Abstract
Blood contains powerful pH-buffering molecules such as hemoglobin (Hb) and albumin, while interstitial fluids have little pH-buffering molecules. Thus, even under metabolic disorder conditions except severe cases, arterial blood pH is kept constant within the normal range (7.35~7.45), but the interstitial fluid pH under metabolic disorder conditions becomes lower than the normal level. Insulin resistance is one of the most important key factors in pathogenesis of diabetes mellitus, nevertheless the molecular mechanism of insulin resistance occurrence is still unclear. Our studies indicate that lowered interstitial fluid pH occurs in diabetes mellitus, causing insulin resistance via reduction of the binding affinity of insulin to its receptor. Therefore, the key point for improvement of insulin resistance occurring in diabetes mellitus is development of methods or techniques elevating the lowered interstitial fluid pH. Intake of weak organic acids is found to improve the insulin resistance by elevating the lowered interstitial fluid pH in diabetes mellitus. One of the molecular mechanisms of the pH elevation is that: (1) the carboxyl group (R-COO−) but not H+ composing weak organic acids in foods is absorbed into the body, and (2) the absorbed the carboxyl group (R-COO−) behaves as a pH buffer material, elevating the interstitial fluid pH. On the other hand, high salt intake has been suggested to cause diabetes mellitus; however, the molecular mechanism is unclear. A possible mechanism of high salt intake-caused diabetes mellitus is proposed from a viewpoint of regulation of the interstitial fluid pH: high salt intake lowers the interstitial fluid pH via high production of H+ associated with ATP synthesis required for the Na+,K+-ATPase to extrude the high leveled intracellular Na+ caused by high salt intake. This review article introduces the molecular mechanism causing the lowered interstitial fluid pH and insulin resistance in diabetes mellitus, the improvement of insulin resistance via intake of weak organic acid-containing foods, and a proposal mechanism of high salt intake-caused diabetes mellitus.
Highlights
Some kinds of food habits with high calorie intake result in metabolic syndrome, which would be a precursor for diseases such as type 2 diabetes mellitus, cardiovascular diseases and cancer [1,2]
One of the most typical, serious phenomena appearing in type 2 diabetes mellitus is insulin resistance, which causes hyperglycemia and results in various types of disorders such as hypertension, vascular dysfunction, hyper-activation of sympathetic nerve, and renal failure [4,5,6,7,8,9,10,11,12]
Weak organic acids such as short-chain fatty acids stimulate the secretion of glucagon-like peptide (GLP) 1 that enhances insulin secretion [71]
Summary
Some kinds of food habits with high calorie intake result in metabolic syndrome, which would be a precursor for diseases such as type 2 diabetes mellitus, cardiovascular diseases and cancer [1,2]. Continuous hyperglycemia in type 2 diabetes mellitus patients with insulin resistance, in general, irreversibly causes macro- and micro-vascular complications [68] This develops stroke, myocardial infarction, obstructive arteriosclerosis, renal dysfunction, blindness, dementia, and peripheral neuropathy. All drugs are only designed to reduce the blood glucose level by blocking glucose production, glucose reuptake or insulin release, but not to improve fundamentally insulin resistance Weak organic acids such as short-chain fatty acids stimulate the secretion of glucagon-like peptide (GLP) 1 that enhances insulin secretion [71]. From a novel viewpoint of ‘regulation of interstitial fluid pH’, I introduce the concept on development of insulin resistance in type 2 diabetes mellitus, the preventing method from insulin resistance with intake of foods containing weak organic acids, and a proposal mechanism of pathogenesis of diabetes mellitus caused by high salt intake
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