A REVIEW ON IMPAIRMENT IN METABOLIC PATHWAYS DUE TO TYPE 2 DIABETES MELLITUS

A REVIEW ON IMPAIRMENT IN METABOLIC PATHWAYS DUE TO TYPE 2 DIABETES MELLITUS

Vishnu Kumar ^{* 1}, Arya Desh Deepak ¹, Vishal Prakash Giri ² and Abhay Kumar ³

Department of Biochemistry ¹, Department of Pharmacology ², Department of E. N. T ³, Autonomous State Medical College, Jignera, Shahjahanpur - 242001, Uttar Pradesh, India.

ABSTRACT: Despite years of intensive research, impairment in metabolic pathways due to type 2 diabetes mellitus continues to be a daunting global challenge. It is equally challenging problem in this region as well. In recent years there is growing clinical and experimental evidence that oxidative stress plays an important role in induction and promotion of diabetes and its associated complications. Lipid peroxides are known to be essential consequence of biological processes of excessive oxidative cellular damage can be a cause of consequences of numerous diseases, micro and macro complications of type 2 diabetes mellitus. There have been reports of elevated lipid peroxide levels in type 2 diabetes. To defend themselves against these free radical attacks, cell has developed different antioxidant systems. There are low molecular weight antioxidant molecules like uric acid, ascorbic acid, etc. and antioxidant enzymes superoxide dismutase, catalase and glutathione peroxidases. Under physiological conditions, these defense mechanisms maintain a low steady-state concentration of free radicals in the cell and their activities are very precisely regulated. The levels of these parameters are altered during the development of diabetes.

Micro and macrovascular complications, Reactive oxygen and Nitrogen species, Metabolic Pathways, Anti-oxidants, Oxidative stress

INTRODUCTION: "All the diseases are the result of a collection of waste materials, the latter being initiated by many causes to produce symptoms; wastes collect due to in correct dieting and living".

– Atharva-Veda

Impairment in metabolic pathways due to type 2 diabetes mellitus, are main causes of morbidity, mortality and third leading cause of death in many developed countries. Diabetic dyslipoproteinemia is the main cause of heart attacks in diabetic patients. Diabetes is one of the major causes of blindness, renal failure, stroke, and nephritis, etc.

Diabetes is as old as mankind and its incidence is considered to be high all over the world (Picup and Williams ¹. In ancient India, diabetes was also known as "Madhumeha" ². The worldwide prevalence of diabetes mellitus has risen dramatically over the past two decades. It is projected that the number of individuals with diabetes mellitus will continue to increase in the future as the prevalence of diabetes mellitus among adults in the United States increased from 12.3% to 13% between 1994 to 2000 ^3-6.

The prevalence of diabetes in our country is 2.4% in rural and 8.2% in urban areas and the rate of prevalence increases per year. It has been reported that in February 2005 approximately 60 million people in India are suffering from this disease ^7-15. Clinically diabetes mellitus is a heterogeneous disease with a common phenotype of impaired glucose tolerance.

More than fifty genes have been identified in the regulation of lipoprotein metabolism, giving rise to a novel molecular pathophysiological basis for dyslipoproteinemia and other disorders related to liver homeostasis ^16-20. The most common abnormalities of lipid metabolism in diabetes are hypertriglyceridemia and hypercholesterolemia. Not only hyperglycemia, but dyslipoproteinemia is also responsible for death in diabetic patients ^21-28.

Diabetes mellitus can be divided in type-I, Insulin-dependent diabetes mellitus (IDDM) and type-II Non-insulin dependent diabetes mellitus (NIDDM), type-I diabetes mainly occurs in childhood and puberty and is characterized by absolute insulin deficiency. Type-II diabetes usually develops in adults over age 40 and is characterized by insulin resistance ^29-30. In the pathogenesis of some forms of diabetes, it is observed that malnutrition is also one of the causes of this disease. Financially weak communities in tropical developing countries are highly prone to malnutrition-related diabetes mellitus, MRDM. Moreover, it has been suggested that the deficiency of antioxidant and trace elements such as Zn, Cu, Cr, Ni, Mn may also play a role in diabetes mellitus with dyslipoproteinemia. Endothelial function is abnormal in both the macro and microcirculation in subjects with type-I and type-II diabetes mellitus ^31-38. Furthermore, endothelial functions are impaired in healthy subjects who are at risk of developing type-II diabetes by virtue of having one or both parents with type-II diabetes, with or without impaired glucose tolerance. Previous studies in children have highlighted the concern for type-II diabetes and pre-diabetes or impaired glucose tolerance ^39-40. This significant clinical issue is greater for overweight children and especially among certain ethnic groups. Insulin resistance in type-II diabetes is developed due to increased levels of plasma free fatty acid.

These free fatty acids promote diabetic dyslipoproteinemia through increasing VLDL synthesis in the liver which generates atherogenic lipoprotein-profile and facilitates the development of atherosclerosis and increases the risk of cardiovascular disease, the most common cause of death in diabetes type-II, patients. High-density lipoprotein and apolipoprotein A^-1 may prevent the origin and development of obstructive disease ^41-52.

The excess release of fatty acids, lipid and fat deposition in various tissues are root causes of atherosclerosis and coronary artery disease. Hemorrhagic abnormalities are also responsible for atherosclerotic processes. Abnormalities in insulin and glucose do not seem to entirely account for the high frequency of cardiovascular disease in patients with type-II diabetes mellitus. An important additional factor may be hyper-triglyceridemic hyper apo-B, an atherogenic dys-lipoproteinemia that is common in these patients. The major feature of hypertriglyceridemic hyper apo-B is hypertriglyceridemia, low levels of high-density lipoprotein cholesterol and increased number of small dense low-density lipoprotein particles ⁵³.

Serum lipoproteins are known to play a key role in the transport and metabolism of lipids. In normal animals, the concentration and distribution of various lipoproteins have definite range. The incidence of hypercholesterolemia and cardio-vascular disease is directly related to the increased lipid contents of lipoproteins. The apolipoproteins have an affinity to bind with phospholipids, triglycerides, cholesterol and form three major types of lipoproteins i.e., low-density lipoprotein, very low-density lipoprotein, and high-density lipoprotein. In recent years series of studies on high-density lipoprotein has drawn much attention due to their significant role in the regulation of lipid metabolism. Apart from the role of high-density lipoprotein to regulate the lipid metabolism in the body it also possesses the property of biological antioxidant ^54-61.

Qualitative or quantitative abnormalities of plasma lipoprotein metabolism are known as dyslipo-proteinemia. Five types of dyslipoproteinemia were identified by scientists. Type-I dyslipoproteinemia occurs in childhood with abdominal pain and pancreatitis. Type-II dyslipoproteinemia or familial hyper cholestrolemia manifests itself clinically by xanthomata, corneal arcus, and premature athero-sclerotic disease. Type-III dyslipoproteinemia manifests clinically by accelerated atherosclerosis of the coronary and peripheral arteries and by characteristic tuberoeruptive and planar xanthomas. Type IV dyslipoproteinemia is characterized by an increased level of plasma triglycerides and very low density lipoprotein.

Type-V dyslipoproteinemia or hyper lipo-proteinemia is characterized by elevated levels of both VLDL and chylomicrons, retinalis, eruptive xanthoma and pancreatitis ^62-79. Free oxygen radicals and oxidative stress is responsible for diabetic dyslipoproteinemia and other secondary complications in diabetes mellitus. Severe hyperglycemia cause generation of reactive oxygen species which are involved in peroxidative degradation of lipid. Increased lipid peroxides have been noted in diabetic patients and experimental animals. Oxidative modification in low-density lipoprotein (LDL) is atherogenic.

Retinal oxidative stress is increased in diabetic patients and rats due to downregulation of antioxidant defense enzymes like glutathione reductase (GSH) ^80-83. Prevention of diabetes still lies in the realm of future on until then tens of millions will continue to suffer from this disease.

Etiology: Diabetes mellitus is characterized by essential biochemical changes like lowered glucose tolerance, hyperglycemia, and glycosuria. The basic defect is an absolute or relative lack of insulin, either due to its antagonism by excessive secretion of other hormones having an opposite action or due to insulin antibodies or due to some other reasons the insulin is not able to act on the target cell which leads to abnormalities not only of carbohydrate but also of fat and protein metabolism. The failure of glucose utilization through the normal pathways for the production of energy in the deficiency of insulin results in fat mobilization from the adipose tissue leading to elevated levels of cholesterol, triglyceride (TG), free fatty acids (FFA), lipoproteins and ketone bodies ^84-95.

Carbohydrate Metabolism: One of the most important actions of insulin is to promote the entry of glucose into the cell from extra cellular fluids. It increases its conversion into glycogen by increasing the activity of glycogen synthetase and thus promotes glycogenesis. It also promotes utilization of glucose in the cell for the production of energy both through Embden Meyerhof pathway, acting on enzyme glucokinase, phosphofructokinase and pyruvate kinase and through HMP shunt by increasing the availability of glucose for glucose 6-phosphate and NADPH (co-factor) in the cell.

It also inhibits gluconeogenesis by inhibiting the enzyme pyruvate carboxylase, phosphoenol pyruvate carboxylase, fructose, 1, 6 bisphosphatase and glucose 6-phosphatase. Due to the above action, it reduces blood sugar level and its deficiency leads to hyperglycemia glycosuria and increased glycosylation of hemoglobin leading to an increased level of HbA₁C in blood ^90-96.

Glycosylated Haemoglobin: The evaluation of glycosylated Hb in diabetes began in 1958 when Allen showed chromatography heterogeneity of hemoglobin ⁹⁷. Tehran first demonstrated elevation of minor hemoglobin in diabetes mellitus introduced the column method of separating out the fast hemoglobin, pointed out that HbA₁C is related to control of diabetes. The advantages of Gly Hb estimation are those of a simple procedure, lack of any need for dietary preparation or for fasting, elimination of the variability usually found an oral glucose tolerance tests as well as an accurate reflection of overall chronic hyperglycemia ^98-101.

Reaction Leading to the Formation of HbA₁C:

FIG. 1: GLYCOSYLATED HAEMOGLOBINS ARE THE RESULT OF SIMPLE CHEMICAL REACTION BETWEEN HAEMOGLOBIN AND SUGARS AFTER SYNTHESIS OF HAEMOGLOBIN IS COMPLETE i.e. POST TRANSLATIONAL MODIFICATIONS

Lipid Metabolism: Insulin promotes the entry of fatty acids from the extracellular fluid into the cell, increases the availability of NADPH from HMP shunt, D-glycerophosphate through glycolysis and acetyl COA from pyruvate, which is derived mainly from carbohydrate and also protein. Thus it promotes fatty acid synthesis in tissues that possess an active HMP shunt. These tissues are specialized in active lipogenesis, e.g., liver, adipose tissue, and lactating mammary glands. Insulin inhibits the mobilization of triglyceride in the form of fatty acids from adipose tissue, inhibiting the activity of hormone-sensitive lipase. In diabetes mellitus, lack of insulin make adipose tissue more sensitive to mobilize an increased amount of free fatty acids in plasma. Plasma concentration of cholesterol and phospholipids undergo very little change in comparison to the other group of neutral lipids. The increased level of plasma cholesterol may also be due to reduced activity of HMGCOA reductase in diabetes. The liver is a major site of synthesis of endogenous triglyceride and the greatest portion of circulating prebeta lipoproteins (VLDL).

An important source of triglyceride synthesis in plasma free fatty acids, the quantity of which is increased primarily by any factor that increases lipolysis or decreases glycerol esterification in adipose tissue. In diabetes, the fasting hyper-lipidemia and hyperlipoproteinnemia occur. Due to increased level of VLDL and triglycerides, an elevated level of cholesterol is usually visible.

It has been reported that the levels of high-density lipoprotein cholesterol (HDL-TC) are decreased or remains unchanged. An elevated level of VLDL triglyceride has been found in all major classes of diabetic patients usually associated with inadequate salinization. In untreated juvenile-onset diabetics, there is little evidence of increased VLDL triglyceride production. The deficiency of insulin appears to result in altered low and high-density lipoprotein composition.

The mechanism for changes in the HDL is unknown but in the light of present knowledge the presence of triglyceride enriched low-density lipoprotein could mean that a less dense moiety of LDL may be accumulating in diabetic plasma and this could be due to altered rates of turnover of Apo-B containing lipoproteins ^102-112.

Lipoprotein Profile: Incubation of LDL cholesterol with glucose, at concentrations observed in diabetic condition, increased susceptibility of LDL to oxidation as measured by TBARS and conjugated diene formation, electrophoretic mobility and degradation by macrophages.  LDL and RBC membranes isolated from type-I and type-II DM patients were much more susceptible to oxidation than LDL from normal subjects. Furthermore, the susceptibility of LDL to oxidation was strongly correlated with the degree of LDL glycosylation. Plasma TRAP (total peroxyl radical trapping potential) was lower and susceptibility of LDL to oxidation as measured by the lay phase of conjugated diene formation after initiation of LDL oxidation by the addition of copper was greater in the poorly controlled type-I diabetic subject than in normal subjects.

In contrast, there was no difference between type-I diabetic patients and non-diabetic subjects in the susceptibility of LDL and VLDL cholesterol to oxidation in a number of studies.  Although,  there was  no  difference  between  the groups for LDL vitamin E content, LDL fatty acid composition in cholesterol esters or triglycerides, LDL glycation was elevated in the type-I DM subjects. Dyslipoproteinemia is involved in the origin of arteriosclerosis by changing the architecture of the coronary artery wall and therefore represents an important factor in the development of coronary artery disease (CAD). High-density lipoprotein (HDL) and apolipoprotein-A1 (Apo-A1) serves a projection against the origin and development of the coronary obstructive disease.

Abnormalities in insulin and glucose metabolism do not seem to entirely account for the high frequency of cardiovascular disease in patients with type-2 diabetes mellitus. An important additional factor may be hypertriglyceridemic hyper apo B and atherogenic dyslipoproteinemia that is common in these patients. Coronary artery disease is becoming more prevalent in developing countries, particularly in urban areas. More than 75% of patients with diabetes mellitus die from acute ischemic events, e.g. myocardial infarction or stroke. Diabetic dyslipoproteinemia characterized by hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol and often elevated low-density lipoprotein (LDL) cholesterol with predominance of small, dense LDL is a strong risk factor for atherosclerosis. Dyslipoproteinemia is probably the principal cause of endothelial dysfunction of conduit arteries in patients with nephrosis and the basis for their increased risk of cardiovascular disease. The strong association between coronary heart disease and dyslipo-proteinemia has often overshadowed the effects of the non- lipid risk factors-smoking, hypertension, obesity and diabetes, and impaired glucose tolerance and even led to questioning the importance of these risk factors in the presence of a  favourable lipoprotein profile.  Elevated levels of plasminogen activator inhibitor-1 (PAI-I) with and without reduction of tissue plasminogen frequently found in patients with diabetes mellitus.

Coronary events have a close association with a low HDL/hypertriglyceridemia (LHDL/HTG) phenotype. As enzymes that hydrolyze triglyceride-rich lipoproteins are associated with modulation of both HDL cholesterol and triglycerides, the mutation in the gene encoding lipoprotein lipase (LPL) or hepatic lipase (HTGL) may contribute to the formation of coronary atherosclerosis and thus, of coronary heart disease (CHD). A primary cause of abnormal lipids and lipoproteins is genetic. There are also a number of secondary causes of lipid and lipoprotein abnormalities. These secondary causes include endocrine problems, metabolic syndrome, certain pharmacologic agents and infection ¹¹³.

In mediating the transfer of cholesterol esterase from anti-atherogenic HDL to proatherogenic apolipoprotein (apo-B) containing lipoprotein particles (including VLDL, IDL, LDL, the cholesterol ester (CE) transfer protein (CETP) plays a critical role not only in the reverse cholesterol transport (RCT) pathway but also in the intravascular remodeling and recycling of HDL particles. Catabolism of circulating triglyceride-rich lipoproteins requires their interaction with lipolytic enzymes available to the plasma space.

As a result of this process, chylomicrons are converted to smaller remnant particles before their uptake by the liver. VLDL is degraded to IDL and then to LDL. This stepwise catabolism of chylomicrons and VLDL may be mediated by more than one enzyme.

Two lipolytic enzymes known to be present on the luminal surface of the endothelial cells are lipoprotein lipase and hepatic triglyceride lipase. The function of (LPL) has been studied extensively over the past 25 years and it now seems clear that this enzyme is primarily responsible for the hydrolysis of most circulating triglyceride. By contrast, the physiologic function of the hepatic triglyceride lipase is not established ^114-124.

Protein Metabolism: Insulin stimulates protein synthesis and amino acid uptake especially in muscle and inhibits protein catabolism and output of amino-acids from muscle. Insulin deficient muscle takes up and incorporates less amino acids into protein resulting in decreased protein synthesis and release more amino acids into the bloodstream. Increased catabolism of protein leads to an increase in the level of urea in the blood. The elevation of especially branched-chain amino-acids in the blood is reported by. Most of the chronic complications of diabetes involve protein changes, particularly in the blood vessel walls. The basement membrane is often altered. Early studies reporting elevated plasma levels of several amino-acids in obese subjects already suggested a link between this hyper amino-acidemia and decreased insulin sensitivity. The amino-acids usually elevated are valine, leucine, isoleucine, phenylalanine, and tyrosine ^125-130.

Lipoprotein Metabolism: Lipoprotein lipase (LPL) hydrolyzes the core of triglyceride-rich lipoproteins into free fatty acids and mono-acylglycerol, facilitating the removal of triglyceride-rich lipoproteins from the bloodstream. Patients with diabetes, especially insulin-deficient diabetes, often manifest a decrease in adipose tissue LPL activity and this is accompanied by an increase in plasma triglyceride. With insulin treatment, there is an improvement in both LPL activity and triglycerides. The regulation of lipoprotein lipase activity is closely linked to insulin levels and nutritional state, as demonstrated by the changes in LPL during cycles of feeding and fasting. Both in rat models of diabetes and human diabetes, the use of drugs to improve diabetes control resulted in increased adipose tissue LPL activity. However, recent studies demonstrated that the treatment of diabetes resulted in increase in LPL protein and LPL synthesis with no change in LPL on RNA levels, suggesting posttranscriptional regulation, possibly at the level of LPL translation. The translational regulation has been identified as an important mechanism for the regulations of LPL in response to catecholamines and thyroid hormone. Lipoprotein lipase is a central enzyme in lipid metabolism, and adipose tissue enzyme is important in the regulation of plasma triglyceride levels and in the accumulation of adipose tissue lipid stores ^131-135.

CONCLUSION: Impairment in metabolic path-ways due to type 2 diabetes mellitus is the root cause of micro and macrovascular complications of type 2 diabetes mellitus. This review article will be very helpful in the study of understanding the causes of type 2 diabetic complications. This review article will be also helpful in the sequencing of pre-existing knowledge, regarding learning with an understanding of micro and macrovascular complications of type 2 diabetes mellitus. Review articles would facilitate in the study of the promotion of knowledge regarding the regulation of different types of diabetic-dys-lipoproteinemias.

Studies on diabetic-dys-lipoproteinemia and oxidative stress would further contribute to a better understanding of the progression of diabetic complications. All over the world millions of people are suffering from microvascular (nephritis, retinopathy, blindness, and macrovascular (atherosclerosis) complications of diabetes mellitus, and these complications are mainly responsible for mortality in diabetes. This review article will be of great national and international importance due to its significant content regarding metabolic pathways to understand the process of micro and macrovascular complications in type 2 diabetes mellitus.

ACKNOWLEDGEMENT: One of us (Dr Vishnu Kumar) is grateful to the Director, Central Drug Research Institute (CDRI), Lucknow and Principal, ASMC, Shahjahanpur for moral support

CONFLICTS OF INTEREST: The authors declare that they have no conflict of interest.

REFERENCES:

1. Singh M, Anwer E and Kumar V: Assessment of bioche-mical parameters in the patients of coronary artery disease with type 2 diabetes mellitus. IJPSR 2017; 8(3): 1420-26.
2. Neerja J, Verma P, Kumar V, Mahdi F, Mahdi AA, Khanna AK and Singh RK: Antidyslipidemic and Antioxidant activity of medicinal plants in rat model of hyperlipidemia. IJPSR 2016; (11): 4579-87.
3. Verma P, Rathore B, Kumar V, Mahdi AA and Singh RK: Allium sativum regulates lipid metabolism in alloxan induced diabetic rats. IJPSR 2016; 7(12): 4949-55.
4. Verma P, Kumar V, Rathore B, Singh RK and Mahdi AA: Antidiabetic and anti-oxidienant prpperties of Aloe vera in alloxan induced diabetic rats. IJP 2016; 3(7): 319-24.
5. Verma P, Kumar V, Rathore B, Singh RK and Mahdi AA: Hypolipidemic activity of Aloe vera in hyperlipidemic rats IJP 2016; 3(4): 196-200.
6. Kumar V, Mahdi F, Singh R, Mahdi AA and Singh RK: A clinical trial to assess the anti-diabetic, antidyslipidemic and antioxidant activities of Tinospora cordifolia in management of type – 2 diabetes mellitus. International Journal of Pharma Sci and Research 2016; 7(2): 757-64.
7. Kumar V, Karoli R, Singh M, Misra A and Mahdi F: Evaluation of oxidative stress, antioxidant enzymes, lipid and lipoprotein profile in type-2 diabetic patients. Int J Bio Assay 2015; 4(10): 4365-68.
8. Kumar V, Mishra D, Khanna P, Karoli R and Mahdi F: A review of antioxidant enzymes, oxidative stress, lipid profile and lipoprotein constituent in the patients of coronary artery disease (cad) with type 2 diabetes mellitus (t2dm). Int J Bio Assay 2015; 4(10): 4443-47.
9. Kumar V, Mahdi F, Chander R, Khanna AK, Singh R, Saxena JK, Mehdi AA and Singh RK: Cassia tora regulates lipid metabolism in alloxan induced diabetic rats. IJPSR 2015; 6(8): 3484-89.
10. Ameis D, Creten H and Schotz MC: Hepatic and plasma lipase. in seminars in liver disease. Thiema Med Publ New York 1992; 12: 397.
11. Singh RK and Kumar V: Hydroalcoholic extract of Ocimum sanctum regulates lipid metabolism in alloxan induced diabetic rats. IJRSR 2019; 133-39.
12. Aragno M, Tamagno E, Gatto V, Brignardello E and Boccuzzi G: Dehydro epiandrosterone protect tissues of streptozotocin treated rats against oxidative stress. Free Radic Biol Med 1999; 26(11/12): 1467-74.
13. Arai K, Lizuka S, Tada Y, Oikawa K and Taniguelui N: Increase in the glycosylated form of erythrocyte Cu-Zn SOD in diabetes and association of non enzymatic glycosylation with enzyme activity. Biochem Bio Phys Acta 1987; 924: 292-96.
14. Ballantyne CM, Herd JA, Feriic LL, Dunn JK, Farmer JA, Jones PH and Scheim JR: Influence of low HDL on progression of coronary artery disease and response to fluvastation therapy. Circulation 1999; 90: 736-43.
15. Ballantyne CM, Olsson AG, Code TJ, Mercuri MF and Pedersen TR: Influence of low high density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 45. Circulation 2001; 104: 3046-51.
16. Barua SK, Saha SK, Patra A and Mitra AK: The structure and steriochemistry of phologantholide – a, a diterpene from phologacanthus a Phytochemistry 1985; 24: 2037-39.
17. Baynes JW: Role of oxidative stress in the development of complications in diabetes. Diabetes 1991; 40: 405-12.
18. Behar-Cohen FF, Heydolph SFV, Drosy-Lefaix MT, Courtious Y and Goureau O: Peroxynitrite cytotoxicity on bovine retinal pigmented epithelial cells in culture. Biochem Biophys. Res Commun 1996; 226: 842-49.
19. Beisiegel U, Weber W and Bengtsson G: Olivecrona lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein. Proc Proceedings of the National Academy of Sciences of the United States of America 1991; 88: 8342-46.
20. Benlian P: New progress and new tools for the study of molecular genetics in dyslipoproteinemia, Bulletin de 1' Academic Nationaled Medicine 2001: 185.
21. Caballero B: Plasma amino acid and insulin levels in obesity: Response to carbohydrate intake and tryptophan supplimentation. Metabolism 1988; 37(7): 672.
22. Bergmeyer HV: Method of enzymatic analysis Verlag chemie GmbH, Weinhein 1974; 674.
23. Bergo M, Olivecrona G and Olinecrona T: Forms of lipoprotein lipase in rat tissues: in adipose tissue the proportion of inactive lipase increases on fasting. J Biochem 1996; 313: 893-98.
24. Berman M, Hall M-III, Levy RI, Eisenberg S, Bilheimer DW, Phair RD and Goebel RH: Metabolism of apo-B and apo-c lipoproteins in man. Kinetic studies in normal and hyperlipoproteinemic subjects. J Lip Res 1978; 19: 38-56.
25. Bhatt RK and Sabata BK: Furanoid diterpene glucoside from cordifolia. Phytochemistry 1989; 28: 2419-22.
26. Bierman EL, Dole VP and Robert TN: Anabnormality of non esterified fatty acids metabolism in diabetes mellitus. Diabetes 1965; 6: 475-79.
27. Bisset NG and Nwaiwu J: Quaternary alkaloids of Tinospora Species. Planta Medica 1983; 48: 275-79.
28. Block G, Christopher DJ, Jason DM, Holland N, Edward PN and Ginger LM: The effect of vit. C and E on biomarkers of oxidative stress depend on baseline level. Free Rad Biol and Med 2008; 45: 377-84.
29. Boucher BJ, Welch SG and Beer MS: Glycosylated haemoglobin in the diagnosis of diabetes mellitus and for the assessment of chronic hyperglycemia. Diabetologia 1981; 21: 34-36.
30. Bowie A, Owens D, Collins P, Johnson A and Tomkin GH: Glycosylated low-density lipoprotein is more sensitive to oxidation. Implication for the diabetic patients. Atherosclerosis 1993; 102: 63-67.
31. Breckenridge WC, Little JA, Alaupovic P, Wang CS, Kuksis A and Kakis G: Lipoprotein abnormalities associated with a familial deficiency of hepatic lipase. Atherosclerosis 1982; 45: 161.
32. Brien SO, Mori TA, Puddey IB and Stanton KG: Absence of increased susceptibility of LDL to oxidation in type-I diabetes. Diabetes Res and Clinical Prac 1995; 30: 195-03.
33. Broijerson A, Eriksson M, Wiman B, Angelin B and Hjemdhal P: Gemfibrozil treatment of combined hyper lipoproteinemia, No improvement of fibrinolysis despite marked reduction of plasma triglyceride levels, arteriosclerosis. Thromb Vasc Biol 1996; 16: 511-16.
34. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC and Morse JS: Simvastation and niacin, antioxidant vitamins or the combination for the prevention of coronary disease. N Engl J Med 2001; 345: 1583-92.
35. Brown MS and Goldstein JL: indicus alkaloids Science. 1986; 232: 34-47.
36. Brown RT and Chapple CL: Anthocephalus alkaoids, 3β dihydrocadambine and 3β isodihydrocadambine. Tetrahyd Lett 1976; 31: 2723-24.
37. Brown RT, Fraser SB and Banerji J: Heart wood of cadams contains glucoalkaloids of isodihydrocadambine. Tetrahed Lett 1974; 29: 3335.
38. Brown RT, Fraser SB and Banerji IJ: Anthocephalus alkaloids Tetrahed. Lett 1974; 37: 3335-38.
39. Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414: 813-20.
40. Brownlee M, Cerami A and Vlassara H: Advanced glycosylation end products in tissue and the biochemical basis of diabetic complication. N Engl J Med 1988; 318: 1315-21.
41. Bunn HF and Koenig RJ: Evaluation of glycosylated hemglobin in diabetic patients. Diabetes 1976; 30: 613-17.
42. Burstein M and Legmann P: Lipoprotein precipitation in monographs as atherosclerosis, Ed., Clarkson T.B. London, Paris, New York. S Karger 1982; 2: 78.
43. Caballero F, Gerez E, Batlle A and Vazquez E: Preventive aspirin treatment of streptozotocin-induced diabetes, blockage of oxidative status and revertion of heme enzymes inhibition. Chem Biol Interact 2000; 126(3): 215-25.
44. Cameron NE, Cotter MA and Hohman TC: Interactions between essential fatty acids, prostanoid, polyol pathway and nitric oxide mechanism in the neurovascular deficit of diabetic rats. Diabetogia 1996; 39: 172-82.
45. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ and Wald FW: Fifteen year mortality in coronary drug project patient’s long-term benefit with niacin. J Am Cell Cardiol 1986; 8: 1245-55.
46. Cardorph HR: Treatment of hypercholesteremia with cholestyramine bile and acid sequestering resin. Vascs Dis 1976; 4: 305-08.
47. Carlson LA, Holmquist L and Ehle NP: Deficiency of hepatic lipase activity in post-heparin plasma in familial hyper-x-triglyceridemia. Acta Med Scand 1986; 219: 435.
48. Carneheim C, Nedergaard J and Cannon B: Cold induced beta-adrengergic recruitment of lipoprotein lipase in brown rat is due to increased transcription. Am J Physiol 1988; 254: 155-61.
49. Carsten RE, Whalen LR and Ishii DN: Impairment of spinal cord conduction velocity in diabetic rats. Diabetes 1989; 38: 730-36.
50. Cederberg J, Basu S and Eriksson UJ: Increased rate of lipid peroxidation and protein carbonylation in experimental diabetic pregnancy. Diabetologia 2001; 44: 766-74.
51. Chakravarthy BR, Wang J, Tremblay R, Atkinson TG, Wang F, Li H, Buchan AM and Durkin JP: Comparison of the changes in protein kinase C induced by glutamate in primary cortical neurons and by in-vivo cerebral ischaemia. Cell Signal 1988; 10(4): 291-95.
52. Chan SH and Koo A: The involvement of medullary reticular formation in the hypotensive effect of extract from seeds of cassia tora. Am J Chines Med 1974; 4: 383-89.
53. Chander R, Singh K K, Kaul SM, Puri A, Saxena R, Bhatia G et al. Antidyslipidemic and antioxidant activities of different fractions of Terminalia Arjuna stem bark. Indian Journal of Clinical Biochem 2004; 19(2): 141-48.
54. Chander R, Khanna AK and Kapoor NK: Lipid lowering activity of Guggulsterone from Commephora mukul in hyperlipidemic rats. Phytother Res 1996; 10: 508-11.
55. Chandra O and Gupta D: A complex polysaccharide from the seeds of Anthocephalus indicus. Carbohydrate Research 1980; 83: 85-92.
56. Chari SN, Nath N and Rathi AB: Glutathione and its redox system in diabetic polymorphonuclear leukocytes. Am J Med Sci 1984; 287: 14-15.
57. Chatterjee A and Pakrashi SC: The Treadi Indian Med Plan 1992; 2: 180.
58. Chattopadhyaya R, Pathak D and Jindal DP: Anti-hyperlipidemic agents. a review. Ind Dru 1996; 33: 85-97.
59. Cheesman KH and Slater TF: An introduction to free radical Biochemistry. Br Med Bull 1993; 49: 481-93.
60. Chevion M, Berenshtein E and Stadman ER: Human studies related to protein oxidation, protein carbonyl content as a marker of damage. Free Rad Res 2000; 33Suppl: 99-08.
61. Chevreul: Cited by Allen FM, Stillman E and Fitz R: Total dietary regulation in the treatment of diabetes, New York Rockefeller Institute for Medical Research 1919; 18: 1815.
62. Chintalwar G, Jain A, Sipahimalani A, Banerji A, Sumariwalla P, Ramakrishanan R and Sainis K: An immunologically active arabinogalactam from Tinospora cordifolia. Phytochemistry 1999; 52: 1089-93.
63. Choi JS, Lee HJ and Kang SS: Alaternin, Cassiaside and subrofusarin gentiobioside, radical scavenging principles from the seeds of cassia tora on 1, 1-diphenyl-2-picrylhydrazyl (D.P.P.H.) radical. Arch of Pharmaceut Res 1994; 17: 462-66.
64. Choi JS, Lee HJ, Park KY, Ha JO and Kang SS: In-vitro anti-mutagenic effects of anthraquinone aglycones and naphopyrone glycosides from Cassia tora. Planta Medica 1997; 63: 11-14.
65. Chopra RN, Chopra IC, Handa KL and Kapur LD: Indigenous Drugs of India. Calcutta ed. 2^nd 1958: 426.
66. Chopra RN, Chopra IC and Varma BS: Supplement to glossary of Indian Medicinal plants. New Delhi. India 1969: 39.
67. Chopra RN, Nair SL and Chopra IC: Glossary of Indian Medicinal plants, publication and information directorate, CSIR, hill-side road, New Delhi 1916: 20.
68. Cinar MG, Ulker S, Alper G and Evinc A: Effect of dietary Vit E supplementation on vascular reactivity of thoracic aorta in streptozotocin-diabetic rats. Pharmacology 2001; 62(1): 56-64.
69. Clark CMJ and Lee DA: Prevention and treatment of the complications. N Engl J Med 1995; 332: 1210-17.
70. Collier A, Rumley A, Rumby AG, Paterson JR, Leach JP and Lowe GD: Free radical activity and hemostatic factors in NIDDM patient with and without micro albumin urea. Diabetes 1992; 41: 909-13.
71. Colwell JA: Macroangiography in Alberti KGMM, Eds Krdi LP. The diabetes Annual New York. Elsever 1998.
72. Cotunnius Nepropathy in diabetes. Disch Med Wochenschr 1770; 107: 732-35.
73. Cullen Complication in diabetes. Diabetes 1776; 31: 846-48.
74. Dandona P, Thusu K, Cook S, Snyder B, Makowski J, Armstrong D and Nicotera T: Oxidative damage to DNA in diabetes mellitus. Lancet 1996; 347: 444-45.
75. Daniel E, Peavy JM and Leonard S: Jefferson correlation of Albumin production rates and albumin mRNA levels in livers of normal, diabetic and insulin treated diabetic rats. PNAS 1978; 75(12): 5879-83.
76. Daniels SR: Lipid metabolism and secondary forms of dyslipoproteinemia in children. Prog Pediatr Cardiol 2003; 17(2): 135-40.
77. Das B, Venkakaiah B and Das R: Lighans, promising anticancer agents. in role of biotechnology in medicinal and aromatic plants. Khan IA and Khanum A (eds) Ukaaz Publication, Hyderabad 2001; 4(4): 2-49.
78. Datta S, Luo CC, Li WH, Van Tuinen P, Led better DH, Brown MA, Chen SH, Liu SW and Chan L: Human hepatic lipase. J Biol Chem 1998; 263: 1107.
79. Davies RC, Stahnke G, Wong H, Doolittle MH and Ameis D: Hepatic lipase: Site directed mutagenesis of a serine residue important for catalytic activity. J Biol Chem 1990; 265: 6291.
80. Davies RC, Wong H, Nikazy J, Wang K, Han Q and Schotz MC: Chimeras of hepatic and lipoprotein lipase. Domain localization of enzyme-specific properties. J Biol Chem 1992; 267: 21499.
81. De Luca C and Olefsky JM: Inflammation and Insulin resistance. FEBS Lett 2008; 582(1): 97-105.
82. Demant T, Carlson LA, Holmquist L, Karpe F, Nilsson Ehle P, Packard CJ and Shepard J: Lipoprotein metabolism in hepatic lipase deficiency: studies on the turnover of apolipoprotein B and on the effect of hepatic lipase on high density lipoprotein. J Lipid Res 1988; 29: 1603.
83. Demattia G, Laurenti O, Bravi C, Ghiselli A, Iuliano L and Balsano F: Effect of aldose reductase inhibition on glutathione redox status in erythrocytes of diabetic patients. Metabolism 1994; 43: 965-68.
84. Derewenda ZS and Cambillau C: Effects of gene mutations in lipoprotein and hepatic lipase as interpreted by a molecular model of the pancreatic triglyceride lipase. J Biol Chem 1991; 266: 23112.
85. Dibirov AD, Petukhov VA, Son DA and Bryush YA: Morphofunctional changes in hepatopancreatobiliary organs in experimental dyslipoproteinemia, Bullet. Experiment Biol and Med 2000; 130(7): 649-54.
86. Dixit SN and Khosa RL: Chemical investigation of cordifolia. Indian J Appl Chem 1971; 34: 46-47.
87. Duan RD and Erlanson-Albertson C: Pancreatic Lipase and Colipase Activity increase in Pancreatic Acinar Tissue of Diabetic rats. Pancreas 1989; 4(3): 329-34.
88. Dwivedi RM, Pandey SP and Tripathi VJ: Role of Japa pushpa (Hibiscus rosa sinensis) in the treatment of arterial hypertension. A trial study. J Res Indian Med Yoga and Homeopathy 1977; 12: 13-36.
89. Eckel RH: Lipoprotein lipase: A multifunctional enzyme relevent to common metabolic diseases. N Engl J Med 1989; 320: 1060-68.
90. Eckel RH: Lipoprotein lipases and diabetes mellitus In: (Drazin B, Eckel RH, eds.) diabetes and atherosclerosis. New York: Elsevier Science 1993; 77-102.
91. Ehnholm C, Shaw W, Greten H and WV: Purification from human plasma of a heparin released lipase with activity against triglyceride and phospholipd. J Biol Chem 1979; 250: 6750-51.
92. Eisenberg S: Very low-density lipoprotein metabolism. Prog. Biochem. Pharmacol 1979; 15: 139-65.
93. Elkeles RS and Hambley J: The effect of fasting and streptozotocin diabetes on hepatic triglyceride lipase activity in the rat. Diabetes 1977; 26(1): 58-60.
94. Emami SA, Asili J, Mohaghezhi Z and Hassanzadeh MK: Antioxidant activity of leaves and fruits of Iranian Conifers. Evi Based Com and Alter Med 2007; 4: 313-19.
95. Esterbauer H, Koller E, Slee RG and Koster JF: Possible involvement of the lipid peroxidation product and hydroxynonental in the formation of fluorescent chromolipids. Biochem J 1985; 239: 405-09.
96. Kumar V, Salam A, Misra A, Jafri TR, Anwer E and Singh S: The prevelence of obesity and overweight amongst students and staff of era’s lucknow medical college & hospital lucknow. EJMR 2018; 5(1): 9-16.
97. Singh S, Kumar V, Singh K, Karoli R and Mahdi F: Status of TNF-α and insulin in obese and diabetic obese subjects of western Lucknow. EJMR 2018; 5(1): 17-21.
98. Kumar V and Salam A: A review on antioxidants and oxidative stress in type-2 diabetes mellitus. EJMR 2017; 4(2): 47-51.
99. Kumar V, Mahdi F, Saxena JK, Singh RK, Srivastava MR and Ahmad S: Effects of natural products on body weight and biochemical parameters in healthy rats. EJMR 2017; 4(2): 30-37.
100. Kumar V, Mahdi F, Saxena JK, Singh RK, Akhter N and Ahmad S: Experimental validation of antidiabetic and antioxidant potential of cordifolia stems (m.): an indigenous medicinal plant EJMR 2017; 4(2): 10-15.
101. Kumar V and Abdussalam: A review on reactive oxygen and nitrogen species EJMR 2017; 4(2): 40-45.
102. Kumar V: A review on etiopathogenesis of type-2 diabetes mellitus EJMR 2017; 4(1): 49-53.
103. Kumar V: Medicinal properties of anthocephalus indicus (kadam): an indigenous medicinal plant. EJMR 2017; 4(1): 63-67.
104. Singh M, Choudhury I, Pallinti V, Jothimalar R, Kumar V and Misra A: Association between PRO12ALA polymorphism at the PPARϒ2 gene and insulin sensitivity in south Indian population with type 2 diabetes mellitus. Indian J Basic and Applied Med Res 2016; 5(3): 733-41.
105. Kumar V: Antidyslipidemic and anti-oxidant activities of tinospora, cordifolia stem extract in alloxan induced diabetic rats. Ind J of Clin Biochem 30(4); 2015: 473-78.
106. Gavin LA, Cavalieri RR, Moeller M, McMahon FA, Castle JN and Gulli R: Brain lipoprotein lipase is responsive to nutritional and hormonal modulation. Metabolism 1987; 36: 919-24.
107. Ghosal S and Vishwakarma RA: Tinocordiside, a new rearranged cadinane sesquiterpene glycoside from Tinospora cordifolia. Journal of Natural Products 1997; 60: 839-41.
108. Giugliano D, Ceriello A and Paolisso G: Diabetes mellitus, hypertension and cardiovascular disease: which role for oxidative stress? Metabolism 1995; 44: 363-68.
109. Goel HC and Kumar PI: Free Radical scavenging and metal chelation by Tinospora cordifolia, a possible role in radioprotection. Ind J of Experi Biology 2002; 40: 727-34.
110. Goldberg IJ: Lipoprotein lipase and lipolysis: Central roles in lipoprotein metabolism and atherogenesis. J Lipid Res 1996; 37: 693-07.
111. Grossen J, Schrecker O and Greten H: Function of hepatic triglyceride lipase in lipoprotein metabolism. J Lipid Res 1981; 22: 437-42.
112. Gupta SS, Verma SCL, Garg VP and Mahesh R: Anti diabetic effect of Tinospora cordifolia part-I. Effect on fasting blood sugar level, glucose tolerance and adrenaline induced hyperglycemia. Indian J Med Res 1967; 55(7): 733-45.
113. Hackman A: Levels of soluble cell adhesion molecules in patients with dyslipidemia. Circulation 1996; 37: 1334-38.
114. Haffiner SM, Agil A, Mykkaner L, Stern MP and Jailal I: Plasma oxidizability in subjects with normal glucose tolerance and NIDDM Diabetes Care 1995; 18: 646-53.
115. Hailer S, Pogarell O, Keller C and Wolfrom G: Effect of fluvastatin or bezafibrate on the distribution of HDL subpopulation in patients with familial hyper-choles-trolemia. Arznein-Forschi Drug Res 1996; 46: 879-83.
116. Halliwell B and Whiteman M: Measuring reactive species and oxidatives damage in-vivo and in cell culture: how should you do it and what do the results mean? Br J Pharmacol 2004; 142: 231-52.
117. Halliwell B: Oxygen radicals, a common sense look at their nature and medical importance. Lancet 1984; 1: 1328-29.
118. Halliwell B and Gutteridge JM: Role of free radicals and catalytic metal ions in human disease, an overview. Meth Enzymol 1990; 186: 1-85.
119. Halliwell B, Gutteridge JMC and Cross CE: Free radicals and human disease – where are we now? J Laborat and Clin Med 1992; 119: 598-20.
120. Halliwell B, Murcia MA, Chirico S and Aruoma OI: Free radical and antioxidants in food and in-vivo. what they do and how they work. Critical Reviews in Food Science and Nutrition 1995; 35: 7-20.
121. Halliwell B: Food – derived antioxidants: how to evaluate their importance in food in-vivo. A Hand Book of Antioxidants 2002: 1-3.
122. Yusuf H: Chairman, CIPLA, Business Today 2005; 27: 1-30.
123. Hanuman JB, Mishra AK and Sabata BK: A natural phenolic lignan from Tinospora cordifolia J Chem Soc Perkin Trans 1986; 7: 1181-86.
124. Harman D: Aging – a theory based on free radical and radiation chemistry. J Gerontol 1956; 11: 298-300.
125. Harris ED: Regulation of antioxidant enzymes. FASEB J 1998: 2675-83.
126. Hatano T, Uebayashi H, Ito H, Shiota S, Tsuchiya T and Yoshida T: Phenolic constituents of Cassia tora seeds and antibacterial effect of some naptolenes and anthraquinones on methicillin-resistant Staphylococcus aureus Chemic and Pharmaceuti Bulle (Tokyo). 1999; 47: 1121-27.
127. Hegele RA, Little JA, Vezina C, Maguire GF, Tu L, Wolever TS, Jenkins DJA and Cannelly PW: Hepatic lipase deficiency, clinical, biochemical and molecular genetic characteristics. Arteriosclerosis, Thrombosis and Vascular Biology 1993; 13: 720.
128. Hermes Lima M, Willmore WG and Storey KB: Quantification of lipid peroxidation in tissue extracts based on Fe (III) Xylenol orange complex formation. Free Radical Biology and Medicine 1995; 19: 271-80.
     

     ---

     How to cite this article:

     Kumar V, Deepak AD, Giri VP and Kumar A: A review on impairment in metabolic pathways due to type 2 diabetes mellitus. Int J Pharm Sci & Res 2020; 11(3): 1089-97. doi: 10.13040/IJPSR.0975-8232.11(3).1089-97.

     ---

     All © 2013 are reserved by the International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

     ---