scholarly journals The Proposal of Molecular Mechanisms of Weak Organic Acids Intake-Induced Improvement of Insulin Resistance in Diabetes Mellitus via Elevation of Interstitial Fluid pH

2018 ◽  
Vol 19 (10) ◽  
pp. 3244 ◽  
Author(s):  
Yoshinori Marunaka
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Organic Acids ◽  
Molecular Mechanism ◽  
Interstitial Fluid ◽  
Molecular Mechanisms ◽  
Salt Intake ◽  
High Salt ◽  
Weak Organic Acids ◽  
High Salt Intake

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.

scholarly journals High-Salt Intake Ameliorates Hyperglycemia and Insulin Resistance in WBN/Kob-Leprfa/fa Rats: A New Model of Type 2 Diabetes Mellitus

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Yoshiichi Takagi ◽  
Taichi Sugimoto ◽  
Masaya Kobayashi ◽  
Mitsuyuki Shirai ◽  
Fumitoshi Asai
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glucose Homeostasis ◽  
Salt Intake ◽  
Urine Volume ◽  
High Salt ◽  
High Salt Intake

High-salt intake is a major risk factor for developing hypertension in type 2 diabetes mellitus, but its effects on glucose homeostasis are controversial. We previously found that high-salt intake induces severe hypertension in WBN/Kob diabetic fatty (WBKDF) rats. In the present study, we examined the effects of a high-salt intake on glucose homeostasis in WBKDF rats. Male WBKDF rats and age-matched Wistar rats at 6 weeks of age were each divided into two groups and fed either a normal-sodium (NS, 0.26%) diet or high-sodium (HS, 8%) diet for 7 weeks. Systolic blood pressure and urine volume were increased in WBKDF-HS and Wistar-HS. Body weight gain and food consumption were comparable between NS and HS in both strains. Plasma and urine glucose levels were significantly increased in WBKDF-NS but not in WBKDF-HS. HOMA-IR in WBKDF-HS was significantly lower compared with that in WBKDF-NS. The high plasma adiponectin level in WBKDF-NS compared with that in Wistar-NS was further enhanced in WBKDF-HS. Glycogen deposits and fat droplets in the livers of WBKDF-HS were reduced compared with those of WBKDF-NS. The present study demonstrated that HS intake ameliorated hyperglycemia and insulin resistance in WBKDF rats, which may be due to increased plasma levels of adiponectin.

Roles of interstitial fluid pH and weak organic acids in development and amelioration of insulin resistance

2021 ◽  
Author(s):  
Yoshinori Marunaka
Keyword(s):  
Insulin Resistance ◽  
Organic Acids ◽  
Binding Affinity ◽  
Interstitial Fluid ◽  
Ph Value ◽  
Insulin Binding ◽  
The Body ◽  
Weak Organic Acids ◽  
Arterial Blood ◽  
Blood Ph

Type 2 diabetes mellitus (T2DM) is one of the most common lifestyle-related diseases (metabolic disorders) due to hyperphagia and/or hypokinesia. Hyperglycemia is the most well-known symptom occurring in T2DM patients. Insulin resistance is also one of the most important symptoms, however, it is still unclear how insulin resistance develops in T2DM. Detailed understanding of the pathogenesis primarily causing insulin resistance is essential for developing new therapies for T2DM. Insulin receptors are located at the plasma membrane of the insulin-targeted cells such as myocytes, adipocytes, etc., and insulin binds to the extracellular site of its receptor facing the interstitial fluid. Thus, changes in interstitial fluid microenvironments, specially pH, affect the insulin-binding affinity to its receptor. The most well-known clinical condition regarding pH is systemic acidosis (arterial blood pH < 7.35) frequently observed in severe T2DM associated with insulin resistance. Because the insulin-binding site of its receptor faces the interstitial fluid, we should recognize the interstitial fluid pH value, one of the most important factors influencing the insulin-binding affinity. It is notable that the interstitial fluid pH is unstable compared with the arterial blood pH even under conditions that the arterial blood pH stays within the normal range, 7.35–7.45. This review article introduces molecular mechanisms on unstable interstitial fluid pH value influencing the insulin action via changes in insulin-binding affinity and ameliorating actions of weak organic acids on insulin resistance via their characteristics as bases after absorption into the body even with sour taste at the tongue.

scholarly journals SKIN LYMPHATIC SYSTEM IN THE PATHOGENESIS OF ARTERIAL HYPERTENSION – REVIEW AND CRITIQUE

Lymphology ◽  
2021 ◽  
Vol 53 (3) ◽  
Author(s):  
A Chachaj ◽  
A Szuba
Keyword(s):  
Blood Pressure ◽  
Molecular Mechanisms ◽  
Lymphatic System ◽  
Salt Intake ◽  
Lymphatic Vessels ◽  
High Salt ◽  
Large Reservoir ◽  
Inactive Form ◽  
High Salt Intake ◽  
Factor C

Although numerous studies have confirmed the relationship between high salt intake and elevated blood pressure, the exact molecular mechanisms of this relationship are still unclear. There is growing evidence that skin interstitium, as well as the skin lymphatic system, are important regulators of both sodium (Na+) balance and blood pressure. Skin is in itself a large reservoir of Na+ ions which are stored in an osmotically inactive form on glycosaminoglycans (GAGs). Local hypertonicity due to extensive accumulation of Na+ within the skin as a result of a high-salt diet was demonstrated to induce macrophages to express a transcription factor termed tonicity-responsive enhancer binding protein (TonEBP) and subsequently to secrete vascular endothelial growth factor-C (VEGF-C), activating lymphangiogenesis within the skin. This regulatory axis seems to be adaptive in maintaining blood pressure in high salt-load states. Recent studies have added new insights into the functioning of lymphatic vessels and the pathogenesis of salt-sensitive hypertension as well as questioned the classic view of Na+ homeostasis. This review aims to summarize recent findings pertaining to the involvement of the skin lymphatic system in Na+ and blood pressure regulation.

β-blockade prevents coronary macro- and microvascular dysfunction induced by a high salt diet and insulin resistance in the Goto–Kakizaki rat

2021 ◽  
Vol 135 (2) ◽  
pp. 327-346
Author(s):  
James T. Pearson ◽  
Hamish P. Thambyah ◽  
Mark T. Waddingham ◽  
Tadakatsu Inagaki ◽  
Vijayakumar Sukumaran ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Endothelial Dysfunction ◽  
Wistar Rats ◽  
Nitrosative Stress ◽  
Salt Intake ◽  
Microvascular Dysfunction ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake

Abstract A high salt intake exacerbates insulin resistance, evoking hypertension due to systemic perivascular inflammation, oxidative-nitrosative stress and endothelial dysfunction. Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARBs) have been shown to abolish inflammation and redox stress but only partially restore endothelial function in mesenteric vessels. We investigated whether sympatho-adrenal overactivation evokes coronary vascular dysfunction when a high salt intake is combined with insulin resistance in male Goto–Kakizaki (GK) and Wistar rats treated with two different classes of β-blocker or vehicle, utilising synchrotron-based microangiography in vivo. Further, we examined if chronic carvedilol (CAR) treatment preserves nitric oxide (NO)-mediated coronary dilation more than metoprolol (MET). A high salt diet (6% NaCl w/w) exacerbated coronary microvessel endothelial dysfunction and NO-resistance in vehicle-treated GK rats while Wistar rats showed modest impairment. Microvascular dysfunction was associated with elevated expression of myocardial endothelin, inducible NO synthase (NOS) protein and 3-nitrotyrosine (3-NT). Both CAR and MET reduced basal coronary perfusion but restored microvessel endothelium-dependent and -independent dilation indicating a role for sympatho-adrenal overactivation in vehicle-treated rats. While MET treatment reduced myocardial nitrates, only MET treatment completely restored microvessel dilation to dobutamine (DOB) stimulation in the absence of NO and prostanoids (combined inhibition), indicating that MET restored the coronary flow reserve attributable to endothelium-derived hyperpolarisation (EDH). In conclusion, sympatho-adrenal overactivation caused by high salt intake and insulin resistance evoked coronary microvessel endothelial dysfunction and diminished NO sensitivity, which were restored by MET and CAR treatment in spite of ongoing inflammation and oxidative-nitrosative stress presumably caused by uninhibited renin–angiotensin–aldosterone system (RAAS) overactivation.

Adipocytes initiate an adipose-cerebral-peripheral sympathetic reflex to induce insulin resistance during high-fat feeding

2019 ◽  
Vol 133 (17) ◽  
pp. 1883-1899 ◽  
Author(s):  
Wei Cao ◽  
Meng Shi ◽  
Liling Wu ◽  
Jiaxin Li ◽  
Zhichen Yang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
White Adipose Tissue ◽  
Salt Intake ◽  
High Salt ◽  
High Fat ◽  
Efferent Nerve ◽  
Salt Loading ◽  
High Salt Intake

Abstract The underlying mechanism by which amassing of white adipose tissue in obesity regulates sympathetic nerve system (SNS) drive to the tissues responsible for glucose disposal, and causes insulin resistance (IR), remains unknown. We tested the hypothesis that high-fat (HF) feeding increases afferent impulses from white adipose tissue that reflexively elevate efferent nerve activity to skeletal muscle (SM) and adipose tissue to impair their local glucose uptake. We also investigated how salt-intake can enhance IR. HF-fed rats received a normal salt (0.4%) or high salt (4%) diet for 3 weeks. High-salt intake in HF fed rats decreased insulin-stimulated 2-deoxyglucose uptake by over 30% in white adipose tissue and SM, exacerbated inflammation, and impaired their insulin signaling and glucose transporter 4 (Glut4) trafficking. Dietary salt in HF fed rats also increased the activity of the adipose-cerebral-muscle renin–angiotensin system (RAS) axes, SNS, and reactive oxygen species (ROS). Insulin sensitivity was reduced by 32% in HF rats during high-salt intake, but was improved by over 62% by interruption of central RAS and SNS drive, and by over 45% by denervation or deafferentation of epididymal fat (all P<0.05). Our study suggest that a HF diet engages a sympathetic reflex from the white adipose tissue that activates adipose-cerebral-muscle RAS/ROS axes and coordinates a reduction in peripheral glucose uptake. These are all enhanced by salt-loading. These findings provide new insight into the role of a reflex initiated in adipose tissue in the regulation of glucose homeostasis during HF feeding that could lead to new therapeutic approaches to IR.

scholarly journals High salt intake causes leptin resistance and obesity in mice by stimulating endogenous fructose production and metabolism

2018 ◽  
Vol 115 (12) ◽  
pp. 3138-3143 ◽  
Author(s):  
Miguel A. Lanaspa ◽  
Masanari Kuwabara ◽  
Ana Andres-Hernando ◽  
Nanxing Li ◽  
Christina Cicerchi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Liver ◽  
Salt Intake ◽  
Dietary Guidelines ◽  
High Salt ◽  
Leptin Resistance ◽  
Healthy Population ◽  
Food Groups ◽  
Obesity And Diabetes ◽  
High Salt Intake

Dietary guidelines for obesity typically focus on three food groups (carbohydrates, fat, and protein) and caloric restriction. Intake of noncaloric nutrients, such as salt, are rarely discussed. However, recently high salt intake has been reported to predict the development of obesity and insulin resistance. The mechanism for this effect is unknown. Here we show that high intake of salt activates the aldose reductase–fructokinase pathway in the liver and hypothalamus, leading to endogenous fructose production with the development of leptin resistance and hyperphagia that cause obesity, insulin resistance, and fatty liver. A high-salt diet was also found to predict the development of diabetes and nonalcoholic fatty liver disease in a healthy population. These studies provide insights into the pathogenesis of obesity and diabetes and raise the potential for reduction in salt intake as an additional interventional approach for reducing the risk for developing obesity and metabolic syndrome.

scholarly journals High Salt Intake and Stroke: Meta-analysis of the Epidemiologic Evidence

2012 ◽  
Vol 18 (8) ◽  
pp. 691-701 ◽  
Author(s):  
Xiu-Yang Li ◽  
Xian-Lei Cai ◽  
Ping-Da Bian ◽  
Liu-Ru Hu
Keyword(s):  
Salt Intake ◽  
Meta Analysis ◽  
High Salt ◽  
Epidemiologic Evidence ◽  
High Salt Intake
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