IMPACT OF VITAMINS IN PREVENTION OF RISK FACTORS ASSOCIATED WITH TYPE-2 DIABETES MELLITUS

IMPACT OF VITAMINS IN PREVENTION OF RISK FACTORS ASSOCIATED WITH TYPE-2 DIABETES MELLITUS

V.K. Gupta*¹, Asha Pathak ¹, Manoj Gahlot ², R.C. Verma ¹ and C.V. Singh ¹

Department of Pharmacology, Uttar Pradesh Rural Institute of Medical Sciences & Research ¹, Saifai, Etawah, Uttar Pradesh, India

Department of Pharmaceutical Sciences, SGRRIST ², Patel Nagar, Dehradun, Uttarakhand, India

ABSTRACT: Diabetes mellitus is one of the most common metabolic disorders that cause micro and macro vascular complications. Because of additive effects of hyperglycaemia and hyperlipidaemia for cardiovascular disease, serum lipid and glucose level should be closely monitored in diabetes. Chronic Hyperglycaemia resulting from diabetes has profound effects on nearly every system of the body. The toxic effects of hyperglycaemia may result from accumulation of nonenzymatically glycosylated products, increased sorbitol production in tissue, formation of diacylglycerol leading to activation of protein kinase C or by free radical generation. Since type 2 DM is a major public health problem, accounting for significant premature mortality and morbidity, every possible effort should be made to minimize its complications. Studies have shown that diabetes is accompa­nied by an increased oxidative damage to all the bimolecules. Enhanced oxidative stress contributes to the development of the diabetic complications. Over the last 5 years, a number of large observational studies have suggested an association between the onset of type 2 diabetes and Vitamin deficiencies. As vitamins have important effects on insulin action, serum lipid and glucose and may have impact on a number of pathways which may be of importance in the development of type 2 diabetes. This article reviews the evidence linking role of Vitamins in the prevention of risk factors associated with type 2 diabetes, and suggests current recommendations for supplementation and the most pertinent research on the use of key vitamins in diabetes management.

Type-2 DM, Insulin, Oxidative stress, Inflammation, Micronutrients

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is currently considered as a global health problem where about six people die every minute from the disease worldwide

This rate will make T2DM one of the world’s most prevalent causes of preventable mortality ¹.

T2DM is caused by impaired glucose tolerance (IGT) as a result of insulin resistance and consequent islet β- cell exhaustion, with ensuring insulin deficiency ². In individuals with IGT, numerous genetic, host-related, and environmental factors contribute to the progression of insulin resistance in T2DM ³. The prevalence of type 2 diabetes continues to increase with increasing number of patients at risk of serious diabetes-related complications. Having type 2 diabetes increase the risk of a myocardial infarction two times and the risk of suffering a stroke two to four times. It is also a leading cause of blindness, limb amputation and kidney failure ⁴.

Diabetes is accompanied by severe oxidative stress which is caused by increased oxygen free radi­cal production. Toxic oxygen free radicals have been implicated in the pathogenesis of Diabetes mellitus, and its micro and macro vascular complications⁵. An imbalance which results from an increased production and/or the reduced scavenging of these free radicals leads to a metabolic state of oxidative stress, which consequently leads to tissue damage. Auto glycosylation reac­tions, alterations in the sorbitol pathway and hyperglycemia have been proposed as some of the mechanisms which are respon­sible for this increased oxidative stress ⁵.

Within the last decade, a hypothesis was proposed to explain the pathogenesis of T2DM that connects the disease to a state of subclinical chronic inflammation ⁶. The influence of fat is well known, current thinking suggests that abnormal levels of chemokines released by the expanding adipose tissue in obesity activate monocytes and increase the secretion of pro-inflammatory adipokines. Such cytokines in turn enhance insulin resistance in adipose and other tissues, thereby increasing the risk for T2DM ⁷. Together, lipid toxicity and low-grade inflammation appear to be major assaults on insulin sensitivity in insulin-responding tissues ^{8, 56}.

Activation of innate immunity promotes various inflammatory reactions that provide the first line of defence the body invokes against microbial, chemical, and physical injury, leading to repair of damage, isolation of microbial infectious threats and restoration of tissue homeostasis ⁹. Previous studies have found that appropriate lifestyle intervention and/or drug treatments are effective in delaying or preventing both diabetes and its complications ¹⁰.

This article was undertaken in an attempt to evaluate the current knowledge linking various risk factors associated with type 2 diabetes mellitus and role of vitamins in attenuating inflammation, oxidative stress and thereby reducing the risk of T2DM and its complications.

Epidemiology of Type 2 Diabetes: The world prevalence of diabetes in 2010 among adults aged 20-79 years is estimated to 6.4%, affecting 285 million adults¹¹. Between 2010 and 2030, there is an expected 70% increase in numbers of adults with diabetes in developing countries and a 20% increase in developed countries ¹¹. Each year more than 231,000 people in the United States and more than 3.96 million people worldwide die from diabetes and its complications ¹². This number is expected to increase by more than 50 percent over next decade ⁴.

Estimated global healthcare expenditures to treat and prevent diabetes and its complications is at least 376 billion US Dollar (USD) in 2010. By 2030, this number is projected to exceed some 490 billion USD¹³. These costs are mainly due to treatment of concomitant CVD ¹⁴. It has been shown in several studies that a clustering of features, such as high plasma glucose, obesity, dyslipidemia (high triglyceride and total cholesterol levels, low high density lipoprotein (HDL) cholesterol levels and hypertension, referred to as insulin resistance or the metabolic syndrome, is a marker of increased risk for the development of type 2 diabetes as well as for CVD ¹⁵. Environmental and lifestyle factors are the main causes of the dramatic increase in type 2 diabetes prevalence ^{16, 3}. Genetic factors probably identify those most vulnerable to these changes. Furthermore, studies have shown certain ethnic groups to be more susceptible to developing diabetes than others ¹⁷. Wild et al ¹ ranked the countries with the largest numbers of diabetes (Table 1).

Risk factors for Type 2 Diabetes: Many studies have elaborated the associations between several risk factors and the risk of type 2 diabetes. Body mass index (BMI), lipids, hypertension, smoking, physical inactivity, low education, dietary patterns, family history, and recently specific genes are also the most frequently documented risk factors for type 2 diabetes ⁴².

Overweight, BMI and Diabetes: The pathogenesis of T2DM associated with obesity involves abnormal insulin secretion as a consequence of β-cell failure and the development of insulin resistance. Many longitudinal studies have reported that increased BMI is a strong risk factor for type 2 diabetes ^{19, 24}. A strong positive association between obesity and type 2 diabetes is found both in men ¹⁹, and women ¹⁹.

TABLE 1: COUNTRIES WITH THE HIGHEST NUMBERS OF ESTIMATED CASES OF DIABETES FOR YEAR 2000 AND 2030

 Obesity is associated with increased risk of developing insulin resistance and type 2 diabetes. In obese individuals adipose tissue releases increased amounts of non-esterified fatty acids, glycerol, hormones, pro-inflammatory cytokines and other factors involved in the development of insulin resistance. When insulin resistance is accompanied by dysfunction of the beta cells, the fall in insulin secretion results in failure to control blood glucose level, leading to type 2 diabetes.

Many genes interact with the environment leading to obesity and in some also to diabetes. Many genes have been shown to be involved in determining the whole range of BMI in a population, with each gene only explaining a few hundred gram difference in body weight ²⁰. Genes responsible for obesity and insulin resistance interact with environmental factors such as increased fat/ calorie intake and decreased physical activity resulting in the development of obesity and insulin resistance followed ultimately by the development of type 2 diabetes ²¹.

TABLE 2: ²² HEALTHY WEIGHT IN RELATION TO HEIGHT USING BMI

Men are at high risk if they have a waist circumference of 94-102 cm (37-40 inches). Women are at high risk if they have a waist circumference of 80-88 cm (31.5-35 inches)

Abnormal Lipid Level and Diabetes: An abnormal blood lipid profile has been reported as a risk factor for type 2 diabetes by several prospective studies ^{19, 23, 24}. An inverse relationship between HDL cholesterol and risk of type 2 diabetes have been documented in several of these ^{23, 24}. Some studies found low HDL cholesterol to be a stronger risk factor for type 2 diabetes in women only ^{39, 48}. Only one previous study measuring non-fasting triglycerides found an independent risk of type 2 diabetes connected to elevated triglyceride levels ¹⁹.

High plasma triglycerides and low plasma HDL cholesterol levels are both seen in the insulin resistance syndrome, which is a pre-diabetic state ¹⁵, suggesting that non fasting triglycerides and HDL cholesterol levels reflect the degree of insulin resistance. The mechanisms suggested are increased circulating levels of free fatty acids due to increased insulin levels and increased chylomicron-assembly and secretion in the gut, the latter process being a result of localized insulin resistance in the intestine.

Cross sectional studies have shown that high BMI is associated with a higher level of total cholesterol and unfavourable lipids pattern, with low concentrations of HDL cholesterol and high triglycerides concentrations ²⁵. Longitudinal studies have shown BMI change over time to be positively associated with changes in total cholesterol, triglycerides, and low density lipoprotein (LDL) cholesterol and negatively associated with HDL cholesterol change ²⁶. Apart from triglycerides, all these lipids have been shown to convey diabetes risk independently of BMI, but how they interact have been little studied.

Hypertension and Diabetes: Several possible factors are likely to be associated between type 2 diabetes and hypertension. A case control studies have shown that hypertension progression is an independent predictor of type 2 diabetes ²⁷. Studies have shown that markers of endothelial dysfunction are associated with new-onset of diabetes ²⁸ and endothelial dysfunction is closely related to blood pressure and hypertension ³¹. Markers of inflammation such as C-reactive protein have been consistently related to incident of type 2 diabetes ³⁰ and to increasing blood pressure levels ³¹ suggesting that inflammation might be another explanatory factor for the association between blood pressure, the metabolic syndrome, and incidence type 2 diabetes ³². In addition evidence from cross sectional and cohort studies suggests strong relationship between blood pressure and BMI and risk of type 2 diabetes ²⁶.

Smoking and Diabetes: Several prospective studies reported that smoking is a risk factor for developing type 2 diabetes ³³. Recently, a meta analysis including 25 prospective studies showed that smoking was associated with a 44% increased risk of diabetes ³⁴. The association between smoking and type 2 diabetes was stronger for heavy smokers compared with light smokers or former smokers ³⁴. In addition some studies found an increased risk of type 2 diabetes in the first 2-3 years after smoking cessation ³³. This could be due to a direct effect of nicotine or other components of cigarette smoke on beta cells of the pancreas as suggested by the association of cigarette smoking with chronic pancreatitis and pancreatic cancer ³⁶.

Also, some studies suggest that heavy smokers with evidence of increased systemic inflammation, who gain substantial weight after quitting, are at high risk of developing type 2 diabetes ³⁷. However over longer follow up, smoking cessation is associated with a reduction in risk of developing type 2 diabetes ³⁸.

Physical inactivity and Diabetes: Physical activity has been shown to be inversely related with obesity and fat distribution, particularly visceral obesity. Studies have shown that physical activity may reduce risk of type-2 diabetes both directly by improving insulin sensitivity and indirectly by producing beneficial changes in body mass and body composition ³⁹. Longitudinal studies have found physical inactivity to be a strong risk factor for type 2 diabetes ¹⁹. Prolonged television watching as a surrogate marker of sedentary lifestyle was reported to be positively associated with diabetes risk in both men and women ⁴⁰. Moderate and vigorous physical activity was associated with a lower risk of type 2 diabetes ²⁴. Evidence from clinical trials which included physical activity as an integral part of life style interventions suggested that onset of type 2 diabetes can be prevented or delayed by successful lifestyle interventions that included physical activity as a part of this interventions ¹⁰. Physical activity plays an important role in delaying or prevention of development of type 2 diabetes in those at risk both directly by improving insulin sensitivity and reducing insulin resistance, and indirectly by beneficial changes in body mass and body composition ⁴¹.

Illiteracy and Diabetes: Previous prospective studies have examined the association between educational attainment and the incidence of diabetes and found that low education is significant predictor of type 2 diabetes ⁴². In a cross sectional study of National Population Health Survey found that people with less than high school were almost twice as likely to report having diabetes as those with a bachelor degree or more ⁴³. Another cross sectional study from the National Health Interview Survey found that women with low education had a higher prevalence of diabetes than the better educated.

Furthermore, the association varied by race/ethnicity and gender, with Whites, Hispanics and women exhibiting a stronger association between education and diabetes than blacks and men ⁴⁴. A recent cross sectional study found that type 2 diabetes risks was higher in the least educated who were obese and inactive compared to the more educated ⁴⁵. These studies suggest that educational attainment promote an interest in own health and acquisition of knowledge that strongly influence people’s ability to reduce risk by successfully adopting a healthier life style.

Dietary pattern and Diabetes: Daily in pattern diet intake has a role on increased weight, central obesity and insulin resistance and causing future development of diabetes. There are growing evidences that an increased level of free fatty acid and more importantly the relative amounts of saturated and unsaturated fatty acids play an important role in development of insulin resistance. Cross sectional epidemiological studies demonstrate positive associations between intake of saturated fat and heyperinsulinemia ⁴⁶.

Diet with high saturated fat causes decreased the insulin sensitivity that progress to dysfunction of pancreatic beta cells and causes diabetes. Several large prospective cohort studies showed negative association between dietary fiber intake and risk of developing type 2 diabetes ⁴⁷. Higher dietary glycemic index has been consistently associated with elevated risk of type 2 diabetes in prospective cohort studies ⁴⁸. The relative risk (RR) for type 2 diabetes highest to the lowest glycemic index was; for quintiles 1–5, respectively: 1, 1.15, 1.07, 1.27, and 1.59 (P for trend 0.001), whereas cereal fiber intake was associated with a decreased risk for quintiles 1–5, respectively: 1, 0.85, 0.87, 0.82, and 0.64 (P for trend 0.004) ⁴⁸.

The possible mechanisms suggested are that insoluble fibre intake was consistently associated with improved insulin sensitivity and decreases risk of type 2 diabetes ⁴⁹. Furthermore large observational studies have suggested an association between low vitamin D status or low vitamin D intake and increased incidence of type 2 diabetes ⁵⁰. The suggested mechanisms are that vitamin D deficiency may contribute to beta cell dysfunction, insulin resistance and inflammation that may result in type 2 diabetes. The effect of dietary habits has in all these studies been shown to be independent of BMI change.

Genetics and Diabetes: Several studies have found that a genetic component plays an important role in pathogenesis of type 2 diabetes ¹⁶. Several prospective studies and cross sectional studies have reported that positive family history among first degree relatives confers an increased risk of type 2 diabetes and the risk is greater when both parents are affected ⁵¹. A study on twins have demonstrated that concordance estimate for type 2 diabetes is high in monozygotic compared to dizygotic and the rate increases with duration of follow up.

Also, diabetes prevalence varies substantially among different ethnic groups ¹⁶, and this observation of substantial variation of disease prevalence across ethnic groups that share a similar environment, supports the idea that genetic factors contribute to disease predisposition ⁵². Data from multiple laboratories support that genetic factors predispose to development of type 2 diabetes by reducing insulin sensitivity and insulin secretion which deteriorate in parallel in most human type 2 diabetes cases ⁵². Recent studies have identified variants in 11 genes (TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX) to be significantly associated with the risk of type 2 diabetes independently of other clinical risk factors and variants in 8 of these genes were associated with impaired beta-cell function ¹⁸.

Among these genes expressed in pancreatic cells and involved in impairment of insulin secretion, the transcription factors 7-like 2 (TCF7L2), is the locus with the highest risk of type 2 diabetes (HR 1.5) ¹⁸. This corresponds to an attributable risk of 25%, due to an average single allele frequency 18-30% in Northern Europeans ⁵³. Still the value of genetic information decreased by duration of follow up and eventually only increases the receiver operating characteristics (ROC ) achieved by clinical risk factors from 0.74 to 0.75 ( p <0.0001)¹⁸. So far genetic information is of interest for research purposes only.

Type 2 Diabetes and role of Vitamin Supplementation: A simple, sensitive and acceptable screening tool is vital in early identification and intervention of type 2 diabetes. A recent study on early detection of type 2 diabetes mellitus in Chinese and Indian adult populations found age, obesity and family history of diabetes to be moderately discriminative for early detection of diabetes with only an ROC of 62% in men and  64% in women ⁵⁴, clearly showing the need for screening tools incorporating more risk factors. Indeed, exploring the possibility that supplementation with selected micronutrients can attenuate various risk factors and also obesity-related inflammation in order to delay the development of T2DM should be considered alongside existing public health practices to reduce the disease rising rates.

Micronutrients, T2DM and inflammation: The feasibility of modulating innate immunity-related inflammation as an approach for the prevention of T2DM is based on reports that evaluated the efficacy of anti-inflammatory pharmaceutical agents on disease manifestation ⁷. A therapeutic strategy for T2DM that would act primary on the inflammatory system has been proposed in the form of salicylates, an anti-inflammatory agent long known to have a hypoglycemic effect ⁵⁵.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are able to enhance glucose-induced insulin release, improve glucose tolerance, and increase the effect of insulin in patients with T2DM ⁵⁶.

In humans, treatment with NSAIDs improved various biochemical indices associated with T2DM ⁵⁷. With respect to T2DM, the consensus of available information suggests that micronutrient intake modulates the innate immune system ⁵⁸ and can subsequently influence the predisposition (to and prevention) of disease ⁵⁸. By virtue of this observation, the hope is that the outcome of nutritional supplementation can be simply monitored via its modifying action on the levels of inflammatory biomarkers.

Many micronutrients exhibit well-characterized anti-inflammatory or immunomodulatory functions⁵⁷. Vitamins (e.g., D, E, and C), certain fatty acids (e.g., omega-3 fatty acid) and trace elements (e.g., selenium, zinc, copper and iron) are known to improve the overall function of the immune system, prevent excessive expression and synthesis of inflammatory cytokines, and the ‘oxidative burst’ potential of macrophages ⁵⁷.

Vitamin B: Vitamin B1 (Thiamine), Vitamin B6 (Pyridoxin), Vitamin B9 (Folic acid) and Vitamin B12 (Cobalamin) are members of vitamin B family. Recently in a pilot scale, placebo-controlled intervention trial, high-dose Vitamin B1 (Thiamine) supplementation of patients with type 2 diabetes mellitus and early stage diabetic nephropathy (microalbuminuria) improved renal function in all patients and produced regression of microalbuminuria in some individuals ⁵⁹. High-dose thiamine therapy holds promise as a novel additional treatment for early-stage diabetic nephropathy.

Combination therapy with vitamins B₆, B₉ and B₁₂ is a therapeutic intervention to decrease levels of plasma homocysteine and the risk of cardiovascular disease. However, a recent trial found that cosupplementation with these vitamins exacerbated the decline in renal function and increased the risk of vascular disease in patients with diabetic nephropathy. Confidence in this high-dose vitamin supplement is shaken. High concentrations of plasma total homocysteine are known to be associated with the risk of developing diabetes-related cardiovascular disease, nephropathy and proliferative retinopathy.

Cosupplementation of pyridoxine (vitamin B₆), folic acid (vitamin B₉) and vitamin B₁₂ has been used to decrease levels of plasma homocysteine and the risk of cardiovascular disease. A study by House et al ⁶⁰ has now shown substantial adverse outcomes associated with high-dose vitamin B₆, B₉ and B₁₂ co supplementation in patients with advanced diabetic nephropathy.

In an another trial, the Heart outcomes Prevention evaluation (HOPE-2) study, ⁶¹ involved 5,522 patients with vascular disease or diabetes mellitus and found no effect of high dose B₆, B₉ and B₁₂ co supplementation on death from cardiovascular disease, whereas the risk of stroke was decreased and the risk of unstable angina requiring hospitalization was increased. The Homocysteinemia in Kidney and end stage renal Disease (HOST) study ⁶² involved 2,056 patients with advanced kidney disease and found no effect of high-dose vitamin B₆, B₉ and B₁₂ supplements on survival or risk of cardiovascular disease-related events.

Previous studies with high-dose pyridoxine treatment of patients with ischemic heart disease ⁶³ and high-dose treatment with the related compound pyridoxamine is so called vitamer as it fulfils the same specific vitamin function in patients with advanced diabetic nephropathy ⁶⁴ gave no evidence of acceleration of decline in glomerular filtration rate or increased cardiovascular disease events and mortality.

A further factor underlying the association of high-dose vitamin B₆, B₉ and B₁₂ supplements and metabolic dysfunction in diabetic nephropathy could be the effect of high-dose folic acid on metabolite transport via the folate transporter 1 (RFC-1). In addition to facilitating transport of folate, RFC-1 is also a transporter of thiamine monophosphate (TMP) and thiamine pyrophosphate (TPP) ⁶⁵. Diabetic nephropathy occurs within a background of thiamine (vitamin B₁) deficiency owing to impaired renal reuptake of thiamine.

Plasma thiamine concentrations were inversely linked to plasma soluble vascular cell adhesion protein 1 (sVCAM-1)- a risk marker of cardiovascular disease ⁶⁶. Folate binds to and is transported into cells by the RFC-1 transporter ⁶⁵. High-dose folic acid supplementation might exacerbate thiamine deficiency at susceptible sites, such as the kidney and vascular cells in diabetic nephropathy, by competing with TMP and TPP and impairing their uptake into tissues, thereby inhibiting sharing of thiamine metabolites between tissues rich in thiamine and those deficient in it ⁶⁶. Preclinical investigations are now required to test this and other possible mechanisms underlying adverse effects of high dose vitamin B₆, B₉ and B₁₂ supplementation.

Vitamin C: Vitamin C is an important antioxidant in human, capable of scavenging oxygen derived free radicals. The daily recommended dietary allowance for vitamin C is 75 mg for women and 90 mg for men, with an additional 35 mg for smokers due to the higher metabolic turnover of the vitamin in this group as compared to non-smokers ⁶⁷. Ascorbate appears in the urine at intakes of roughly 60 mg/day. However, the results of a depletion/repletion study in healthy young women showed that ascorbate plasma and white blood cell concentrations only saturate at intakes of 200 mg/day or higher ⁶⁸. These results suggest that the current dietary recommendations may not provide tissue-saturating ascorbate concentrations ⁶⁹.

Indeed, epidemiologic findings suggest that serum ascorbic acid deficiency may be relatively common. For example, a recent crosssectional survey of healthy young adults of the Toronto Nutrigenomics and Health (TNH) Study reported that 1 out of 7 individuals are deficient in serum ascorbic acid ⁷⁰. Vitamin C has an important role in immune function and various oxidative and inflammatory processes, such as scavenging reactive oxygen species (ROS), preventing the initiation of chain reactions that lead to protein glycation ⁶⁷ and protecting against lipid peroxidation ⁶⁷. The oxidized products of vitamin C, ascorbyl radical and dehydroascorbic acid are easily converted to ascorbic acid by glutathione, NADH or NADPH ⁶⁷.

For this reason, there has been interest in determining whether vitamin C might be used as a therapeutic agent against the oxidative stress and subsequent inflammation associated with T2DM. A variety of epidemiologic studies have assessed the effect of vitamin C on biomarkers of oxidation, inflammation and/or T2DM risk ⁷¹. A large cross-sectional evaluation of healthy elderly men from the British Regional Heart Study reported that plasma vitamin C, dietary vitamin C and fruit intake were inversely correlated with serum CRP and tissue plasminogen activator [TPA], a biomarker of endothelial dysfunction ⁷⁰. However, only plasma vitamin C was inversely associated with fibrinogen levels ⁷¹.

A significant inverse association was found between plasma levels of vitamin C and risk of diabetes (OR=0.38, 95% CI=0.28-0.52). In the same study, a similar association was observed between fruit and vegetable intake and T2DM risk (OR=0.78, 95% CI=0.60-1.00) ⁷². One randomized, cross-over, double-blind intervention trial reported no improvement in fasting plasma glucose and no significant differences in levels of CRP, IL-6, IL-1 receptor agonist or oxidized LDL after supplementation with 3000 mg/day of vitamin C for 2 weeks in a group of 20 T2DM patients, compared to baseline levels ⁷³. Chen and colleagues performed a randomized, controlled, double-blind intervention on a group of 32 diabetic subjects with inadequate levels of vitamin C and found no significant changes in either fasting glucose or fasting insulin after intake of 800 mg/day of vitamin C for 4 weeks ⁷⁴.

On the other hand, Wang and colleagues showed that the red blood cell sorbitol/plasma glucose ratio was reduced after supplementation with 1000 mg/day vitamin C for 2 weeks in a group of eight diabetics, although no differences were found in fasting plasma glucose⁷⁵. Since sorbitol is a product of the pro-oxidative polyol pathway, this observation may suggest an inhibition of the polyol pathway by vitamin C among subjects with diabetes.

Another study has shown that daily intake of ascorbic acid at 2000 mg/day improved fasting plasma glucose, HbA1c, cholesterol levels and triglycerides in 56 diabetics ⁷⁶. In agreement, Paolisso et. al. found that 1000 mg/day of vitamin C for 4 months improved LDL and total cholesterol, fasting plasma insulin and free radicals, although it did not affect triglycerides or HDL levels in a group of 40 diabetics ⁷⁷. Overall, it remains unclear whether vitamin C intake has an effect on factors related to T2DM. Further research and long-term prospective studies are needed to elucidate the role of vitamin C as a modulator of inflammation and T2DM risk, and to evaluate its potential role as a preventive agent at a population level.

Vitamin D: The role of vitamin D in calcium and phosphorus homeostasis and bone metabolism is well understood. However, more recently vitamin D and calcium homeostasis have also been linked to a number of conditions, such as neuromuscular function, cancer, and a wide range of chronic diseases, including autoimmune diseases, atherosclerosis, obesity, cardiovascular diseases, diabetes and associated conditions such as the metabolic syndrome and insulin resistance ^{57, 58, 80}.

In T2DM, the role of vitamin D was suggested from the presence of vitamin D receptors (VDR) in the pancreatic β-islet cells ⁵⁸. In these cells, the biologically active metabolite of vitamin D (i.e., 1,25-dihydroxy-vitamin D; 1,25[OH]D)⁷⁸ enhances insulin production and secretion via its action on the VDR ⁵⁸. Indeed, the presence of vitamin D binding protein (DBP), a major predictor of serum levels of 25(OH)D and response to vitamin D supplementation ⁷⁹ and VDR initiated several studies demonstrating a relationship between single nucleotide poly-morphisms (SNPs) in the genes regulating VDR and DBP and glucose intolerance and insulin secretion ⁵⁰.

This further supports a role for vitamin D in T2DM and may explain the reduced overall risk of the disease in subjects who ingest >800 IU/d of vitamin D ⁸⁰. However, an alternative, and perhaps related, explanation was recently proposed for the role of vitamin D in T2DM prevention based on its potent immunomodulatory functions ⁸¹.

1,25(OH)D modulates the production of the immunostimulatory IL-12 and the immunosuppressive IL-10 ⁸² and VDRs are present in most types of immune cells ⁸³. In this respect, supplementation with vitamin D ⁸⁴ or its bioactive form, 1,25(OH)D ⁷⁸, improved insulin sensitivity by preventing the excessive synthesis of inflammatory cytokines. This effect of vitamin D on cytokine synthesis is due to its interaction with vitamin D response elements (VDRE) present in the promoter region of cytokine-encoding genes.

This interaction downregulates the transcriptional activities of cytokine genes and attenuates the synthesis of the corresponding proteins⁸⁴. Vitamin D also deactivates NFκB, which transcriptionally up regulates the pro-inflammatory cytokine-encoding genes ⁸⁵.

Down regulating the expression of NFκB and downstream cytokine genes inhibits β-cell apoptosis and promotes their survival ⁸². As reviewed by Pittas et al ⁸², a number of cross-sectional studies in both healthy and diabetic cohorts have shown an inverse association between serum 25(OH)D and glycemic status measures such as fasting plasma glucose, oral glucose tolerance tests, hemoglobin A1c (HbA1c), and insulin resistance as measured by the homeostatic model assessment (HOMAR), as well as the metabolic syndrome ^{87, 88}.

Data from the National Health and Nutrition Examination Survey (NHANES) showed an inverse, dose-dependent association between serum 25(OH)D and diabetes prevalence in non-Hispanic whites and Mexican Americans, but not in non-Hispanic blacks ^{80, 87}. The same inverse trend was observed between serum 25(OH)D and insulin resistance as measured by HOMA-R, but there was no correlation between serum levels of vitamin D and β-cell function, as measured by HOMA-β ^{87, 88}. Data from the same cohort also showed an inverse association between 25(OH)D and prevalence of the metabolic syndrome ⁸⁸.

In prospective studies, dietary vitamin D intake has been inversely associated with incidence of T2DM. For example, data from the Women’s Health Study showed that, among middle aged and older women, taking >511 IU/day of vitamin D reduced the risk of developing T2DM, as compared to ingesting 159 IU/day ⁸⁹. Furthermore, data from the Nurses Health Study also found a significant inverse correlation between total vitamin D intake and T2DM risk, even after adjusting for BMI, age, and non-dietary covariates ⁸⁰. Intervention studies have shown conflicting results about the effect of vitamin D on T2DM incidence.

One study reported that supplementation with 1,25[OH]2D3 for 1 week did not affect fasting glucose or insulin sensitivity in 18 young healthy men ⁹⁰. Another study found that, among 14 T2DM patients, supplementing with 80 IU/day of 1 α-OHD3 ameliorated insulin secretion but did not improve glucose tolerance after a 75 g oral load ⁹¹. Yet another study showed that, among 65 middle-aged men who had IGT or mild T2DM and adequate serum vitamin D levels at baseline, supplementation with 30 IU/day of 1-α-OHD3 for 3 months affected neither fasting nor stimulated glucose tolerance ⁹². However, in a cross-over design, 20 diabetics with inadequate vitamin D serum levels who were given 40 IU/day of 1,25-OHD for 4 days had improved insulin secretion, but showed no changes in fasting or stimulated glucose or insulin concentrations ⁹³. Although the short duration of this cross-over trial may account for the lack of a significant overall effect, the results suggest that improving vitamin D status can modulate factors associated with the development and progression of T2DM. The data from a 2-year-long trial designed to assess the effects of vitamin D3 or 1-α-OHD3 supplementation on bone health in non-diabetic postmenopausal women were analyzed a posterior and found no significant effect on fasting glucose levels ⁹⁴.

A post-hoc analysis of data from a 3-year trial for bone health showed that daily supplementation with 700 IU of vitamin D3 and 500 mg of calcium citrate malate did not change blood glucose levels or insulin resistance in elderly adults with normal glucose tolerance. These measures, however, were significantly improved in subjects with IGT at baseline ¹⁰. In this trial the effect of fasting glucose levels in the high-risk group (i.e., IGT) was similar to that observed in the Diabetes Prevention Program after an intensive lifestyle intervention or metformin treatment ⁹⁵. Taken together, the available information warrants exploring the possibility that vitamin D (alone or in combination with calcium) can be employed in developing population-based strategies for T2DM prevention and control.

Vitamin E: Vitamin E encompasses a group of 8 compounds, including α, β, γ, and δ tocopherols and α, β, γ, and δ tocotrienols, with differing biological activities. Each compound contains a hydroxyl-containing chromanol ring with a varying number and position of methyl groups between the α, β, γ, and δ forms ⁹⁶. It is known to have a significant impact on improving a variety of immune functions ⁹⁷. Supplementation with vitamin E increases the rate of lymphocyte proliferation by enhancing the ability of T cells to undergo cell division cycles. The effective anti-inflammatory action of vitamin E was substantiated from observations such as the increased expression of the IL-2 gene and IL-1 receptor antagonist and the decreased expression of IL-4 following vitamin E supplementation in animal models.

Furthermore, vitamin E reduced the serum levels of inflammatory factors such as IL-1β, IL-6, TNF-α , PAI-1, and CRP in T2DM patients ^{94, 99}. Furthermore, vitamin E downregulates NFκB ⁹⁹, the principal mediator of inflammatory signalling cascade and its potent lipophilic antioxidant effect on internal and external cell membranes as well as plasma lipoproteins, notably LDL. Based on this latter characteristic, studies in both animal models and humans have demonstrated that vitamin E intake blocks LDL lipid peroxidation, prevents the oxidative stress linked to T2DM-associated abnormal metabolic patterns [hyperglycaemia, dyslipidemia, and elevated levels of FFAs], and, subsequently, attenuates cytokine gene expression ^{97, 99}.

Despite these findings, a recent study evaluated the effects of a combination of vitamin C (1000 mg/day) and vitamin E (400 IU/day) for four weeks on insulin sensitivity in untrained and trained healthy young men and concluded that such supplementation may preclude the exercise-induced amelioration of insulin resistance in humans ¹⁰⁰. This may relate to the source of vitamin E used, i.e., α-, β-, γ-, or δ-tocopherol ¹⁰¹.

Overall, the immunomodulatory, anti-inflammatory and anti-oxidative functions of vitamin E strongly support its possible application in designing effective prevention and/or treatment protocols for T2DM ⁵⁷. Current practices for diabetes prevention in the general population include lifestyle change, dietary intervention and exercise.

Vitamin E supplementation may further aid in T2DM prevention and control through its anti-oxidant, anti-inflammatory and immunomodulatory properties. It seems reasonable, therefore, to suggest supplementation with vitamin E together with lifestyle change may be combined into a single program to enhance the success and effectiveness of intervention. This strategy could be more efficient in reducing the low-grade inflammation associated with pre-clinical T2DM and, subsequently the disease burden, than when a single approach is considered.

Moreover, such a combined strategy can be introduced in general practice settings and in a population-based fashion with low expenditure and minimal side effects.

CONCLUSION: Understanding diabetes, its risk factors and the measures used to evaluate the progression of the disease can help in controlling the disease. Supplementation of vitamins, lifestyle changes including diet, exercise, smoking cessation, education and reducing stress are the most important elements for successfully avoiding the complications of diabetes. In a chronic disease without a cure, all treatments, conventional medications and alternative therapies, have a role in treating the disease; as a culture with increasing rates of diabetes and a medical system with fewer and fewer effective options left, new ideas and approaches are required.

ACKNOWLEDGMENT: The authors acknowledge work of Josepha Joseph, University of Tromso, Norway and Alaa Badawi et al., licensee In Tech without which the present article would not be so graceful.

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     How to cite this article:

     Gupta VK, Pathak A, Gahlot M, Verma RC and Singh CV: Impact of Vitamins in prevention of risk factors associated with Type-2 Diabetes mellitus. Int J Pharm Sci Res 2013; 4(4); 1335-1347.

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