Diabetes mellitus is a bihormonal disorder with hyperglycemia due to deficiency of insulin and hypersecretion of glucagon. To improve diabetes treatment it is important to clarify the signal transduction of glucagon secretion. The cytoplasmic Ca2+ concentration ([Ca2+]i), an important determinant of hormone secretion, and the membrane potential were recorded in individual mouse α-cells. Glucagon and insulin secretion were measured from mouse islets and glucagon secretion from hamster glucagonoma cells. Glucose inhibited glucagon secretion from islets and glucagonoma cells with maximal effect at 7 mM, indicating a direct action on the α-cells. High concentrations of glucose paradoxically stimulated glucagon secretion. Whereas glucose inhibition of glucagon release was associated with lowering of [Ca2+]i, stimulation of secretion at high glucose concentrations was Ca2+-independent. Adrenaline, which is a potent stimulator of glucagon secretion, increased [Ca2+]i by α1- and β-adrenergic mechanisms involving mobilization of intracellular Ca2+ from the endoplasmic reticulum (ER) and influx of the ion across the plasma membrane. Ca2+ mobilization could be attributed to generation of inositol 1,4,5-trisphosphate and cAMP, and influx occurred through voltage-dependent L-type channels activated by a depolarizing store-operated current. Glucose hyperpolarized the α-cells and inhibited adrenaline-induced [Ca2+]i signalling. At 3 mM, glucose had a pronounced stimulatory effect on Ca2+ sequestration in the ER, shutting off store-operated Ca2+ influx. The α-cells express ATP-regulated K+ channels but pharmacological blockade of these channels neither interfered with the hyperpolarizing and [Ca2+]i lowering effects of glucose nor with the inhibition of glucagon secretion. In contrast, activation of the depolarizing store-operated mechanism prevented glucose-induced, hyperpolarization, lowering of [Ca2+]i and inhibition of glucagon secretion. It is proposed that adrenaline stimulation and glucose inhibition of glucagon release involve modulation of a store-operated depolarizing current. The U-shaped dose response relationship for glucose-regulated glucagon secretion may explain the hyperglucagonemia in diabetes.
| Identifer | oai:union.ndltd.org:UPSALLA1/oai:DiVA.org:uu-6319 |
| Date | January 2006 |
| Creators | Vieira, Elaine |
| Publisher | Uppsala universitet, Institutionen för medicinsk cellbiologi, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, info:eu-repo/semantics/doctoralThesis, text |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1651-6206 ; 103 |
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