Dakhale GN, Chaudhari HV, Shrivastava M . Advances in Pharmacological Sciences, 2011

1. Supplementation of vitamin C reduces blood glucose and improves glycosylated hemoglobin in T2DM Mellitus: a randomized, double-blind study. Dakhale GN, Chaudhari HV, Shrivastava M. Advances in Pharmacological Sciences, 2011 Julia Simpson and Dana Mills

2. Background • In the US • 25.8 million (8.3% of US population) have diabetes • 1.9 million new cases diagnosed in 2010 • If trend continues, 1 in 3 people in the US will have diabetes by 2050 • Worldwide • 346 million have diabetes • 90-95% of cases are Type 2

3. Background (cont.) OXIDATIVE STRESS IN T2DM • Increased production of superoxide • Excess nutrient intake and inactive lifestyle causes an excess of glucose and fatty acids in body tissues – especially adipose and muscle. • Overloaded electron transport chain in mitochondria “leaks” out superoxide radical • Thought that superoxide radical plays a role in beta cell dysfunction and insulin resistance • Superoxide reacts with NO to create peroxynitrite • Extremely damaging to endothelium • Normal fx of NO (vasodilation) is impaired • Contributes to athersclerosis and heart disease • In those with T2DM, circulating inflammatory cytokines are elevated (TNF, interleukines) • Oxidative stress associated with inflammation

4. Purpose • To study the effect of supplemental Vitamin C in conjunction with metformin on the following markers: • Fasting blood glucose (FBG) • Post-prandial blood glucose (PPBG) • Glycosylated hemoglobin (HbA1C) • Plasma ascorbic acid (AA)

5. Methods • Randomized, placebo-controlled, double-blind study • Nagpur, India • 12 weeks • 70 participants with the following inclusion criteria • Diagnosed with T2DM • On metformin for 0-6 months • FBG of 126 – 250 mg/dL • Age 30-60 • No coexisting medical conditions • No substance use (alcohol, tobacco, psychotropic drugs) • No use of vitamin C or other antioxidant supplements in prior 6 months

6. Methods (cont.) • Prior to baseline measurements • All participants put on a controlled vitamin C poor diet for one week • Baseline measurements • Blood samples taken and analyzed for FBG, PPBG, HbA1C, and serum ascorbic acid • Participants randomized into two groups • 1. Placebo: placebo + 500 mg metformin twice daily • 2. Vitamin C: 500 mg vitamin C + 500 mg metformin twice daily • Diet during study • Followed a diet void of vitamin C rich foods • Monthly 24 hour diet recalls to check compliance

7. Results • Placebo group: FBG and PPBG levels significantly reduced compared to pre-treatment levels • Plasma AA levels increased, and HbA1C reduced, but insignificantly • Vitamin C-treated group: FBG, PPBG and HbA1C levels significantly reduced • Plasma AA levels significantly increased

8. Results • Comparison of the effects of metformin with vitamin C and placebo on FBG, PPBG, HbA1C, and plasma AA at 12 weeks in patients with T2DM • Taking into account baseline levels for each group (all values in mg/dL) Ganesh DN, Harshal CV, Shrivastava M. Advances in Pharmacological Sciences. 2011

9. Study Conclusions • Study results were favorable—blood glucose markers were significantly reduced with vitamin C treatment in addition to metformin • Researchers proposed several mechanisms that may have produced these results: • Antioxidant activity of vitamin C may have reduced oxidative damage associated with T2DM • Vitamin C may help preserve pancreatic β-cell function, and therefore preserve ability to secrete insulin. • Vitamin C may compete with glucose to bind to amino groups on Hb, effectively reducing HbA1C.

10. STUDY LIMITATIONS • Four primary limitations: • Small sample size (65 patients completed the study) • Short follow-up period (12 weeks) • Variable patient diets • Diet conformance monitored by 24-hour recall • Differing patient intake of other antioxidants, CHO and fat could alter experiment results • Researchers could not determine direct mechanism of vitamin C in the reduction of blood glucose • Unclear as to whether the restoration of adequate vitamin C, or the effects of vitamin C in the treatment of T2DM produced study results

11. Proposed CONSTITUENTS OF Future Studies • Treatment of several hundred patients, with a follow-up period of at least 6 months • Include an additional T2DM test group fed a vitamin C-rich diet prior to the start of the study • Follow-up results would provide further distinction between the effects of vitamin C as related to a pre-existing deficiency or mechanism specific to T2DM • Monitor additional antioxidant levels to illuminate the specific role of vitamin C and/or other antioxidants in T2DM treatment

12. FUTURE IMPLICATIONS • Vitamin C and/or antioxidant supplementation as part of T2DM primary Medical Nutrition Therapy • Formulation of T2DM allopathic treatments with natural supplements (vitamin C and additional antioxidants) • Naturopathic options for the treatment of T2DM

13. Quiz Time • Which mechanism was proposed for the effects of vitamin C in this study? • Vitamin C may have regenerated adequate levels of vitamin E to prevent further oxidative damage in T2DM patients • Vitamin C may compete with glucose to bind to amino groups on Hb, effectively reducing HbA1C • Repletion of vitamin C levels in patients with T2DM automatically lowers HbA1C • Vitamin C is a natural form of insulin

14. Answer…! (b) Vitamin C may compete with glucose to bind to amino groups on Hb, effectively reducing HbA1C

15. References • Dakhale GN, Chaudhari HV, and Shrivastava M. Supplementation of vitamin C reduces blood glucose and improves glycosylated hemoglobin in type 2 diabetes mellitus: a randomized, double-blind study. Advanced in Pharmacological Sciences. 2011:1-5. • Wright Jr, E, Scism-Bacon JL, Glass LC. Oxidative stress is type 2 diabetes: the role of fasting and postprandial glycaemia. Int J ClinPract 2006;60(3):308—314. • http://www.who.int/mediacentre/factsheets/fs312/en/ • http://www.cdc.gov/chronicdisease/resources/publications/AAG/ddt.htm