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


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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