Molecular Mechanisms of Obesity-Induced Development of Insulin Resistance and Promotion of Amyloid-β Accumulation: Dietary Therapy Using Weak Organic Acids via Improvement of Lowered Interstitial Fluid pH

Abstract

Insulin resistance is one of the etiologies of type 2 diabetes mellitus (T2DM) and has been suggested to contribute to the development of Alzheimer’s disease by promoting amyloid-β accumulation. Various causes of insulin resistance have been suggested; however, mechanisms of insulin resistance development remain to be elucidated in many respects. Elucidating the mechanisms underlying the development of insulin resistance is one of the key factors in developing methods to prevent the onset of T2DM and Alzheimer’s disease. It has been suggested that the body pH environment plays an important role in the control of cellular functions by regulating the action of hormones including insulin and the activity of enzymes and neurons, thereby maintaining homeostatic conditions of the body. This review introduces: (1) Mitochondrial dysfunction through oxidative stress caused by obesity-induced inflammation. (2) Decreased pH of interstitial fluid due to mitochondrial dysfunction. (3) Development of insulin resistance due to diminution of insulin affinity to its receptor caused by the lowered interstitial fluid pH. (4) Accelerated accumulation of amyloid-β due to elevated activities of β- and γ-secretases caused by the lowered interstitial fluid pH. (5) Diet therapies for improving insulin resistance with weak organic acids that act as bases in the body to raise the pH of lowered interstitial fluid and food factors that promote absorption of weak organic acids in the gut.