Diabetes mellitus: A disease of abnormal cellular calcium metabolism?

Levy, Joseph; Gavin, James R.; Sowers, James R.

doi:10.1016/0002-9343(94)90152-x

Cited by 221 publications

(153 citation statements)

References 122 publications

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“…The patient with Ile 753 ®Leu mutation was slightly overweight and had good glucose control on modest doses of insulin. Based on these observations, all four missense mutations identified in this study could potentially impair Ca 2+ uptake via SERCA resulting in changed Ca 2+ homeostasis which has been connected with the development of Type II diabetes [7,8]. Moreover, the unusual phenotypes could be in accord with clinical expression of these missense mutations.…”

Section: Discussionmentioning

confidence: 70%

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Sequence variants of the sarco(endo)plasmic reticulum Ca 2+ -transport ATPase 3 gene (SERCA3) in Caucasian Type II diabetic patients (UK Prospective Diabetes Study 48)

et al. 1999

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Genetic factors play an important part in the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus, a heterogeneous disorder characterised by defects in insulin action as well as insulin secretion [1]. Investigations of candidate genes for Type II diabetes have led to the identification of polymorphisms of several genes. Major genetic causes of this disease, however, remain elusive.Glucose-dependent sequestration of Ca 2+ into endoplasmic reticulum and its subsequent release play an important part in the control of intracellular Ca 2+ concentration, which regulates insulin secretion in pancreatic beta cells [2]. The active uptake of cytosolic Ca 2+ into endoplasmic reticulum is mediated by sarco(endo)plasmic reticulum Ca 2+ -transport ATPases (SERCAs) Abstract Aims/hypothesis. Type II (non-insulin-dependent) diabetes mellitus is a common heterogeneous metabolic disorder of largely unknown genetic aetiology. The sarco(endo)plasmic reticulum Ca 2+ -transport ATPase (SERCA) plays an important part in the glucose-activated beta-cell Ca 2+ signalling that regulates insulin secretion. Impaired function and expression of SERCA have been shown in islets of Langerhans from diabetic animal models and have also been associated with beta-cell apoptosis. Thus, the SERCA3 encoding gene is a plausible candidate for a primary pancreatic beta-cell defect. Methods. In this study, the entire coding and the promoter regions of SERCA3 gene were screened by single-strand conformation polymorphism analysis in white Caucasian Type II diabetic patients. Results. We found four rare missense mutations [Exon 4: Gln 108 ®His (CAG®CAT), Exon 14: Val 648 ®Met (GTG®ATG) and Arg 674 ®Cys (CGC® TGC), and Exon 15: Ile 753 ®Leu (ATC®CTC)]. The patients with Gln 108 ®His, Val 648 ®Met and Arg 674 ®Cys mutations, which may affect the E1P-E2P transition of SERCA3 during its enzyme cycle, had normal body weight with marked hyperglycaemia and beta-cell dysfunction. That is an unusual phenotype only found in 6 % of the Type II diabetic patients recruited for the UK Prospective Diabetes Study. In addition, five silent polymorphisms, six intron variants and two polymorphisms in the 3' untranslated region of exon 22 were found with similar frequency in diabetic and control subjects. Conclusion/interpretation. Our result suggests that in white Caucasians, the SERCA3 locus possibly contributes to the genetic susceptibility to Type II diabetes [Diabetologia (1999.

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Section: Discussionmentioning

confidence: 70%

“…It has been proposed that abnormalities in Ca 2+ signalling cause insulin resistance and impair insulin secretion and therefore possibly are a basic common pathology of Type II diabetes [7,8]. Aberrant SERCA function was responsible for impaired glucose responses and defective insulin secretion in db/db mouse [8].…”

mentioning

confidence: 99%

Sequence variants of the sarco(endo)plasmic reticulum Ca 2+ -transport ATPase 3 gene (SERCA3) in Caucasian Type II diabetic patients (UK Prospective Diabetes Study 48)

et al. 1999

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“…This concept has been developed in different cell systems derived fom target organs for the complications of diabetes [26,27]. Extensive evidence has been provided that mesangial cells of the kidney glomerulus grown in high glucose media express a secretory phenotype, with increased matrix production and a decreased proliferative rate [28][29][30][31].…”

Section: Discussionmentioning

confidence: 99%

High glucose level inhibits capacitative Ca 2 + influx in cultured rat mesangial cells by a protein kinase C-dependent mechanism

et al. 1997

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Diabetic glomerulopathy is a common long-term complication of insulin-dependent diabetes mellitus [1]. Hyperfiltration, resulting from a fall of afferent arteriolar resistances with increased glomerular capillary pressure, is an early sign of glomerular involvement [1,2]. Such haemodynamic changes are believed to result from reduced vascular sensitivity to vasoconstrictors [3]. Arteriolar relaxation could be explained by enhanced production of vasodilators, such as prostaglandins [4], or atrial natriuretic peptides [5]. Alternatively, reduced responsiveness of the contractile apparatus of the glomerulus should be considered [3,6]. Diabetologia (1997) Summary In cultured mesangial cells (MC), capacitative Ca 2 + influx via store-operated channels (SOC) is potentiated by agents that release Ca 2 + from intracellular stores, and inhibited by protein kinase C (PKC). Cells grown under high glucose conditions, as a model of the diabetic microenvironment, display reduced Ca 2 + signalling in response to vasoconstrictors, probably due to downregulation by elevated PKC activity. Since SOC might be relevant to this phenomenon, we assessed Ca 2 + influx by microfluorometry of fura-2-loaded rat MC cultured for 5 days in normal (5.5 mmol/l, NG) or high glucose (30 mmol/l, HG). The addition of 1-10 mmol/l Ca 2 + to NG cells equilibrated in Ca 2 + -free media induced an immediate Ca 2 + influx with a free cytosolic Ca 2 + ([Ca 2 + ] i ) plateau of 155 ± 50 and 318 ± 114 nmol/l, respectively. Basal influx was reduced to 88 ± 8 and 145 ± 17 nmol/l [Ca 2 + ]i (1-10 mmol/l Ca 2 + , p < 0.01) by 30 mmol/l d -glucose. This effect of HG was confirmed by Mn 2 + quenching of fura-2, indicating reduced entry of divalent cations via the capacitative pathway. Equimolar l -glucose had no effect on Ca 2 + influx, consistent with a non-osmotic mechanism.Arginine vasopressin (10 m mol/l) elicited weaker release of stored Ca 2 + and subsequent influx in HG cells (191 ± 33 vs 153 ± 24 nmol/l, 400 ± 76 vs 260 ± 33 nmol/l, 1-10 mmol/l Ca 2 + , NG/HG, p < 0.05). To examine the involvement of PKC in the effect of HG on capacitative Ca 2 + influx, the enzyme was activated or downregulated by treatment with 0.1 m mol/l phorbol myristate acetate (PMA) for 3 min or 24 h, respectively. PMA acutely inhibited Ca 2 + influx in NG cells, while PKC downregulation restored it in HG cells. Similarly, the PKC inhibitors staurosporin or H-7 normalized SOC activity in HG cells. In summary, impairment of Ca 2 + influx via SOC by HG is one mechanism of the reduced MC [Ca 2 + ] i responsiveness to vasoconstrictors. This event is mediated by PKC and may contribute to the glomerular haemodynamic changes in the initial stages of diabetes mellitus. [Diabetologia (1997) 40: 521-527]

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“…Rising intracellular Ca 2ϩ ([Ca 2ϩ ] i ) is an obligated step for glucose induced insulin secretion (1,23). Abnormal [Ca 2ϩ ] i is a common defect in both insulin-dependent type 1 diabetes and insulinindependent type 2 diabetes (24). Altered Ca 2ϩ metabolism has also been reported to affect ␤-cell function including insulin biosynthesis (25,26).…”

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confidence: 99%

Insulin Receptor Substrate 1-induced Inhibition of Endoplasmic Reticulum Ca2+ Uptake in β-Cells

Gao

Borge

et al. 1999

Journal of Biological Chemistry

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To understand the role of the insulin receptor pathway in ␤-cell function, we have generated stable ␤-cells (␤IRS1-A) that overexpress by 2-fold the insulin receptor substrate-1 (IRS-1) and compared them to vector-expressing controls. IRS-1 overexpression dramatically increased basal cytosolic Ca 2؉ levels from 81 to 278 nM, but it did not affect Ca 2؉ response to glucose. Overexpression of the insulin receptor also caused an increase in cytosolic Ca 2؉ . Increased cytosolic Ca 2؉ was due to inhibition of Ca 2؉ uptake by the endoplasmic reticulum, because endoplasmic reticulum Ca 2؉ uptake and content were reduced in ␤IRS1-A cells. Fractional insulin secretion was significantly increased 2-fold, and there was a decrease in ␤IRS1-A insulin content and insulin biosynthesis. Steady-state insulin mRNA levels and glucose-stimulated ATP were unchanged. High IRS-1 levels also reduced ␤-cell proliferation. These data demonstrate a direct link between the insulin receptor signaling pathway and the Ca 2؉ -dependent pathways regulating insulin secretion of ␤-cells. We postulate that during regulated insulin secretion, released insulin binds the ␤-cell insulin receptor and activates IRS-1, thus further increasing cytosolic Ca 2؉ by reducing Ca 2؉ uptake. We suggest the existence of a novel pathway of autocrine regulation of intracellular Ca 2؉ homeostasis and insulin secretion in the ␤-cell of the endocrine pancreas.

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Diabetes mellitus: A disease of abnormal cellular calcium metabolism?

Cited by 221 publications

References 122 publications

Sequence variants of the sarco(endo)plasmic reticulum Ca 2+ -transport ATPase 3 gene (SERCA3) in Caucasian Type II diabetic patients (UK Prospective Diabetes Study 48)

Sequence variants of the sarco(endo)plasmic reticulum Ca 2+ -transport ATPase 3 gene (SERCA3) in Caucasian Type II diabetic patients (UK Prospective Diabetes Study 48)

High glucose level inhibits capacitative Ca 2 + influx in cultured rat mesangial cells by a protein kinase C-dependent mechanism

Insulin Receptor Substrate 1-induced Inhibition of Endoplasmic Reticulum Ca2+ Uptake in β-Cells

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