Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications

Abstract

Considerable data have accumulated over the past 20 years, indicating that the human kidney is involved in the regulation of glucose via gluconeogenesis, taking up glucose from the circulation, and by reabsorbing glucose from the glomerular filtrate. In light of the development of glucose-lowering drugs involving inhibition of renal glucose reabsorption, this review summarizes these data. Medline was searched from 1989 to present using the terms ‘renal gluconeogenesis’, ‘renal glucose utilization’, ‘diabetes mellitus’ and ‘glucose transporters’. The human liver and kidneys release approximately equal amounts of glucose via gluconeogenesis in the post-absorptive state. In the postprandial state, although overall endogenous glucose release decreases substantially, renal gluconeogenesis increases by approximately twofold. Glucose utilization by the kidneys after an overnight fast accounts for ∼10% of glucose utilized by the body. Following a meal, glucose utilization by the kidney increases. Normally each day, ∼180 g of glucose is filtered by the kidneys; almost all of this is reabsorbed by means of sodium–glucose co-transporter 2 (SGLT2), expressed in the proximal tubules. However, the capacity of SGLT2 to reabsorb glucose from the renal tubules is finite and, when plasma glucose concentrations exceed a threshold, glucose appears in the urine. Handling of glucose by the kidney is altered in Type 2 diabetes mellitus (T2DM): renal gluconeogenesis and renal glucose uptake are increased in both the post-absorptive and postprandial states, and renal glucose reabsorption is increased. Specific SGLT2 inhibitors are being developed as a novel means of controlling hyperglycaemia in T2DM.Diabet. Med. 27, 136–142 (2010)

Effect of fasting and fasting-refeeding on the structure, metabolism and transport functions of renal cortical proximal tubules from different kidney regions

“…The enzymes of glucose metabolism and glucose synthesis are differentially distributed in the cortex and medulla [11,15]. The oxidative metabolism and gluconeogenesis is more prevalent in superficial cortex whereas anaerobic glycolysis is in juxta-medullary region [16]. These results suggest that in the absence of food the glucose degradation was slowed down but glucose production by gluconeogenesis was increased and when the food was available during re-feeding the normal metabolic activities were restored.…”

Emerging Roles of Cadmium and Heme Oxygenase in Type-2 Diabetes and Cancer Susceptibility

“…Accumulating human data suggest abnormal liver and kidney metabolic function in type 2-diabetic subjects (Meyer et al 1998;Gerich 2010;Defronzo et al 2012). Expansion of research to other cell types, notably adipose tissues and the brain, is of particular scientific merit, in light of obese phenotype of HO-2 deficient mice and since HO-2 is expressed prominently in the brain.…”

“…This allows for use of urinary cadmium concentration as a measure of cumulative lifetime exposure (Slob and Krajnc 1993;Choudhury et al 2001). Accumulation of cadmium in both liver and kidney is a cause for concern as these two organs contribute to the maintenance of blood glucose levels (Gerich 2010;DeFronzo et al 2012). In the post absorptive state, kidney and liver supply an equal amount of glucose into blood circulation (Stumvoll et al 1997;Gerich 2010;DeFronzo et al 2012).…”

“…Accumulation of cadmium in both liver and kidney is a cause for concern as these two organs contribute to the maintenance of blood glucose levels (Gerich 2010;DeFronzo et al 2012). In the post absorptive state, kidney and liver supply an equal amount of glucose into blood circulation (Stumvoll et al 1997;Gerich 2010;DeFronzo et al 2012). Further, cadmium accumulation in kidney and RPE could contribute to early onset of diabetic nephropathy and retinopathy as seen in the Torres Strait (Australia) population who had elevated dietary cadmium exposures (Satarug et al 2000b;HaswellElkins et al 2007a,b;Haswell-Elkins et al 2008).…”

“…It is fundamental to metabolic adaptation requirements in all nucleated cells. Such research should be directed toward identification of cellular signalling pathways responsive to changes in glucose levels, especially liver and kidney, known as glucose suppliers (Stumvoll et al 1997;Gerich 2010;Defronzo et al 2012), and the brain (astrocytes and neurons), all known as the principal users of glucose and oxygen. A role for Wnt/ β-catenin signalling in the glucose-sensing mechanism has been shown in macrophage cells (Anagnostou and Sheperd 2008), and its connection to heme catabolism needs to be explored.…”