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No acute changes in blood glucose, but extreme changes in insulin levels. How can this trigger a reduction in glycated albumin - How's that possible?

You've read about gamma aminobutyric acid (GABA) at the waredownloadsoft before. While most people think of it mainly as a calming agent, though, waredownloadsoft readers know that it has the remarkable ability to heal the insulin producing β-cell in rodents by stimulating their replication, protecting them against apoptosis, and attenuating insulitis (Soltani. 2011; Tian. 2013; Prud'homme. 2014; Purwana. 2014). And while these favorable effects were first observed in mice, researchers are quite sure that they are valid in humans, too- that's also because said effects have been confirmed only recently by Tian et al. (2014) and Purwana et al. (2014) in vitro as well as in xenotransplanted human islets.
If you know that, the observations researchers from the Fudan University in Shanghai report in their latest study probably won't come as a surprise. In their investigation into the  pharmacokinetics and pharmacodynamics of GABA in healthy volunteers, the researchers found that the chronic provision of 2g of GABA three times per day triggers a highly significant decrease in glycated albumin (GA) levels, the intermediate measure of blood glucose control (in-between acute blood glucose measurements and HbA1c | Roohk. 2008), within only 7 days.

Figure 1: Acute glucose (top) and insulin (bottom) response after single and repeated administration of 2g of GABA (left). Chronic effects of repeated dose-administration of GABA on glycated albumin (right | Li. 2015).

If you scrutinize the data in Figure 1, though, there are a few questions we still need to find answers to. Obviously, the acute administration of GABA (Figure 1, left) lead to significant increases in insulin - both, under either fasting (1.6-fold, single dose; 2.0-fold, repeated dose; p < 0.01) or fed conditions (1.4-fold, single dose; 1.6-fold, repeated dose; p < 0.01).
Usually, this 1.4-fold or 1.6-fold increase in insulin should trigger a significant (at least transient) decrease in blood glucose. Since the latter wasn't the case in either the fasted or the fed tests the scientists conducted on the twelve subjects, who participated in the open-labeled, three-period trial, it appears more than counter-intuitive that the chronic administration of GABA which does not accumulate in the body and was found to be almost completely absorbed in 60 minutes and to have a half-life of 5h still lead to an GA decrease of approximately 11-12%.

Now this obviously confirms that GABA, due to its ability to increase islet hormonal secretion, has potential therapeutic benefits for diabetes, what the study does not tell us, though, is whether the lack of immediate effects on blood glucose levels can, as the scientists suspect, "in part be attributed to GABA-induced counter regulatory mechanisms, especially elevated glucagon" (Li. 2015) which rose so that the insulin-to-glucagon ratio remained unchanged. Yet while the latter could explain why the subjects did not become hypoglycemic in the face of increased insulin levels, the lack of certainty with respect to the underlying mechanisms makes the study results difficult to interpret.
References:

• Li, Junfeng, et al. "Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics." Frontiers in Pharmacology 6 (2015): 260.
• Prud’homme, Gérald J., et al. "GABA protects human islet cells against the deleterious effects of immunosuppressive drugs and exerts immunoinhibitory effects alone." Transplantation 96.7 (2013): 616-623.
• Prud’homme, Gérald J., et al. "GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity." Biochemical and biophysical research communications 452.3 (2014): 649-654.
• Purwana, Indri, et al. "GABA promotes human β-cell proliferation and modulates glucose homeostasis." Diabetes 63.12 (2014): 4197-4205.
• Roohk, H. Vernon, and Asad R. Zaidi. "A review of glycated albumin as an intermediate glycation index for controlling diabetes." Journal of diabetes science and technology 2.6 (2008): 1114-1121.
• Soltani, Nepton, et al. "GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes." Proceedings of the National Academy of Sciences 108.28 (2011): 11692-11697.
• Tian, Jide, et al. "γ-Aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model." The Journal of Immunology 173.8 (2004): 5298-5304.
• Tian, Jide, et al. "Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis." Autoimmunity 44.6 (2011): 465-470.
• Tian, Jide, et al. "γ-Aminobutyric acid regulates both the survival and replication of human β-cells." diabetes 62.11 (2013): 3760-3765.
• Tian, Jide, et al. "Combined Therapy With GABA and Proinsulin/Alum Acts Synergistically to Restore Long-term Normoglycemia by Modulating T-Cell Autoimmunity and Promoting β-Cell Replication in Newly Diabetic NOD Mice." Diabetes 63.9 (2014): 3128-3134.

If Mg is the solution, then in form of high Mg foods, not supplements.

If you've ever googled "magnesium and diabetes", you will probably have read a sentence like this "magnesium (Mg) is actively involved in a number of metabolic reactions as an important co-factor with special emphasis on carbohydrate metabolism (Mooren. 2015). Unlike the latest paper by the German scientists Frank C. Mooren from the Justus-Liebig-University in Giessen from which I've grabbed the previously cited statement, your Google results will yet probably have treated this observation as if it was conclusive evidence that the provision of extra-magnesium would solve the T2DM-crisis of the Western wordl.

In his review, Mooren doesn't make the same mistake, instead he provides a brief, but in-depth overview of the regulation of intra- and extracellular Mg and the regulatory role of Mg in important metabolic pathways involved in energy metabolism and glycaemic control.
An overview Mooren concludes by stating that a "critical consideration of the pros and cons of a Mg replacement therapy" that accounts for various "parameters such as Mg status, stage of disease and glycaemic control" is still lacking.

The fact that we do not yet understand all the confounding factors, though, does not mean that we are still completely in the dark. Rather than that we do know that,,,

• ...diabetes predisposes to magnesium deficiency - It may seem to be a chicken or egg question, but an impartial review of the evidence suggests that diabetes or rather pre-diabetes comes first and hypomagnesaemia = low magnesium levels are a consequence of the development of diabetes.
  
  Next to the low magnesium content of the pro-diabetic junkfood Western diet (Pham. 2014), recent data indicate that hyperglycaemia and resulting osmotic diuresis overwhelm the kidneys’ reabsorption capacity for Mg leading to hypermagnesuria. In conjuction with various disturbances of metabolic and electrolyte variables, such as hypokalaemia and metabolic acidosis, which are common among diabetics, the elevated glucose levels trigger a redistribution of Mg within its compartments that will eventually lead to the depletion of intracellular Mg and an enhanced urinary Mg excretion (Pham. 2014).
• ...hypomagnesaemia accelerates the transition from pre- to full-blown diabetes - The hyperglycemia-induced depletion of magnesium levels triggers a viscous cycle, because a balanced Mg status seems to be an important prerequisite for an adequate carbohydrate metabolism.

Overall, there is no doubt that there is a strong independent relationship between low serum magnesium levels and metabolic syndrome (Odds ratio (OR)=6.8, CI95% 4.2-10.9).
Six cross sectional studies have also reported associations between magnesium intake and risk of metabolic syndrome were reviewed in a recent meta-analysis by Diaba et al. (2014). More than 24,000 individuals of both sexes have been included.

Figure 1: Multivariable adjusted odds ratios (95% CI) of having prevalent metabolic syndrome in participants with the highest level of dietary magnesium intake compared with those with the lowest (Diba. 2014).

Despite the fact that the data shows a 31% reduced risk of metabolic syndrome (see Figure 1) and a 17% reduced risk per 100mg/day of magnesium in the diet in subjects in the highest vs. lowest Mg intake groups, and were compared (OR=0.69, CI95% 0.59-0.81), the evidence from studies investigating the effects of oral Mg supplementation as an adjunct therapy for type 2 diabetes is quite heterogeneous.

Table 1: Absolute changes in fasting plasma glucose after Mg supplementation in people with impaired glucose regulation | FPG – Fasting plasma glucose; * indicates the inclusion of hypomagnesaemic subjects only (Mooren. 2015).

Fourteen randomized controlled studies have been identified which investigated the effect of Mg supplementation on type 2 diabetes (Table 3). In total, 825 people with diabetes were enrolled, who had suffered from the disease for a mean duration of about 10.8+4.1 years. 10 studies reported values for glycosylated haemoglobin (HbA1c) at study onset. Their long term glucose control failed the recommended values for diabetic patients (target range HbA1c from 6.5-7.5 %) as indicated by a mean HbA1c of 9.3+2.1 %. 3 studies included patients with initial HbA1c levels lower than 7.5 %. Serum Mg concentrations at study onset have been reported in 12 studies. 5 out of 12 studies included diabetic people with hypomagnesaemia (Mg < 0.74mmol/l), while patients of another 5 studies showed serum Mg levels in the lower segment of the normal range (between 0.74 and 0.85 mmol/l).

Different Mg salts (Mg-pidolate; Mg-lactate-citrate; Mg-oxide; Mg-chloride; Mg-aspartate; Mg sulfate) were applied during a wide range of treatment periods which lasted from 4-16 weeks (mean treatment duration 9.6 weeks). After Mg supplementation, only 50 % of the studies reported significant improvements in serum Mg (7 out of 14 studies). Such a limited supplementation efficacy might partially result from different bioavailabilities of the various Mg salts (organic vs. inorganic) applied" (Mooren. 2015).

In a similar vein, most of the studies did not observe significant improvements in glucose control and the long-term glucose measure HbA1c in response to magnesium supplementation (only 23% and 18%, respectivels). The closely related triglyceride levels were not affected in any of the studies.
References:

• de Lourdes Lima, Maria, et al. "Serum and intracellular magnesium deficiency in patients with metabolic syndrome—evidences for its relation to insulin resistance." Diabetes research and clinical practice 83.2 (2009): 257-262.
• Dibaba, D. T., et al. "Dietary magnesium intake and risk of metabolic syndrome: a meta‐analysis." Diabetic Medicine 31.11 (2014): 1301-1309.
• Mooren, Frank C. "Magnesium and disturbances in carbohydrate metabolism." Diabetes, Obesity and Metabolism (2015): Accepted Article.
• Pham, Phuong-Chi T., et al. "Hypomagnesemia: a clinical perspective." International journal of nephrology and renovascular disease 7 (2014): 219.