Glucosuria

1. Glucosuria An Overview

2. Glucose Six-carbon reducing sugar Essential for: Production of cellular energy and ATP Most frequently performed chemical analysis in urine Detection and monitoring of: D iabetes mellitus and R enal tubular disorders

3. What is Glycosuria? Appearance of glucose in urine following cessation of active transport (tubular reabsorption) as renal threshold is exceeded What is the renal threshold? 90% filtered glucose is reabsorbed in the PCT Remaining: proximal straight tubule, loop of Henle , collecting duct 0.05% of renal glucose load -> excreted in urine 160 – 180 mg/ dL Tubular maximum for glucose reabsorption: 260-350 mg/min/1.73 m 2

4. Glucose Reagent Strip Provides a specific test for glucose Strip pads are impregnated with glucose oxidase and peroxidase ( double sequential enzyme reaction) False positive: detergent, peroxide, strong oxidizing agents False negative: ascorbic acid, ketones, high specific gravity, low temperature and improper preservation of long-standing urine

5. Random Blood Sugar Glycosylated Hemoglobin Diabetes mellitus until proven otherwise

6. Causes of glycosuria Glycosuria with hyperglycaemia - diabetes,acromegaly , cushing ’ s disease, hyperthyroidism, drugs like corticosteroids. Glycosuria without hyperglycaemia - renal tubular dysfunction

7. Diabetes mellitus Diabetes mellitus (DM) is an important endocrine disorder that presents commonly in children and adolescents. one of the most common chronic diseases in children Characterized by insulin deficiency as a result of autoimmune destruction of pancreatic beta islet cells; Diabetes mellitus Type II Presence of high blood glucose with insulin resistance and relative insulin deficiency Estimated 3600/100,000 cases of type 2 DM in Canadian adolescents and Diabetes mellitus Type I

8. Diabetes mellitus Type I Approximately 2/3 of all new diabetes diagnoses in patients less than 19 years of age in the United States are type 1 DM . A ge of onset has a bimodal distribution , first peak in children 4-6 years old, and the second peak in children 10-14 years old (early puberty) .

9. Glycosuria with Hyperglycemia Approximately 2/3 of all new diabetes diagnoses in patients less than 19 years of age in the United States are type 1 DM . A ge of onset has a bimodal distribution , first peak in children 4-6 years old, and the second peak in children 10-14 years old (early puberty) . Diabetes mellitus Type II Estimated 3600/100,000 cases of type 2 DM in Canadian adolescents and Diabetes mellitus Type I

10. Glycosuria with Hyperglycemia autoimmune-mediated destruction of insulin-producing pancreatic beta cells that results in insulin deficiency. It is a progressive condition A large number of functional beta cells must be lost before clinical symptoms like hyperglycemia occurs. Diabetes mellitus Type I Classic new onset: Hyperglycemia without acidosis

11. Symptoms include: Polyuria – serum glucose > 10 mmol /L (exceeding renal threshold for glucose à increased urinary glucose excretion ) Can present as nocturia , bedwetting, daytime incontinence in a previously continent child Polydipsia – due to increased serum osmolality and hypovolemia Weight loss – due to hypovolemia and increased catabolism Impaired glucose utilization in skeletal muscle and increased fat and muscle breakdown Glycosuria with Hyperglycemia Diabetes mellitus Type I

12. Clinical: polydipsia, polyuria, dehydration, hypotension, ketosis, etc. Metabolic: hyperglycemia, glycosuria, metabolic acidosis, ketonemia , etc. Reported frequency varies between 15-67% Young children (<6) from low socioeconomic backgrounds are more likely to present with diabetic ketoacidosis Silent Presentation Diagnosis before onset of clinical symptoms Typically occurs in children with a family member with type 1 DM (close monitoring) Glycosuria with Hyperglycemia Diabetes mellitus Type I

13. Glycosuria without Hyperglycemia Renal Glycosuria Dysfunction Rare metabolic disorder; excretion of glucose in the urine in the presence of normal plasma glucose levels. I nherited form: involves a reduction in the glucose transport maximum (the maximum rate at which glucose can be resorbed) and subsequent escape of glucose in the urine. Glucose transporters: A cquired form: occurs primarily in advanced chronic kidney disease.

14. Variable amounts of glucose are excreted in the urine at normal concentrations of blood glucose Renal defect is specific for glucose only A benign condition The metabolism, storage and use of carbohydrates and insulin secretions are normal Glycosuria without Hyperglycemia Renal Glycosuria Dysfunction

15. The disorder is typically initially noted on routine urinalysis. Diagnosis is based on finding glucose in a 24-h urine collection (when the diet contains 50% carbohydrate) in the absence of hyperglycemia (serum glucose < 140 mg/ dL ). To confirm that the excreted sugar is glucose and to exclude pentosuria , fructosuria , sucrosuria , maltosuria , galactosuria , and lactosuria , the glucose oxidase M ethod should be used for all laboratory measurements. Some experts require a normal result on an oral glucose tolerance test for the diagnosis. Glycosuria without Hyperglycemia Renal Glycosuria Dysfunction

16. How to Differentiate Renal Glucosuria Diabetes mellitus VS. Fasting Blood Sugar OGTT

17. Autosomal recessive, some autosomal dominant Mechanism: isolated, selective defect in the proximal tubular glucose trasnport Two Types: Type A or Classic Renal Glycosuria: Minimal glucose threshold and maximum rate of glucose reabsorption are reduced Reflects reduction in the capacity of the glucose transport system which might arise from a uniform defect in all nephrons Type B Minimal glucose threshold is reduced Decrease in the affinity of the transport system Glycosuria without Hyperglycemia Renal Glycosuria Dysfunction

18. As of 2000: SGLT2 gene (SLC5A2) -> established to be the mutated gene in hereditary renal glycosuria To date, close to 30 mutations have been identified in patients with hereditary renal glycosuria Type O Rare Tubular reabsorption of glucose is virtually absent and all glucose filtered is excreted in the urine Glycosuria without Hyperglycemia Renal Glycosuria Dysfunction

19. Glycosuria without Hyperglycemia Renal Glycosuria Dysfunction Defect in the early proximal tubule, R eabsorbs most renal tubular glucose, P roduce type A or type O, classic renal glycosuria H as no effect on glucose absorption in the intestine. Defect in the late proximal tubule (which also carries galactose ) M ediates residual glucose reabsorption in the renal tubule and, when defective as in glucose- galactose malabsorption , causes only mild type B renal glycosuria. Defect in glucose cotransporter (SGLT2/SLC5A2) Defect in SGLT1 /SLC5A1, glucose cotransporter

20. As of 2000: SGLT2 gene (SLC5A2) -> established to be the mutated gene in hereditary renal glycosuria Other mutations of SLC5A2 Renal glycosuria + generalized aminoaciduria  a feature of MODY 3 (maturity-onset diabetes of the young type 3) Glycosuria without Hyperglycemia Renal Glycosuria Dysfunction

21. Glucose- Galactose Malabsorption Potentially lethal disease Autosomal recessive disease Missense mutation in the intestinal brush-border SGLT1 N + -glucose cotransporter HOMOZYGOTES: neonatal onset of severe atry diarrhea that results in death unless glucose and galactose are removed Glycosuria without Hyperglycemia Renal Glycosuria Dysfunction

22. Glucose- Galactose Malabsorption Jejunal biopsy: defect in intestinal Na + - dependent glucose transport Mild defect in renal tubular reabsorption of glucose with decreased renal threshold for glucose Renal glycosuria: mutation in SGLT2 No defect in intestinal D- gluose absorption Glycosuria without Hyperglycemia Renal Glycosuria Dysfunction

23. Glycosuria without Hyperglycemia Renal Glycosuria Dysfunction Defect in the early proximal tubule, R eabsorbs most renal tubular glucose, P roduce type A or type O, classic renal glycosuria H as no effect on glucose absorption in the intestine. Defect in the late proximal tubule (which also carries galactose ) M ediates residual glucose reabsorption in the renal tubule and, when defective as in glucose- galactose malabsorption , causes only mild type B renal glycosuria. Defect in glucose cotransporter (SGLT2/SLC5A2) Defect in SGLT1 /SLC5A1, glucose cotransporter

24. Mutations on the gene GLUT2 (SLC2A2) - - the glucose transported on the basolateral membrane-bound Associated with glycosuria in the Fanconi -Bickel Syndrome Fanconi -Bicke l Syndrome Autosomal recessive Hepatorenal glycogen accumulation Fasting hypoglycemia Impaired utilization of glucose and galactose Glycosuria without Hyperglycemia Renal Glycosuria Dysfunction

25. Rickets, stunted growth, fanconi syndrome Renal loss of glucose Due to the transport defect for monosaccharides across the basolateral membrane Glycosuria without Hyperglycemia Renal Glycosuria Dysfunction