The big news from the 2015 European Association for the Study of Diabetes (EASD) meeting in Stockholm was that diabetic patients treated with a sodium-glucose co-transporter 2 (SGLT2) inhibitor experienced better cardiovascular outcomes than those treated with placebo and standard of care. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) examined cardiovascular morbidity and mortality in more than 7000 adults with type 2 diabetes and a high risk for cardiovascular events.1 Trial participants randomized to the SGLT2 inhibitor demonstrated a very significant reduction in cardiovascular death compared to the control arm.

Several SGLT2 inhibitors are currently used to improve glucose control, body weight and blood pressure in patients with type 2 diabetes. As a high proportion of people with type 2 diabetes die from cardiovascular disease, the cardiovascular protective effect observed in the EMPA-REG OUTCOME trial was good news. Diabetic cardiomyopathy occurs without the hypertension and coronary artery disease that usually precede heart disease. Despite this promising result, the mechanisms leading to diabetic cardiomyopathy are still poorly defined as are the cardio-protective mechanisms of SLGT2 inhibitors.

One research group is examining molecular mechanisms of action using a diabetic dyslipidemia mouse model. The Chinese research team led by Qian Chi2 investigated the impact of phlorizin, which inhibits both SGLT1 and SGLT2 in the gastrointestinal tract and kidneys. Phlorizin is a natural compound first isolated from the bark of apple trees by French chemists in 1835 and has been used to study diabetes and renal function for decades.3 Similar to the results of EMPA-REG OUTCOMES trial, these researchers demonstrated that phlorizin has a cardio-protective effect.

The research team compared diabetic dyslipidemic mice administered with phlorizin to untreated diabetic dyslipidemic controls and normal mice. During the 10-week study, the phlorizin-treated diabetic mice gained less weight than the untreated diabetic mice, but more weight than the normal mice. At the end of the study, fasting glucose and blood lipids were collected, measured and compared. Similarly, the phlorizin-treated diabetic mice had lower serum glucose and lipids than the untreated diabetic mice, but higher levels than the normal mice. This is consistent with the results of SGLT2 inhibitors in humans.

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As diabetic cardiomyopathy is characterized by structural and functional changes in heart tissue, researchers examined the cellular structure of the diabetic mouse hearts. The hearts of the phlorizin-treated mice showed less cellular damage and fewer histological abnormalities than those of the untreated diabetic mice, but more than the normal mice.

Employing mass spectrometry, they identified 1627 proteins from the different heart tissue samples. Of the 113 differentially expressed proteins, 29 were elevated and 84 were reduced in the non-treated diabetic mice as compared to the normal mice. Phlorizin-treated diabetic mice had moderate levels of these increased and decreased proteins compared to the non-treated diabetic mice.

The team’s analysis suggests that the differentially expressed proteins are likely involved in lipid metabolism, mitochondrial function and cardiomyopathy.

The diabetic dyslipidemic mice used in this study show many of the characteristics of human disease including hyperglycemia, obesity, insulin resistance and, eventually, renal damage. In this study, phlorizin treatment reduced the effects of diabetes and diabetic cardiomyopathy, as measured by blood biochemistry and heart tissue histology. This resulted from phlorizin’s ability to reduce the differential expression of proteins related to diabetic cardiomyopathy in the mouse model. The authors suggest that phlorizin may protect against diabetic cardiomyopathy by modulating cardiac lipid and energy metabolism and by altering the expression of proteins involved in cardiac damage.

  1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. NEJM, September 17, 2015. DOI: 10.1056/NEJMoa1504720 http://www.nejm.org/doi/full/10.1056/NEJMoa1504720
  2. Cai Q, Li B, Yu F. et al. Investigation of the Protective Effects of Phlorizin on Diabetic Cardiomyopathy in db/db Mice by Quantitative Proteomics. Journal of Diabetes Research, Volume 2013 (2013), Article ID 263845, http://dx.doi.org/10.1155/2013/263845
  3. White Jr, JR. Apple Trees to Sodium Glucose Co-Transporter Inhibitors: A Review of SGLT2 Inhibition. Clinical Diabetes January 1, 2010 28 no. 1 5-10. doi: 10.2337/diaclin.28.1.5