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

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

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

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)

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  No coexisting medical conditions  No substance use (alcohol, tobacco, psychotropic drugs)  No use of vitamin C or other antioxidant supplements in prior 6 months

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 mg metformin twice daily  2. Vitamin C: 500 mg vitamin C mg metformin twice daily  Diet during study  Followed a diet void of vitamin C rich foods  Monthly 24 hour diet recalls to check compliance

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

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) Parameter Change from baseline at 12 weeks P (unpaired) Group A (vitamin C) Group B (placebo) FBG − ± 3.80 − 5.42 ± 2.65 <0.05 PPBG − ± 2.42 − 6.93 ± 2.99 <0.05 HbA1C − ± 0.07 − ± 0.10 <0.05 Plasma AA0.19 ± ± 0.01<0.001 Ganesh DN, Harshal CV, Shrivastava M. Advances in Pharmacological Sciences. 2011

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: 1. Antioxidant activity of vitamin C may have reduced oxidative damage associated with T2DM 2. Vitamin C may help preserve pancreatic β -cell function, and therefore preserve ability to secrete insulin. 3. Vitamin C may compete with glucose to bind to amino groups on Hb, effectively reducing HbA1C.

STUDY LIMITATIONS  Four primary limitations: 1. Small sample size (65 patients completed the study) 2. Short follow-up period (12 weeks) 3. Variable patient diets  Diet conformance monitored by 24-hour recall  Differing patient intake of other antioxidants, CHO and fat could alter experiment results 4. 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

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

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

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

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

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 Clin Pract 2006;60(3):308—314.  