SERCA2 Deficiency Impairs Pancreatic β-Cell Function in Response to Diet-Induced Obesity

Tong, Xin; Kono, Tatsuyoshi; Anderson-Baucum, Emily; Yamamoto, Wataru; Gilon, Patrick; Lebeche, Djamel; Day, Richard N.; Shull, Gary E.; Evans‐Molina, Carmella

doi:10.2337/db16-0084

Cited by 74 publications

(108 citation statements)

References 49 publications

(59 reference statements)

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“…102 While there still is not direct demonstration of ferroptosis by lipotoxic stimuli in beta cells, the contribution of iron overload for the development of beta cell failure in human T2D has significant evidence making ferroptosis a potential pathway involved in beta cell demise under overnutrition. 104 High concentrations of FA have been shown to deplete [Ca 2+ ] ER in beta cells 105,106 by reducing expression of pumps that regulate [Ca 2+ ] ER homeostasis, such as sarco/ER Ca 2+ -ATPase 2B (SERCA2B), 107 sorcin, 108 and stromal interaction molecule 1 (STIM1). 104 High concentrations of FA have been shown to deplete [Ca 2+ ] ER in beta cells 105,106 by reducing expression of pumps that regulate [Ca 2+ ] ER homeostasis, such as sarco/ER Ca 2+ -ATPase 2B (SERCA2B), 107 sorcin, 108 and stromal interaction molecule 1 (STIM1).…”

Section: Stress Pathways That Contribute To Beta Cell Dysfunction Undmentioning

confidence: 99%

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

Imai

Cousins

Liu

et al. 2019

Annals of the New York Academy of Sciences

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Obesity is the major contributing factor for the increased prevalence of type 2 diabetes (T2D) in recent years. Sustained positive influx of lipids is considered to be a precipitating factor for beta cell dysfunction and serves as a connection between obesity and T2D. Importantly, fatty acids (FA), a key building block of lipids, are a double‐edged sword for beta cells. FA acutely increase glucose‐stimulated insulin secretion through cell‐surface receptor and intracellular pathways. However, chronic exposure to FA, combined with elevated glucose, impair the viability and function of beta cells in vitro and in animal models of obesity (glucolipotoxicity), providing an experimental basis for the propensity of beta cell demise under obesity in humans. To better understand the two‐sided relationship between lipids and beta cells, we present a current view of acute and chronic handling of lipids by beta cells and implications for beta cell function and health. We also discuss an emerging role for lipid droplets (LD) in the dynamic regulation of lipid metabolism in beta cells and insulin secretion, along with a potential role for LD under nutritional stress in beta cells, and incorporate recent advancement in the field of lipid droplet biology.

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Section: Stress Pathways That Contribute To Beta Cell Dysfunction Undmentioning

confidence: 99%

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

Imai

Cousins

Liu

et al. 2019

Annals of the New York Academy of Sciences

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“…89 Cytosol-to-ER lumen calcium pumping in various tissues is driven by members of the SERCA protein family, 90 of which SERCA2b is a major contributor to ER calcium as well as a contributor to the differentiated function of beta cells, 91,92 which may account for the observation that thapsigargin, a pan-SERCA pump inhibitor, impairs proinsulin export from the ER 93 and induces beta cell ER stress. 94 …”

Section: Misfolded Proinsulin Molecules Occur In Conjunction With Permentioning

confidence: 99%

Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes

Arunagiri

Haataja

Cunningham

et al. 2018

Annals of the New York Academy of Sciences

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The endoplasmic reticulum (ER) is broadly distributed throughout the cytoplasm of pancreatic beta cells, and this is where all proinsulin is initially made. Healthy beta cells can synthesize 6000 proinsulin molecules per second. Ordinarily, nascent proinsulin entering the ER rapidly folds via the formation of three evolutionarily conserved disulfide bonds (B7-A7, B19-A20, and A6-A11). A modest amount of proinsulin misfolding, including both intramolecular disulfide mispairing and intermolecular disulfide-linked protein complexes, is a natural by-product of proinsulin biosynthesis, as is the case for many proteins. The steady-state level of misfolded proinsulin-a potential ER stressor-is linked to (1) production rate, (2) ER environment, (3) presence or absence of naturally occurring (mutational) defects in proinsulin, and (4) clearance of misfolded proinsulin molecules. Accumulation of misfolded proinsulin beyond a certain threshold begins to interfere with the normal intracellular transport of bystander proinsulin, leading to diminished insulin production and hyperglycemia, as well as exacerbating ER stress. This is most obvious in mutant INS gene-induced Diabetes of Youth (MIDY; an autosomal dominant disease) but also likely to occur in type 2 diabetes owing to dysregulation in proinsulin synthesis, ER folding environment, or clearance.

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“…Chronic inflammatory cytokine treatment results in reduced levels of PC1/3 and PC2 in human islets . Islets isolated from mice with β‐cell‐specific mTOR deletion, sarcoendoplasmic reticulum Ca 2+ ATPase 2 (SERCA2) haploinsufficiency, or on a high‐fat diet, as well as human islets from T2D donors, all have reduced CPE levels . Silencing of TCF7L2 (a T2D susceptibility gene) in human islets also leads to reduced PSCK1 transcript levels .…”

Section: Islet Endocrine Cell Prohormone Processingmentioning

confidence: 99%

Islet prohormone processing in health and disease

Chen

Taylor

Verchere

2018

Diabetes Obesity Metabolism

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Biosynthesis of peptide hormones by pancreatic islet endocrine cells is a tightly orchestrated process that is critical for metabolic homeostasis. Like neuroendocrine peptides, insulin and other islet hormones are first synthesized as larger precursor molecules that are processed to their mature secreted products through a series of proteolytic cleavages, mediated by the prohormone convertases Pc1/3 and Pc2, and carboxypeptidase E. Additional posttranslational modifications including C-terminal amidation of the β-cell peptide islet amyloid polypeptide (IAPP) by peptidyl-glycine α-amidating monooxygenase (Pam) may also occur. Genome-wide association studies (GWAS) have showed genetic linkage of these processing enzymes to obesity, β-cell dysfunction, and type 2 diabetes (T2D), pointing to their important roles in metabolism and blood glucose regulation. In both type 1 diabetes (T1D) and T2D, and in the face of metabolic or inflammatory stresses, islet prohormone processing may become impaired; indeed elevated proinsulin:insulin (PI:I) ratios are a hallmark of the β-cell dysfunction in T2D. Recent studies suggest that genetic or acquired defects in proIAPP processing may lead to the production and secretion of incompletely processed forms of proIAPP that could contribute to T2D pathogenesis, and additionally that impaired processing of both PI and proIAPP may be characteristic of β-cell dysfunction in T1D. In islet α-cells, the prohormone proglucagon is normally processed to bioactive glucagon by Pc2 but may express Pc1/3 under certain conditions leading to production of GLP-1(7-36 ). A better understanding of how β-cell processing of PI and proIAPP, as well as α-cell processing of proglucagon, are impacted by genetic susceptibility and in the face of diabetogenic stresses, may lead to new therapeutic approaches for improving islet function in diabetes.

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SERCA2 Deficiency Impairs Pancreatic β-Cell Function in Response to Diet-Induced Obesity

Cited by 74 publications

References 49 publications

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes

Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes

Islet prohormone processing in health and disease

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