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

Li, Changhong; Liu, Chengyang; Nissim, Itzhak; Chen, Jie; Chen, Pan; Doliba, Nicolai M.; Zhang, Tingting; Nissim, Ilana; Daikhin, Yevgeny; Stokes, David; Yudkoff, Marc; Bennett, Michael J.; Stanley, Charles A.; Matschinsky, Franz M.; Naji, Ali

doi:10.1074/jbc.m112.385682

Cited by 90 publications

(107 citation statements)

References 62 publications

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“…This has been attributed in part to declined intraislet insulin (21), decreased intraislet GABA levels (22), and/or reduced GABA receptor signaling (23). These reports are consistent with clinical observations that T2D patients have exaggerated glucagon responses under glucagon stimulatory conditions (24).…”

Section: Discussionsupporting

confidence: 79%

GABA Promotes Human β-Cell Proliferation and Modulates Glucose Homeostasis

et al. 2014

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γ-Aminobutyric acid (GABA) exerts protective and regenerative effects on mouse islet β-cells. However, in humans it is unknown whether it can increase β-cell mass and improve glucose homeostasis. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-γ mice with streptozotocin-induced diabetes. GABA treatment increased grafted β-cell proliferation, while decreasing apoptosis, leading to enhanced β-cell mass. This was associated with increased circulating human insulin and reduced glucagon levels. Importantly, GABA administration lowered blood glucose levels and improved glucose excursion rates. We investigated GABA receptor expression and signaling mechanisms. In human islets, GABA activated a calcium-dependent signaling pathway through both GABA A receptor and GABA B receptor. This activated the phosphatidylinositol 3-kinase–Akt and CREB–IRS-2 signaling pathways that convey GABA signals responsible for β-cell proliferation and survival. Our findings suggest that GABA regulates human β-cell mass and may be beneficial for the treatment of diabetes or improvement of islet transplantation.

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Section: Discussionsupporting

confidence: 79%

GABA Promotes Human β-Cell Proliferation and Modulates Glucose Homeostasis

et al. 2014

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“…GlyR in human islets is recently reported to be expressed specifically in a-cells but not b-cells (35), supported by the finding that glycine stimulated glucagon but not insulin secretion from human islets. However, the experiments were performed in the absence of glucose, which leads to the activation of unphysiologically large K ATP currents in b-cells and may prevent any glycine effect on the membrane potential.…”

Section: Discussionsupporting

confidence: 54%

“…However, the experiments were performed in the absence of glucose, which leads to the activation of unphysiologically large K ATP currents in b-cells and may prevent any glycine effect on the membrane potential. Li et al (35) observed [Ca 2+ ] i responses upon glycine application in a subset of dispersed islet cells, but an unequivocal identification of the cell types was not performed. Our data clearly demonstrate that among human islet cells, GlyR and glycine-activated Cl -currents are most active in b-cells.…”

Section: Discussionmentioning

confidence: 99%

A Glycine-Insulin Autocrine Feedback Loop Enhances Insulin Secretion From Human β-Cells and Is Impaired in Type 2 Diabetes

et al. 2016

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The secretion of insulin from pancreatic islet β-cells is critical for glucose homeostasis. Disrupted insulin secretion underlies almost all forms of diabetes, including the most common form, type 2 diabetes (T2D). The control of insulin secretion is complex and affected by circulating nutrients, neuronal inputs, and local signaling. In the current study, we examined the contribution of glycine, an amino acid and neurotransmitter that activates ligand-gated Cl− currents, to insulin secretion from islets of human donors with and without T2D. We find that human islet β-cells express glycine receptors (GlyR), notably the GlyRα1 subunit, and the glycine transporter (GlyT) isoforms GlyT1 and GlyT2. β-Cells exhibit significant glycine-induced Cl− currents that promote membrane depolarization, Ca2+ entry, and insulin secretion from β-cells from donors without T2D. However, GlyRα1 expression and glycine-induced currents are reduced in β-cells from donors with T2D. Glycine is actively cleared by the GlyT expressed within β-cells, which store and release glycine that acts in an autocrine manner. Finally, a significant positive relationship exists between insulin and GlyR, because insulin enhances the glycine-activated current in a phosphoinositide 3-kinase–dependent manner, a positive feedback loop that we find is completely lost in β-cells from donors with T2D.

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“…Triglycerides (TG) or free fatty acids in plasma or tissues were assayed with the Infinity TM triglyceride reagent kit or Biovision kit, respectively. Plasma insulin, glucagon (31), leptin, and adiponectin were determined using ELISA kits. Tissue protein was determined by Coomassie Blue (Thermo Scientific).…”

Section: Lc/ms/ms Gc-ms and Nmrmentioning

confidence: 99%

The Molecular and Metabolic Influence of Long Term Agmatine Consumption

Nissim

Horyn

Daikhin

et al. 2014

Journal of Biological Chemistry

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Background:Little is known about the molecular and metabolic impact of agmatine consumption. Results: We scrutinized the impact of long term agmatine treatment on whole body metabolic profiling and gene expression in rats. Agmatine elevated [cAMP] and triggered widespread changes in gene expression and metabolomic profiling. Conclusion: Agmatine influences on metabolism may be mediated via cAMP-PKA. Significance: Agmatine may curtail the metabolic and hormonal derangements associated with obesity.

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

Cited by 90 publications

References 62 publications

GABA Promotes Human β-Cell Proliferation and Modulates Glucose Homeostasis

GABA Promotes Human β-Cell Proliferation and Modulates Glucose Homeostasis

A Glycine-Insulin Autocrine Feedback Loop Enhances Insulin Secretion From Human β-Cells and Is Impaired in Type 2 Diabetes

The Molecular and Metabolic Influence of Long Term Agmatine Consumption

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