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SGLT2 Inhibitors and Beta-Cell Preservation

Phuong Nguyen, Doctor of Pharmacy Candidate, LECOM, College of Pharmacy

Studies investigating both mice and humans have shown that chronic hyperglycemia may shift the balance of B-cell proliferation and apoptosis toward cell death, consequently resulting in B-cell deficiency and impaired insulin secretion. Idris and Donnelly (2009) studied the effect of T-1095, an analog of phlorizin, an SGLT2 inhibitor. T-1095 is a pro-drug that is rapidly converted to an active metabolite, T-1095A in the liver, which has high affinity and selectivity for human SGLT2 in the kidney. Rats treated for 32 weeks with T-1095 partially restored B-cell function after week 8. Inhibition of glucose reabsorption leads to urinary glucose excretion and concurrent glucose lowering. Accordingly, this reduces the effects of glucose toxicity on pancreatic B-cells preserving B-cell functioning….

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Another study by Stenlof et al (2013), found improvements in B-cell function with canagliflozin 100 and 300 mg compared with placebo. Increases in fasting insulin secretion were observed with both doses of canagliflozin over placebo.

A study by Jurczak et al (2011), proposed that SGLT2 deletion results in decreased glucose toxicity, thus preserving islet mass and improving glucose homeostasis. The authors investigated the behavioral and metabolic consequences including pancreatic B-cell functioning, as a result of SGLT2 deletion in diabetic mice models. Eighty islets isolated from mice pancreases were picked and loaded into perifusion chambers. Islet DNA was isolated and quantified for normalization of insulin and glucagon data. Frequency of cell death was calculated as a number of insulin/TUNEL (transferase-mediated dUTP nick-end labeled pancreas) -positive cells. Islet number was determined by counting all islets within a given field, corrected to pancreas area. 30 fields were taken at random, and 3 sections per mice were analyzed.

After regular chow (18% fat, 58% carbohydrates, 24% protein by calories) feeding, SGLT2 knockout mice had significantly lower fasting plasma glucose concentrations and a nonsignificant reduction in plasma insulin concentrations compared with the wild type mice. After 4 weeks of high-fat diet (55% fat, 24% carbohydrate, 21% protein, by calories), fasting glucose was drastically reduced in SGLT2 knockout mice compared with wild type mice.

The correlation between glucose toxicity and B-cell failure led the researchers to assess glucose stimulated insulin secretion in tested subjects. When assessing the same net change in plasma glucose concentration (hyperglycemic clamp at 200mg/dL above subjects’ basal plasma glucose), SGLT2 knockout mice displayed a significant increase in plasma insulin levels. Plasma insulin levels were 2.4 fold greater in SGLT2 knockout mice compared to the wild type and calculations of change in plasma insulin from baseline demonstrated approximately a 2 fold increase in glucose stimulated insulin secretion in the SGLT2 knockout mice — consistent with improved B-cell function in-vivo.

Isolated pancreatic islets from wild type and SGLT2 knockout mice were perifused to determine if there was a change in islet function. Surprisingly, there was no difference between glucose stimulated insulin secretion or glucagon suppression between groups, suggesting that individual islet function and perifusion studies do not account for the in vivo differences.

The difference between the hyperglycemic clamp and islet perifusion results suggest that changes in B-cell mass might account for the increased insulin secretion observed in vivo. Compared with wild type mice, relative B-cell volume was increased 5.4 fold for SGLT2 knockout mice (p <0.001), suggesting compensatory hypertrophy due to insulin resistance. There was a 63% increase in relative B-cell volume in SGLT2 knockout mice compared with the wild type. The difference in the islet mass between the groups appeared to be a function of increased islet size rather than number. There was no difference in frequency of the B-cells, suggesting that B-cell proliferation rates were not increased in the SGLT2 knockout mice; however, the frequency of Transferase-mediated dUTP nick-end labeled (TUNEL) pancreatic cells were 64% less in the SGLT2 knockout mice indicating that rates of cell death were slower.

The researchers concluded that improvements in B-cell function observed in vivo may result from a maintained B-cell mass due to a reduced frequency of B-cell death. The lack of difference in islet function during isolation and perifusion described in this study suggests that the primary mechanism by which reduced glucose toxicity improved glucose-stimulated insulin secretion was through preservation of islet mass rather than a change in B-cell function.

Reference

Jurczak MJ, Lee HY, Birkenfeld AL, Jornayvaz FR, Frederick DW, Pongratz RL, et.al. SGLT2 Deletion Improves Glucose Homeostasis and Preserves Pancreatic B-cell Function. Diabetes. 2011 March; 60(3) 890-898. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046850/

Idris I and Donelly R. Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diabetes, Obesity, and Metabolism, 2009 Feb; 11(2): 79-88. http://onlinelibrary.wiley.com/doi/10.1111/j.1463-1326.2008.00982.x/pdf

Stenlöf K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, et. al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab. 2013 Apr;15(4):372-82. http://onlinelibrary.wiley.com/doi/10.1111/dom.12054/pdf

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