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renal threshold for glucose

Renal threshold for glucose

Renal threshold for glucose excretion is defined as the plasma glucose concentration at which renal tubular reabsorption of glucose is exceeded; therefore, when glucose concentrations are above this threshold (renal threshold for glucose excretion), urinary glucose excretion increases linearly, glucosuria is maximal; below the renal threshold for glucose excretion concentration, glucosuria is minimal 1. Renal threshold for glucose in healthy subjects is ∼ 180 mg/dL, while renal threshold for glucose in patients with type 2 diabetes mellitus rises to ∼ 240 mg/dL. This higher value appears to be due to increased sodium glucose co-transporter 2 (SGLT-2) expression in type 2 diabetes mellitus patients.

The kidneys play an important role in regulating glucose homeostasis through utilization of glucose, gluconeogenesis, and glucose reabsorption via sodium glucose co-transporters (SGLTs) and glucose transporters, filtering 160 to 180 g of glucose per day in healthy individuals, which is all reabsorbed within the proximal tubules 2. Glucose transporter expressed within the distal proximal tubule (sodium:glucose ratio of 2:1) and then reabsorbed into the blood via glucose transporter 1 (GLUT1) 3. The renal threshold for glucose excretion is increased in patients with type 2 diabetes mellitus, possibly due to upregulation of sodium glucose co-transporter 2 (SGLT-2) and sodium glucose co-transporter 1 (SGLT-1) expression. The resulting increase in renal glucose reabsorption is thought to contribute to the maintenance of hyperglycemia in patients with type 2 diabetes mellitus. Selective sodium glucose co-transporter 2 (SGLT-2) inhibitors reduce the renal threshold for glucose, thereby increasing glucosuria, and have demonstrated favorable efficacy and safety in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise and other glucose-lowering treatments.

The physiologic relationship between plasma glucose concentration and renal glucose flux (i.e, filtration, reabsorption, and excretion) has typically been described as a threshold-type relationship (Figure 1) 4. The amount of glucose filtered by the kidneys increases in a linear manner with increasing plasma glucose concentration and decreases with declining glomerular filtration rate (GFR); renal glucose reabsorption increases linearly until a certain concentration of plasma glucose is present 2. However, there is a distinct deviation (the“splay”) from this linear relationship as the renal capacity to reabsorb glucose nears saturation that is thought to be due to variability in the maximal reabsorptive capacity between individual nephrons 2.

Under normal conditions in healthy individuals, nearly all filtered glucose is reabsorbed in the renal tubules 3. However, when the filtered glucose load exceeds the tubular maximum glucose reabsorptive capacity (renal threshold for glucose; approximately 375 mg/min [425 g/day] in healthy individuals), excess glucose is excreted in the urine (Figure 1) 5. A novel method for measuring renal threshold for glucose in the clinical trial setting, which uses data collected from a mixed-meal tolerance test, has recently been developed and validated 6. The parameters of blood glucose concentration, urinary glucose excretion and estimated GFR (eGFR) are used to calculate renal threshold for glucose excretion when 24-hour urinary glucose excretion is more than 600 mg. This may provide a simple tool for the further investigation of the role of renal threshold for glucose during hyperglycemia.

Increased tubular reabsorption in the context of diabetes has been observed using a rat model of diabetes—renal threshold for glucose levels ofapproximately 415 mg/dL (23 mmol/L) were seen and glucosuria was not evident until blood glucose levels were above 400 mg/dL (22 mmol/L) 7. Consistent with this, renal threshold for glucose is often reported to be approximately 180 to 200 mg/dL (10–11 mmol/L) in healthy individuals 4; whereas, in patients with type 2 diabetes mellitus, renal threshold for glucose is elevated (Figure 2) 8. While studies evaluating renal threshold for glucose in patients with type 2 diabetes mellitus suggest some interindividualvariability, many patients demonstrate elevated values abovethe normal range, with values ranging from 112 to 240 mg/dL (6.2–13.3 mmol/L) 8.

Renal threshold for glucose may also be elevated in individuals with diabetes, contributing to the worsening of hyperglycemia 9. Increased tubular reabsorption may be due to an increase in glucose transporter (GLUT) expression or activity, with upregulation of SGLT2 or GLUT2 being possible mechanisms for the increase in glucose reabsorption. In one study, proximal tubular cells were isolated from the urine of patients with type 2 diabetes mellitus and healthy controls 10. In a hyperglycemic culture environment, both SGLT2 and GLUT2 mRNA levels and glucose transport were significantly higher in the type 2 diabetes mellitus group versus controls. Rodent models of diabetes have produced similar results, reporting that expression of renal SGLT2, GLUT2, and SGLT1 was significantly increased compared with normal controls 11.

The increases in tubular reabsorption in individuals with type 2 diabetes mellitus lead to an increase in glucose flux into the blood, resulting in an exacerbation of hyperglycemia 2. Based on observations that mean renal threshold for glucose is approximately 40 mg/dL (2.2 mmol/L) higher in patients with type 2 diabetes mellitus 8 than the commonly reported values of 180 to 200 mg/dL (10–11 mmol/L) in healthy individuals 12 and using a mean GFR of 100 mL/min, calculations suggest that elevated renal threshold for glucose leads to an average of approximately 50 to 70 mg/min of additional glucose reabsorbed into the circulation when plasma glucose is above the renal threshold for glucose, relative to glucose reabsorption if renal threshold for glucose was not increased. For comparison, elevated hepatic glucose production is estimated to contribute approximately 24 mg/min of additional glucose in a 100-kg patient with type 2 diabetes mellitus (assuming a 12% increase from a baseline value of 2 mg/kg/min) 13. Thus, both the kidney and the liver substantially contribute to the hyperglycemia seen in patients with type 2 diabetes mellitus. However, it should be noted that additional renal glucose reabsorption may be substantially lower in patients with impaired renal function, since their GFR will be lower than 100 mL/min.

Figure 1. Kidney threshold for glucose

Renal threshold for glucose

Footnote: Renal glucose handling. Flux rates (filtration, reabsorption, and excretion) were calculated using a glomerular filtration rate of 120 mL/min per 1.73 m² and a renal threshold of 180 mg/dL (10 mmol/L). As plasma glucose concentrations and glucose filtration rates increase, reabsorption rises linearly to its maximum (TmG) at a splayed plasma glucose threshold (traditionally, 180 mg/dL), after which excretion linearly begins to increase.

Figure 2. Kidney threshold for glucose

kidney threshold for glucose

Footnote: Linear relationship between urinary glucose excretion (UGE) and plasma glucose concentration in healthy individuals and patients with type 2 diabetes mellitus (T2DM). The actual relationship between plasma glucose concentration and urinary glucose excretion (UGE) contains some splay in the region near renal threshold for glucose (RTG) 14; an idealized relationship is depicted here.

Inhibition of SGLT2 has emerged as a focus for the develop-ment of novel treatments for patients with type 2 diabetes mellitus 5. These therapies reduce blood glucose concentrations by lowering the renal threshold for glucose and inducing glucosuria in an insulin-independent manner 5. Two SGLT2 inhibitors, canagliflozin and dapagliflozin, are currently approved for use in patients with type 2 diabetes mellitus in over 30 countries worldwide, including the United States and the European Union, and other drugs are currently in clinical development 15.

Canagliflozin is an orally active inhibitor of SGLT2 that lowers elevated plasma glucose concentrations by reducing reabsorption of filtered glucose in patients with type 2 diabetes mellitus 8. Canagliflozin’s affinity for SGLT2 is approximately 150-foldgreater than its affinity for SGLT1 16.Treatment with canagliflozin has been shown to decrease 24-hour mean renal threshold for glucosein a dose-dependent manner, with maximal suppression (at doses >100 mg once daily) to approximately 60 mg/dL (3.3 mmol/L) in healthy individuals 4 and to approximately 70 to 90 mg/dL (3.9–5.0 mmol/L) in patients with type 2 diabetes mellitus 17. Analysis of data from four Phase 1 pharmacodynamic studies of canagliflozin has shown that renal threshold for glucoseis consistentlycorrelated with 24-hour mean plasma glucose concentrationin patients with type 2 diabetes mellitus 17. The 300-mg dose ofcanagliflozin has been shown to provide a greater reduction inpostprandial plasma glucose excursion than that observedwith the 100-mg dose 18. This effect may be due, in part, to local inhibition of intestinal SGLT1 (an important intestinal GLUT) related to transient high concentrations of canagliflozin in the intestinal lumen prior to medicinal product absorption (canagliflozin is a low potency inhibitor of SGLT1) 19. However, systemic levels of canagliflozin 300 mg did not meaningfully inhibit SGLT1 and studies have shown no glucose malabsorption with canagliflozin 20.

As monotherapy oras adjunctive treatment to existing oral antidiabetic drugs,canagliflozin has been shown to significantly reduce HbA1c and fasting plasma glucose compared with placebo 21. The increased urinary glucose excretion with SGLT2 inhibition also translates to osmotic diuresis, with the diuretic effect leading to reductions in systolic blood pressure compared with placebo. The increase in urinary glucose excretion also results in a net loss of calories and, therefore, a sustained reduction in body weight, as has been demonstrated in clinical trials of up to 2 years in duration conducted inpatients with type 2 diabetes mellitus 22.

Dapagliflozin is an orally active SGLT2 inhibitor with selectivity for SGLT2 that is more than 1400-fold greater relative to SGLT1 23. Treatment with dapagliflozin has been shown to lower renal threshold for glucose and induce urinary glucose excretion, resulting in significantly decreased plasma glucose concentrations in healthy individuals 24 and in patients with type 2 diabetes mellitus 25. In randomized, placebo- and active-controlled trials, dapagliflozin provided statistically significant improvements in terms of HbA1c and fasting plasma glucose 26; body weight and systolic blood pressurereductions were non-glycemic benefits observed in these studies 26.

References
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  20. Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion. Diabetes Care 2013 Aug; 36(8): 2154-2161. https://doi.org/10.2337/dc12-2391
  21. Lavalle-González, F.J., Januszewicz, A., Davidson, J. et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia 56, 2582–2592 (2013). https://doi.org/10.1007/s00125-013-3039-1
  22. Canagliflozin Compared With Sitagliptin for Patients With Type 2 Diabetes Who Do Not Have Adequate Glycemic Control With Metformin Plus Sulfonylurea. Guntram Schernthaner, Jorge L. Gross, Julio Rosenstock, Michael Guarisco, Min Fu, Jacqueline Yee, Masato Kawaguchi, William Canovatchel, Gary Meininger. Diabetes Care Sep 2013, 36 (9) 2508-2515; DOI: 10.2337/dc12-2491
  23. Wilding, John. (2014). The role of the kidneys in glucose homeostasis in type 2 diabetes: Clinical implications and therapeutic significance through sodium glucose co-transporter 2 inhibitors. Metabolism. 63. 10.1016/j.metabol.2014.06.018.
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