Thiamine Deficiency and its Implications on Microvascular Complications of Diabetes Mellitus
Ann V Chacko
Department of Pharmacy Practice, T John College of Pharmacy,
Rajiv Gandhi University of Health Sciences, Bengaluru, India.
*Corresponding Author E-mail: annsara.chacko@gmail.com
ABSTRACT:
Thiamine is the first vitamin discovered and belongs to Vit B family. The main effect seen with thiamine deficiency is Beri-Beri, Wernicke’s encephalopathy, Wernicke-Korsak off syndrome and are considered as a serious condition but often can be reversed. The deficient status of thiamine can also cause varied affects and can overlap with other conditions to exacerbate its potent effects. It is seen that thiamine is necessary for the metabolism of glucose in the form of cofactors, deficiency of which leads to accumulation of toxic glucose metabolites leading to formation of free radicals and oxidative stress. Glucose is not only important for the formation of energy but its improper metabolism proves to have deleterious effects in the body. In this review, an attempt is made to correlate microvascular complications of diabetes with thiamine deficiency and can be discerned that oxidative stress is one of the important factors for the progress of microvascular complications, as well as diabetic ketoacidosis, atherosclerosis and cardiovascular damage in patients with diabetes mellitus and these can be prevented or maintained by optimizing thiamine levels in the body.
KEYWORDS: Diabetes Mellitus, Microvascular Complications, Oxidative Stress, Thiamine Deficiency, Benfotiamine.
INTRODUCTION:
Christiaan Eijkmanwas the first man that discovered thiamine, while working on rice hulls and showed that it could reverse the effect of beriberi in animals, during the year 1890 to 1900and in 1929 was awarded Nobel Prize in Physiology for its discovery. Later, R R Williams purified the compound and called it thiamine (currently spelt as thiamin) it was initially recognized as oryzanine and was patented as aberic acid and orizanin1,2. It is the first water soluble, heat labile Vitamin that was discovered, which belongs to the Vitamin B family and is considered as an essential vitamin, as humans cannot synthesize thiamin and needs an exogenous source of intake. The sources from which thiamine are obtained are whole grain, pork, meat, fish, bread, milk, cereals and infant formulas3,4,5.
It can also be consumed as a dietary supplement present in the form of thiamin mononitrate and thiamin hydrochloride in most of the multivitamin formulation. As it’s a water-soluble vitamin around 20-30% of its concentration is lost during heating or pasteurization. The daily recommended intake of thiamine varies with age and health status, but averages about 1.2mg and 1.1 mg in adult male and female respectively. The age wise requirements are as follows. 1.27mg for ages 2-5years, 1.54mg for ages 6-11 years and 1.68mg for ages 12-19 years from food sources and dietary supplement contain 1.5mg of thiamine. Higher levels of thiamine intake have a negative correlation with adverse effects and hence is thought to be safer and doesn’t have a tolerable upper intake level4.
Physiology:
Thiamine can be spelled with or without an ‘e’, the use of ‘e’ was due to the assumption that it was an amine. Its IUPAC name is 2-[3-[(4-amino-2-methylpyrimidin-5-yl) methyl]-4-methyl-1,3-thiazol-3-ium-5-yl] ethanol and consists of a pyrimidine ring and a thiazolium ring joined by methylene bridge6,7.
Thiamine is rapidly absorbed into the small intestine either though active transport or passive transport depending on nutritional or pharmacological doses respectively. It gets phosphorylated into thiamine monophosphate (TMP), thiamine pyrophosphate (diphosphate) (TPP) and thiamine triphosphate (TTP) and each has a role in various biological functions. The phosphorylation process takes place in most tissues but is particularly seen in liver and is concentrated at the heart, kidney, liver and brain4,8. Thiamine is transported and delivered across the body into the tissues via the two transporters THTR1 and THTR2 both of which are present in high amounts in placental, liver, and kidney tissues; however, THTR1 is also detected in skeletal muscles and cardiac tissue9.
It then gets dephosphorylated in the kidney and the free thiamine is excreted in the urine, due to the high turnover rate and short half-life continuous intake of thiamine is necessary and a thiamine deficit diet for 2 weeks or less can result in depletion of thiamine from the body stores4,8.
Biochemical Functions:
Thiamine is present mainly in four forms i.e., thiamine monophosphate [TMP], thiamine diphosphate or thiamine pyrophosphate [TPP], thiamine triphosphate [TTP] and unphosphorylated thiamine or free thiamine.
Thiamine acts as a coenzyme for glucose metabolism, HMP shunt pathway and citric acid cycle. The first form, of thiamine - TMP act as an intermediate in the formation of TPP and TTP and along with thiamine gets actively transported into the central nervous system and helps in proper conduction of nerve impulses by maintaining sodium and potassium gradients across the membranes and thereby maintaining the neurologic activity10.
TPP is a cofactor for 4 main enzymatic reactions many others as well; such as decarboxylation of pyruvate (formed as an end product of glycolysis to form acetyl CoA, which acts as the starting reactant for citric acid cycle) with the help of pyruvate dehydrogenase complex. Decarboxylation of alpha ketoglutarate dehydrogenase to form succinyl CoA in citric acid cycle (main component of mitochondrial antioxidant system), branched chain alpha-keto acid dehydrogenase which catalyses branched chain amino acid (leucine, valine, isoleucine) into respective keto acid. Transketolase seen in the pentose phosphate pathway is also depended on TPP, to supply pentose phosphate and reduced NADP for nucleotide synthesis and various synthetic reactions11,12. These reactions are seen during the process of energy formation and catabolism of carbohydrates and thereby can be inherited that the role of thiamine is important for metabolism.
TTP is considered to have a non-cofactor role and is said to be a neuroactive compound, the role of which is still not completely known6,12.
Causes of thiamine deficiency:
Deficiency of thiamine can result due to a number of factors like decreased intake of thiamine resulting due to long term administration of parenteral nutrition without thiamine supplementation, chronic alcoholism, diet containing consumptions of food with prolonged cook period, polished food and grain and as well consumption of food that contains high level of thiaminase like raw shellfish and freshwater fish, milled rice and ferns and consumption of anti-thiamine compounds like tea, betel nuts, coffee, fish paste. Secondly, poor absorption due to malnutrition, gastric bypass surgery or malabsorption syndrome. Thirdly, increased loss developed due to diarrhoea, increased use of diuretics, hyperemesis gravidarum and conditions resulting in increased thiamine utilization such as pregnancy, lactation, hyperthyroidism, refeeding syndrome13,14.
Thiamine deficiency can be predisposed due to certain conditions and disorders. Psychiatric conditions like alcohol abuse, anorexia nervosa, anorexia bulimia, binge-eating disorder, medical conditions like PUD, Crohn’s disease, severe obesity, intestinal obstruction, pancreatitis, pyloric stenosis, and certain cancers of the gastrointestinal tract; systemic diseases like AIDS/HIV, chronic infectious state with fever and renal diseases which finally leads to a state of reduced thiamine levels in the body15.
THIAMINE AND ITS RELATION TO VARIOUS COMPLICATIONS IN DIABETES MELLITUS:
In this review, we mainly focus on thiamine deficiency and how it worsens the condition of diabetes mellitus (DM) and whether or not it plays a role in the disease progression and emergence of microvascular complications associated with DM. To counteract the toxic effect caused by oxidative stress, the body utilizes substrates that helps in negating its effect and they are called antioxidants. Vitamin C, Vitamin E, selenium, zinc have shown to help reduce oxidative stress, but their potential effect was not proved to be effective to counteract the oxidative stress seen in diabetes mellitus 16,17.
Epidemiology:
Diabetes mellitus is a chronic metabolic syndrome characterized by hyperglycaemia, it can be caused due to decreased insulin secretion from the pancreas and/or decreased insulin resistance18. As per the statistics of International Diabetes Federation (IDF), it is estimated that 8.8% of the global population have diabeteswith a slight increase in the predominance in males (9.6%) in comparison to females (9.0%). The actual numbers range up to 374 million in prediabetic state and 463 million with diabetes19. Diabetes can cause an array of complications in the form of microvascular complications like diabetic retinopathy, diabetic neuropathy and diabetic nephropathy and macrovascular complications like atherosclerosis, coronary artery disease, stroke, cerebrovascular disease, peripheral vascular disease and others like diabetic ketoacidosis, diabetic foot and is a leading cause of morbidity and mortality worldwide20,21,22. It is to be noted that population in developing and under developed countries are unaware of Diabetes, thereby leading to delayed diagnosis and treatment. The delay in time of diagnosis would have led to the evolvement of diabetic complication. Even in population that are diagnosed early, lack of knowledge regarding the complications of diabetes can be observed23,24.
Diabetic state is characterized by the lack of insulin production or insulin resistance, which can cause decrease in absorption of thiamine from diet and its reabsorption from proximal convoluted tubule and increased thiamine clearance, especially in individuals with microalbuminuria25,26. Studies have shown that there can be a decrease in plasma thiamine concentration by 76% in type 1 diabetes mellitus and 75% in type 2 diabetes mellitus, by this it can be inferred that thiamine deficiency can be seen in patient with diabetes mellitus27,28.
Effect Of Thiamine in Diabetes Mellitus:
The main characteristic feature in DM is hyperglycaemia, when the cytosol concentration of glucose increases, the excess glucose passes down to alternate pathways (i.e., glycolysis) resulting in accumulation of triosephosphates and further causing an increase in the glycating agent methylglyoxal (MGO), a reactive oxygen species (ROS) and reacts with phospholipids and proteins to form advanced glycation end products (AGE) and stable adducts. MGO generated from glycolysis interacts with cellular proteins and nucleic acids to speed up AGE formation, causing pancreatic-cell cytotoxicity further aggravating hyperglycaemia, setting off biochemical dysfunction giving rise to complications associated with diabetes29,30,31,32. Thiamine deficiency impairs pentose phosphate pathway which is required for the downregulation of triosephosphate, it is seen in both experimental and clinical diabetes and the consequent increase in triosephosphate and MPO. The correction of thiamine deficiency in experimental diabetes has shown reduction in biochemical dysfunction such as deactivation of hexosamine pathway and protein kinase C and decreased glycation and oxidative stress response and thereby preventing the development of diabetic nephropathy, retinopathy and neuropathy33,34.
Thiamine is also essential for the endocrine and exocrine functioning of pancreas and its deficiency can result in impairment of insulin synthesis and secretionand as well impede glycolysis and beta-oxidation pathway that provides energy to tissues35,36,37,38. Increased glucose levels and increased glucose oxidation is one of the primary stimuli for the secretion of insulin from beta cells of the pancreas39. Thiamine deficiency can affect this process by interfering with the metabolism of glucose i.e., glycolysis resulting in decreased glucose oxidation and resultant increase in glucose levels, which initially is responded by increased insulin secretion, but due to thiamine’s interference with glucose metabolism and stimulation of glucose dependent insulin secretion (GDIS) mechanism, it can lead to the creation of reactive oxygen species (ROS) and oxidative stress on beta cells. The ROS like superoxide anion, hydroxyl radicals, hydrogen peroxide, nitric oxide affect beta cell functioning in Type 2 Diabetes and autoimmune attack, cytokine activity is seen on beta cells in patients with Type 1 Diabetes32. It is also seen that a mutation of SLC19A2 gene, can lead to Thiamine responsive megaloblastic anaemia (TRMA), the defective gene affects the transport of thiamine in to the cells of pancreas causing a thiamine deficit state and thereupon development of diabetes mellitus35,36.
THIAMINE AND MICROVASCULAR COMPLICATIONS OF DIABETES:
Diabetic Retinopathy:
Diabetic retinopathy is one of the seriouscomplications of diabetes and a leading cause of visual disturbances and blindness41. It can beseen as non-proliferative diabetic retinopathy (NPDR) wherehaemorrhagicspots and microaneurysms are noticed and proliferative diabetic retinopathy (PDR) which is the progressed form where neovascularization, fibroplasia, scar tissue formation and finally retinal detachment is noticed42,43. Various retinal cells utilize glucose for the energy and undergo aerobic glycolysis, majorly in photoreceptors. This makes the cells dependent on insulin, such that during hyper glycaemic states due to reduced insulin secretion and/or resistance and the inability to convert them to glycogen, the cells would be susceptible to glucose-induced damage. Key factors for the occurrence of diabetic retinopathy are hyperglycaemia, redox homeostasis and oxidative stress, of which oxidative stress not only contributes towards the formation of diabetic retinopathy but also to the resistance of retinopathy44,45,46. Oxidative stress results in the accumulation of ROS,the highly reactive glycolysis intermediates and their build up in the cytoplasm, speeding up the four metabolic processes: polyol, hexosamine, de novo protein kinase C production, and AGE formation44. Protein kinase C is required for is required for signal transduction, activation of which results in vascular and basement membrane modifications, including capillary blockage, angiogenic growth factor release, vascular stasis, and enhanced vascular permeability47. Due to increased deposition and decreased clearance of ROS, oxidative stress occurs on retinal cells causing inflammation, endothelial damage and retinal detachment, mitochondrial dysfunction and finally apoptosis of the retina48.
Along with hyperglycaemia induced processes, decreased thiamine leads to disruption inKrebs cycle, resulting in accumulation of pyruvate and lactate, which further leads to increase hypoxia-inducible factor-1 α (HIF-1α) and vascular endothelial growth factor (VEGF) and hence aggravating diabetic retinopathy49. A comparative cross-sectional study showed that the mean blood concentration of TPP in healthy individuals was 80nmol/L and in patients with NPDR the level reduced to 64nmol/L and 60nmol/L with PDR on an average, this study was able to correlate the progress of DR and the reduced concentration of TPP, thereby linking them and showing the significance of the role of thiamine in DR50.
Thiamine is an important cofactor for glucose metabolism, especially for transketolase which helps in transferring excess metabolites from glycolysis to pentose phosphate pathway. In microvascular cells, it can also mitigate damage caused by HG by restoring normal metabolic pathways and lowering the generation of ROS and as well reduces glycation of basement membrane proteins, potentially preventing pericytes from detaching from the retinal capillary wall51. The entry of thiamine is mediated by high affinity thiamine transporters THTR1 and THTR2. At pharmacological concentration, movement of thiamine is regulated by passive diffusion and at physiological concentrations i.e., low concentration, the entry into the cells is regulated by these transporters. In hyperglycaemic state the proximal tubular epithelium of the renal cells downregulates thiamine transporter and when thiamine is available atleast in low concentration, upregulation of thiamine and expression of THTR2 takes place. In hyperglycaemic and thiamine deficit conditions, movement of thiamine into the retinal cells gets disturbed, as their levels are low and transporters are unavailable. It is also seen that insulin independent cells are more prone to hyperglycaemic damage due to the inability of tissues devoid of insulin to absorb sufficient thiamine to compensate for excessive glucose exposure52,53.
The first evidence on beneficial effects of thiamine for microvascular complication was seen in the study conducted by La Selva and group, in the year 1996, they showed that supplementation of thiamine has shown a decline in lactate production and AGE formation which are the toxic effects of high glucose concentration and thereby preserve cell function in bovine retinal cells44. Another experiment on rat, with three cohorts i.e., healthy group, diabetic control group and a TPP administered group. The results showed that TPP administration reduced malondialdehyde and increased various endogen antioxidants as opposed to hyperglycaemic state. The thiamine administered group had reduced neovascularization and edema as opposed to the diabetic control group. This study helped to show that thiamine administration is helpful in the prevention of progression of DR54.
Diabetic Neuropathy:
Thiamine is involved in the creation of nucleic acids and neurotransmitters and acts as a modulator of neuronal and neuromuscular transmission, most likely through regulating ionic channels55. Deficiency of which results in beriberi, a painful peripheral neuropathy and cardiomyopathy and may also play a role in the genesis of diabetic neuropathy by inhibiting nerve fibre glycation and endothelial cell death56.
It is also seen that carbohydrate is redirected to alternate pathways due to decrease in transketolase- dependent thiamine action and has a pathological impact on the complication of diabetes by affecting the signalling pathways due to ROS generation55. The brain shows high oxygen consumption rate and rich lipid content and as well has a relative lack of antioxidant enzymes compared to other tissues and hence it is particularly prone to oxidative damage. ROS are involved in many neurodegenerative diseases including diabetes because neuronal cells are particularly vulnerable to oxidative stress57, it is also seen that it affects the peripheral neurons and Schwann cells impeding peripheral nervous system function and exacerbate diabetic polyneuropathic symptoms55.
Diabetic patients are seen to have peripheral neuropathy in 60 to 70% of cases of which distal sensorimotor polyneuropathy (DSP)is common. According to the Rochester Diabetes Project, this form of neuropathy accounts for 72 percent of the neuropathies experienced by patients with type 2 diabetes. Thiamine insufficiency causes axonal degeneration, which is characterised as DSP and has a similar clinical presentation as diabetic DSP. Clinicians have long observed parallels between diabetic DSP and DSP caused by thiamine shortage, but a study in 1961 done to study this correlation was unsuccessful55.
Methylglyoxal, is one of precursor of AGE and plays a role in the pathogenesis of diabetic related complications. Through the cation channel transient receptor potential ankyrin 1(TRAP1), MGO causes behavioural nociception by raising intracellular calcium in sensory neurons, leading to pain associated with diabetic neuropathy. A study conducted to understand the effects of thiamine deficiency and oxidative stress induced by MGO formation, showed that rats which were supplemented with thiamine in their diet did not relatively experience oxidative stress or had relatively low MGO adduct levels in their blood. While the thiamine deficient rats had higher levels of oxidative stress which was noticed as weight reduction. This review throws light on the possible association of oxidative stress and the protective effect thiamine plays in alleviate nociception seen in diabetic neuropathy58,59.
A three week, controlled, randomized pilot study (BEDIP study) on the treatment of diabetic polyneuropathy with benfotiamine, a synthetic lipid soluble derivative of thiamine showed that patients who were treated with 50mg dose given 4 times a day exhibited a reduction in pain compared to the control group60. Another study conducted to assess the long-term effects of benfotiamine, administered as 300mg two times a day vs placebo administered two times a day is underway. Previous experimental studies had showed that after six months of supplementation with benfotiamine, nerve conduction velocity (NCV) was almost back to normal, neural imidazole-type AGE production was inhibited, and diabetes-induced glycoxidation products were totally avoided. These studies and processes again weigh in the beneficial role of thiamine in diabetic neuropathy61.
Diabetic Nephropathy:
Diabetic nephropathy is another microvascular complication that develops over 5-40 years after the start of diabetes62. The metabolic malfunction that leads to diabetic nephropathy is triggered by the accumulation of triosephosphates which is formed by excessive cytosolic glucose concentrations duringhyperglycaemic states63. Triosephosphates can show a detrimental action on the kidneys leading to increased excretion of albumin in urine, which is the first sign of the development of diabetic nephropathy62. ROS, AGE products formed due to thiamine deficiency also plays role64.
Several experimental studies, pilot studies have shown that with the administration of` high dose thiamine, it is possible to prevent and correct early-stage diabetic nephropathy, as well reverse urinary excretion of albumin49,62. This occurs via rectifying diabetes-related increased thiamine clearance and preserving the activity and expression of thiamine pyrophosphate-dependent enzymes that help counteract the negative effects of high glucose levels, particularly transketolase63,65. It is also shown to lower protein kinase C activation, as well as lower protein glycation and oxidative stress, the three main metabolic dysfunction pathways in hyperglycaemia63. A randomized study showed that supplementation with thiamine helped to achieve thiamine concentration and improve transketolase activity, but failed to show a significant reduction in the markers of nephropathy, it did not show blood or urinary reduction of AGE levels, plasma biomarkers of chronic low-grade inflammation and endothelial damage. This warrants further long-term study and a change in assessment to show the potential benefit of thiamine supplementation and protection against diabetic nephropathy66.
CONCLUSION:
Thiamine has clearly shown to play an important role not only in the metabolism but also in the maintenance between reactive oxygen species and antioxidant effect, thereby proving to be beneficial to counteract the oxidative stress seen in microvascular complication and prevent the progression of these complications in patients with diabetes. Research and various studies have shown the experimental and small-scale clinical benefit in the prevention and maintenance of microvascular complication seen in diabetes especially in diabetic retinopathy and neuropathy, large scale studies are either underway or warranted to provide firm evidence on its benefits in humans.
The role of thiamine supplementation is still not fully understood and have not yet shown sufficient evidence to prove its preventive or counteraction against diabetic nephropathy. Large scale studies are difficult to test for thiamine’s efficacy, as it’s a costly process and biomarkers for the assessment of the study is hard to evaluate. In several studies as well as in studies conducted in experimental diabetes it is seen that administration of high dose thiamine and benfotiamine has decreased glucose levels, improved transketolase levels and decreased the levels of harmful reactive oxygen species. The beneficial role of thiamine can be summarized as, increases transketolase activity, reduction in ROS, normalization of AGE’s production, reduction of DNA glycation and other glycation related activities. Point should can be noted that thiamine is a vitamin having very minimal harm, usually gastrointestinal side effects, so routine administration of thiamine should be promoted in patients with diabetes especially in case of subjects who are at risk for the development of microvascular complications, along with or other treatment choices.Additionally, the role of the thiamine’s protective and preventive function is also seen with other inflammatory conditions, diabetic ketoacidosis and heart failure.
CONFLICTS OF INTEREST:
There are no conflicts of interest.
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Received on 05.11.2023 Modified on 06.04.2024
Accepted on 11.07.2024 ©Asian Pharma Press All Right Reserved
Asian J. Res. Pharm. Sci. 2024; 14(3):256-262.
DOI: 10.52711/2231-5659.2024.00042