The Link Between Vitamin A Deficiency And Diabetes Mellitus
Vitamin A is a complex alcohol and is represented by retinol. Its oxidative products retinaldehyde (also called retinal as well as retinene) is also a biologically active compound. Vitamin A is quite heat stable, but it is destroyed at high temperatures in the presence of oxygen or air. Vitamin A has been synthesized (Gerster, 1997). Vitamin A occurs as such in nature only in the animal kingdom. It occurs in highest concentration in the liver oils of certain species of fish, e. g. halibut (richest source), shark and cod; it also occurs in the livers of other animals, egg yolk, butter, cheese and whole milk. In plants it occurs as its precursors, pro-vitamins A i. e., carotenes which are yellow-red pigments found specially in carrots, yellow corn, sweet potato, peaches and spinach. The carotenes do not have any vitamin A activity, but these are converted to vitamin A in the liver. The conversion of carotenes to vitamin A is decreased in diabetes mellitus and hypothyroidism. Of many carotenes, β-Carotene is the most efficient precursor of vitamin A due to its symmetrical structure.
Vitamin A occurs in nature as its esters which are hydrolyzed by esterase present in the pancreatic juice to fatty acids and free vitamin A alcohol. Its intestinal absorption is brought about by carrier-mediated facilitatory transport with the help of a protein present in the cytosol of the intestinal epithelial cells; this is called cellular binding protein-Ⅱ(CRBP-Ⅱ); a similar protein occurs in other cells and is called simply CRBP. Vitamin A is then re-esterified within the mucosal cells of the small intestine from where it is absorbed along with lymph chylomicrons (Soprano, 1994). Carotenes are absorbed in the small intestine as such or after being cleaved into their retinaldehyde components bile salts help in carotenes and vitamin A absorption. The retinoids, a family of molecules that are related to retinol (vitamin A) are essential for vision as retinaldehyde is necessary for the production of a vision pigment called Rhodopsin which involve in low light vision. It also involve in the process of normal growth and development (including fetal growth), for maintenance of skeletal and epithelial tissues, reproduction and in immunological functions. On the other side Abortions, increased prevalence of retained fetal membranes and increased calf morbidity and mortality are indicators of vitamin A deficiency.
Night blindness is the best-defined symptom of vitamin A deficiency followed by degenerative changes in the retina, as the isomer 11-cis vitamin A in the aldehyde form occurs only in the retina. It combine with the epsilon amino group of a protein namely scotopsin (one of the several protein called opsin) to form a conjugated protein called rhodopsin or visual purple which is present in rods and is essential for vision in dim light. Rhodopsin has a mol. Wt. of 41, 000 and is one of the many serpentine receptors coupled to G protein. This pigment is very sensitive to light which hydrolyses it to scotopsin, an opsin, and all-trans vitamin A aldehyde also called all-trans retinal (C19H27CHO) retinaldehyde. Many intermediate compounds are formed in this process; these include bathorhodopsin, lumirhodopsin and metarrhodopsins І and Ⅱ. If intense light is thrown into the eyes, all the rhodopsin gets bleached and the person becomes unable to see there for some time. When there is darkness, the synthesis of rhodopsin re-start, and after some time the person begins to see more clearly in the dim light. The regeneration time of rhodopsin depends upon the intensity of light thrown into the eyes and the availability of vitamin A in the body.
If vitamin A is not available, synthesis of rhodopsin cannot take place and the person unable to see in dim light (night blindness). Experimentation on rats indicated that at first by applying food deficient with vitamin A in the retina the level of rhodopsin declines, the logarithm of the visual threshold reciprocally rising, marking the beginning of night-blindness. After few weeks the level of opsin in the retina also begins to fall due to this the rod outer segments starts to weaken anatomically. Opsin as compared to rhodopsin is very less stable protein in an aqueous solution. It is quickly denatured by exposures to acids, alkalis or heat, while rhodopsin remains unaffected. In case of vitamin A deficiency the anatomical structure of opsin lost and can’t do any its function related to vision. Xerophthalmia and keratomalacia occur. Xerophthalmia is characterized by small triangular white patches on the outer and inner side of cornea covered by material resembling white foam; these patches are termed Bitot’s spots. However, , Bitot’s spots are not specific for vitamin A deficiency and occurs in other conditions as well. Keratomalacia occurs usually in the five year of life. The cornea becomes dull and insensitive; the infiltrate increases until finally the cornea necroses and may appear to melt away within a matter of hours resulting in loss of vision.
Diabetes mellitus (DM) is not one disease, but rather is a heterogeneous group of syndromes characterized by an elevation of fasting blood glucose level caused by a relative or absolute deficiency in insulin. It is an important cause of retinopathy leading to adult’s blindness and amputation, and a major cause of renal failure heart attacks, and strokes. Despite this common clinical consequence of each the uncontrolled vitamin A deficiency and DM, it's solely very recently that some vital studies are allotted linking the two conditions. A hypothesis that vitamin A metabolism could also be altered in DM stemmed from early studies reporting prevalence of hypercarotenemia (Basu and Basualdo, 1997) suggesting an impaired conversion of carotenes to vitamin A. Vitamin A metabolism may also affected by Hyperzincuria, which is another clinical feature of diabetes. Retinol is transported by retinol-binding protein (RBP) from its hepatic stores to target cells and Zinc is involved in the preparation of these RBP. In case of diabetes, Hyperzincuria may cause tissue depletion of zinc and thus alter the metabolic availabilities of vitamin A.
More recent studies have shown that DM, particularly once poorly controlled, might so have an effect on the tissue and circulatory levels of vitamin A carrier proteins. This proof suggesting that uncontrolled diabetes might have an effect on the metabolic accessibility of vitamin A. Streptozotocin (STZ)-induced diabetic rats are related to a decrease in plasma and a rise in hepatic vitamin A concentrations compared to nondiabetic animals. it had been of interest that the diabetic animals had lower plasma concentrations of vitamin A despite its raised food intake by 50%. A decrease within the concentration of 11-cis-retinal, an integral part of visul protein within the membrane of the attention was conjointly according in parallel with a decrease in circulatory level of vitamin A in diabetic rats that were pair-fed with control animals. In these pair-fed animals within which the control and diabetic rats got equal amounts of vitamin A, not like the diabetic animals given free access to feed, the entire hepatic concentration of vitamin A was the same as that within the control animals. Like within the STZ-induced rats, patients with insulin-dependent diabetes (IDDM) have additionally been found to possess lower serum concentrations of retinol. However, the plasma levels of vitamin A seem to be unaffected in patients with noninsulin dependent diabetes (NIDDM) (Driscoll et al. 1987).
In the mechanism for the dejected circulatory retinol in IDDM, the factors that will have an effect on blood retinol status include its dietary intake and absorption in addition to its transport proteins. Neither the intake nor the enteric absorption of vitamin A has been found to be affected within the presence of DM. In fact, the intake of food and therefore vitamin A, is markedly accumulated, as shown in STZ-induced diabetic rats. Recently, we have a tendency to examined the impact of diabetes on the vitamin A carrier proteins in experimental animals. The results of this study showed important reductions in concentrations of each RBP (retinol-binding protein) and TTR (transthyretin) within the plasma and urinary organ (kidney). These results are in contract with the studies involving IDDM patients during which plasma RBP and TTR concentrations were conjointly found to be considerably reduced in parallel with retinols factor (Reaven, 1988). It's potential that the decreases in plasma retinol, RBP, and TTR concentrations were a response to polygenic disorder (diabetes) or diabetes- induced trauma, since neither pair-feeding nor fat-soluble vitamin supplementation to STZ-induced diabetic rats changed these effects.
Furthermore, the concentrations of the vitamins in hepatic tissues of these animals increases and this increase becomes more within supplemented diabetic animals. So observations shown in an uncontrolled diabetic state that there would be an impaired metabolic availability of vitamin A from its hepatic stores. There appears to be a considerable amount of evidence linking vitamin A status and insulin secretion. The metabolism accessibility of vitamin A becomes stable by applying Insulin treatment to STZ- induced DM. From earlier studies, it was found that rats receiving insulin intra muscularly and intra peritoneally had a bigger rate of vitamin A depletion from the liver than rats receiving insulin subcutaneously. Recently, in vitro studies with isolated rat islets and in vivo studies involving depletion and repletion of vitamin A in rats, have conjointly incontestable that retinoids are needed for insulin secretion.
Vitamin A deficiency affected diabetes-resistant rats in developing diabetes and protect diabetes-prone rats. As rats take retinyl palmitate but not retinoic acid posses higher rate of diabetes because of less production of insulin. Vitamin A status doesn't seem to be affected in patients with NlDDM. NIDDM, in distinction to IDDM could lead to high blood insulin levels, a significance of reduced insulin sensitivity or insulin resistance. Actually, a study associating patients with NIDDM to age and sex matched controls found that retinol levels were higher in patients with NIDDM. Another study, comparing patients with and without neuropathy to healthy controls, also reported normal vitamin A and beta-carotene levels. Plasma concentrations of RBP and TTR have also been reported to be normal in NIDDM.
T2DM is caused by lower level of insulin secretion. Lack of vitamin A concentration in different food products as liver, fish-oil, fruits and vegetables may play a major role in the disease. Due to VAD the ability of beta cells to fend off inflammation becomes lesser, while beta cells die in a complete absence of vitamin A. Destruction of β cells causes T1DM, so VAD is involved in both types of diabetes i. e. type-1 diabetes mellitus and T2DM. Difference in both types of diabetes relies in the ability of body to either yield or expend insulin. About 90% of people suffered from T2DM. Mainly physical inactivity and obesity are the major causes of it (Amos et al. , 1997). Hyperglycemia caused by disturbance in function of beta cells as well as insulin sensitivity of tissues like liver, adipose, and pancreas by the involvement of both physical and genetic factors, as gene mutation is responsible for diabetes e. g. ABCC8 (sulphonyl urea receptor), SLC2A2 (GLUT2), INS (Insulin) etc. About 2-5% of diabetic symptoms of patients possess due to their family history and enhances the liability to T2DM with MODY (mature onset diabetes of young). Age is another element that is also involved in damage to β-cell and oxidative offense. Studies shows that age limit for T2DM patients lies in 45 and beyond, now recent work indicated a downward shift in this limit also.
T2DM pathogenesis is linked with mitochondrial dysfunctions due to insulin release and energy homeostasis. Intramyocellular lipid accumulation causes insulin resistance in elderly persons by loss of mitochondrial functions so in T2DM patients. Low density of mitochondria has been reported. Reactive oxygen species (ROS) are produced as a result of incomplete electron transport in mitochondria, which results in the pathogenesis. A lot of complications regarding diabetes progression are driven by increased oxidative stress. Persistent hyperglycemia responsible for production of ROS by a number of pathways viz. , polyol pathway. It results in non-enzymatic glycation of proteins leading to activation of PKC that ultimately acts via mitochondria. In uncontrolled diabetes the level of neutralization of ROS by cellular antioxidant systems are altered. Cardiovascular complications are also come into existence by deficient antioxidant status of T2DM patients (Baynes, 1991). To release stress exogenous supplementation of antioxidants also play a role in this regard. To improve endurance in T2DM patient’s antioxidant’s dietary intake, it has been used as medication strategy.
Antioxidant enzymes, like Superoxide dismutase SOD, catalase and glutathione peroxidase, are synthesized within the body and are effective in the detoxification of free radicals. Specifically, catalase is mainly located in cellular peroxisomes and changes hydrogen peroxides to water and oxygen. Increasing proof In each experimental and clinical studies suggests that oxidative stress plays a serious role in the pathological process of both types of diabetes mellitus. Free radicals are formed excessively in diabetes by oxidation of glucose, nonenzymatic glycation of proteins, and the successive oxidative degradation of glycated proteins. Abnormally high levels of free radicals and the instantaneous decline of antioxidant defense to mechanisms will result in impairment of cellular organelles and enzymes, higher level of lipid peroxidation, and in production of insulin resistance.
Higher concentration of vitamin A leads in saturation of retino-binding capacity of the retinol binding protein due to which cell are showed to unbound retinol. In case of sever hypervitaminosis A as after eating rich source of vitamin A some symptoms like dizziness, sleepiness, vomiting, headache, nausea, seizures and peeling of skin occurs. During pregnancy level of vitamin A should be in control concentration because higher doses of it can leads to congenital malformations, that comprise craniofacial anomalies and valvular heart diseases. In the developing world the deficiency of vitamin A (VAD) becomes dominant as it is the major cause of childhood visual disorder in every year leads to death of many children. Among this VAD also in response of reduce immunity higher level of severity and infections as measles and diarrhea in children. One million deaths of children as well as other immune patients including diabetic patients can be prevent by improving vitamin A status, which leads less rate of maternal mortality as well. In this way, the World Health Organization, UNICEF, USAID, the Canadian Aid Agency, the World Bank and also the Food and Agriculture Organization, among others, have launched a worldwide effort to regulate vitamin A deficiency among a decade.
