Renal glucose reabsorption inhibitors to treat diabetes

doi:10.1016/j.tips.2010.11.011

Trends in Pharmacological Sciences

Volume 32, Issue 2, February 2011, Pages 63-71

https://doi.org/10.1016/j.tips.2010.11.011 Get rights and content

Current therapies to reduce hyperglycaemia in type 2 diabetes mellitus (T2DM) mostly involve insulin-dependent mechanisms and lose their effectiveness as pancreatic β-cell function declines. In the kidney, filtered glucose is reabsorbed mainly via the high-capacity, low-affinity sodium glucose cotransporter-2 (SGLT2) at the luminal surface of cells lining the first segment of the proximal tubules. Selective inhibitors of SGLT2 reduce glucose reabsorption, causing excess glucose to be eliminated in the urine; this decreases plasma glucose. In T2DM, the glucosuria produced by SGLT2 inhibitors is associated with weight loss, and mild osmotic diuresis might assist a reduction in blood pressure. The mechanism is independent of insulin and carries a low risk of hypoglycaemia. This review examines the potential of SGLT2 inhibitors as a novel approach to the treatment of hyperglycaemia in T2DM.

Section snippets

Treating hyperglycaemia

Treatment of hyperglycaemia in type 2 diabetes mellitus (T2DM) is necessary to relieve acute symptoms and to reduce the risk of chronic vascular complications. Lifestyle interventions, notably diet and exercise, are important but are generally insufficient to achieve or maintain glycaemic control. Most current glucose-lowering therapies act to address the underlying endocrine pathogenesis of insulin resistance and β-cell dysfunction. However, these therapies usually lose their effectiveness

Role of the kidney in glucose balance

The renal cortex produces glucose by gluconeogenesis, mainly for utilization in the renal medulla [9]. In T2DM, both the liver and kidney contribute to excess glucose production, and renal glucose production can contribute up to ∼20% of the total glucose released into the circulation in the post-absorptive state 9, 10. However, the kidneys substantially affect the circulating glucose pool through reabsorption of glucose filtered by the glomeruli. Renal glucose reabsorption is a constitutive

Sodium glucose co-transporters

SGLT proteins are encoded by the solute carrier 5 (SLC5) subfamily of sodium/substrate symporter genes [12]. The SCL5 genes code for several proteins (∼75 kDa) with >59% amino acid identity, among which SGLT1 and SGLT2 are the most well characterized [12]. SGLT1 is predominantly expressed in enterocytes, where it mediates glucose and galactose uptake from the gut lumen 12, 13. SGLT1 is also expressed in the more distal segments (S2–3) of the proximal convoluted tubule, where it mediates the

Experiments of nature: familial renal glucosuria

Urinary glucose excretion can occur in the absence of either generalized proximal tubular dysfunction or hyperglycaemia in inherited disorders of familial renal glucosuria (FRG) 21, 22, 23. Mutations in the SLC5A2 gene are responsible for most FRG; heterozygous individuals usually develop mild glucosuria (<10 g/1.73 m²/day) or sometimes no glucosuria, whereas those with homozygous or compound heterozygous SCL5A2 mutations show more severe glucosuria 21, 22, 23. Twenty different mutations of the

Development of SGLT inhibitors

Phlorizin (Figure 4) is a naturally occurring phenol glycoside first isolated from the bark of apple trees in 1835 [28]. In the late 19th and early 20th centuries, it was shown that orally administered phlorizin increases urinary glucose excretion and loss of body weight. By the 1960s, it was known that phlorizin inhibits glucose transport by erythrocytes and cells in the kidney and small intestine [28]. Proof of principle that promotion of renal glucose excretion could be used in the treatment

Concluding remarks

Because T2DM is a progressive disease, glucotoxicity poses an insidious cumulative risk that requires early and effective intervention to prevent, defer and ameliorate chronic complications [47]. Glucotoxicity represents a pathogenic spiral that is caused by insulin resistance and β-cell dysfunction and also aggravates these conditions. Indeed, chronic hyperglycaemia can accelerate the loss of β-cell function and mass by generating reactive oxygen species and through wide daily fluctuations in

Disclosure statement

Professor Bailey has received research grants from and provided remunerated ad hoc consultancy to pharmaceutical companies that produce antidiabetic and antiobesity agents. He has undertaken research on dapagliflozin (Bristol-Myers Squibb and AstraZeneca) but records no conflict of interest for this review.

Acknowledgements

The author gratefully acknowledges the assistance of Dr Ann P. Tighe of Parexel, which receives funding from Bristol-Myers Squibb and AstraZeneca.

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Citation Excerpt :
The SGLT receptors are sodium-glucose cotransporters located in the gastrointestinal (GI) tract (SGLT1) and kidney (SGLT1 and SGLT2). Most SGLT-active drugs are SGLT2 inhibitors, and work in the proximal tubule of the kidney to block the reuptake of glucose, which is filtered into the urine, leading to its excretion.1 Prolonged hyperglycemia leads to hyperfiltration due to suppressed tubuloglomerular feedback from decreased sodium delivery to the distal tubule.
Adjunctive therapies to insulin for treatment of type 1 diabetes mellitus (T1D) have gained popularity in efforts to achieve glycemic targets, and sodium-glucose transporter (SGLT) inhibitors are an appealing option due to associated weight loss, low risk of hypoglycemia, and improved cardiorenal outcomes seen in persons with type 2 diabetes mellitus. The increased risk of diabetic ketoacidosis (DKA), including euglycemic DKA, has led many to be wary of their use in T1D, especially given limited pediatric data and data regarding cardiorenal protection in this population. The phase 3 trials of these agents in T1D have yielded lower HbA1c, decreased total daily insulin dose, and small but significant weight loss with no increase in hypoglycemia. These trials also reported increased risks of genital mycotic infection and DKA. SGLT inhibitors have been approved as adjunctive therapy to insulin in adults with T1D in Europe and Japan, but the United States Food and Drug Administration has rejected similar applications. Although approaches to mitigate the risk of DKA have been developed, no randomized trials using such tools have been conducted. More research is needed to minimize the risk of DKA and to better evaluate the cardiorenal impact of these agents in persons with T1D.

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Trends in Pharmacological Sciences

ReviewRenal glucose reabsorption inhibitors to treat diabetes

Section snippets

Treating hyperglycaemia

Role of the kidney in glucose balance

Sodium glucose co-transporters

Experiments of nature: familial renal glucosuria

Development of SGLT inhibitors

Concluding remarks

Disclosure statement

Acknowledgements

Endocr. Pract.

Kidney Int. Suppl.

Kidney Int.

Lancet

Diabetes Metab.

Clin. Ther.

Kidney Int.

Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group

J. Am. Med. Assoc.

Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes

N. Engl. J. Med.

Optimal insulin treatment in type 2 diabetes

N. Engl. J. Med.

Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes

Diabetes Care

The impact of weight gain on motivation, compliance, and metabolic control in patients with type 2 diabetes mellitus

Postgrad. Med.

Mechanisms linking obesity to insulin resistance and type 2 diabetes

Nature

Effect of intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)

Lancet

Causes of weight gain during insulin therapy with and without metformin in patients with type II diabetes mellitus

Diabetologia

Renal gluconeogenesis: its importance in human glucose homeostasis

Diabetes Care

Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus

J. Clin. Invest.

Active sugar transport in health and disease

J. Intern. Med.

Tissue expression profiling of the sodium-glucose co-transporter (SGLT) family: implication for targeting SGLT2 in type 2 diabetes patients

Diabetes

Renal Na+-glucose cotransporters

Am. J. Physiol. Renal Physiol.

The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose

J. Clin. Invest.

Molecular physiology of sodium-glucose transporters

Physiol. Rev.

Maximum tubular reabsorption capacity for glucose and renal hemodynamcis during rapid hypertonic glucose infusion in normal and diabetic subjects

Scand. J. Clin. Lab. Invest.

Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes

Diabetes

Na+-glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity

Endocrinology

Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion

Nephrol. Dial. Transplant.

Molecular analysis of the SGLT2 gene in patients with renal glucosuria

J. Am. Soc. Nephrol.

Long-term outcome of renal glucosuria type 0: the original patient and his natural history

Nephrol. Dial. Transplant.

Is renal glycosuria a benign condition?

Proc. Eur. Dial. Transplant Assoc.

Immunological characterization of renal glycosuria patients

Clin. Exp. Immunol.

Familial renal glucosuria and SGLT2; from a Mendelian trait to a therapeutic target

Clin. J. Am. Soc. Nephrol.

Phlorizin: a review

Diabetes Metab. Res. Rev.

Review
Renal glucose reabsorption inhibitors to treat diabetes

Renal Na⁺-glucose cotransporters

The human kidney low affinity Na⁺/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose

Na⁺-glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity