Associations between genetic variants and the severity of metabolic syndrome in subjects with type 2 diabetes

Yl, Chen; D, Pei; Yj, Hung; Ch, Lee; Fc, Hsiao; Wu, Chung Ze; Jd, Lin; Ch, Hsu; Jb, Chang; Ch, Hsieh

doi:10.4238/2015.march.30.10

Cited by 18 publications

(16 citation statements)

References 26 publications

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“…In addition, several polymorphisms have also been identified in genes that affect insulin secretion or metabolic parameters, such as the L-type calcium channel, the K ATP channel, G-protein coupled receptors and syntaxin 33 , 45 – 48 . Furthermore, SNPs in the human gene for Snap25 have been associated with glycemic parameters or severity of metabolic syndrome in type 2 diabetes patients 49 , 50 . In this context it is noteworthy, that the metabolic phenotype in our SNAP-25b-deficient mice became severely worsened in combination with a Western diet intervention 35 .…”

Section: Discussionmentioning

confidence: 99%

SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca2+oscillations in β cell networks

Daraio

Bombek

Gosak

et al. 2017

Sci Rep

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SNAP-25 is a protein of the core SNARE complex mediating stimulus-dependent release of insulin from pancreatic β cells. The protein exists as two alternatively spliced isoforms, SNAP-25a and SNAP-25b, differing in 9 out of 206 amino acids, yet their specific roles in pancreatic β cells remain unclear. We explored the effect of SNAP-25b-deficiency on glucose-stimulated insulin release in islets and found increased secretion both in vivo and in vitro. However, slow photo-release of caged Ca2+ in β cells within pancreatic slices showed no significant differences in Ca2+-sensitivity, amplitude or rate of exocytosis between SNAP-25b-deficient and wild-type littermates. Therefore, we next investigated if Ca2+ handling was affected in glucose-stimulated β cells using intracellular Ca2+-imaging and found premature activation and delayed termination of [Ca2+]i elevations. These findings were accompanied by less synchronized Ca2+-oscillations and hence more segregated functional β cell networks in SNAP-25b-deficient mice. Islet gross morphology and architecture were maintained in mutant mice, although sex specific compensatory changes were observed. Thus, our study proposes that SNAP-25b in pancreatic β cells, except for participating in the core SNARE complex, is necessary for accurate regulation of Ca2+-dynamics.

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Section: Discussionmentioning

confidence: 99%

SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca2+oscillations in β cell networks

Daraio

Bombek

Gosak

et al. 2017

Sci Rep

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“…These genes also are expressed in other excitable cells, including neurons, and therefore it is possible to envisage a scenario similar to that of our SNAP-25b-deficient mice in which a small imbalance in stimulus-dependent exocytosis mechanisms in excitable cells deregulates the interplay of metabolic signals and is followed by obesity and T2D. A recent publication also links the severity of T2D to an SNP in the human Snap25 gene (33). Therefore it would be interesting to investigate mouse mutants targeting other genes identified in GWAS as susceptibly genes for T2D and obesity and directly or indirectly involved in the control of regulated membrane fusion.…”

Section: (E and F) Hypothalamic Pstat3 Is Decreased In All Experimentmentioning

confidence: 99%

“…Polymorphisms in the human Snap25 gene have been associated with weight gain after antipsychotic treatment, with altered levels of serum triglycerides (31,32), and also with the severity of the metabolic syndrome in T2D (33). Furthermore, polymorphisms in genes expressing proteins directly interacting with SNAP-25 have been implicated in childhood obesity, impaired glucose metabolism and obesity, age of onset of T2D, and insulin requirement in T2D (34)(35)(36).…”

mentioning

confidence: 99%

Replacing SNAP-25b with SNAP-25a expression results in metabolic disease

Valladolid‐Acebes

Daraio

Brismar

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Synaptosomal-associated protein of 25 kDa (SNAP-25) is a key molecule in the soluble N-ethylmaleimide-sensitive factor attachment protein (SNARE) complex mediating fast Ca 2+ -triggered release of hormones and neurotransmitters, and both splice variants, SNAP-25a and SNAP-25b, can participate in this process. Here we explore the hypothesis that minor alterations in the machinery mediating regulated membrane fusion can increase the susceptibility for metabolic disease and precede obesity and type 2 diabetes. Thus, we used a mouse mutant engineered to express normal levels of SNAP-25 but only SNAP-25a. These SNAP-25b-deficient mice were exposed to either a control or a high-fat/high-sucrose diet. Monitoring of food intake, body weight, hypothalamic function, and lipid and glucose homeostases showed that SNAP-25b-deficient mice fed with control diet developed hyperglycemia, liver steatosis, and adipocyte hypertrophy, conditions dramatically exacerbated when combined with the high-fat/high-sucrose diet. Thus, modified SNARE function regulating stimulus-dependent exocytosis can increase the vulnerability to and even provoke metabolic disease. When combined with a high-fat/high-sucrose diet, this vulnerability resulted in diabesity. Our SNAP-25b-deficient mouse may represent a diabesity model.O n-going lifestyle changes, including oversized meals with excessive amounts of sugar and fat, have led to a worldwide pandemic of obesity and type 2 diabetes (T2D) (1). These diseases and their comorbidities cause individual suffering and represent a heavy financial burden on society (2, 3). The term "diabesity" is used to define the coincidence of obesity with T2D under conditions of exaggerated intake of energy-dense diets (4-6). Moreover, genomewide association studies (GWAS) have identified polymorphisms associated with obesity and T2D, indicating that genetic factors predispose certain individuals to diabesity (7-11).Signs of metabolic diseases include impaired regulated release of hormones, particularly insulin as in T2D (4, 12). Likewise, the secretion of inflammatory markers and other peripheral bioactive peptides is either increased (e.g., leptin, resistin, and adipsin) or decreased (e.g., ghrelin and adiponectin) (13-16). Synaptic and nonsynaptic transmission involving the release of neuropeptides and neurotransmitters, especially in hypothalamic areas controlling eating behavior and energy balance, are involved too (17)(18)(19).In excitable cells, the release of messenger molecules is a consequence of regulated membrane fusion and involves soluble N-ethylmaleimide-sensitive factor attachment proteins (SNAREs) (20, 21), including synaptosomal-associated protein of 25 kDa (SNAP-25). SNAP-25 is expressed as two developmentally regulated and alternatively spliced isoforms, SNAP-25a and SNAP-25b, which differ in only 9 of 206 amino acids (22, 23). In the mouse brain, SNAP-25a precedes SNAP-25b expression during development, but by the second postnatal week SNAP-25b becomes the major splice variant, concomitantly with a dr...

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“…Therefore, they have attracted wide investigation interest around the world. [1][2][3][4][5][6][7][8][9][10][11][12][13] Capacitance (C) characteristics can provide a powerful method to understand the physical mechanisms of OLEDs. Negative capacitance (NC) is one of the most notable phenomena in OLEDs.…”

Section: Introductionmentioning

confidence: 99%

Space charges and negative capacitance effect in organic light-emitting diodes by transient current response analysis

et al. 2017

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Associations between genetic variants and the severity of metabolic syndrome in subjects with type 2 diabetes

Cited by 18 publications

References 26 publications

SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca2+oscillations in β cell networks

SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Ca2+oscillations in β cell networks

Replacing SNAP-25b with SNAP-25a expression results in metabolic disease

Space charges and negative capacitance effect in organic light-emitting diodes by transient current response analysis

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