Glucosuria Is Not Always Due to Diabetes

Diagnosis

The differential homed in on a targeted defect in the proximal tubular SGLT2 gene as the final diagnosis causing isolated glucosuria. Familial renal glucosuria (FRG), a condition caused by a mutation in the SLC5A2 gene that codes for the SGLT2 has been identified in the literature as causing cases with nearly identical presentations to this patient.^2,3 This condition is often found in otherwise healthy, asymptomatic patients in whom isolated glucosuria was identified on routine urinalysis testing.

Due to isolated case reports sharing this finding and the asymptomatic nature of the condition, specific data pertaining to its prevalence are not available. Case studies of other affected individuals have not noted adverse effects (AEs), such as UTIs or hypotension specifically^.2,3 The patient was referred for genetic testing for this gene mutation; however, he was unable to obtain the test due to lack of insurance coverage. Mr. A has no other family members that have been evaluated for or identified as having this condition. Despite the name, FRG has an unknown inheritance pattern and is attributed to a variety of missense mutations in the SLC5A2 gene.^4,5

Discussion

The SGLT2 gene believed to be mutated in this patient has recently become wellknown. The inhibition of the SGLT2 transport protein has become an important tool in the management of type 2 diabetes mellitus (T2DM) independent of the insulin pathway. The SGLT2 in the proximal convoluted tubule of the kidney reabsorbs the majority, 98%, of the renal glucose for reabsorption, and the remaining glucose is reabsorbed by the SGLT2 gene in the more distal portion of the proximal tubule in healthy individuals.^4,6 The normal renal threshold for glucose reabsorption in a patient with a normal glomerular filtration rate is equivalent to a serum glucose concentration of 180 mg/dL, even higher in patients with T2DM due to upregulation of the SGLT2 inhibitors. SGLT2 inhibitors, such as canagliflozin, dapagliflozin, and empagliflozin, selectively inhibit this cotransporter, reducing the threshold from 40 to 120 mg/dL, thereby significantly increasing the renal excretion of glucose.⁴ The patient’s mutation in question and clinical presentation aligned with a naturally occurring mimicry of this drug’s mechanism of action (Figure).

Arguably, one of the more significant benefits to using this new class of oral antihyperglycemics, aside from the noninferior glycemic control compared with that of other first-line agents, is the added metabolic benefit. To date, SGLT2 inhibitors have been found to decrease blood pressure in all studies of the medications and promote moderate weight loss.⁷ SGLT2 inhibitors have not only demonstrated significant cardiovascular (CV) benefits, linked with the aforementioned metabolic benefits, but also have reduced hospitalizations for heart failure in patients with T2DM and those without.⁷ The EMPA-REG OUTCOME trial showed a 38% relative risk reduction in CV events in empagliflozin vs placebo.^4,8 However, it is unknown whether patients with the SLC5A2 mutation also benefit from these CV benefits akin to the SGLT2 inhibiting medications, and it is and worthy of studying via longterm follow-up with patients similar to this.

This SLC5A2 mutation causing FRG selectively inhibiting SGLT2 function effectively causes this patient’s natural physiology to mimic that of these new oral antihyperglycemic medications. Patients with FRG should be counseled regarding this condition and the implications it has on their overall health. At this time, there is no formal recommendation for short-term or longterm management of patients with FRG; observation and routine preventive care monitoring based on US Preventive Services Task Force screening recommendations apply to this population in line with the general population.

This condition is not known to be associated with hypotension or hypoglycemia, and to some extent, it can be theorized that patients with this condition may have inherent protection of development of hyperglycemia. ⁴ Akin to patients on SGLT2 inhibitors, these patients may be at an increased risk of UTIs and genital infections, including mycotic infections due to glycemic-related imbalance in the normal flora of the urinary tract.⁹ Other serious AEs of SGLT2 inhibitors, such as diabetic ketoacidosis, osteoporosis and related fractures, and acute pancreatitis, should be shared with FRG patients, though they are unlikely to be at increased risk for this condition in the setting of normal serum glucose and electrolyte levels. Notably, the osteoporosis risk is small, and specific other risk factors pertinent to individual patient’s medical history, and canagliflozin exclusively. If a patient with FRG develops T2DM after diagnosis, it is imperative that they inform physicians of their condition, because SGLT2-inhibiting drugs will be ineffective in this subset of patients, necessitating increased clinical judgment in selecting an appropriate antihyperglycemic agent in this population.

Conclusions

FRG is an uncommon diagnosis of exclusion that presents with isolated glucosuria in the setting of normal serum glucose. The patient generally presents asymptomatically with a urinalysis completed for other reasons, and the patient may or may not have a family history of similar findings. The condition is of particular interest given that its SGLT2 mutation mimics the effect of SGLT2 inhibitors used for T2DM. More monitoring of patients with this condition will be required for documentation regarding long-term implications, including development of further renal disease, T2DM, or CV disease.