Variants in the Cav2.3 (α1E) Subunit of Voltage-Activated Ca2+ Channels Are Associated With Insulin Resistance and Type 2 Diabetes in Pima Indians

Muller, Yunhua L.; Hanson, Robert L.; Zimmerman, Collin; Harper, Ian S.; Sutherland, Jeff; Kobes, Sayuko; Knowler, William C.; Bogardus, Clifton; Baier, Leslie J.

doi:10.2337/db07-0587

Cited by 29 publications

(27 citation statements)

References 24 publications

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“…These findings are somewhat difficult to interpret, since mice of various ages (12-50 weeks) were used without appropriate age-matching or discrimination between male and female animals. The concept is nevertheless intriguing, as several studies have since linked variants in the gene encoding Ca v 2.3 channels to impaired glucose homeostasis in human T2DM patients [66][67][68]. Most notably, the region on chromosome 1q21-25, where the human Ca v 2.3 gene is located, has been linked to young-onset T2DM in Pima Indians [67].…”

Section: Pathophysiological Implicationsmentioning

confidence: 98%

“…The concept is nevertheless intriguing, as several studies have since linked variants in the gene encoding Ca v 2.3 channels to impaired glucose homeostasis in human T2DM patients [66][67][68]. Most notably, the region on chromosome 1q21-25, where the human Ca v 2.3 gene is located, has been linked to young-onset T2DM in Pima Indians [67]. Subjects with the risk allele display significantly higher blood glucose concentrations 30 min, 60 min, and 120 min after glucose challenge and higher mean fasting insulin and glucose levels than control persons [67].…”

Section: Pathophysiological Implicationsmentioning

confidence: 99%

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Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion

Drobinskaya

Neumaier

Pereverzev

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Peptide-hormone secretion is partially triggered by Ca2+ influx through voltage-gated Ca2+ channels (VGCCs) and gene inactivation of Zn2+-sensitive Cav2.3-type VGCCs is associated with disturbed glucose homeostasis in mice. Zn2+ has been implicated in pancreatic islet cell crosstalk and recent findings indicate that sudden cessation of Zn2+ supply during hypoglycemia triggers glucagon secretion in rodents. Here we show that diethyldithiocarbamate (DEDTC), a chelating agent for Zn2+ and other group IIB metal ions, differentially affects blood glucose and serum peptide hormone level in wild-type mice and mice lacking the Cav2.3-subunit. Fasting glucose and glucagon level were significantly higher in Cav2.3-deficient compared to wild-type mice, while DEDTC Zn2+-chelation produced a significant and correlated increase of blood glucose and serum glucagon concentration in wild-type but not Cav2.3-deficient mice. Glucose tolerance tests revealed severe glucose intolerance in Zn2+-depleted Cav2.3-deficient but not vehicle-treated Cav2.3-deficient or Zn2+-depleted wildtype mice. Collectively, these findings indicate that Cav2.3 channels are critically involved in the Zn2+-mediated suppression of glucagon secretion during hyperglycemia. Especially under conditions of Zn2+ deficiency, ablation or dysfunction of Cav2.3 channels may lead to severe disturbances in glucose homeostasis.

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Section: Pathophysiological Implicationsmentioning

confidence: 98%

Section: Pathophysiological Implicationsmentioning

confidence: 99%

Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion

Drobinskaya

Neumaier

Pereverzev

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…2). Another example of a Ca 2ϩ sensor having a role in modulating insulin sensitivity is the ␣1-subunit of the voltage-dependent calcium channel, which has been previously associated with insulin resistance and type 2 diabetes in animal models (21) and humans (22). The Ca 2ϩ sensor PCLO could potentially interact with the voltage-dependent calcium channel to influence insulin sensitivity.…”

Section: Resultsmentioning

confidence: 99%

PCLO Variants Are Nominally Associated With Early-Onset Type 2 Diabetes and Insulin Resistance in Pima Indians

Hanson

Que

et al. 2008

Diabetes

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OBJECTIVE-A prior genome-wide association (GWA) study in Pima Indians identified variants within PCLO that were associated with early-onset type 2 diabetes. PCLO encodes a presynaptic cytomatrix protein that functions as a Ca 2ϩ sensor that may be involved in insulin secretion and/or insulin action. Therefore, PCLO was analyzed as a candidate gene for type 2 diabetes. RESEARCH DESIGN AND METHODS-Sequencing of PCLOidentified four nonsynonymous variants and a 10 -amino acid insertion. These variants, together with 100 additional variants identified by sequencing or chosen from databases, were genotyped for association analysis in the same 895 subjects analyzed in the prior GWA study (300 case subjects with diabetes onset at aged Ͻ25 years, 334 nondiabetic control subjects aged Ͼ45 years, and 261 discordant siblings of the case or control subjects for within-family analyses), as well as 415 nondiabetic Pima Indians who had been metabolically phenotyped for predictors of diabetes. Selected variants were further genotyped in a population-based sample of 3,501 Pima Indians.RESULTS-Four variants were modestly associated with earlyonset type 2 diabetes in both general and within-family analyses (P ϭ 0.004 -0.04, recessive model), where the diabetes risk allele was also nominally associated with a lower insulin-mediated glucose disposal rate (P ϭ 0.009 -0.14, recessive model) in nondiabetic Pima Indians. However, their association with diabetes in the population-based sample was weaker (P ϭ 0.02-0.20, recessive model). T he Pima Indians of Arizona have an extremely high prevalence of type 2 diabetes (1). Their diabetes is characterized by obesity, dysfunction of insulin secretion, insulin resistance (decreased insulin-mediated glucose disposal), and increased rate of endogenous glucose output (2). Studies have shown that type 2 diabetes, insulin action, acute insulin response to glucose, and obesity are highly heritable in this population (3-5). To identify genes that underlie the development of type 2 diabetes in Pima Indians, we recently completed a genome-wide association (GWA) study using the Affymetrix 100K SNP genotyping array (6). Two single nucleotide polymorphisms (SNPs), rs10487656 and rs10487657, that ranked among the top 1% for a general association with early-onset type 2 diabetes (defined as age of onset Ͻ25 years) mapped within an intron of the PCLO gene. PCLO is located on chromosome 7q21 and encodes for a presynaptic cytomatrix protein that functions as a Ca 2ϩ sensor that could potentially have a role in insulin secretion and/or insulin action (7-10); therefore, PCLO was analyzed as a positional and physiological candidate gene for type 2 diabetes. CONCLUSIONS-Variation RESEARCH DESIGN AND METHODSAll subjects are part of our ongoing longitudinal study of the etiology of type 2 diabetes among the Gila River Indian Community in Central Arizona (1). Diabetes status is determined by a 75-g orally administered glucose tolerance test, with results interpreted according to the criteria of the World Health Orga...

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“…This is just the opposite in delta cells (see section on "Delta Cells"). Notably, a functional variant in the gene encoding Ca v 2.3 contributes to the susceptibility of Pima Indians to type 2 diabetes mellitus (Muller et al 2007). Induction of electrical activity by glucose is a prerequisite for insulin secretion.…”

Section: Role In β Cell Stimulus-secretion Couplingmentioning

confidence: 99%

Electrophysiology of Islet Cells

Drews

Koehler

Düfer

2014

Islets of Langerhans

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Variants in the Cav2.3 (α1E) Subunit of Voltage-Activated Ca2+ Channels Are Associated With Insulin Resistance and Type 2 Diabetes in Pima Indians

Abstract: A functional variant in CACNA1E contributes to type 2 diabetes susceptibility by affecting insulin action. This variant partially explains the linkage to type 2 diabetes on chromosome 1q21-25 in Pima Indians.

Cited by 29 publications

References 24 publications

Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion

Diethyldithiocarbamate-mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion

PCLO Variants Are Nominally Associated With Early-Onset Type 2 Diabetes and Insulin Resistance in Pima Indians

Electrophysiology of Islet Cells

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