Their effects on the kidneys regarding glucose release in humans are not completely deciphered. In the postprandial state the situation changes significantly. Postprandial glucose levels in the plasma are determined by insulin and glucagon levels. After glucose ingestion, plasma glucose levels reach the peak in 60—90 minutes and they return to post-absorptive levels in almost 3—4 h.
Meyer et al. This is happening because this period determines the refilling of hepatic glycogen stores and inhibition of endogenous glucose release is able to limit postprandial hyperglycaemia. This mechanism is believed to facilitate the repletion of glycogen stocks in the liver. A new concept of hepatorenal glucose reciprocity emerged from the differences observed in regulation and interchange between renal and hepatic glucose release [ 24 ].
This concept refers to the facts that a pathological or physiological reduction in glucose release by kidney or liver determines a compensatory increase in glucose release of the other one liver or kidney in order to avoid hypoglycaemia. This situation occurs in the anhepatic phase during liver transplantation, prolonged fasting, meal ingestion, acidosis and insulin overdoses in diabetes mellitus [ 24 ].
Glycogenolysis is the breakdown of glycogen to glucosephosphate and a hydrolysis reaction using glucosephosphatase in order to free glucose. The liver is the only organ that contains glucosephosphatase. So, the cleavage of hepatic glycogen releases glucose, while the cleavage of glycogen from other sources can release only lactate.
Lactate, that is generated via glycolysis, is often absorbed by other organs and helps regenerating glucose [ 6 ]. Apart from the important role in gluconeogenesis and the role of renal cortex in glucose uptake, the kidneys contribute to glucose homeostasis by filtering and reabsorbing glucose. In normal conditions, the kidneys can reabsorb as much glucose as possible, the result being a virtually glucose free urine. Approximately grams of glucose are filtered by the glomeruli from plasma, daily but all of this quantity is reabsorbed through glucose transporters that are present in cell membranes located in the proximal tubules [ 24 ].
These glucose transporters have a limited capacity of reabsorption. If this capacity is exceeded, glucose usually appears in the urine. When the blood glucose is very high and the TmG is reached, the transporters cannot reabsorb all the glucose and glucosuria occurs Figure 2.
Nevertheless, there can be slight differences between the nephrons and the inaccurate nature of biological systems may potentially lead to the development of glucosuria when blood glucose is below TmG. Glucosuria may occur at lower plasma glucose levels in certain conditions of hyperfiltration eg. Renal glucose handling. TmG, transport maximum for glucose. Adapted from [ 26 ]. In a given day, the kidneys can produce, via gluconeogenesis, 15—55g glucose and it can metabolize 25—35g glucose.
Regarding the glucose metabolic pathways, it is obvious that renal reabsorption represents the main mechanism by which the kidney is involved in glucose homeostasis. Therefore, the change in tubular glucose reabsorption may have a considerable impact on glucose homeostasis [ 4 ]. Glucose is a polar compound with positive and negative charged areas; therefore it is soluble in water. Its transport into and across cells is dependent on two specialized carrier protein families: the GLUTs facilitated glucose transporters and the SGLTs sodium-coupled glucose cotransporters.
These transporters are responsible for glucose passage and reabsorption in several tissue types, including the proximal renal tubule, blood-brain barrier, small intestine [ 27 ].
GLUTs are responsible for the passive transport of glucose across cell membranes, in order to equilibrate its concentrations across a membrane. SGLTs, on the other hand, are involved in active transport of glucose against a concentration gradient by means of sodium-glucose cotransport [ 27 ].
The sodium glucose co-transporter family adapted from [ 27 ]. The renal glucose transport was investigated by analyzing the gene mutations within SGLT family.
These can lead to several inherited diseases presenting renal glucosuria that include familial renal glucosuria FRG and glucose-galactose malabsorption GGM. Its main characteristic is persistent glucosuria without hyperglycemia or renal tubular dysfunction. Nevertheless, there is a severe form of FRG, known as type O, where mutations of the SGLT2 gene lead to a complete lack of renal tubular glucose reabsorption. This condition is still associated with a good prognosis.
Due to the fact that FRG is mainly asymptomatic, subjects with this condition are discovered through routine urinalysis [ 24 ]. Glucose filtration and reabsorption in the proximal tubule of the kidney adapted from [ 28 ]. GGM represents a more serious disease. It is inherited autosomal recessive and is caused by mutation of the SGLT1 transporter.
Its main characteristics are represented by intestinal symptoms. They appear in the first few days of life and determine glucose and galactose malabsorption.
The consequences are severe; diarrhea and subsequent dehydration may become fatal unless a special diet glucose- and galactose-free is initiated. Some patients with GGM may present glucosuria but it is typically mild, and some other subjects have no sign of urinary glucose excretion.
This confirms that SGLT1 has a minor role in renal reabsorption of glucose [ 24 ]. The mutations involving the GLUT family are associated with more severe consequences, because these transporters are more widespread throughout the major organ systems. SGLT2 and SGLT1 are located mainly in the renal system, but GLUT2 is present almost everywhere in the organism, having an important role in glucose homeostasis through its involvement in intestinal glucose uptake, renal reabsorption of glucose, and hepatic uptake and release of glucose [ 24 ].
Direct in vivo experiments of Vallon et al. According to this study, in wild-type mice, The results of the study of Gorboulev et al. All the metabolic pathways regarding the involvement of the kidney in glucose homeostasis are modified in subjects with diabetes mellitus. Subjects with type 2 diabetes mellitus T2DM have an increased renal release of glucose into the circulation in the fasting state [ 34 ]. Although one can think that the liver determines increased glucose release into the circulation in diabetes, the liver and the kidneys have comparable increase in renal glucose release 2.
Gluconeogenesis, in the kidney, could explain this glucose increase, in the fasting state [ 34 ]. In postprandial state, renal glucose release is greater increased in subjects with T2DM than in people without glucose metabolism abnormalities [ 35 ]. They found that it was significantly greater in diabetic patients than in normal subjects The result was determined by a higher endogenous glucose release because the general appearance of ingested glucose was only 7 g greater in the subjects with DM.
This fact was determined mainly by impaired suppression of endogenous glucose release and secondary by reduced initial splanchnic sequestration of ingested glucose.
This effect is expected in diabetic patients that have decreased postprandial insulin release and insulin resistance, taking into account that renal glucose release is regulated by insulin [ 4 ]. Both renal glucose uptake and glucose production are increased in both the postprandial and post-absorptive states in diabetic patients [ 35 ]. Over time, high sugar levels in the blood can cause these vessels to become narrow and clogged.
Without enough blood, the kidneys become damaged and albumin a type of protein passes through these filters and ends up in the urine where it should not be. Nerves in your body. Diabetes can also cause damage to the nerves in your body. Nerves carry messages between your brain and all other parts of your body, including your bladder.
They let your brain know when your bladder is full. But if the nerves of the bladder are damaged, you may not be able to feel when your bladder is full. The pressure from a full bladder can damage your kidneys. Urinary tract. If urine stays in your bladder for a long time, you may get a urinary tract infection. This is because of bacteria. Bacteria are tiny organisms like germs that can cause disease.
They grow rapidly in urine with a high sugar level. Most often these infections affect the bladder, but they can sometimes spread to the kidneys. How do I know if I have kidney damage? If I have diabetes and kidney damage, what should I do?
The following things can help your kidneys work better and last longer: Controlling your blood sugar The best way to prevent or slow kidney damage is to keep your blood sugar well controlled. This is usually done with diet, exercise, and, if needed, insulin or hypoglycemic pills to lower your blood sugar level. Controlling high blood pressure High blood pressure can increase your chances of getting kidney failure. Plasma glucose concentrations are determined by the relative rates of glucose entry into, and removal from, the circulation.
Normally, despite wide daily fluctuations in the rate of delivery of glucose into the circulation e. This is in contrast to other substrates such as glycerol, lactate, free fatty acids FFAs and ketone bodies, for which daily fluctuation is much greater 5. Teleologically, this can be explained by the fact that, on the one hand, the body must defend itself from hyperglycaemia, which is associated with both chronic effects including retinopathy, neuropathy, nephropathy and premature atherosclerosis 6 — 9 and acute effects including diabetic ketoacidosis and hyperosmolar hyperglycaemic state, which have significant associated morbidity and mortality ; on the other hand, the body must also defend itself against hypoglycaemia, which can cause cardiac arrhythmias, neurological dysfunction, coma, seizures and death Brain function is particularly dependent on having adequate levels of plasma glucose because the brain is unable to either store or produce glucose and alternative sources of energy are either in short supply e.
FFAs The precise regulation of plasma glucose concentrations is mainly determined by hormonal and neural factors, which regulate endogenous production of glucose Acute glucoregulatory mechanisms involve insulin, glucagon and catecholamines, which can effect changes in plasma glucose levels over a matter of minutes. Glucagon has no effect on the kidney, but increases both gluconeogenesis and glycogenolysis in the liver Catecholamines have multiple acute actions, including stimulation of renal glucose release, inhibition of insulin secretion, stimulation of glucagon secretion, and increases in gluconeogenic substrate supply, stimulation of lipolysis and reduced tissue glucose uptake.
Growth hormone, thyroid hormone and cortisol influence glucose levels over a period of hours by altering the sensitivity of the liver, kidney, adipose tissue and muscle to insulin, glucagon and catecholamines, and by altering the activity of key enzymes, which effect glycogen stores and availability of gluconeogenic precursors lactate, glycogen and amino acids In the post-absorptive state, glucose uptake by tissues is largely dependent on tissue needs and the mass-action effects of the ambient plasma glucose concentration and, to a lesser extent, on the permissive actions of insulin and counter-regulatory hormones e.
In these circumstances, most uptake of glucose occurs in tissues that do not require insulin e. Proportion of glucose utilization as a result of specific tissues in the fasting and postprandial state 5 , The kidney is unable to release glucose through glycogenolysis because it contains very little glycogen and those renal cells that are able to synthesize glycogen lack the enzyme glucosephosphatase and therefore cannot release glucose In humans, only the liver and kidney contain significant amounts of the enzyme glucosephosphatase and therefore are the only organs that are able to perform gluconeogenesis.
As the duration of fasting increases, glycogen stores in the liver become further depleted until, after 48 h, virtually all the glucose released into the circulation is derived from gluconeogenesis 4 , Consequently, as the length of fast increases, the proportion of overall glucose release accounted for by renal gluconeogenesis increases Mechanisms and sources of glucose release into the circulation in the post-absorptive state 10 , 13 , It is important to note that kidney and liver differ in their use of gluconeogenic precursors and the effect of hormones on their release of glucose.
Utilization of substrates for gluconeogenesis With respect to hormonal influences, insulin suppresses glucose release by both organs with roughly comparable efficacy 18 , whereas glucagon normally stimulates hepatic glucose release only, mainly via an early action on glycogenolysis Catecholamines normally exert a direct effect on renal glucose release only 19 , 20 , although they may indirectly affect both hepatic and renal glucose release by increasing availability of gluconeogenic substrates and by suppressing insulin secretion.
Cortisol, growth hormone and thyroid hormones have long-term stimulatory influences on hepatic glucose release over a period of days Their effects on renal glucose release in humans have yet to be determined. Classically, metabolic studies have usually been undertaken in the post-absorptive state i. However, most of the day people are in the postprandial state as this includes 4—6 h on three occasions during the day.
Postprandial plasma glucose levels are critically influenced by insulin and glucagon levels. Following ingestion of glucose, plasma glucose levels peak in 60—90 min and slowly return to post-absorptive levels after 3—4 h. Meyer et al. Teleologically, this is understandable because this period is responsible for replenishment of hepatic glycogen stores.
Furthermore, suppression of endogenous glucose release limits postprandial hyperglycaemia. This has been hypothesized to facilitate efficient repletion of glycogen stores in the liver These differences in regulation and reciprocal change in renal and hepatic glucose release have led to the concept of hepatorenal glucose reciprocity This concept refers to the situations in which a physiological or pathological decrease in glucose release by kidney or liver is associated with a compensatory increase in glucose release by liver or kidney so as to prevent hypoglycaemia or to optimize homeostasis.
Examples of this include the anhepatic phase after liver transplantation, prolonged fasting, acidosis, meal ingestion and insulin overdoses in diabetes mellitus 22 — After meal ingestion their glucose utilization increases in an absolute sense.
The metabolic fate of glucose is different in different regions of the kidney. Because of its low oxygen tension, and low levels of oxidative enzymes, the renal medulla is an obligate user of glucose for its energy requirement and does so anaerobically. Consequently, lactate is the main metabolic end product of glucose taken up in the renal medulla, not carbon dioxide CO 2 and water.
In contrast, the renal cortex has little glucose phosphorylating capacity but a high level of oxidative enzymes. Consequently, this part of the kidney does not take up and use very much glucose, with oxidation of FFAs acting as the main source of energy.
A major energy-requiring process in the kidney is the reabsorption of glucose from glomerular filtrate in the proximal convoluted tubule In addition to releasing glucose into the circulation by synthesizing new glucose molecules via gluconeogenesis and its utilization of glucose, the kidney can also influence glucose homeostasis by returning glucose to the circulation via the reabsorption of glucose from glomerular filtrate.
Normally, approximately l of plasma are filtered by the kidneys each day. In healthy individuals, virtually all of this is reabsorbed into the circulation and the urine is essentially free from glucose. To put this into perspective, in a given day, the kidneys produce 15—55 g glucose via gluconeogenesis and metabolize 25—35 g glucose.
Therefore, in terms of glucose economy, it is clear that renal reabsorption is the primary mechanism by which the kidney influences glucose homeostasis. Alterations in renal tubular glucose reabsorption may therefore be expected to have a considerable impact on glucose homeostasis.
Reabsorption of glucose from glomerular filtrate occurs by means of sodium—glucose co-transporters SGLTs in the proximal convoluted tubulae. SGLT2 is thought to be located exclusively on the luminal surface of the epithelial cells lining the S1 and S2 segments of the proximal tubule 28 , Transport of sodium and glucose by SGLT2 occurs in a ratio 27 , SGLT1 is also extensively expressed in the small intestine and in other tissues SGLT-mediated glucose transport is an active process, moving glucose against a concentration gradient, utilizing energy derived from the sodium electrochemical potential gradient across the brush border membrane and maintained by the transport of intracellular sodium into the blood via sodium:potassium adenosine triphosphatase ATPase pumps at the basolateral membrane In contrast, GLUTs facilitate passive transport equilibration of glucose across membranes and do not require an energy source The sodium glucose co-transporter family Glucose is freely filtered in the glomerulus, so that, as plasma glucose levels increase, the amount of glucose in the glomerular filtrate increases linearly.
Reabsorption of filtered glucose also increases linearly until the maximal reabsorptive capacity is exceeded. Above this plasma glucose concentration, the percentage of filtered glucose that is reabsorbed decreases and the percentage of the filtered load of glucose that is excreted in the urine increases, resulting in glucosuria. 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.
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.
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. ESRD spending represents 6. The epidemic growth in ESRD cases has led to skyrocketing utilization of healthcare resources.
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. 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. 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. Under normal circumstances, glucose filtered by glomeruli is completely reabsorbed, but in conditions of hyperglycemia or reduced resorptive capacity, glucosuria may occur.
Hyperglycemia in turn detrimentally affects the kidneys by damaging glomeruli, ultimately causing microalbuminuria and nephropathy. Author disclosure: Dr Triplitt reports being a consultant or a member of the advisory board for Roche and Takeda Pharmaceuticals. Authorship information: Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.
Institute for Value-Based Medicine. About AJMC. April 11, Curtis L. 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. Glucose Reabsorption D In addition to their important role in gluconeogenesis, the kidneys contribute to glucose homeostasis by filtering and reabsorbing glucose.
Conclusion The regulation of glucose production, uptake, reabsorption, and elimination is handled by several organs, most notably historically the pancreas and liver. Address correspondence to: E-mail: Curtis. Triplitt uhs-sa. Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis. Am J Physiol Endocrinol Metab.
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