Dr. Ron’s Research Review – July 24, 2013

© 2013

This week’s research review focuses on GABA and diabetes.

Pancreatic islet beta-cells produce large amounts of GABA, which is co-released with insulin. GABA inhibits glucagon secretion by hyperpolarizing alpha-cells via type-A GABA receptors. (Bansal, Wang et al. 2011) (Bansal, Wang et al. 2011)

GABA exerts anti-diabetic effects by acting on both the islet β-cells and immune system. GABA therapy preserves β-cell mass and prevents the development of T1D in vivo. Remarkably, in severely diabetic mice, GABA restores β-cell mass and reverses the disease. Furthermore, GABA suppresses insulitis and systemic inflammatory cytokine production. (Soltani, Qiu et al. 2011)

Oral treatment with GABA significantly reduced the concentrations of fasting blood glucose, and improved glucose tolerance and insulin sensitivity in the HFD-fed mice. More importantly, after the onset of obesity and T2DM, oral treatment with GABA inhibited the continual HFD-induced gain in body weights, reduced the concentrations of fasting blood glucose and improved glucose tolerance and insulin sensitivity in mice. In addition, oral treatment with GABA reduced the epididymal fat mass, adipocyte size, and the frequency of macrophage infiltrates in the adipose tissues of HFD-fed mice. (Tian, Dang et al. 2011)

The mice were fed water containing 2 mg/ml of GABA. Water intake (according to Figure 1) was about 25 ml/day. That would be 50 mg/day. Body weight was about 40 g.

Metabolism

Glutamine is a common precursor for the biosynthesis of both glutamate and GABA. The GABA shunt converts glutamate, the principal excitatory neurotransmitter, into the principal inhibitory neurotransmitter (GABA).

Glutamine ↔ Glutamate ↔ GABA

Dr. Ron

Articles

Gamma-aminobutyric acid (GABA), Monograph

         (2007) Download

GABA coordinates with insulin in regulating secretory function in pancreatic INS-1 beta-cells

         (Bansal, Wang et al. 2011) Download

Pancreatic islet beta-cells produce large amounts of gamma-aminobutyric acid (GABA), which is co-released with insulin. GABA inhibits glucagon secretion by hyperpolarizing alpha-cells via type-A GABA receptors (GABA(A)Rs). We and others recently reported that islet beta-cells also express GABA(A)Rs and that activation of GABA(A)Rs increases insulin release. Here we investigate the effects of insulin on the GABA-GABA(A)R system in the pancreatic INS-1 cells using perforated-patch recording. The results showed that GABA produces a rapid inward current and depolarizes INS-1 cells. However, pre-treatment of the cell with regular insulin (1 microM) suppressed the GABA-induced current (I(GABA)) by 43%. Zinc-free insulin also suppressed I(GABA) to the same extent of inhibition by regular insulin. The inhibition of I(GABA) occurs within 30 seconds after application of insulin. The insulin-induced inhibition of I(GABA) persisted in the presence of PI3-kinase inhibitor, but was abolished upon inhibition of ERK, indicating that insulin suppresses GABA(A)Rs through a mechanism that involves ERK activation. Radioimmunoassay revealed that the secretion of C-peptide was enhanced by GABA, which was blocked by pre-incubating the cells with picrotoxin (50 microM, p<0.01) and insulin (1 microM, p<0.01), respectively. Together, these data suggest that autocrine GABA, via activation of GABA(A)Rs, depolarizes the pancreatic beta-cells and enhances insulin secretion. On the other hand, insulin down-regulates GABA-GABA(A)R signaling presenting a feedback mechanism for fine-tuning beta-cell secretion.


GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes

         (Soltani, Qiu et al. 2011) Download

Type 1 diabetes (T1D) is an autoimmune disease characterized by insulitis and islet beta-cell loss. Thus, an effective therapy may require beta-cell restoration and immune suppression. Currently, there is no treatment that can achieve both goals efficiently. We report here that GABA exerts antidiabetic effects by acting on both the islet beta-cells and immune system. Unlike in adult brain or islet alpha-cells in which GABA exerts hyperpolarizing effects, in islet beta-cells, GABA produces membrane depolarization and Ca(2+) influx, leading to the activation of PI3-K/Akt-dependent growth and survival pathways. This provides a potential mechanism underlying our in vivo findings that GABA therapy preserves beta-cell mass and prevents the development of T1D. Remarkably, in severely diabetic mice, GABA restores beta-cell mass and reverses the disease. Furthermore, GABA suppresses insulitis and systemic inflammatory cytokine production. The beta-cell regenerative and immunoinhibitory effects of GABA provide insights into the role of GABA in regulating islet cell function and glucose homeostasis, which may find clinical application.


Oral treatment with gamma-aminobutyric acid improves glucose tolerance and insulin sensitivity by inhibiting inflammation in high fat diet-fed mice

         (Tian, Dang et al. 2011) Download

Adipocyte and beta-cell dysfunction and macrophage-related chronic inflammation are critical for the development of obesity-related insulin resistance and type 2 diabetes mellitus (T2DM), which can be negatively regulated by Tregs. Our previous studies and those of others have shown that activation of gamma-aminobutyric acid (GABA) receptors inhibits inflammation in mice. However, whether GABA could modulate high fat diet (HFD)-induced obesity, glucose intolerance and insulin resistance has not been explored. Here, we show that although oral treatment with GABA does not affect water and food consumption it inhibits the HFD-induced gain in body weights in C57BL/6 mice. Furthermore, oral treatment with GABA significantly reduced the concentrations of fasting blood glucose, and improved glucose tolerance and insulin sensitivity in the HFD-fed mice. More importantly, after the onset of obesity and T2DM, oral treatment with GABA inhibited the continual HFD-induced gain in body weights, reduced the concentrations of fasting blood glucose and improved glucose tolerance and insulin sensitivity in mice. In addition, oral treatment with GABA reduced the epididymal fat mass, adipocyte size, and the frequency of macrophage infiltrates in the adipose tissues of HFD-fed mice. Notably, oral treatment with GABA significantly increased the frequency of CD4(+)Foxp3(+) Tregs in mice. Collectively, our data indicated that activation of peripheral GABA receptors inhibited the HFD-induced glucose intolerance, insulin resistance, and obesity by inhibiting obesity-related inflammation and up-regulating Treg responses in vivo. Given that GABA is safe for human consumption, activators of GABA receptors may be valuable for the prevention of obesity and intervention of T2DM in the clinic.


References

(2007). "Gamma-aminobutyric acid (GABA), Monograph." Altern Med Rev 12(3): 274-9. [PMID: 18072823]

Bansal, P., S. Wang, et al. (2011). "GABA coordinates with insulin in regulating secretory function in pancreatic INS-1 beta-cells." PLoS One 6(10): e26225. [PMID: 22031825]

Soltani, N., H. Qiu, et al. (2011). "GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes." Proc Natl Acad Sci U S A 108(28): 11692-7. [PMID: 21709230]

Tian, J., H. N. Dang, et al. (2011). "Oral treatment with gamma-aminobutyric acid improves glucose tolerance and insulin sensitivity by inhibiting inflammation in high fat diet-fed mice." PLoS One 6(9): e25338. [PMID: 21966503]