"Greedy Organs Hypothesis" for sugar and salt in the pathophysiology of non-communicable diseases in relation to sodium-glucose co-transporters in the intestines and the kidney

Abstract

Deposition of visceral fat and insulin resistance play central role in the development of non-communicable diseases (NCDs) including obesity, hypertension and type 2 diabetes. However, we shed more light upon the intestines and the kidney as a strong driver of NCDs. Based upon unexpected outcomes of clinical trials using sodium-glucose cotransporter (SGLT) 2 inhibitors to demonstrate their actions for not only body weight reduction and blood glucose fall but also remarkable cardiorenal protection, we speculate that hyperfunction of the intestines and the kidney is one of critical contributing factors for initiation of NCDs. By detecting high amount of glucose and sodium chloride around them by sweet/salt taste sensors, the intestines and the kidney are designed to (re)absorb these nutrients by up-regulating SGLT1 or SGLT2. We designate these hyperfunctioning organs for nutrient uptake as "greedy organs". The greedy organs can induce NCDs ("greedy organ hypothesis"). SGLTs are regulated by glucose and sodium chloride, and SGLTs or other genes can be "greedy genes." Regulating factors for greedy organs are renin-angiotensin system, renal sympathetic nervous activity, gut inflammation/microbiota or oxidative stress. Mitigation of organ greediness by SGLT2 inhibitors, ketone bodies, bariatric surgery, and regular lifestyle to keep rhythmicity of biological clock are promising.

Keywords: Chronic kidney disease; Diabetes mellitus; Metabolic syndrome; Non-communicable diseases; Obesity; Sodium-glucose cotransporter.

Graphical abstract

Fig. 1

“Metabolic Domino” (adapted from reference 2) The collapse of “Metabolic Domino” starts with slight derangement in lifestyle, that is, more food intake and less exercise, which leads to visceral obesity, insulin resistance and causes hyperglycemia, high BP and dyslipidemia. The cluster of these pathological states is called metabolic syndrome. These metabolic abnormalities induce a variety of non-communicable diseases and organ dysfunctions, that are the cases of poor quality of life and short healthy life expectancy. ASO = arteriosclerosis obliterans. ED = erectile dysfunction.

Fig. 2

“Greedy organs” and lifestyle-related diseases The kidney and intestines absorb excessive nutrients for the production of ATP in mitochondria and become “greedy.” Excessive salt intake through SGLT2 makes the kidney greedy to induce hypertension/CKD. Excessive food intake through SGLT1 make the intestines greedy to induce obesity/DM. There is a “crossing” relationship between “greedy organs” and lifestyle-related disease, that is, “greedy kidney” can cause obesity/DM and “greedy intestines” can cause hypertension/CKD. ATP = adenosine triphosphate. CKD = chronic kidney disease. SGLT = sodium-glucose cotransporter.

Fig. 3

Possible coordination among GLUT2, SGLT2, and Na⁺-K⁺-ATPase for effective glucose reabsorption from the urine When GLUT2 in the proximal tubule senses glucose in basolateral side, importin-α1 and HNF-1α dissociate from the GLUT2 and translocate into the nucleus, then SGLT2 expression increases. SGLT2 at the enhanced level transports more sodium and glucose simultaneously into the renal tubular cells using energy generated by Na⁺-K⁺-ATPase. Then, glucose and sodium are transported into the bloodstream through GLUT2 and Na⁺-K⁺-ATP channel, respectively. ADP = adenosine diphosphate. ATP = adenosine triphosphate. Glu = glucose. GLUT = glucose transporter. HNF = hepatocyte nuclear factor. SGLT = sodium-glucose cotransporter.