Editors' ChoiceType 1 Diabetes

Proliferation and Protection of Pancreatic β Cells

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Science Translational Medicine  13 Jul 2011:
Vol. 3, Issue 91, pp. 91ec108
DOI: 10.1126/scitranslmed.3002849

First used to treat type 1 diabetes (T1D) in 1922, insulin has served us well. But this steadfast treatment doesn’t address the underlying defects of the disease. Now, Soltani et al. show that a versatile neurotransmitter, γ-aminobutyric acid (GABA), reverses established disease in two mouse models of T1D by means of two distinct mechanisms.

T1D is characterized by the immune system’s destruction of the pancreatic islets and consequent loss of β cells, which make and secrete insulin. Obliteration of the insulin-synthesizing machinery thwarts the body’s ability to control blood glucose concentrations, causing a variety of health problems that include neuropathy, cardiovascular disease, retinopathy, and kidney failure. Best known as a brain neurotransmitter, GABA functions in neuronal cell proliferation and maturation of the developing brain. However, GABA receptors are expressed outside the nervous system by various immune cells, and GABA appears to exert immunoinhibitory effects. Furthermore, GABA is produced by pancreatic β cells and can act on nearby α cells to suppress secretion of glucagon, a hormone that increases blood glucose. Bringing together these lines of evidence, the authors investigated the effects of GABA on pancreatic β cells and T1D.

First, Soltani et al. demonstrated that GABA promoted proliferation and survival of cultured rat β cells. The researchers then explored the effects of GABA administration in two mouse models of T1D. In the first model (MDSD, multiple low-dose STZ-induced diabetes), treatment with a chemical (streptazosin) produces severe β-cell destruction and diabetes. Pretreatment of MDSD mice with GABA inhibited streptazosin-induced β-cell loss, resulting in higher and lower levels of circulating insulin and glucagon, respectively, and nearly normal blood glucose concentrations. Next, in a spontaneous autoimmune mouse model of T1D (NOD) the researchers showed that GABA treatment was associated with decreased β-cell death, increased β-cell proliferation, and nearly normal blood glucose concentrations relative to untreated nonobese diabetic (NOD) mice, which suffered severe diabetes and complete loss of β cells. When GABA was given to already severely diabetic MDSD or NOD mice, they recovered β-cell mass and displayed increased insulin production and improved blood glucose concentrations. The effective reversal of diabetes in these mice suggests that GABA has a stimulatory effect on β-cell regeneration. The authors attributed the reduction in β-cell destruction and recovery of β-cell mass to significant decreases in circulating inflammatory cytokines and an increase in regulatory T cells in the GABA-treated diabetic mice. These findings suggest a new therapeutic strategy aimed directly at the underlying causes of T1D.

N. Soltani et al., GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc. Natl. Acad. Sci. U.S.A. 27 June 2011 (10.1073/pnas.1102715108). [Abstract]

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