion inhibition, inhibition of gastric emptying and glucagon secretion (Hay et al 2015). Endogenous amylin and its analogue and receptor agonist, salmon calcitonin (sCT), exert anorexigenic properties by signalling satiation (Lutz et al 1995;Lutz et al 2000;Reidelberger et al 2004;Mack et al 2007;Lutz 2012).…”

Section: Introductionmentioning

confidence: 99%

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

2018

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Alcohol expresses its reinforcing properties by activating areas of the mesolimbic dopamine system, which consists of dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens. The findings that reward induced by food and addictive drugs involve common mechanisms raise the possibility that gut-brain hormones, which control appetite, such as amylin, could be involved in reward regulation. Amylin decreases food intake, and despite its implication in the regulation of natural rewards, tenuous evidence support amylinergic mediation of artificial rewards, such as alcohol. Therefore, the present experiments were designed to investigate the effect of salmon calcitonin (sCT), an amylin receptor agonist and analogue of endogenous amylin, on various alcohol-related behaviours in rodents. We showed that acute sCT administration attenuated the established effects of alcohol on the mesolimbic dopamine system, particularly alcohol-induced locomotor stimulation and accumbal dopamine release. Using the conditioned place preference model, we demonstrated that repeated sCT administration prevented the expression of alcohol's rewarding properties and that acute sCT administration blocked the reward-dependent memory consolidation. In addition, sCT pre-treatment attenuated alcohol intake in low alcohol-consuming rats, with a more evident decrease in high alcohol consumers in the intermittent alcohol access model. Lastly, sCT did not alter peanut butter intake, blood alcohol concentration and plasma corticosterone levels in mice. Taken together, the present data support that amylin signalling is involved in the expression of alcohol reinforcement and that amylin receptor agonists could be considered for the treatment of alcohol use disorder in humans.

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“…Islet amyloid formation in patients with type 2 diabetes contributes to progressive beta cell death [3][4][5]. Unlike in type 2 diabetes, amyloid forms rapidly in cultured [6][7][8] and transplanted human islets [9,10], and this is associated with beta cell dysfunction and death in vitro [6][7][8], and with islet graft failure leading to recurrence of hyperglycaemia in animal models of type 1 diabetes [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

“…Three major factors contribute to human islet amyloid polypeptide (hIAPP) aggregation in type 2 diabetes: (1) presence of an amyloidogenic sequence in the hIAPP molecule [4]; (2) elevated beta cell production and secretion of hIAPP due to increased insulin demand [16,17]; and (3) impaired prohIAPP processing and/or trafficking due to beta cell dysfunction [17][18][19]. Impaired clearance of secreted hIAPP because of disrupted blood vessels in isolated islets may also potentiate amyloid formation.…”

Section: Introductionmentioning

confidence: 99%

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The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

et al. 2014

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Aims/hypothesis Reduced beta cell mass due to increased beta cell apoptosis is a key defect in type 2 diabetes. Islet amyloid, formed by the aggregation of human islet amyloid polypeptide (hIAPP), contributes to beta cell death in type 2 diabetes and in islet grafts in patients with type 1 diabetes. In this study, we used human islets and hIAPP-expressing mouse islets with beta cell Casp8 deletion to (1) investigate the role of caspase-8 in amyloid-induced beta cell apoptosis and (2) test whether caspase-8 inhibition protects beta cells from amyloid toxicity. Methods Human islet cells were cultured with hIAPP alone, or with caspase-8, Fas or amyloid inhibitors. Human islets and wild-type or hIAPP-expressing mouse islets with or without caspase-8 expression (generated using a Cre/loxP system) were cultured to form amyloid. Caspase-8 and -3 activation, Fas and FLICE inhibitory protein (FLIP) expression, islet beta cell and amyloid area, IL-1β levels, and the beta:alpha cell ratio were assessed. Results hIAPP treatment induced activation of caspase-8 and -3 in islet beta cells (via Fas upregulation), resulting in apoptosis, which was markedly reduced by blocking caspase-8, Fas or amyloid. Amyloid formation in cultured human and hIAPP-expressing mouse islets induced caspase-8 activation, which was associated with Fas upregulation and elevated islet IL-1β levels. hIAPP-expressing mouse islets with Casp8 deletion had comparable amyloid, IL-1β and Fas levels with those expressing hIAPP and Casp8, but markedly lower beta cell apoptosis, higher beta:alpha cell ratio, greater beta cell area, and enhanced beta cell function. Conclusions/interpretation Beta cell Fas upregulation by endogenously produced and exogenously applied hIAPP aggregates promotes caspase-8 activation, resulting in beta cell apoptosis. The prevention of amyloid-induced caspase-8 activation enhances beta cell survival and function in islets.

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Islet Amyloid Polypeptide, Islet Amyloid, and Diabetes Mellitus

Cited by 902 publications

References 441 publications

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

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

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets

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