IV- Modulation of β-cell function by secretory products

1. Autoregulation of insulin secretion

Insulin release from β cells is directly controlled by the blood glucose level and modulated by the autonomous nervous system and autocrine and paracrine regulations. The latter is facilitated by the architecture of human islets, with non–β cells distributed throughout the islet, rather than confined to the islet periphery as in rodents.
■ γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter contained in insulin secretory granules. It is thus released from β cells upon glucose stimulation by Ca2+- dependent exocytosis, but also via a nonvesicular and glucose-independent pathway. GABA stimulates insulin secretion and inhibits glucagon secretion in rodent islets by activating ligand-gated Cl- channel GABAA receptors (GABAAR) in α cells. However, through G-protein coupled GABAB receptors (GABABR), GABA inhibits GIIS in rodents and human. Braun and colleagues showed that in human islets, GABA stimulates β-cell insulin secretion by activating GABAAR and that glucose stimulates vesicular release of GABA from β cells. This suggests that signaling via GABA and GABAAR stimulates insulin secretion by a positive autocrine feedback loop in human β cells. Moreover, the presence of GABAAR in non–β cells suggests that GABA may also be involved in the regulation of somatostatin and glucagon secretion.28
■ ATP is released by β cells upon glucose stimulation and Ca2+-dependent exocytosis, with IAPP and serotonin. Interestingly, through its binding on P2X3 receptor, a ligand-gated, nonselective cation-conducting channel, extracellular ATP was shown to stimulate membrane depolarization and GIIS in human islets in a positive feedback pathway.29
■ Zinc is co-released with insulin during exocytosis and was reported as a paracrine inhibitor of glucagon secretion by α cells through a KATP channel–dependent mechanism. Polymorphisms of the zinc efflux transporter ZnT8 gene were shown to increase the risk of T2D in human. Moreover, mice with a β-cell–specific ZnT8 deletion are glucose intolerant and have reduced GIIS and insulin-processing enzyme transcripts and increased proinsulin levels, suggesting that ZnT-8 is absolutely essential for proper β-cell function. In contrast, mice with α-cell–specific ZnT8 deletion show no evident abnormalities in plasma glucagon and glucose homeostasis (Matthias Braun, Lecture).30

2. Insulin positive feedback on -cell function and effects of intensified insulin treatment in T2D

The role of insulin in β-cell insulin secretion in human was long unclear because of the difficulty to distinguish between the role of endogenous and exogenous infused insulin. However, an isoglycemic-hyperinsulinemic clamp procedure using B28-Aspinsulin (which can be distinguished immunologically from endogenous insulin) was recently used to show that insulin does enhance GIIS in healthy humans. Indeed, preexposure to exogenous insulin increased the C-peptide response and the endogenous insulin secretory response to glucose by approximately 40%.31 This effect of insulin was reported to be independent of FFA concentrations in healthy humans32 and was attenuated in insulin-resistant subjects. This is consistent with an effect of insulin to regulate β-cell function in humans in vivo and has glucose-lowering therapeutic implications (Allison Goldfine, Lecture).33 Indeed, antidiabetic medication for T2D treatment acts to prevent the deleterious effects of hyperglycemia, but the medication’s ability to preserve β-cell function may be insufficient,34 and insulin therapy is often ultimately prescribed. However, the use of short-term intensive insulin therapy (IIT) early in the course of T2D—when sufficient β-cell mass remains to enable functional improvement—has emerged as a therapeutic option that may offer favorable long-term effects on β-cell function. IIT is defined as delivering frequent or continuous doses of insulin that are intended to achieve tight glycemic control, which is currently defined as blood glucose levels no more than 150 mg/dL. IIT was shown to induce euglycemia in subjects with newly-diagnosed diabetes, which was maintained during 2 years or more in some patients. Indeed, IIT was shown to partially restore first-phase insulin secretion and improve scores for the Homeostasis Model Assessment of β-cell function (HOMA-B) and the fasting proinsulin/insulin ratio. Interestingly, IIT resulted in significant improvement in quality of life and treatment satisfaction, demonstrating patient acceptability of early insulin therapy (Bernard Zinman, Lecture).35

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The hyperstimulated β cell: prelude to diabetes?
I- What is the role of epigenetics in insulin gene expression and insulin secretion and action
II- Impact of insulin resistance on β-cell function
III- Intrinsic hyperstimulation of β-cells
IV- Modulation of β-cell function by secretory products
V- Conclusion
Lectures during IGIS meeting