Glucagon and diabetes: A reappraisal

Lefèbvre, Pierre; Luyckx, A

doi:10.1007/bf01223153

Cited by 67 publications

(34 citation statements)

References 74 publications

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“…In this context it is also worthy of note that release of somatostatin, which normally inhibits glucagon secretion, is impaired in diabetic subjects (48). Collectively, these considerations reinforce the notion that type 2 diabetes is best characterized as a bihormonal (49) or even trihormonal disorder. We acknowledge that so far we have only explored the effects of palmitate during short-term exposure.…”

Section: Discussionsupporting

confidence: 51%

Palmitate Stimulation of Glucagon Secretion in Mouse Pancreatic α-Cells Results From Activation of l-Type Calcium Channels and Elevation of Cytoplasmic Calcium

et al. 2004

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We have investigated the short-term effects of the saturated free fatty acid (FFA) palmitate on pancreatic ␣-cells. Palmitate (0.5 or 1 mmol/l bound to fatty acidfree albumin) stimulated glucagon secretion from intact mouse islets 1.5-to 2-fold when added in the presence of 1-15 mmol/l glucose. Palmitate remained stimulatory in islets depolarized with 30 mmol/l extracellular K ؉ or exposed to forskolin, but it did not remain stimulatory after treatment with isradipine or triacsin C. The stimulatory action of palmitate on secretion correlated with a 3.5-fold elevation of intracellular free Ca 2؉ when applied in the presence of 15 mmol/l glucose, a 40% stimulation of exocytosis (measured as increases in cell capacitance), and a 25% increase in whole-cell Ca 2؉ current. The latter effect was abolished by isradipine, suggesting that palmitate selectively modulates L-type Ca 2؉ channels. The effect of palmitate on exocytosis was not mediated by palmitoyl-CoA, and intracellular application of this FFA metabolite decreased rather than enhanced Ca 2؉ -induced exocytosis. The stimulatory effects of palmitate on glucagon secretion were paralleled by a ϳ50% inhibition of somatostatin release. We conclude that palmitate increases ␣-cell exocytosis principally by enhanced Ca 2؉ entry via L-type Ca 2؉ channels and, possibly, relief from paracrine inhibition by somatostatin released by neighboring ␦-cells.

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Section: Discussionsupporting

confidence: 51%

Palmitate Stimulation of Glucagon Secretion in Mouse Pancreatic α-Cells Results From Activation of l-Type Calcium Channels and Elevation of Cytoplasmic Calcium

et al. 2004

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“…These effects correlated with the presence of a small (0.13 nS) sulfonylurea-sensitive conductance in wild-type but not in SUR1 ؊/؊ ␣-cells. T he metabolic derangements associated with type 2 diabetes result from the combination of insulin deficiency and glucagon excess (1,2). Type 2 diabetes is associated with serious abnormalities of glucagon secretion.…”

mentioning

confidence: 99%

ATP-Sensitive K+ Channel–Dependent Regulation of Glucagon Release and Electrical Activity by Glucose in Wild-Type and SUR1−/− Mouse α-Cells

Ma²,

et al. 2004

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Patch-clamp recordings and glucagon release measurements were combined to determine the role of plasma membrane ATP-sensitive K ؉ channels (K ATP channels) in the control of glucagon secretion from mouse pancreatic ␣-cells. In wild-type mouse islets, glucose produced a concentration-dependent (half-maximal inhibitory concentration [IC 50 ] ‫؍‬ 2.5 mmol/l) reduction of glucagon release. Maximum inhibition (ϳ50%) was attained at glucose concentrations >5 mmol/l. The sulfonylureas tolbutamide (100 mol/l) and glibenclamide (100 nmol/l) inhibited glucagon secretion to the same extent as a maximally inhibitory concentration of glucose. In mice lacking functional K ATP channels (SUR1 ؊/؊ ), glucagon secretion in the absence of glucose was lower than that observed in wild-type islets and both glucose (0 -20 mmol/l) and the sulfonylureas failed to inhibit glucagon secretion. Membrane potential recordings revealed that ␣-cells generate action potentials in the absence of glucose. Addition of glucose depolarized the ␣-cell by ϳ7 mV and reduced spike height by 30% Application of tolbutamide likewise depolarized the ␣-cell (ϳ17 mV) and reduced action potential amplitude (43%). Whereas insulin secretion increased monotonically with increasing external K ؉ concentrations (threshold 25 mmol/l), glucagon secretion was paradoxically suppressed at intermediate concentrations (5.6 -15 mmol/l), and stimulation was first detectable at >25 mmol/l K ؉ . In ␣-cells isolated from SUR1 ؊/؊ mice, both tolbutamide and glucose failed to produce membrane depolarization. These effects correlated with the presence of a small (0.13 nS) sulfonylurea-sensitive conductance in wild-type but not in SUR1

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“…In vitro studies have shown that glucagon increases the mobilization of glucose, free fatty acids, and ketone bodies, which are metabolites produced in excess in diabetes mellitus (24). For these reasons, interest has focused on the biosynthesis of glucagon and related peptides.…”

mentioning

confidence: 99%

Mammalian pancreatic preproglucagon contains three glucagon-related peptides.

Lopez¹,

Frazier²,

Su³

et al. 1983

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

202

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We have isolated cDNA clones encoding bovine pancreatic preproglucagon. Twenty-five putative preproglucagon clones were selected by screening 3,100 clones of a fetal bovine pancreas cDNA library with a synthetic oligodeoxynucleotide probe. The probe was a mixture of synthetic 17-base DNA oligomers constructed to correspond to the six carboxyl-terminal amino acids (residues 24-29) of mature glucagon. Restriction mapping of six of these clones suggested that they represented a single mRNA species. Primary sequence analysis of one clone containing a 1,200-base-pair DNA insert revealed that it contained an essentially fulllength copy of glucagon mRNA. Analysis of the cDNA suggested a protein coding sequence of 540 nucleotides and 5'-and 3'-untranslated regions of 90 and 471 nucleotides, respectively. This cDNA sequence encoded a 20-amino acid signal sequence followed by one for glicentin, a 69-amino acid polypeptide containing an internal glucagon moiety that has been found in porcine intestines. Glicentin is followed by two additional glucagon-like peptides, each flanked by paired basic amino acids (Lys, Arg) characteristic of prohormone processing. These polypeptide sequences show striking homology with those for glucagon and other members of the glucagon family of peptides.

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Glucagon and diabetes: A reappraisal

Cited by 67 publications

References 74 publications

Palmitate Stimulation of Glucagon Secretion in Mouse Pancreatic α-Cells Results From Activation of l-Type Calcium Channels and Elevation of Cytoplasmic Calcium

Palmitate Stimulation of Glucagon Secretion in Mouse Pancreatic α-Cells Results From Activation of l-Type Calcium Channels and Elevation of Cytoplasmic Calcium

ATP-Sensitive K+ Channel–Dependent Regulation of Glucagon Release and Electrical Activity by Glucose in Wild-Type and SUR1−/− Mouse α-Cells

Mammalian pancreatic preproglucagon contains three glucagon-related peptides.

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