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 

-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.

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.

 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.

 These findings have provided considerable insight into the myriad of pathophysiologic mechanisms involved in the development of hyperglycemia and type 2 diabetes mellitus (T2DM).

 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.

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.

 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.

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.

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.

 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.

 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).

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).

 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.

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.

With regard to glucose utilization, the kidney may be perceived as 2 separate organs, with glucose utilization occurring predominantly in the renal medulla and glucose release limited to the renal cortex. These activities are separated as a result of differences in the distribution of various enzymes along the nephron. To this point, cells in the renal medulla (which, like the brain, are obligate users of glucose) have significant glucose-phosphorylating and glycolytic enzyme activity, and can therefore phosphorylate and accumulate glycogen. However, since these cells lack glucose-6-phosphatase and other gluconeogenic enzymes, they cannot release free glucose into the circulation. On the other hand, renal cortex cells do possess gluconeogenic enzymes (including glucose-6-phosphatase), and therefore can make and release glucose into the circulation. But because these cells have little phosphorylating capacity, they cannot synthesize glycogen.

The magnitude of renal glucose release in humans is somewhat unclear, with inconclusive evidence regarding the contribution of the kidneys to total body gluconeogenesis.

 One analysis of 10 published studies concluded that the renal contribution to total body glucose release in the postabsorptive state is approximately 20%. Based on the assumption that gluconeogenesis accounts for approximately half of all circulatory glucose release during the fasting state, renal gluconeogenesis is projected, although not conclusively proven, to potentially be responsible for approximately 40% of all gluconeogenesis.

 Taking into consideration the potential contribution of renal gluconeogenesis, the kidneys appear to play a substantial role in overall glucose release in normal as well as pathophysiologic states (eg, hepatic insufficiency, counterregulation of hypoglycemia). To this point, evidence suggests that in patients with T2DM, renal glucose release is increased in both the postprandial and postabsorptive states, implicating the kidneys’ contribution to the hyperglycemia that characterizes this condition.

 In one study, a 3-fold increase in renal glucose release was observed in patients with diabetes versus those without.

 In contrast, hepatic glucose release increased by only 30% in the diabetic state. Potential mechanisms involved in excessive renal glucose release in T2DM include fasting gluconeogenesis, decreased postprandial insulin release, insulin resistance (known to suppress renal/hepatic insulin release), increased free fatty acid (FFA) concentrations (FFAs stimulate gluconeogenesis), greater availability of gluconeogenic precursors, and increased glycogenolysis.

 Again, it is clear that there is a renal contribution to glucose output in the body, but the actual contribution in individual patients with T2DM is still controversial.

In addition to their important role in gluconeogenesis, the kidneys contribute to glucose homeostasis by filtering and reabsorbing glucose. Under normal conditions, the kidneys retrieve as much glucose as possible, rendering the urine virtually glucose free. The glomeruli filter from plasma approximately 180 grams of 

-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. This maximum capacity, known as the tubular maximum for glucose (TmG), ranges from 260 to 350 mg/min/1.73 m

 in healthy adults and children, and corresponds to a plasma glucose level of approximately 200 mg/dL.

 Once the TmG (the threshold) is reached and transporters are unable to reabsorb all the glucose (as in T2DM), glucosuria ocurrs.

 The correlation between the degree of hyperglycemia and degree of glucosuria becomes linear when blood glucose concentrations have increased beyond a threshold.

 It should be noted that slight differences between individual nephrons and the imprecise nature of biological systems may alter this linear concentration/reabsorption curve, as indicated by a splay from the theoretical as the TmG is approached.

 As such, glucosuria may potentially develop before the expected TmG is reached. Glucosuria may also occur at lower plasma glucose concentrations in certain conditions of hyperfiltration (eg, pregnancy), but as a consequence of hyperfiltration rather than significant hyperglycemia.

The transport of glucose (a polar compound with positive and negative charged areas, making it soluble in water) into and across cells is dependent on specialized carrier proteins in 2 gene families: the facilitated glucose transporters (GLUTs) and the sodium-coupled glucose cotransporters (SGLTs). These transporters control glucose transport and reabsorption in several tissue types, including the proximal renal tubule, small intestine, blood-brain barrier, and peripheral tissues (

 GLUTs are involved in the passive transport of glucose across cell membranes, facilitating its downhill movement as it equilibrates across a membrane. SGLTs, on the other hand, mediate active transport of glucose against a concentration gradient by means of cotransport with sodium. Of the various SGLT proteins expressed in the kidneys, SGLT2 is considered most important; based on animal studies, it is responsible for reabsorbing 90% of the glucose filtered at the glomerulus.

 SGLT1 contributes to the other 10% of glucose reabsorbed in the proximal tubule. This predominant role of SGLT2 in renal reabsorption of glucose raises the prospect of therapeutically blocking this protein in patients with diabetes. Of the various GLUT proteins expressed in the kidneys, GLUT2 is the major transporter, releasing into circulation the glucose reabsorbed by SGLTs in the proximal tubular cells (

In examining disorders involving renal glucose transport, gene mutations within SGLTs lead to inherited disorders of renal glucosuria, including familial (primary) renal glucosuria (FRG) and glucose-galactose malabsorption (GGM). FRG, an autosomal recessive or autosomal dominant disorder resulting from several different SGLT2 mutations, is characterized by persistent glucosuria in the absence of hyperglycemia or general renal tubular dysfunction. Because the majority of patients with FRG have no clinical manifestations, FRG is commonly described as a “nondisease” and is synonymous with the condition known as benign glucosuria. Even the most severe form of FRG (type O), where nonfunctioning mutations within the SGLT2 gene result in a complete absence of renal tubular glucose reabsorption, is associated with a favorable prognosis. Because FRG is generally asymptomatic, affected individuals are identified through routine urinalysis.

GGM, a more serious autosomal recessive disease caused by mutation of the SGLT1 transporter, is characterized by intestinal symptoms that manifest within the first few days of life and result from failure to absorb glucose and galactose from the intestinal tract. The resultant severe diarrhea and dehydration may be fatal if a glucose- and galactose-free diet is not initiated. In some patients with GGM, glucosuria is present but typically mild, while in others, no evidence of abnormal urinary glucose excretion exists, affirming the minor role of SGLT1 in renal glucose reabsorption of glucose.

Gene mutations involving GLUTs are associated with more severe consequences, as these transporters are more widespread throughout the major organ systems. Compared with SGLT2 and SGLT1, which are present mostly in the renal system, GLUT2 is a widely distributed facilitative glucose transporter that has a key role in glucose homeostasis through its involvement in intestinal glucose uptake, renal reabsorption of glucose, glucosensing in the pancreas, and hepatic uptake and release of glucose.

 Mutations of the gene encoding this protein result in Fanconi-Bickel syndrome, a rare autosomal recessive glycogen storage disease that encompasses a multitude of complications (glucose and galactose intolerance, postprandial hyperglycemia, fasting hypoglycemia, tubular nephropathy, hepatomegaly, renomegaly, rickets, and stunted growth). Because GLUT2 is involved in the tubular reabsorption of glucose, glucosuria is a feature of the nephropathy.

While renal glucose reabsorption is a glucose-conserving mechanism in normal physiologic states, it is known to contribute to hyperglycemia in conditions such as T2DM.

 Renal glucose reabsorption tends to increase with plasma glucose levels, up to plasma concentrations of 180 mg/dL to 200 mg/dL.

 Among patients with diabetes, an excess of approximately 13 grams of glucose is taken up from the systemic circulation, of which 85% is attributed to increased renal glucose uptake.

 Evidence suggesting a higher TmG in patients with diabetes compared with healthy controls attests to the increased state of renal glucose reabsorption seen in chronic hyperglycemia, which in turn can increase the risk of microvascular complications.

 Over time, the glomeruli become damaged and are unable to filter blood efficiently and glomerular membranes leak protein (more than 50% of the protein is albumin) into the urine.

 In patients with diabetes, the kidneys may be particularly susceptible to the effects of hyperglycemia, as many kidney cells are unable to sufficiently decrease glucose transport rates to prevent intracellular hyperglycemia in states of increased glucose concentration.

Diabetes has become the most common single cause of endstage renal disease (ESRD) in the United States and Europe; this is most likely due to several evolving factors, including an increased prevalence of T2DM, longer life spans among patients with diabetes, and better formal recognition of renal insufficiency.

 Based on the most current (2008) US statistics from the American Diabetes Association, diabetes accounted for more than 40% of new cases of kidney failure, with 48,374 patients with diabetes beginning treatment for ESRD, and 202,290 people with diabetes-related ESRD on chronic dialysis or undergoing a kidney transplant.

 Compared with patients with type 1 diabetes mellitus, a considerably smaller fraction of those with T2DM progress to ESRD, but due to the much higher prevalence of T2DM, these individuals constitute over half of those with diabetes on dialysis. Considerable racial/ethnic variability exists in this regard, with Native Americans, Hispanics (especially Mexican Americans), and African Americans at much greater risk of developing ESRD than non-Hispanic whites with T2DM.

Dialysis is a very expensive therapy, costing more than $50,000 per patient per year. Total medical spending for the approximately 400,000 patients with ESRD (representing those with and without diabetes) was $22.8 billion in 2001, an almost 3-fold increase over the 1991 to 2001 decade. ESRD spending represents 6.4% of the total Medicare budget, a 33% increase from 4.8% in 1991. The epidemic growth in ESRD cases has led to skyrocketing utilization of healthcare resources.

The earliest clinical evidence of nephropathy is the appearance of low, but abnormal, levels (≥30 mg/day or 20 μg/min) of albumin in the urine (referred to as microalbuminuria).

 Although the course for each patient with T2DM is different, once albumin is detected in the urine, the chance of progression to more persistent albuminuria, progressive decline in GFR, raised arterial blood pressure, and increased cardiovascular morbidity and mortality is increased. Since undetected T2DM may be present for many years, a higher proportion of individuals with T2DM (vs type 1 diabetes mellitus) have microalbuminuria and overt nephropathy shortly after diagnosis. Without specific interventions, 20% to 40% of patients with T2DM and microalbuminuria progress to overt nephropathy; however, within 20 years of onset of overt nephropathy, only 20% will have progressed to ESRD.

 This may be attributable to the greater risk of dying from associated coronary artery disease than progressing to ESRD among the older diabetic population. As interventions for coronary artery disease continue to improve, however, more patients with T2DM may survive long enough to develop renal failure.

Increasing evidence demonstrates that the onset and course of diabetic nephropathy may be significantly altered by several interventions (eg, tight glucose control, use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers), all of which have their greatest impact if instituted early. As such, annual screening for microalbuminuria is critical since it leads to early identification of nephropathy. Well-known data from the Diabetes Control and Complications Trial and the United Kingdom Prospective Diabetes Study established that intensive glycemic control may significantly reduce the risk of developing microalbuminuria and overt nephropathy.

 Recent research (eg, the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE] trial) offers more perspective on the effects of tight glucose control and reduction of nephropathy.

 ADVANCE evaluated progression to major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy) in 11,140 patients with T2DM randomly assigned to undergo standard or intensive glucose control (glycated hemoglobin level ≤6.5%). After a median of 5 years, intensive glucose control produced a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a result of a 21% relative reduction in the risk of developing new or worsening nephropathy. The intensive glucose control group was also associated with a 9% reduction in new onset microalbuminuria, but a higher incidence of severe hypoglycemia (2.7% vs 1.5% in the standard control group). The observed reduction in nephropathy is important, since indices of renal impairment are strongly associated with future risk of major vascular events, ESRD, and death in patients with diabetes.

The regulation of glucose production, uptake, reabsorption, and elimination is handled by several organs, most notably (historically) the pancreas and liver. While not traditionally discussed, the kidneys’ contributions to maintaining glucose homeostasis are multifaceted and include such functions as gluconeogenesis and glucose reabsorption, the latter being mediated by active (SGLT) and passive (GLUT) transporters. Under normal circumstances, glucose filtered by glomeruli is completely reabsorbed, but in conditions of hyperglycemia or reduced resorptive capacity, glucosuria may occur. In hyperglycemia, the kidneys may play an exacerbating role by reabsorbing excess glucose, ultimately contributing to chronic hyperglycemia, and subsequently to pancreatic β-cell failure, insulin resistance, and decreased glucose uptake. Hyperglycemia in turn detrimentally affects the kidneys by damaging glomeruli, ultimately causing microalbuminuria and nephropathy. Knowledge of the kidneys’ role in glucose homeostasis and the effect of glucose dysregulation on the kidneys is critical to optimal management of T2DM and prevention of associated renal complications.

Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio; and Texas Diabetes Institute, San Antonio, TX.

This activity is supported by an educational grant from Bristol-Myers Squibb and AstraZeneca LP.

Dr Triplitt reports being a consultant or a member of the advisory board for Roche and Takeda Pharmaceuticals. He also reports being a member of the speakers’ bureau for Amylin, Eli Lilly, and Pfizer.

Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Address correspondence to: E-mail: Curtis.Triplitt@uhs-sa.com.

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Articles

ARTICLES

Understanding the Kidneys' Role in Blood Glucose Regulation

The prevalence of diabetes mellitus (DM) increased by 49% between 1990 and 2000, reaching nearly epidemic proportions. In 2010, DM (type 1 or 2) was estimated to affect nearly 30% (10.9 million) of people 65 years and older and 215,000 of those younger than 20 years. Macrovascular and microvascular complications can occur; DM is a major cause of heart disease and stroke, and is the seventh leading cause of death in the United States. Based on 2007 data, the economic impact of DM is considerable, with total costs, direct medical costs, and indirect costs estimated at $174 billion, $116 billion, and $58 billion, respectively. Normal glucose regulation is maintained by an intricate interaction between pancreatic β-cells (insulin/amylin), pancreatic α-cells (glucagon), and associated organs (eg, intestines, liver, skeletal muscle, adipose tissue). Newly elucidated mechanisms include the involvement of the kidneys in glucose regulation, as well as central glucose regulation by the brain. The central defects in type 2 diabetes mellitus (T2DM) are decreased insulin secretion, glucoregulatory hormone deficiency/resistance, and insulin resistance, resulting in abnormal glucose homeostasis. This article provides an extensive review of mechanisms involved in physiologic blood glucose regulation and imbalances in glucose homeostasis.

Despite vigorous research aimed at combating type 2 diabetes mellitus (T2DM) and the availability of numerous medications, this disease continues to affect people of all ages, and the prevalence of diabetes mellitus (DM) has reached epidemic proportions. Currently, an estimated 25.8 million individuals are affected by DM (both type 1 and type 2).

 From 1990 to 2000, the prevalence of DM increased by 49%, a rise that appears linked to the increasing rate of obesity.

 In 2010, type 1 or 2 DM was estimated to affect nearly 30% (10.9 million) of people 65 years and older, and 215,000 of those younger than 20 years. Approximately 1.9 million people older than 20 years were newly diagnosed with DM, and up to 45% of newly diagnosed children had T2DM, with the majority being overweight or obese.

In 2005 to 2008, based on fasting glucose or glycated hemoglobin (A1C) levels, 35% of adults older than 20 years, and 50% of those older than 65 years, had prediabetes. Applying this percentage to the entire US population in 2010 yields an estimated 79 million American adults older than 20 years with prediabetes.

DM is a major cause of heart disease and stroke, and is the seventh leading cause of death in the United States. DM is also the leading cause of kidney failure, nontraumatic lower-limb amputations, and new cases of blindness among adults.

 With respect to complications, the rising incidence of T2DM in children is particularly alarming, because as people develop the disease at a younger age, they may experience significant morbidity and potential mortality in their fourth decade of life.

 The aging of the population is also expected to drive a substantial increase in the incidence of DM and associated complications, particularly since research has found that elderly people with newly diagnosed DM experience much higher rates of complications in the years after diagnosis than do their peers without DM.

Based on 2007 data, the economic impact of DM is considerable, with total costs, direct medical costs, and indirect costs (eg, disability, work loss, premature mortality) estimated at $174 billion, $116 billion, and $58 billion, respectively.

 Medical costs attributed to DM include $27 billion for direct care of the disease, $58 billion for treatment of DM-related chronic complications (

), and $31 billion in excess general medical costs.

 The largest components of medical expenditures attributed to DM are hospital inpatient care (50% of total cost), medication and supplies for DM (12%), retail prescriptions for DM complications (11%), and physician office visits (9%). People with diagnosed DM incur average expenditures of $11,744 per year, of which $6649 is attributed directly to the disease.

 After adjusting for population age and sex differences, average medical expenditures among people diagnosed with DM are estimated to be 2.3 times higher than what expenditures would be in the absence of the disease. Factoring in additional costs of undiagnosed DM, prediabetes, and gestational DM brings the total costs of DM to $218 billion, with $18 billion for people with undiagnosed DM, $25 billion for adults with prediabetes, and $623 million for women with gestational DM.

 The burden of DM is imposed on all sectors of society, through, for example, higher insurance premiums paid by employees and employers, reduced earnings as a result of productivity loss, and reduced overall quality of life for patients and their families.

In broad terms, the most recognized pathophysiologic defects in T2DM are decreased insulin secretion and insulin resistance, but in order to fully examine these and other pathophysiologic origins of DM, it is critical to review the mechanisms involved in normal and abnormal glucose homeostasis.

Glucose, a fundamental source of cellular energy, is released by the breakdown of endogenous glycogen stores that are primarily located in the liver. Glucose is also released indirectly in the muscle through intermediary metabolites. These whole-body energy stores are replenished from dietary glucose, which, after being digested and absorbed across the gut wall, is distributed among the various tissues of the body.

 Although glucose is required by all cells, its main consumer is the brain in the fasting or “postabsorptive” phase, which accounts for approximately 50% of the body’s glucose use. Another 25% of glucose disposal occurs in the splanchnic area (liver and gastrointestinal tissue), and the remaining 25% takes place in insulin-dependent tissues, including muscle and adipose tissue.

 Approximately 85% of endogenous glucose production is derived from the liver, with glycogenolysis (conversion of glycogen to glucose) and gluconeogenesis (glucose formation) contributing equally to the basal rate of hepatic glucose production. The remaining ~15% of glucose is produced by the kidneys.

Normally, following glucose ingestion, the increase in plasma glucose concentration triggers insulin release, which stimulates splanchnic and peripheral glucose uptake and suppresses endogenous (primarily hepatic) glucose production. In healthy adults, blood glucose levels are tightly regulated within a range of 70 to 99 mg/dL, and maintained by specific hormones (eg, insulin, glucagon, incretins) as well as the central and peripheral nervous system, to meet metabolic requirements.

 Various cells and tissues (within the brain, muscle, gastrointestinal tract, liver, kidney, and adipose tissue) are also involved in blood glucose regulation by means of uptake, metabolism, storage, and excretion (

 This highly controlled process of glucose regulation may be particularly evident during the postprandial period, during which, under normal physiologic circumstances, glucose levels rarely rise beyond 140 mg/dL, even after consumption of a high-carbohydrate meal.

Among the various hormones involved in glucose regulation, insulin and glucagon (both produced in the pancreas by islets of Langerhans) are the most relevant.

 Within the islets of Langerhans, β-cells produce insulin and α-cells produce glucagon. Insulin, a potent antilipolytic (inhibiting fat breakdown) hormone, is known to reduce blood glucose levels by accelerating transport of glucose into insulin-sensitive cells and facilitating its conversion to storage compounds via glycogenesis (conversion of glucose to glycogen) and lipogenesis (fat formation).

 Glucagon, which also plays a central role in glucose homeostasis, is produced in response to low normal glucose levels or hypoglycemia and acts to increase glucose levels by accelerating glycogenolysis and promoting gluconeogenesis.

 After a glucose-containing meal, however, glucagon secretion is inhibited by hyperinsulinemia, which contributes to suppression of hepatic glucose production and maintenance of normal postprandial glucose tolerance.

 The hormone amylin contributes to reduction in postprandial glucagon, as well as modest slowing of gastric emptying.

Incretins, which include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), are also involved in regulation of blood glucose, in part by their effects on insulin and glucagon.

 However, both GLP-1 and GIP are considered glucose-dependent hormones, meaning that they are secreted only when glucose levels rise above normal fasting plasma glucose levels; they do not directly stimulate insulin secretion. Normally, these hormones are released in response to meals and, by activating certain receptors (G protein—coupled) on pancreatic β-cells, they aid in stimulation of insulin secretion. When glucose levels are low, however, GLP-1 and GIP levels (and their stimulating effects on insulin secretion) are diminished.

Since glucose cannot readily diffuse through (impermeable) cell membranes, it requires assistance from both insulin and a family of transport proteins (facilitated glucose transporter [GLUT] molecules) in order to gain entry into most cells.

 Essentially, GLUTs act as shuttles, forming an aqueous pore across otherwise hydrophobic cellular membranes, through which glucose can move more easily.

 Of the 12 known GLUT molecules, GLUT4 is considered the major transporter for adipose, muscle, and cardiac tissue, whereas GLUTs 1, 2, 3, and 8 facilitate glucose entry into other organs (eg, brain, liver), though we continue to learn more about the role of GLUTs in DM.

 Activation of GLUT4 and, in turn, facilitated glucose diffusion into muscle and adipose tissue, is dependent on the presence of insulin, whereas the function of other GLUTs is more independent of insulin.

 Once glucose enters cells, it is phosphorylated (via glucokinase in the liver and hexokinase in most other cells), after which it cannot diffuse out of cells and can then be either used for energy production or converted to a storage compound (ie, glycogen, fat).

Major Systems Involved in Glucose Utilization and Regulation

The majority of glucose uptake (≥80%) in peripheral tissue occurs in muscle, where glucose may either be used immediately for energy or stored as glycogen.

 As stated previously, skeletal muscle is insulin-dependent, and thus requires insulin for activation of the major enzyme (glycogen synthase) that regulates production of glycogen.

 While adipose tissue is responsible for a much smaller amount of peripheral glucose uptake (2%-5%), it plays an important role in the maintenance of total body glucose homeostasis by regulating the release of free fatty acids (which increase gluconeogenesis) from stored triglycerides, influencing insulin sensitivity in the muscle and liver.

While the liver does not require insulin to facilitate glucose uptake, it does need insulin to regulate glucose output.

 So, for example, when insulin concentrations are low, hepatic glucose output rises.

 Additionally, insulin helps the liver store most of the absorbed glucose in the form of glycogen.

The kidneys are increasingly recognized to play an important role in glucose homeostasis via release of glucose into the circulation (gluconeogenesis), uptake of glucose from the circulation to meet renal energy needs, and reabsorption of glucose at the proximal tubule.

 The kidneys also aid in elimination of excess glucose (when levels exceed approximately 180 mg/dL, though this threshold may rise during chronic hyperglycemia) by facilitating its excretion in the urine.

 In DM, where glucose levels are high and may exceed the threshold of glucose reabsorption, more glucose may be excreted in the urine if concentrations in filtered urine become high.

DM is a group of metabolic diseases characterized by hyperglycemia. The hallmark state of chronic hyperglycemia is associated with long-term damage, dysfunction, and potential failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels.

 Numerous factors contribute to the development of T2DM, with the central defects being inadequate insulin secretion (insulin deficiency) and/ or diminished tissue responses to insulin (insulin resistance) at 1 or more points in the complex pathways of hormone action.

 Insulin deficiency and insulin resistance frequently coexist, though the contribution to hyperglycemia can vary widely along the spectrum of T2DM.

The pancreas has a remarkable capacity to adapt to conditions of increased insulin demand (eg, in obesity, pregnancy, cortisol excess) to maintain normoglycemia. Compensatory hyperinsulinemia maintains glucose homeostasis. However, when β-cell secretion of insulin becomes inadequate for the glucose load, hyperglycemia occurs. Progressive deterioration in β-cell function and mass is well known to occur over time in T2DM and the resultant state of impaired insulin secretion is found uniformly in T2DM patients of all ethnic backgrounds.

 Research has shown that at time of diagnosis, islet cell function/responsiveness to glucose is approximately 30% to 50% of normal, and β-cell mass is reduced by about 60%; both of these are important determinants of the amount of insulin that is secreted.

 Based on analyses from the United Kingdom Prospective Diabetes Study, a direct correlation exists between progressive loss in β-cell function and poor glycemic control (as measured by A1C levels).

 The major factors implicated in progressive loss of β-cell function and mass include glucotoxicity, lipotoxicity, proinflammatory cytokines, leptin, and islet cell amyloid. Research indicates that progressive impaired β-cell function and possibly β-cell mass may be arrested, though clinical evidence in humans remains scarce.

Impaired insulin secretion is often exacerbated by insulin resistance, which is characterized by the inability of insulin to decrease plasma glucose levels through suppression of hepatic glucose production and stimulation of glucose utilization in skeletal muscle and adipose tissue.

 In the presence of physiologically possible levels of insulin in humans, there is decreased glucose uptake in subjects with T2DM versus normal subjects, confirming that glucose uptake is severely impaired due to insulin resistance (

 As a consequence of insulin resistance, inefficient glucose utilization is eventually replaced by cellular utilization of fats and proteins for energy. Insulin resistance is contributed to by genetic and environmental factors. Family history can contribute directly to insulin resistance, but multiple environmental factors such as obesity, comorbidities, and central adiposity (visceral) can all contribute. The exact cause of insulin resistance in any given patient is complex, but may include defects in insulinmediated cell signaling pathways, reduced insulin-stimulated muscle glycogen synthesis,

 or even potentially fewer insulin receptors (particularly in skeletal muscle, liver, and adipose tissue in obese subjects).

The relative contribution of insulin secretion and insulin resistance to the development of hyperglycemia may differ due to the heterogeneity of T2DM. Under most circumstances, insulin resistance is the earliest detectable defect in individuals with prediabetes.

 Initially, enhanced insulin secretion may compensate for the insulin resistance; however, early phase insulin secretion is impaired. In the transition from normal glucose tolerance to impaired glucose tolerance and DM, insulin sensitivity deteriorates about 40%, whereas insulin secretion deteriorates 3- to 5-fold.

 In DM, chronic hyperglycemia may result in further deterioration of insulin sensitivity and secretion (glucotoxicity), which is aggravated by elevated free fatty acids (lipotoxicity).

Other increasingly more well-understood mechanisms contributing to the pathophysiology of T2DM include increased hepatic glucose output and adipocyte dysfunction. Following glucose ingestion, insulin is normally secreted into the portal vein, where it is taken up by the liver and suppresses hepatic glucose output. However, if the liver does not perceive this insulin signal and continues to produce glucose, the 2 sources of glucose input (from the liver and the gastrointestinal tract) will result in marked hyperglycemia.

 The increased hepatic glucose output seen in T2DM is thought to be related partly to insulin resistance and is closely correlated with the severity of fasting hyperglycemia. To the latter point, it has been shown that while the postabsorptive level of chronic hyperinsulinemia seen in mild hyperglycemia (<140 mg/dL) is enough to offset hepatic insulin resistance and maintain a normal basal rate of hepatic glucose output, moderate fasting hyperglycemia is associated with significant increases in hepatic glucose output.

 In individuals with T2DM with overt fasting hyperglycemia (>140 mg/dL), an excessive rate of hepatic glucose output is considered the major abnormality responsible for the elevated fasting plasma glucose.

 Although hyperinsulinemia and hyperglycemia (both certainly present in T2DM) are potent inhibitors of hepatic glucose output, they do not appear to fully correct excessive glucose output by the liver, which is suggestive of existing hepatic resistance to insulin and potential hyperglucagonemia contributing to an elevated plasma glucose.

With regard to adipocyte dysfunction, considerable evidence implicates deranged metabolism and altered disposition of fat in the pathogenesis of glucose intolerance in T2DM.

 Because fat cells are resistant to insulin’s antilipolytic effect, the resultant chronically elevated plasma free fatty acid levels stimulate gluconeogenesis, induce hepatic/ muscle insulin resistance, and impair insulin secretion in predisposed individuals.

 These free fatty acid—induced disturbances are referred to as lipotoxicity. Beyond this phenomenon, dysfunctional fat cells also produce excessive amounts of insulin resistance–inducing, inflammatory, and atherosclerotic-provoking cytokines and fail to secrete normal amounts of insulin-sensitizing adipocytokines (adiponectin).

 Also, the pattern of fat disposition in T2DM is abnormal, essentially because enlarged adipocytes (in visceral fat) are insulin-resistant and have diminished capacity to store fat, which leads to lipid overflow into muscle, liver, and potentially β-cells, further exacerbating muscle/hepatic insulin resistance and impaired insulin secretion. They are also major sources of proinflammatory adipocytokines. Within liver cells, the elevated free fatty acids are converted to triglycerides, which accumulate and cause steatosis (or fatty liver) and consequently may increase the chances of nonalcoholic steatohepatitis (NASH) and even cirrhosis.

 These disturbances in adipocyte function are particularly relevant in light of the fact that many individuals with T2DM are obese.

The development of glucose intolerance in T2DM involves multiple systems including the muscle, liver, β-cell, fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance).

 Collectively, these 8 players comprise the ominous octet and dictate the need for combination therapy. Treatment should be based upon reversal of known pathogenic abnormalities and should not be directed simply at the reduction of A1C. Early initiation of therapy may help to prevent or slow progressive β-cell failure.

The majority of patients with T2DM are either obese (with obesity itself contributing to insulin resistance) or have an increased proportion of body fat in the abdominal region. Many factors increase the risk of developing T2DM, including family history, age, obesity, and lack of physical activity. Also, DM occurs more frequently in women with prior gestational DM and in individuals with hypertension or dyslipidemia.

 T2DM is frequently undiagnosed for many years, since the hyperglycemia develops gradually and, at least in the early stages, is not severe enough to cause clinical symptoms. Symptoms of marked hyperglycemia include polyuria, polydypsia, weight loss, polyphagia, and blurred vision.

Although the degree of hyperglycemia seen with T2DM may not cause symptoms initially, it is sufficient to cause pathologic and functional changes in target tissues, and as such, will increase the risk of microvascular and macrovascular complications.

 Hyperglycemia, or long-term glycemic burden, appears to be cumulative, increasing the chances of complications with longer exposure. These long-term complications include retinopathy with potential loss of vision; nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputations, and Charcot joints; and autonomic neuropathy causing gastrointestinal, genitourinary, and cardiovascular symptoms and sexual dysfunction. Diabetic patients also have an increased incidence of atherosclerotic cardiovascular, peripheral arterial, and cerebrovascular disease.

Glucose, a vital energy source for many cells and tissues, is tightly regulated via a complex interaction between pancreatic β-cells and α-cells, associated organs (eg, intestines, liver, skeletal muscle, adipose tissue), and respective hormones (ie, insulin, glucagon, GLP-1, GIP, amylin, and others). A summary of the major factors responsible for maintenance of normal glucose tolerance in healthy subjects is provided in the 

 Beyond these primary controllers of glucose regulation, incretin hormones (GIP and GLP-1) further assist in maintenance of normal plasma glucose and a host of transport proteins (GLUT molecules) facilitate movement of glucose through otherwise impermeable cellular membranes. The primary tissues involved in glucose utilization include the brain, muscle, fat, and the splanchnic area, with muscle tissue comprising the most important site of peripheral glucose uptake.

Knowledge of the fundamentals of normal glucose homeostasis is essential to understanding the pathophysiologic derangements that may result from glucose imbalance disorders. Conditions such as T2DM are characterized by an imbalance in glucose regulation, causing chronic hyperglycemia and ultimately leading to multiorgan damage. Several factors are implicated in the development of T2DM, including insulin resistance, insulin deficiency, increased hepatic glucose production, and adipocyte dysfunction. An increasingly clear understanding of these derangements has helped both researchers and clinicians to better manage T2DM and improve clinical outcomes.

 Department of Medicine, Division of Diabetes, University of Texas Health Science Center at San Antonio; and Texas Diabetes Institute, San Antonio, TX.

 This activity is supported by an educational grant from Bristol-Myers Squibb and AstraZeneca LP.

 Dr Triplitt reports being a consultant or a member of the advisory board for Roche and Takeda Pharmaceuticals. He also reports being a member of the speakers’ bureau for Amylin, Eli Lilly, and Pfizer.

 Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content. Address correspondence to: E-mail: Curtis.Triplitt@uhs-sa.com.

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Examining the Mechanisms of Glucose Regulation

After reading “Understanding the Mechanisms to Maintain Glucose Homeostasis: A Review for Managed Care,” complete the program evaluation and select the 1 best answer to each of the posttest questions.

A statement of continuing education hours will be provided to those physicians and pharmacists who successfully complete and return the answer form and program evaluation and receive a passing grade of 70% or higher.

CE/CME QUIZ

Understanding the Mechanisms to Maintain Glucose Homeostasis: A Review for Managed Care

 explores mechanisms involved in physiologic blood glucose regulation and imbalances in glucose homeostasis, including the mechanisms by which the kidneys contribute to glucose regulation and the potential impact of glucose imbalance on the kidneys. Specific pharmacologic agents are also discussed, in the context of guidelines from the American Diabetes Association and the European Association for the Study of Diabetes as well as relevant clinical studies. An extensive update on the newest drugs for the management of type 2 diabetes mellitus and managed care aspects of diabetes care is also included.

Assistant Clinical Professor, Clinical Pharmacy Practice

College of Pharmacy and Allied Health Professions

University of Texas Health Science Center at San Antonio

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Consultant/Advisory Board: Roche, Takeda Pharmaceuticals

Understanding the Mechanisms to Maintain Glucose Homeostasis: A Review for Managed Care [CPE]

Understanding the Kidneys' Role in Blood Glucose Regulation

Examining the Mechanisms of Glucose Regulation

Understanding the Mechanisms to Maintain Glucose Homeostasis: A Review for Managed Care

Participating Faculty: Understanding the Mechanisms to Maintain Glucose Homeostasis: A Review for Managed Care

Review of Current and Emerging Therapies in Type 2 Diabetes Mellitus