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Renal sodium glucose cotransporter 2 inhibitors as a novel therapeutic approach to treatment of type 2 diabetes: Clinical data and mechanism of action.

Fujita Y, Inagaki N - J Diabetes Investig (2014)

Bottom Line: Although there are numerous glucose-lowering agents in clinical use, only approximately half of type 2 diabetic patients achieve glycemic control, and undesirable side-effects often hamper treatment in those treated with the medications.The available data suggest a good tolerability profile.However, clinicians should carefully prescribe these drugs in light of already reported and/or unexpected side-effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Diabetes Endocrinology and Nutrition Graduate School of Medicine Kyoto University Kyoto Japan.

ABSTRACT
Type 2 diabetes is characterized by impaired insulin secretion from pancreatic β-cells and/or reduced response of target tissues to insulin. Good glycemic control delays the development and slows the progression of micro- and macrovascular complications. Although there are numerous glucose-lowering agents in clinical use, only approximately half of type 2 diabetic patients achieve glycemic control, and undesirable side-effects often hamper treatment in those treated with the medications. There is a need for novel treatment options that can help overcome these difficulties. Sodium glucose cotransporter 2 (SGLT2) inhibitors have recently been developed as a novel potential therapeutic option for the treatment of type 2 diabetes. These drugs lower the plasma glucose concentration through inhibition of glucose reuptake in the kidney, independent of insulin secretion and insulin action, with a consequent lower risk of hypoglycemia. The data of clinical trials with monotherapy as well as combination therapy show that SGLT2 inhibitors have a blood glucose-lowering effect and also reduce bodyweight. A follow-up study shows long-term efficacy and the durability of these effects. SGLT2 inhibitors have the potential to reverse glucose toxicity, and to improve insulin resistance, blood pressure and lipid profile. The available data suggest a good tolerability profile. However, clinicians should carefully prescribe these drugs in light of already reported and/or unexpected side-effects. Further studies in larger numbers and longer-term clinical use data are required to place these agents in standard treatment of type 2 diabetes.

No MeSH data available.


Related in: MedlinePlus

Renal glucose handling in a non‐diabetic individual. (a) Glucose reabsorption in the kidney. (b) Glucose reabsorption through sodium glucose cotransporter (SGLT)1 and SGLT2 in the proximal renal tubular cell. ADP, adenosine diphosphate; ATP, adenosine triphosphate; GLUT, glucose transporter; S1, segment1; S2, segment 2; S3, segment 3.
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jdi12214-fig-0001: Renal glucose handling in a non‐diabetic individual. (a) Glucose reabsorption in the kidney. (b) Glucose reabsorption through sodium glucose cotransporter (SGLT)1 and SGLT2 in the proximal renal tubular cell. ADP, adenosine diphosphate; ATP, adenosine triphosphate; GLUT, glucose transporter; S1, segment1; S2, segment 2; S3, segment 3.

Mentions: The kidneys play an important role in glucose homeostasis, primarily through reabsorption of filtered glucose, glucose production (gluconeogenesis likely in the liver) and consumption16. The kidneys normally filter approximately 180 g of serum glucose in the glomeruli, which is then reabsorbed completely in the proximal tubules; urine is thus normally negative for glucose15. However, as plasma glucose concentrations approach approximately 180 mg/dL and cross over a threshold, glucose appears in the urine18. Glucose reabsorption at the renal tubules is mediated by two groups of transporters. These include glucose transporters (GLUTs) and sodium‐glucose cotransporters (SGLTs; Figure 1). GLUTs are facilitative or passive transporters that transport glucose along the concentration gradient. SGLTs are a large family of membrane proteins that transport glucose across the brush border membrane of the intestinal epithelium and proximal renal tubules using the electro‐chemical sodium gradient as the source of energy generated by Na+/K+ adenosine triphosphatase16. SGLT1 is a high‐affinity, low‐capacity transporter and is expressed mainly in the small intestine, where it plays a role in the absorption of glucose and galactose, as well as in the proximal tubules in the kidney. SGLT2 is a low‐affinity, high‐capacity transporter and is expressed particularly in proximal tubules in the kidney14. The proximal tubules in the kidney are divided to three segments (S1, S2 and S3) anatomically. SGLT2 is located in S1 and accounts for 90% of the glucose reabsorbed from the kidneys; SGLT1 is located in S2 and S3, and accounts for the remaining 10% (Figure 1).


Renal sodium glucose cotransporter 2 inhibitors as a novel therapeutic approach to treatment of type 2 diabetes: Clinical data and mechanism of action.

Fujita Y, Inagaki N - J Diabetes Investig (2014)

Renal glucose handling in a non‐diabetic individual. (a) Glucose reabsorption in the kidney. (b) Glucose reabsorption through sodium glucose cotransporter (SGLT)1 and SGLT2 in the proximal renal tubular cell. ADP, adenosine diphosphate; ATP, adenosine triphosphate; GLUT, glucose transporter; S1, segment1; S2, segment 2; S3, segment 3.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4020327&req=5

jdi12214-fig-0001: Renal glucose handling in a non‐diabetic individual. (a) Glucose reabsorption in the kidney. (b) Glucose reabsorption through sodium glucose cotransporter (SGLT)1 and SGLT2 in the proximal renal tubular cell. ADP, adenosine diphosphate; ATP, adenosine triphosphate; GLUT, glucose transporter; S1, segment1; S2, segment 2; S3, segment 3.
Mentions: The kidneys play an important role in glucose homeostasis, primarily through reabsorption of filtered glucose, glucose production (gluconeogenesis likely in the liver) and consumption16. The kidneys normally filter approximately 180 g of serum glucose in the glomeruli, which is then reabsorbed completely in the proximal tubules; urine is thus normally negative for glucose15. However, as plasma glucose concentrations approach approximately 180 mg/dL and cross over a threshold, glucose appears in the urine18. Glucose reabsorption at the renal tubules is mediated by two groups of transporters. These include glucose transporters (GLUTs) and sodium‐glucose cotransporters (SGLTs; Figure 1). GLUTs are facilitative or passive transporters that transport glucose along the concentration gradient. SGLTs are a large family of membrane proteins that transport glucose across the brush border membrane of the intestinal epithelium and proximal renal tubules using the electro‐chemical sodium gradient as the source of energy generated by Na+/K+ adenosine triphosphatase16. SGLT1 is a high‐affinity, low‐capacity transporter and is expressed mainly in the small intestine, where it plays a role in the absorption of glucose and galactose, as well as in the proximal tubules in the kidney. SGLT2 is a low‐affinity, high‐capacity transporter and is expressed particularly in proximal tubules in the kidney14. The proximal tubules in the kidney are divided to three segments (S1, S2 and S3) anatomically. SGLT2 is located in S1 and accounts for 90% of the glucose reabsorbed from the kidneys; SGLT1 is located in S2 and S3, and accounts for the remaining 10% (Figure 1).

Bottom Line: Although there are numerous glucose-lowering agents in clinical use, only approximately half of type 2 diabetic patients achieve glycemic control, and undesirable side-effects often hamper treatment in those treated with the medications.The available data suggest a good tolerability profile.However, clinicians should carefully prescribe these drugs in light of already reported and/or unexpected side-effects.

View Article: PubMed Central - PubMed

Affiliation: Department of Diabetes Endocrinology and Nutrition Graduate School of Medicine Kyoto University Kyoto Japan.

ABSTRACT
Type 2 diabetes is characterized by impaired insulin secretion from pancreatic β-cells and/or reduced response of target tissues to insulin. Good glycemic control delays the development and slows the progression of micro- and macrovascular complications. Although there are numerous glucose-lowering agents in clinical use, only approximately half of type 2 diabetic patients achieve glycemic control, and undesirable side-effects often hamper treatment in those treated with the medications. There is a need for novel treatment options that can help overcome these difficulties. Sodium glucose cotransporter 2 (SGLT2) inhibitors have recently been developed as a novel potential therapeutic option for the treatment of type 2 diabetes. These drugs lower the plasma glucose concentration through inhibition of glucose reuptake in the kidney, independent of insulin secretion and insulin action, with a consequent lower risk of hypoglycemia. The data of clinical trials with monotherapy as well as combination therapy show that SGLT2 inhibitors have a blood glucose-lowering effect and also reduce bodyweight. A follow-up study shows long-term efficacy and the durability of these effects. SGLT2 inhibitors have the potential to reverse glucose toxicity, and to improve insulin resistance, blood pressure and lipid profile. The available data suggest a good tolerability profile. However, clinicians should carefully prescribe these drugs in light of already reported and/or unexpected side-effects. Further studies in larger numbers and longer-term clinical use data are required to place these agents in standard treatment of type 2 diabetes.

No MeSH data available.


Related in: MedlinePlus