Supplement

Understanding the Kidneys’ Role in Blood Glucose Regulation

Published Online: April 11, 2012
Curtis L. Triplitt, PharmD, CDE
While not traditionally discussed, the kidneys’ contributions to maintaining glucose homeostasis are significant and include such functions as release of glucose into the circulation via gluconeogenesis, uptake of glucose from the circulation to satisfy their energy needs, and reabsorption of glucose at the level of the proximal tubule. Renal release of glucose into the circulation is the result of glycogenolysis and gluconeogenesis, respectively involving the breaking down and formation of glucose-6-phosphate from precursors (eg, lactate, glycerol, amino acids). With regard to renal reabsorption of glucose, the kidneys normally retrieve as much glucose as possible, rendering the urine virtually glucose free. The glomeruli filter from plasma approximately 180 grams of D-glucose per day, all of which is reabsorbed through glucose transporter proteins that are present in cell membranes within the proximal tubules. If the capacity of these transporters is exceeded, glucose appears in the urine. The process of renal glucose reabsorption is mediated by active (sodium-coupled glucose cotransporters) and passive (glucose transporters) transporters. In hyperglycemia, the kidneys may play an exacerbating role by reabsorbing excess glucose, ultimately contributing to chronic hyperglycemia, which in turn contributes to chronic glycemic burden and the risk of microvascular consequences. This article provides an extensive review of the kidneys’ role in normal human physiology, the mechanisms by which they contribute to glucose regulation, and the potential impact of glucose imbalance on the kidneys.

(Am J Manag Care. 2012;18:S11-S16)
Published studies over the last 60 years have provided considerable evidence regarding the ability of the kidneys to make and release glucose under various physiologic conditions. Yet traditionally, the kidneys have not been considered an important source of glucose (except during acidosis or after prolonged fasting), with most clinical discussions on glucose dysregulation centering on the intestine, pancreas, liver, adipose tissue, and muscle.1-3 More recently, however, the full significance of the kidneys’ contribution to glucose homeostasis, under both physiologic and pathologic conditions, has become well recognized, and is thought to involve functions well beyond glucose uptake and release. Besides the liver, the kidney is the only organ capable of generating sufficient glucose (gluconeogenesis) to release into the circulation, and it is also responsible for filtration and subsequent reabsorption or excretion of glucose.2-4 These findings have provided considerable insight into the myriad of pathophysiologic mechanisms involved in the development of hyperglycemia and type 2 diabetes mellitus (T2DM).5,6 This article provides a review of the kidneys’ role in normal human physiology, the mechanisms by which they contribute to glucose regulation, and the potential impact of glucose imbalance on the kidneys.

Overview of Renal Physiology

The kidneys are essentially designed to filter large quantities of plasma, reabsorb substances that the body must conserve, and secrete substances that must be eliminated. These basic functions are critical to regulation of fluid and electrolyte balance, body fluid osmolality, acid-based balance, excretion of metabolic waste and foreign chemicals, arterial pressure, hormone secretion, and, most relevant to this discussion, glucose balance.7,8 The 2 kidneys produce a total of approximately 120 mL/min of ultrafiltrate, yet only 1 mL/min of urine is produced. The basic urine-forming unit of the kidney is the nephron, which serves to filter water and small solutes from plasma and reabsorb electrolytes, amino acids, glucose, and protein. The nephron, of which there are approximately 1 million in each kidney, consists of a filtering apparatus (the glomerulus) that is connected to a long tubular portion that reabsorbs and conditions the glomerular ultrafiltrate. Fluid filtered from the glomerular capillaries flows into the tubular portion, which is made up of a proximal tubule, the Loop of Henle, and the distal tubule, all of which assist in reabsorbing essential substances and converting filtered fluid into urine.7

Evaluation of renal function is an important part of care, and with that, creatinine clearance (CrCl) or glomerular filtration rate (GFR), most frequently estimated (eGFR), are considered most useful in determining the degree of renal insufficiency and the stage of chronic kidney disease in accordance with the National Kidney Foundation classification system. Since alterations in all renal functions (ie, filtration, secretion, reabsorption, endocrine and metabolic function) have been associated primarily with GFR, this quantitative index may be used to measure any functional changes that result from kidney-related disease progression, therapeutic intervention, or toxic insult.9

Mechanisms of Glucose Homeostasis in the Kidneys

As described in greater detail in the first article in this supplement, maintenance of glucose homeostasis is crucial in preventing pathological consequences that may result from hyperglycemia or hypoglycemia. Chronically uncontrolled hyperglycemia leads to a higher risk of macrovascular and microvascular complications, such as cardiovascular disease, nephropathy, neuropathy, and retinopathy.10 Hypoglycemia, on the other hand, may lead to a myriad of central nervous system complications (eg, confusion, behavioral changes, seizures, loss of consciousness, and even death), since the brain is the body’s largest consumer of glucose in the fasting or “postabsorptive” state.10,11 Maintenance of glucose homeostasis involves several complementary physiologic processes, including glucose absorption (in the gastrointestinal tract), glycogenolysis (in the liver), glucose reabsorption (in the kidneys), gluconeogenesis (in the liver and kidneys), and glucose excretion (in the kidneys).10,12

As alluded to previously, the kidneys are capable of synthesizing and secreting many important hormones (eg, renin, prostaglandins, kinins, erythropoietin) and are involved in a wide variety of metabolic processes such as activation of vitamin D3, gluconeogenesis, and metabolism of numerous endogenous compounds (eg, insulin, steroids).9 With respect to renal involvement in glucose homeostasis, the primary mechanisms include release of glucose into the circulation via gluconeogenesis, uptake of glucose from the circulation to satisfy the kidneys’ energy needs, and reabsorption of glucose at the level of the proximal tubule.13

Glycogenolysis and Gluconeogenesis

Renal release of glucose into the circulation is the result of glycogenolysis and gluconeogenesis. Glycogenolysis involves the breakdown of glycogen to glucose-6-phosphate from precursors (eg, lactate, glycerol, amino acids) and its subsequent hydrolysis (via glucose-6-phosphatase) to free glucose. Conversely, gluconeogenesis involves formation of glucose-6-phosphate from those same precursors and subsequent conversion to free glucose. Interestingly, the liver and skeletal muscles contain most of the body’s glycogen stores, but only the liver contains glucose-6-phosphatase. As such, the breakdown of hepatic glycogen leads to release of glucose, whereas the breakdown of muscle glycogen leads to release of lactate. Lactate (generated via glycolysis of glucose by blood cells, the renal medulla, and other tissues) may be absorbed by organs and reformed into glucose.2

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