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

Amino acids, neurotransmitters and hormones can stimulate electrical activity and insulin release in human β-cells only in the presence of a permissive concentration of glucose.

“Amino acids (arginine and glycine)(744), neurotransmitters (like adenine nucleotides, GABA and acetylcholine) (89, 92, 347, 568) and hormones (618) can also stimulate electrical activity and insulin release but only in the presence of a ‘permissive’ concentration of glucose.”

These glycine receptor currents become detectable at ~30 μM, are half-maximal at 100 μM, and are maximal between 0.3-1 mM glycine.

“These become detectable at ~30 μM, are half-maximal at 100 μM, and are maximal between 0.3-1 mM glycine.”

Activation of GlyR Cl- channels results in membrane depolarization because of high intracellular Cl- and thereby increases action potential firing in human β-cells exposed to 6 mM glucose.

“Activation of GlyR Cl- channels results in membrane depolarization because of the high intracellular Cl- (see Section VII.C.4) and thereby increases action potential firing in human β-cells exposed to 6 mM glucose (744).”

Glycine is stored within secretory granules and coreleased with insulin from β-cells.

“Glycine is stored within the secretory granules and coreleased with insulin from β-cells, providing a mechanism for autocrine stimulation of insulin secretion similar to that observed for GABA(744).”

In human β-cells, activation of glycine receptors gives rise to sustained inward Cl- currents with an amplitude of 20-25 pA/pF.

“In human β-cells, activation of glycine receptors gives rise to sustained inward Cl- currents with an amplitude of 20-25 pA/pF(744).”

Expression of glycine receptor α-subunits in mouse β-cells is very low, in agreement with small amplitude of glycine-activated Cl-currents in mouse β-cells.

“Expression of glycine receptor α-subunits in mouse β-cells is very low, in agreement with the small amplitude of glycine-activated Cl-currents in mouse β-cells (744).”

β-cells have been genetically engineered for detection of ATP, GABA or glycine release by adenoviral infection with ATP-activated P2X2 receptors, GABAA receptors or glycine receptors.

“For example, β-cells have been genetically engineered for detection of ATP, GABA or glycine release by adenoviral infection with ATP-activated P2X2 receptors (P2X2R) (484), GABAA receptors (GABAAR) (93) or glycine receptors (GlyR) (744).”