Regulation of Glucagon Secretion in Normal and Diabetic Human Islets by Gamma-Hydroxybutyrate and Glycine.

The Children's Hospital of Philadelphia, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2012; 288(6). DOI: 10.1074/jbc.M112.385682
Source: PubMed

ABSTRACT Paracrine signaling between pancreatic islet β-cells and α-cells has been proposed to play a role in regulating glucagon responses
to elevated glucose and hypoglycemia. To examine this possibility in human islets, we used a metabolomic approach to trace
the responses of amino acids and other potential neurotransmitters to stimulation with [U-13C]glucose in both normal individuals and type 2 diabetics. Islets from type 2 diabetics uniformly showed decreased glucose
stimulation of insulin secretion and respiratory rate but demonstrated two different patterns of glucagon responses to glucose:
one group responded normally to suppression of glucagon by glucose, but the second group was non-responsive. The non-responsive
group showed evidence of suppressed islet GABA levels and of GABA shunt activity. In further studies with normal human islets,
we found that γ-hydroxybutyrate (GHB), a potent inhibitory neurotransmitter, is generated in β-cells by an extension of the
GABA shunt during glucose stimulation and interacts with α-cell GHB receptors, thus mediating the suppressive effect of glucose
on glucagon release. We also identified glycine, acting via α-cell glycine receptors, as the predominant amino acid stimulator
of glucagon release. The results suggest that glycine and GHB provide a counterbalancing receptor-based mechanism for controlling
α-cell secretory responses to metabolic fuels.

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Available from: Jie Chen, Dec 05, 2014
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    • "from T2D organ donors (Figure 7A); the remaining preparations exhibited normal glucose regulation. Thus, T2D islets are heterogeneous with respect to the dysregulation of glucagon secretion, in agreement with a recent report (Li et al., 2013). Intriguingly, the inverted response to glucose seen in some T2D islet preparations can be mimicked in ND islets by a small increase (0.5%) in K ATP -channel activity produced by diazoxide (Figure 7B). "
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    ABSTRACT: Glucagon, secreted by pancreatic islet α cells, is the principal hyperglycemic hormone. In diabetes, glucagon secretion is not suppressed at high glucose, exacerbating the consequences of insufficient insulin secretion, and is inadequate at low glucose, potentially leading to fatal hypoglycemia. The causal mechanisms remain unknown. Here we show that α cell KATP-channel activity is very low under hypoglycemic conditions and that hyperglycemia, via elevated intracellular ATP/ADP, leads to complete inhibition. This produces membrane depolarization and voltage-dependent inactivation of the Na(+) channels involved in action potential firing that, via reduced action potential height and Ca(2+) entry, suppresses glucagon secretion. Maneuvers that increase KATP channel activity, such as metabolic inhibition, mimic the glucagon secretory defects associated with diabetes. Low concentrations of the KATP channel blocker tolbutamide partially restore glucose-regulated glucagon secretion in islets from type 2 diabetic organ donors. These data suggest that impaired metabolic control of the KATP channels underlies the defective glucose regulation of glucagon secretion in type 2 diabetes.
    Cell metabolism 12/2013; 18(6):871-82. DOI:10.1016/j.cmet.2013.10.014 · 17.57 Impact Factor
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    ABSTRACT: The pancreatic islet β cell senses circulating levels of calorigenic nutrients to secrete insulin according to the needs of the organism. Altered insulin secretion is linked to various disorders such as diabetes, hypoglycemic states, and cardiometabolic diseases. Fuel stimuli, including glucose, free fatty acids, and amino acids, promote insulin granule exocytosis primarily via their metabolism in β cells and the production of key signaling metabolites. This paper reviews our current knowledge of the pathways involved in both positive and negative metabolic signaling for insulin secretion and assesses the role of established and candidate metabolic coupling factors, keeping recent developments in focus.
    Cell metabolism 06/2013; 18(2). DOI:10.1016/j.cmet.2013.05.018 · 17.57 Impact Factor
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    ABSTRACT: ATP-sensitive potassium channels (KATP channels) link cell metabolism to electrical activity by controlling the cell membrane potential. They participate in many physiological processes but have a particularly important role in systemic glucose homeostasis by regulating hormone secretion from pancreatic islet cells. Glucose-induced closure of KATP channels is crucial for insulin secretion. Emerging data suggest that KATP channels also play a key part in glucagon secretion, although precisely how they do so remains controversial. This Review highlights the role of KATP channels in insulin and glucagon secretion. We discuss how KATP channels might contribute not only to the initiation of insulin release but also to the graded stimulation of insulin secretion that occurs with increasing glucose concentrations. The various hypotheses concerning the role of KATP channels in glucagon release are also reviewed. Furthermore, we illustrate how mutations in KATP channel genes can cause hyposecretion or hypersecretion of insulin, as in neonatal diabetes mellitus and congenital hyperinsulinism, and how defective metabolic regulation of the channel may underlie the hypoinsulinaemia and the hyperglucagonaemia that characterize type 2 diabetes mellitus. Finally, we outline how sulphonylureas, which inhibit KATP channels, stimulate insulin secretion in patients with neonatal diabetes mellitus or type 2 diabetes mellitus, and suggest their potential use to target the glucagon secretory defects found in diabetes mellitus.
    Nature Reviews Endocrinology 09/2013; 9(11). DOI:10.1038/nrendo.2013.166 · 13.28 Impact Factor
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