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Objective: We studied how glucose and ATP-sensitive K(+) (K(ATP)) channel modulators affect alpha-cell [Ca(2+)](c).Research Design and Methods: GYY mice (expressing enhanced yellow fluorescent protein in alpha-cells) and NMRI mice were used. [Ca(2+)](c), the K(ATP) current (I(KATP), perforated mode) and cell metabolism [NAD(P)H fluorescence] were monitored in single alpha-cells and, for comparison, in single beta-cells.Results: In 0.5 mmol/l glucose, [Ca(2+)](c) oscillated in some alpha-cells and was basal in the others. Increasing glucose to 15 mmol/l decreased [Ca(2+)](c) by approximately 30% in oscillating cells and was ineffective in the others. alpha-Cell I(KATP) was inhibited by tolbutamide and activated by diazoxide or the mitochondrial poison azide, as in beta-cells. Tolbutamide increased alpha-cell [Ca(2+)](c), whereas diazoxide and azide abolished [Ca(2+)](c) oscillations. Increasing glucose from 0.5 to 15 mmol/l did not change I(KATP) and NAD(P)H fluorescence in alpha-cells in contrast to beta-cells. The use of nimodipine showed that L-type Ca(2+) channels are the main conduits for Ca(2+) influx in alpha-cells. gamma-Aminobutyric acid and zinc did not decrease alpha-cell [Ca(2+)](c), and insulin, although lowering [Ca(2+)](c) very modestly, did not affect glucagon secretion.Conclusions: alpha-Cells display similarities with beta-cells: K(ATP) channels control Ca(2+) influx mainly through L-type Ca(2+) channels. However, alpha-cells have distinct features from beta-cells: Most K(ATP) channels are already closed at low glucose, glucose does not affect cell metabolism and I(KATP), and it slightly decreases [Ca(2+)](c). Hence, glucose and K(ATP) channel modulators exert distinct effects on alpha-cell [Ca(2+)](c). The direct small glucose-induced drop in alpha-cell [Ca(2+)](c) contributes likely only partly to the strong glucose-induced inhibition of glucagon secretion in islets. [ABSTRACT FROM AUTHOR]

OBJECTIVE--We studied how glucose and ATP-sensitive K+ (KATP) channel modulators affect α-cell [Ca2+]c. RESEARCH DESIGN AND METHODS--GYY mice (expressing enhanced yellow fluorescent protein in α-cells) and NMRI mice were used. [Ca2+]c, the KATP current (IKATP, perforated mode) and cell metabolism [NAD(P)H fluorescence] were monitored in single α-cells and, for comparison, in single β-cells. RESULTS--In 0.5 mmol/l glucose, [Ca2+]c oscillated in some α-cells and was basal in the others. Increasing glucose to 15 mmol/l decreased [Ca2+]c by ∼30% in oscillating cells and was ineffective in the others, α-Cell IKATP Was inhibited by tolbutamide and activated by diazoxide or the mitochondrial poison azide, as in β-cells. Tolbutamide increased α-cell [Ca2+]c, whereas diazoxide and azide abolished [Ca2+]c oscillations. Increasing glucose from 0.5 to 15 mmol/l did not change IKATP and NAD(P)H fluorescence in n-cells in contrast to β-cells. The use of nimodipine showed that L-type Ca2+ channels are the main conduits for Ca[sup 2+] influx in α-cells. γ-Aminobutyric acid and zinc did not decrease α-cell [Ca2+]c, and insulin, although lowering [Ca2+]c very modestly, did not affect glucagon secretion. CONCLUSIONS--α-Cells display similarities with β-cells: KATP channels control Ca2+ influx mainly through L-type Ca2+ channels. However, α-cells have distinct features from β-cells: Most KATP channels are already closed at low glucose, glucose does not affect cell metabolism and IKATP, and it slightly decreases [Ca2+]c. Hence, glucose and KATP channel modulators exert distinct effects on α-cell [Ca2+]c. The direct small glucose-induced drop in α-cell [Ca2+]c contributes likely only partly to the strong glucose-induced inhibition of glucagon secretion in islets. Diabetes 58:412-421, 2009 [ABSTRACT FROM AUTHOR]

Congenital hyperinsulinism of infancy (CHI) is characterized by severe hypoglycemia due to dysregulated insulin secretion, associated with either focal or diffuse pathology of the endocrine pancreas. The focal condition is caused by a paternally inherited mutation in one of the genes encoding the subunits of the β-cell ATP-sensitive potassium channel (SUR1/ABCC8 or Kir6.2/KCNJ11) and somatic loss of maternal 11p15 alleles within the affected area. Until now, preoperative diagnostics have relied on technically demanding and invasive catheterization techniques. We evaluated the utility of fluorine-18 L-3,4-dihydroxyphenylalanine ([18F]-DOPA) positron emission tomography (PET) to identify focal pancreatic lesions in 14 CHI patients, 11 of which carried mutations in the ABCC8 gene (age 1-42 months). To reduce bias in PET image interpretation, quantitative means for evaluation Of pancreatic [18SF]-DOPA uptake were established. Five patients had a visually apparent focal accumulation of [18F]-DOPA and standardized uptake value (SUV) >50% higher (mean 1.8-fold) than the maximum SUV of the unaffected part of the pancreas. When these patients were operated on, a focus of 4-5 x 5-8 mm matching with the PET scan was found, and all were normoglycemic after resection of the focus. The remaining nine patients had diffuse accumulation of [18F]-DOPA in the pancreas (SUV ratio < 1.5). Diffuse histology was verified in four of these, and pancreatic catheterization was consistent with diffuse pathology in four cases. In conclusion, [18F]-DOPA PET is a promising noninvasive method for the identification and localization of the focal form of CHI. [ABSTRACT FROM AUTHOR]

Two sarcoendoplasmic reticulum Ca(2+)-ATPases, SERCA3 and SERCA2b, are expressed in pancreatic islets. Immunocytochemistry showed that SERCA3 is restricted to beta-cells in the mouse pancreas. Control and SERCA3-deficient mice were used to evaluate the role of SERCA3 in beta-cell cytosolic-free Ca(2+) concentration ([Ca(2+)](c)) regulation, insulin secretion, and glucose homeostasis. Basal [Ca(2+)](c) was not increased by SERCA3 ablation. Stimulation with glucose induced a transient drop in basal [Ca(2+)](c) that was suppressed by inhibition of all SERCAs with thapsigargin (TG) but unaffected by selective SERCA3 ablation. Ca(2+) mobilization by acetylcholine was normal in SERCA3-deficient beta-cells. In contrast, [Ca(2+)](c) oscillations resulting from intermittent glucose-stimulated Ca(2+) influx and [Ca(2+)](c) transients induced by pulses of high K(+) were similarly affected by SERCA3 ablation or TG pretreatment of control islets; their amplitude was increased and their slow descending phase suppressed. This suggests that, during the decay of each oscillation, the endoplasmic reticulum releases Ca(2+) that was pumped by SERCA3 during the upstroke phase. SERCA3 ablation increased the insulin response of islets to 15 mmol/l glucose. However, basal and postprandial plasma glucose and insulin concentrations in SERCA3-deficient mice were normal. In conclusion, SERCA2b, but not SERCA3, is involved in basal [Ca(2+)](c) regulation in beta-cells. SERCA3 becomes operative when [Ca(2+)](c) rises and is required for normal [Ca(2+)](c) oscillations in response to glucose. However, a lack of SERCA3 is insufficient in itself to alter glucose homeostasis or impair insulin secretion in mice. [ABSTRACT FROM AUTHOR]

Quantifies total pancreatic beta-cell mass in diabetic patients in relation to obesity and treatment. Influence of insulin resistance and beta cell defect on type 2 diabetes; Evaluation of relative insulin content; Result of the abnormal coupling of insulin secretion to glycemia.