Friday, March 5, 2010

Familial renal glucosuria and a new drug for diabetes mellitus

The kidney contributes to glucose homeostasis by reabsorbing ~180 grams of glucose daily. Two sodium-coupled glucose transporters play an important role in this process, SGLT1 and SGLT2. Of these two, SGLT2 (encoded by the gene SLC5A2 on chromosome 16p11.2) is the transporter which is predominantly expressed in the luminal brush border of the proximal tubule (S1 segment) and mediates primarily renal glucose re-absorption.

Glucosuria, in the absence of diabetes mellitus, can occur in the setting of global dysfunction of the proximal tubule (PT), known as Renal Fanconi Syndrome. The latter is typically accompanied by excessive urinary excretion of amino acids, phosphate and bicarbonate. The occurrence of glucosuria in the absence of PT dysfunction and hyperglycemia is known as renal glucosuria or familial renal glucosuria (FRG) as it is recognized as an inherited disorder.

Patients with FRG have decreased renal tubular reabsorption of glucose from the urine in the absence of hyperglycemia or any other signs of tubular dysfunction. Glucosuria can range from 1 - 150 grams/1.73m2 per day. The majority of affected patients does not develop significant clinical problems and individuals are typically picked up during routine clinical tests. However, higher levels of glucosuria lead to osmotic diuresis and could cause volume contraction when access to fluid is limited.

Both, autosomal recessive and dominant pattern of inheritance for FRG have been reported. Mutations in SCL5A2 (encoding SGLT2) account for the majority if not all families with this condition. So far ~44 different mutations in 14 exons have been reported for FRG. Establishing a definite genotype-phenotype correlation has been difficult due to variable expressivity of SGLT2 and other genes that may have an overall impact on renal glucose reabsorption. In general, heterozygous mutations lead likely to mild glucosuria Here's a nice review.

In summary, FRG is a relatively benign condition nephrologists should be familiar with, especially with the availability of Dapagliflozin, a new drug for treatment of diabetes mellitus. First trials look promising since inhibiting SGLT2 appears effective and relatively safe.


abraham said...

The SGLT-1 transporter is also expressed in the gut .

Anonymous said...

Excellent review of FRG. Very much appreciated. Definitely at the standard of Nate. Appreciate very much this post.

Anonymous said...

As correctly discussed, the kidney glucose transporter is SGLT-2. The glucose uptake transporter in the intestine ist SGLT-1 which was regarded as also regarded as a potential target. However, the adverse event profile (diarrhea due to solvent drag, flatulence etc.) isn't too attractive....

Kenar D. Jhaveri, MD said...

excellent review. I had recently done this on my blog as well.
Keep up the excellent work as Nate did.
He was an inspiration.