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Understanding the Kidneys' Role in Blood Glucose Regulation

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Understanding the Kidneys' Role in Blood Glucose Regulation n REPORTS n Understanding the Kidneys’ Role in Blood Glucose Regulation Curtis L. Triplitt, PharmD, CDE ublished studies over the last 60 years have provided considerable evidence regarding the ability of the kid- Abstract neys to make and release glucose under various physi- While not traditionally discussed, the kid- ologic conditions. Yet traditionally, the kidneys have neys’ contributions to maintaining glucose Pnot been considered an important source of glucose (except during homeostasis are significant and include acidosis or after prolonged fasting), with most clinical discussions such functions as release of glucose into on glucose dysregulation centering on the intestine, pancreas, the circulation via gluconeogenesis, uptake liver, adipose tissue, and muscle.1-3 More recently, however, the of glucose from the circulation to satisfy full significance of the kidneys’ contribution to glucose homeosta- their energy needs, and reabsorption of glucose at the level of the proximal tubule. sis, under both physiologic and pathologic conditions, has become Renal release of glucose into the circula- well recognized, and is thought to involve functions well beyond tion is the result of glycogenolysis and glucose uptake and release. Besides the liver, the kidney is the gluconeogenesis, respectively involving the only organ capable of generating sufficient glucose (gluconeogen- breaking down and formation of glucose- esis) to release into ©the Managed circulation, Care and it & is also responsible for 6-phosphate from precursors (eg, lactate, glycerol, amino acids). With regard to filtration and subsequent reabsorption or excretion of glucose.2-4 Healthcare Communications, LLC renal reabsorption of glucose, the kidneys These findings have provided considerable insight into the myriad normally retrieve as much glucose as pos- of pathophysiologic mechanisms involved in the development of sible, rendering the urine virtually glucose hyperglycemia and type 2 diabetes mellitus (T2DM).5,6 This article free. The glomeruli filter from plasma provides a review of the kidneys’ role in normal human physiology, approximately 180 grams of D-glucose per the mechanisms by which they contribute to glucose regulation, day, all of which is reabsorbed through glucose transporter proteins that are pres- and the potential impact of glucose imbalance on the kidneys. ent in cell membranes within the proximal tubules. If the capacity of these transporters Overview of Renal Physiology is exceeded, glucose appears in the urine. The kidneys are essentially designed to filter large quantities The process of renal glucose reabsorption of plasma, reabsorb substances that the body must conserve, and is mediated by active (sodium-coupled glu- cose cotransporters) and passive (glucose secrete substances that must be eliminated. These basic functions transporters) transporters. In hyperglyce- are critical to regulation of fluid and electrolyte balance, body mia, the kidneys may play an exacerbating fluid osmolality, acid-based balance, excretion of metabolic waste role by reabsorbing excess glucose, ulti- and foreign chemicals, arterial pressure, hormone secretion, and, mately contributing to chronic hyperglyce- most relevant to this discussion, glucose balance.7,8 The 2 kidneys mia, which in turn contributes to chronic produce a total of approximately 120 mL/min of ultrafiltrate, yet glycemic burden and the risk of microvas- cular consequences. This article provides only 1 mL/min of urine is produced. The basic urine-forming unit an extensive review of the kidneys’ role in of the kidney is the nephron, which serves to filter water and normal human physiology, the mechanisms small solutes from plasma and reabsorb electrolytes, amino acids, by which they contribute to glucose regula- glucose, and protein. The nephron, of which there are approxi- tion, and the potential impact of glucose mately 1 million in each kidney, consists of a filtering apparatus imbalance on the kidneys. (the glomerulus) that is connected to a long tubular portion that (Am J Manag Care. 2012;18:S11-S16) reabsorbs and conditions the glomerular ultrafiltrate. Fluid filtered For author information and disclosures, see end of text. from the glomerular capillaries flows into the tubular portion, which is made up of a proximal tubule, the Loop of Henle, and VOL. 18, NO. 1 n THE AMERICAN JOURNAL OF MANAGED CARE n S11 Reports the distal tubule, all of which assist in reabsorbing essential from precursors (eg, lactate, glycerol, amino acids) and its substances and converting filtered fluid into urine.7 subsequent hydrolysis (via glucose-6-phosphatase) to free Evaluation of renal function is an important part of care, glucose. Conversely, gluconeogenesis involves formation of and with that, creatinine clearance (CrCl) or glomerular glucose-6-phosphate from those same precursors and subse- filtration rate (GFR), most frequently estimated (eGFR), quent conversion to free glucose. Interestingly, the liver and are considered most useful in determining the degree of skeletal muscles contain most of the body’s glycogen stores, renal insufficiency and the stage of chronic kidney disease but only the liver contains glucose-6-phosphatase. As such, in accordance with the National Kidney Foundation clas- the breakdown of hepatic glycogen leads to release of glucose, sification system. Since alterations in all renal functions whereas the breakdown of muscle glycogen leads to release of (ie, filtration, secretion, reabsorption, endocrine and meta- lactate. Lactate (generated via glycolysis of glucose by blood bolic function) have been associated primarily with GFR, this cells, the renal medulla, and other tissues) may be absorbed quantitative index may be used to measure any functional by organs and reformed into glucose.2 changes that result from kidney-related disease progression, With regard to glucose utilization, the kidney may be therapeutic intervention, or toxic insult.9 perceived as 2 separate organs, with glucose utilization occur- ring predominantly in the renal medulla and glucose release Mechanisms of Glucose Homeostasis in the Kidneys limited to the renal cortex. These activities are separated as As described in greater detail in the first article in this a result of differences in the distribution of various enzymes supplement, maintenance of glucose homeostasis is crucial in along the nephron. To this point, cells in the renal medulla preventing pathological consequences that may result from (which, like the brain, are obligate users of glucose) have hyperglycemia or hypoglycemia. Chronically uncontrolled significant glucose-phosphorylating and glycolytic enzyme hyperglycemia leads to a higher risk of macrovascular and activity, and can therefore phosphorylate and accumulate microvascular complications, such as cardiovascular disease, glycogen. However, since these cells lack glucose-6-phospha- nephropathy, neuropathy, and retinopathy.10 Hypoglycemia, tase and other gluconeogenic enzymes, they cannot release on the other hand, may lead to a myriad of central nervous free glucose into the circulation. On the other hand, renal system complications (eg, confusion, behavioral changes, cortex cells do possess gluconeogenic enzymes (including glu- seizures, loss of consciousness, and even death), since the cose-6-phosphatase), and therefore can make and release glu- brain is the body’s largest consumer of glucose in the fasting cose into the circulation. But because these cells have little or “postabsorptive” state.10,11 Maintenance of glucose homeo- phosphorylating capacity, they cannot synthesize glycogen.2 stasis involves several complementary physiologic processes, The magnitude of renal glucose release in humans is including glucose absorption (in the gastrointestinal tract), somewhat unclear, with inconclusive evidence regarding the glycogenolysis (in the liver), glucose reabsorption (in the kid- contribution of the kidneys to total body gluconeogenesis.4 neys), gluconeogenesis (in the liver and kidneys), and glucose One analysis of 10 published studies concluded that the renal excretion (in the kidneys).10,12 contribution to total body glucose release in the postabsorp- As alluded to previously, the kidneys are capable of syn- tive state is approximately 20%. Based on the assumption thesizing and secreting many important hormones (eg, renin, that gluconeogenesis accounts for approximately half of all prostaglandins, kinins, erythropoietin) and are involved in circulatory glucose release during the fasting state, renal glu- a wide variety of metabolic processes such as activation of coneogenesis is projected, although not conclusively proven, vitamin D3, gluconeogenesis, and metabolism of numerous to potentially be responsible for approximately 40% of all endogenous compounds (eg, insulin, steroids).9 With respect gluconeogenesis.2 Taking into consideration the potential to renal involvement in glucose homeostasis, the primary contribution of renal gluconeogenesis, the kidneys appear mechanisms include release of glucose into the circulation to play a substantial role in overall glucose release in normal via gluconeogenesis, uptake of glucose from the circulation to as well as pathophysiologic states (eg, hepatic insufficiency, satisfy the kidneys’ energy needs, and reabsorption of glucose counterregulation of hypoglycemia). To this point, evidence at the level of the proximal tubule.13 suggests that in patients with T2DM, renal glucose release is increased in both the postprandial and postabsorptive
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