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Physiology, Glycosuria


Physiology, Glycosuria

Article Author:
Maria Nataly Liman
Article Editor:
Ishwarlal Jialal
Updated:
4/24/2020 2:49:09 PM
For CME on this topic:
Physiology, Glycosuria CME
PubMed Link:
Physiology, Glycosuria

Introduction

Glycosuria is a term that defines the presence of reducing sugars in the urine, such as glucose, galactose, lactose, fructose, etc. Glucosuria connotes the presence of glucose in the urine and is the most frequent type of glycosuria and is the focus of this review. It happens when the glomerulus filters more glucose than the proximal tubule can reabsorb. In normal individuals, glucosuria can be up to 0.25 mg/ml, and more than 0.25 mg/ml in random fresh urine is consider increased glucosuria and can be due to elevated plasma glucose, or renal glucose absorption impairment, or both.[1][2] Physiologic glucosuria is a  condition where individuals consume an excessive amount of carbohydrates. 

Small amounts of glucose present in the urine are considered normal, but the term glucosuria usually refers to pathologic conditions where the amounts of urine glucose are more than 25 mg/dl in random fresh urine. Normally, the renal tubule will reabsorb almost all (leaving less than 25 mg/dl urine glucose) glucose present in the normal glomerular filtrate. When the glucose filtrated by glomerular exceeds the capacity of the renal tubule to absorb it, the loss of balance occurs. It can happen due to elevated plasma glucose as in diabetes mellitus or when the ability of tubule to absorb glucose is impaired e.g., Fanconi syndrome with impairment in the absorption of phosphate, amino acids, or isolated glucosuria as an inherited disorder termed Familial Renal glucosuria.

Issues of Concern

Some limitations of urine glucose testing are the ability of most commercial semiquantitative urine test to detect glucose in the urine only until it reaches a level of 50 to 250 mg/dl. Also, errors can stem from an altered renal threshold. There are known variations in the renal threshold among individuals that can lead to significantly misleading data.

Organ Systems Involved

Renal tubule plays a significant role in glucose reabsorption. If the plasma glucose rises, renal tubular reabsorption of glucose will increase linearly until it reaches its maximum tubular resorptive capacity. The capacity of proximal tubule to reabsorb glucose to prevent its passing to the urine is known as the renal threshold.[2][3]

Membrane proteins that are responsible for glucose reabsorption in the proximal convoluted tubule (PCT) from the glomerular filtrate are sodium-glucose cotransporters SGLT1 and SGLT2, located in the apical membrane of proximal tubular cells and GLUT2, a uniporter, located in the basolateral membrane. The first stage is glucose being transported across the apical membrane by SGLTs.  These transporters bind to Na before they bind to glucose, the electrochemical sodium gradient that is generated by the Na/K-ATPase is the driving force for the symporter activity, which then leads to glucose accumulation in the epithelium. It causes glucose concentration gradient between the cell and plasma, driving to the second stage, which is a passive exit of glucose through the basolateral membranes, via GLUT2. SGLT1 functions in segments 1 and 2 of the PCT and SGLT1 functions in segment 3.[4][5]

Mechanism

In healthy individuals, the renal system filters approximately 180 g of glucose daily. The glucose that entered the tubular system is reabsorbed along with the segments of the proximal convoluted tubule (PCT). In diabetic patients, as a result of the increase in the plasma glucose, the filtered glucose exceeds the capacity of the tubular system and results in glucosuria. The majority of glucose uptake of greater than 90 percent occurs in the proximal tubule, mediated by SGLT2, a low-affinity/high capacity transporter. The remaining glucose will then be reabsorbed by the distal parts of the proximal tubule via the high-affinity/low-capacity SGLT1.[6]

Kidneys play a significant role in maintaining glucose homeostasis and preventing an individual from developing hypoglycemia. The maintenance of glucose homeostasis by the kidney includes glucose reabsorption in the PCT,  gluconeogenesis, and the clearance of important hormones such as insulin.[7]

Related Testing

In a patient with glucosuria, diabetes is confirmable by measurement of fasting or random plasma glucose and glycated hemoglobin(HbA1c). In Fanconi syndrome, a generalized defect of the PCT, there is hypophosphatemia with metabolic acidosis (due to bicarbonate wasting)  in the presence of phosphaturia, aminoaciduria, and glucosuria. 

Pathophysiology

Glucose filters through glomeruli, and then it is reabsorbed by the proximal renal tubule. Less than 0.1% of glucose is not reabsorbed by the kidneys (less than 0.25 mg/ml), and most of the standard test does not detect this level.  The causes of glucosuria can group under two classes, the inability of PCT to reabsorb glucose and where there is an increase in the concentration of glucose in the circulating blood.[8] 

Defects in the PCT, either primary or secondary, can result in glucosuria.  Examples include pregnancy, Fanconi syndrome, and acute tubular necrosis. In a normal condition, when the plasma glucose level is increasing, renal tubular reabsorption of glucose will rise linearly until its maximum is reached (ranges from 0.9 to 2.0 mmol/min).[2] As mentioned before, SGLT1, SGLT2, and GLUT2 are the membranes protein that is responsible for glucose reabsorption; mutations in one of these membrane proteins will cause glucosuria.  Mutation in SGLT1 is associated with glucose-galactose malabsorption, a mutation in SGLT2 is associated with familial renal glucosuria (FRG), and mutation in GLUT2 is associated with Fanconi-Bickel syndrome.[5]

Glucosuria can also occur in an increased concentration of glucose in the circulating blood. This phenomenon can also occur in normal individuals who consume excess carbohydrates, known as ‘alimentary glycosuria.’ It also presents in diabetic patients.[8]  In diabetes mellitus, with increasing duration, glomeruli can be damaged, resulting in albuminuria and a decrease in the glomerular filtration rate. In diabetic patients, the kidneys are more susceptible to the effects of hyperglycemia; many of the kidney cells are unable to decrease glucose transport rates and unable to prevent intercellular hyperglycemia in an increased glucose concentration state.[7]

Some conditions are known to raise the renal threshold for glucose, such as age, renal disease (diabetic glomerulosclerosis), heart failure, and chronic hyperglycemia. Also, there are some conditions known to decrease it, such as hyperthyroidism, pregnancy, fever, and exercise. Normal aging and glomerulosclerosis in long-standing diabetes are associated with an increased renal threshold for glucose, and because of that, urine glucose testing becomes of little value, if any.

There is the number of substances that also known for its capability to cause glucosuria such as chloride, iodide, bromide, and nitrate of sodium. Glucosuria can also occur in a condition where there is a lack of oxygenation of the PCT.[8]

Clinical Significance

A study comparing the urine and plasma response 60 minutes after a 50 g oral glucose challenge for patients with potential gestational diabetes mellitus (GDM) screening showed that post-load glycosuria is a poor predictor of GDM, pre-eclampsia and newborn size at birth. It has limited clinical benefit.[9]

In diabetes mellitus type 2, there appears to be a maladaptive upregulation of SGLT2 that contributes to hyperglycemia. A significant advance in the treatment of diabetes is the ushering in of SGLT2 inhibitor class of drugs. These drugs have demonstrated to improve glycemic control with weight loss by inducing glycosuria with calorie loss. They also promote natriuresis resulting in a decrease in blood pressure. However, they can increase the risk of genital and urinary tract infections and dehydration.[10]


References

[1] Ferrannini E, Learning from glycosuria. Diabetes. 2011 Mar;     [PubMed PMID: 21357469]
[2] Cowart SL,Stachura ME, Glucosuria 1990;     [PubMed PMID: 21250089]
[3] Johansen K,Svendsen PA,Lørup B, Variations in renal threshold for glucose in Type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1984 Mar;     [PubMed PMID: 6714538]
[4] Swe MT,Thongnak L,Jaikumkao K,Pongchaidecha A,Chatsudthipong V,Lungkaphin A, Dapagliflozin not only improves hepatic injury and pancreatic endoplasmic reticulum stress, but also induces hepatic gluconeogenic enzymes expression in obese rats. Clinical science (London, England : 1979). 2019 Dec 12     [PubMed PMID: 31769484]
[5] Santer R,Calado J, Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. Clinical journal of the American Society of Nephrology : CJASN. 2010 Jan     [PubMed PMID: 19965550]
[6] Vallon V, Molecular determinants of renal glucose reabsorption. Focus on     [PubMed PMID: 21048164]
[7] Triplitt CL, Understanding the kidneys' role in blood glucose regulation. The American journal of managed care. 2012 Jan;     [PubMed PMID: 22559853]
[8] Fischer MH, The Physiology of Glycosuria. California state journal of medicine. 1907 Sep;     [PubMed PMID: 18734160]
[9] Coolen JC,Verhaeghe J, Physiology and clinical value of glycosuria after a glucose challenge during pregnancy. European journal of obstetrics, gynecology, and reproductive biology. 2010 Jun;     [PubMed PMID: 20207065]
[10] van Bommel EJ,Muskiet MH,Tonneijck L,Kramer MH,Nieuwdorp M,van Raalte DH, SGLT2 Inhibition in the Diabetic Kidney-From Mechanisms to Clinical Outcome. Clinical journal of the American Society of Nephrology : CJASN. 2017 Apr 3     [PubMed PMID: 28254770]