Diabetes mellitus type 2: One monster eating all


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Diabetes mellitus type 2: One monster eating all

  1. 1. Diabetes mellitus type 2: One monster eating all
  2. 2. a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1 e6 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/apme Review Article Diabetes mellitus type 2: One monster eating all Ashwini Kumar a, Sudhanshu Kumar Bharti b, Awanish Kumar c,* a Department of Biotechnology, National Institute of Technology, Raipur 492010, Chhattisgarh, India Department of Biochemistry, Patna University, Patna 800005, Bihar, India c Assistant Professor, Department of Biotechnology, National Institute of Technology, Raipur 492010, Chhattisgarh, India b article info abstract Article history: Diabetes has been considered as the most dreaded non-communicable disease consuming Received 7 January 2014 the mankind rapidly. WHO has predicted the number of diabetics to be approximately 366 Accepted 31 January 2014 millions by 2030. The disease is characterized by hyperglycemia and the basic symptoms Available online xxx are polyphagia, polydipsia and polyuria. The autoimmune type 1 diabetes represent almost 1% of the total diabetic population, the rest being that of type 2 diabetes (T2D). Type 2 Keywords: diabetes has been linked to a variety of factors such as heredity, environmental factors, Diabetes unhealthy eating habits, sedentary lifestyle, stress etc. The uncontrolled hyperglycemia Pathology has profound deleterious effects on almost all the organs and results in various cardio- Cardiovascular vascular disorders, retinopathy, neuropathy, and nephropathy. Recent studies have Retinopathy revealed an array of pulmonary dysfunctions related with T2D ranging from respiratory Nephropathy defects to tuberculosis. Diabetes also predisposes the person to hepatic dysfunctions like NAFLD and HCC and a range of infections at various sites which are difficult to manage. Post-surgical infections are of special interest for subjects with uncontrolled hyperglycemia prior to surgery. Scientists all over the world are revealing different pathways and associated therapies for diabetes in order to control a monster which is destroying almost whole body physiology. Copyright ª 2014, Indraprastha Medical Corporation Ltd. All rights reserved. 1. Introduction Type 2 diabetes mellitus (T2DM) has been one of the most widely diagnosed non-communicable diseases in adults worldwide. The reason expands from genetic predisposition, environmental factors, obesity, sedentary lifestyle, polycystic ovary syndrome (PCOS), unhealthy eating habits etc. The number of diabetic patients, as predicted by WHO would approximately be 366 millions by the year 2030.1 The type 2 diabetes patients experience unusual polyuria (frequent urination mainly nocturia), polydipsia (thirst) and polyphagia (excess hunger) and weight loss as most general symptoms apart from the hyperglycemia.2,3 The uncontrolled high blood glucose leads to serious health complications and may even be fatal. Diabetes has been a major risk factor for cardiovascular disease and stroke and the diabetic adults have 2e4 times increased chance of such pathologies.4 Other major effects include retinopathy, nephropathy and neuropathy. The current most effective parameter for predicting diabetes is the measurement of glycated hemoglobin (HbA1c).4 * Corresponding author. E-mail addresses: drawanishkr@gmail.com, awanik.bt@nitrr.ac.in (A. Kumar). 0976-0016/$ e see front matter Copyright ª 2014, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2014.01.009 Please cite this article in press as: Kumar A, et al., Diabetes mellitus type 2: One monster eating all, Apollo Medicine (2014), http://dx.doi.org/10.1016/j.apme.2014.01.009
  3. 3. 2 a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1 e6 2. Pathophysiology of type 2 diabetes mellitus The glucose obtained from food is either immediately utilized by the body or is converted to liver and muscle glycogen (storage polysaccharide) and adipose triglyceride (energy reservoir) by the action of insulin. Diabetes mellitus is the condition when the body is incapable of utilizing the glucose present in the blood for various cellular activities. According to the Williams Textbook of Endocrinology (10th edition), the pathophysiology of type 2 diabetes primarily demonstrates the following three abnormalities: (i) nonresponsiveness of insulin receptors even though the body exhibits the physiological insulin level; (ii) the body is not manufacturing enough insulin; (iii) increased hepatic glucose production. A decreased insulin secretion results from impairment in glucose response by insulin secreting b-cell of pancreas. A mutation in glucokinase gene, which plays an important role in glucose sensing mechanism of pancreatic beta cells, is also an important factor of impaired glucose tolerance in pancreas. Insulin resistance, on the other hand, is the condition when the insulin receptors become less responsive towards insulin even when the hormone is present in physiological amount. This condition is attributed to many factors major being the obesity which exerts its effect via free fatty acids and inflammatory cytokines (like TNF-a) which downregulate the insulin receptor and insulin receptor substrate (IRS) protein5,6 (Fig. 1). The diagnosis of diabetes depends on the conventional criteria of fasting plasma glucose (FPG) and 2 h post-prandial plasma glucose (2h-PG) where FPG 126 mg/dL (7.0 mmol/L) and 2h-PG 200 mg/dL (11.1 mmol/L). The latest addition to the diabetes diagnosis has been the calculation of glycated hemoglobin (HbA1c) which has been treated as better criterion than the former two as it estimates an average hyperglycemia over several months with International Diabetes Federation (IDF) declared this in 2009 and American Diabetes Association (ADA) adopted in 2010. The cut-off for HbA1c has been 6.5%.7 Fig. 1 e Physiological action of insulin on liver, muscles and adipocytes. 3. Diabetes related complications According to the American Diabetes Association, a diabetes patient, as compared with the normal non-diabetic one, has approximately 7 year shorter life span resulting from various diabetic related complications.7 Some of the major complications include coronary artery disease, stroke, peripheral vascular disorders, nephropathy, neuropathy and diabetic retinopathy. People having diabetes have greater risk of acquiring cancer, cardiovascular complications and renal failure because of their susceptibility towards the diseases7 (Fig. 2). 3.1. Cardiovascular disorders Uncontrolled hyperglycemia results in non-enzymatic glucose (aldose sugar) attachment (glycation) on the physiological proteins and lipids which disrupts their normal function and increases the related pathology. These altered products are known as advanced glycated end-products (AGEs) and the reaction involving the formation is known as Maillard reaction. The AGE receptors, known as RAGE belonging to immunoglobulin superfamily, have been shown to influence the cellular signaling on binding with AGEs. Cross-linking of AGEs with type I collagen and elastin in vessel wall leads to vasculature stiffness. Studies suggest that lipid AGEs like glycated LDL reduces the nitric oxide (NO) production which is a vasodilator and suppresses LDL receptor mediated LDL uptake by endothelial cells. The suppression of NO production from endothelial cells due to action of AGEs in diabetic patients can be an important factor promoting the atherosclerosis since NO show a range of anti-atherogenic actions like inhibition of platelet adhesion and aggregation, leukocyte adhesion to vessel walls etc.8,9 The vascular conditions arising from AGEs namely arterial stiffness and platelets adhesion aggregation can lead to stroke, myocardial infarction, cardiac failure and overall Fig. 2 e Major pathological conditions associated with diabetes type 2. Please cite this article in press as: Kumar A, et al., Diabetes mellitus type 2: One monster eating all, Apollo Medicine (2014), http://dx.doi.org/10.1016/j.apme.2014.01.009
  4. 4. a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1 e6 mortality. Myocardial stiffness due to extracellular matrix collagen e AGEs cross-linking in myocardium may lead to left ventricular hypertrophy (LVH) and pressure overload. The suppression of LDL receptor mediated LDL uptake can pose a significant risk of atherosclerosis leading to hindered blood flow in major coronary arteries. The pathological results begin with hypertension, ischemia, infarction and cardiac attack. Untreated diabetes, thus, pose a critical risk towards cardiovascular disorders.10e12 Studies done in India by Madras Diabetic Research Foundation and Indian Diabetic Research Foundation independently found that Indians, especially south Indians, are at high risk of developing insulin resistance, diabetes and related cardiovascular conditions. The major risk factors observed in study involving children and adolescent subjects were low high density lipoprotein (low HDL) and high triglyceride level and increased risk of metabolic syndrome.13e15 Diabetic cardiomyopathy is defined as myocardial dysfunction seen in subjects with diabetes in absence of CAD, hypertension and valve defects. The development of diabetic cardiomyopathy has been attributed to various factors namely metabolic disturbances, insulin resistance, hyperlipidemia, cardiac autonomic dysfunction etc. Hyperglycemia, hyperinsulinemia and elevated FFA are the major factors leading to cardiac steatosis. Brain natriuretic peptide (BNP) is a biomolecule released from ventricles and found elevated in patients with heart failure. The gene expression of BNP was found to be increased in animal models of insulin resistance and hyperinsulinemia along with other markers such as left ventricular hypertrophy (LVH).16 3.2. Diabetic retinopathy Diabetic retinopathy (DR) is the microvascular damage to the retina because of prolonged hyperglycemia. This kind of retinal damage is irreversible and has been a major cause of blindness in young working population. The disease is characterized by alteration in retinal vasculature and damage to ocular nerves. Study on mice model has revealed a difference in proteome of diabetic, non-diabetic and metformin treated mice and found that many of these proteins were involved in synaptic transmission. The excitatory neurotransmitter glutamate is loaded in synaptic vesicles by the major transporter VGLUT1 and is expressed in photoreceptors. The study has shown a decreased expression of VGLUT1 in diabetic mice retina and was not normalized even after metformin treatment.17 Recent finding has shown that phospholipase A2 (PLA2) is upregulated early in glucose induced alteration of retinal layer. PLA2, VEGF and COX-2 expression level were found to be significantly increased in retinal microvessels of diabetic rat model.18 A study conducted by Diabetic Research Centre India on one thousand patients in 1996 revealed that retinopathy increased linearly with progressing diabetes.19 In a study done by Madras Diabetic Research Foundation India, the diabetic retinopathy was found to be associated with increased thickness of intima-media and arterial stiffness in ocular vessels and that DR begin to develop years before the diagnosis if the hyperglycemia remains untreated for as long as 3e4 years.20 In another study, it was found that retinal hard exudates and macular edema were seen in case of DR and it was positively correlated with dyslipidemia (higher 3 cholesterol and LDL) in patients, but it was not the only risk factor for DR.21 3.3. Diabetic nephropathy Renal disorder and eventual renal failure is the major organ targeted by hyperglycemia after cardiovascular system. Glomerulosclerosis induced renal pathology in uncontrolled diabetes include increased thickness of basement membrane, diffuse mesangial sclerosis with nodule formation, microaneurysm, hyaline arteriosclerosis which result in microalbuminuria, followed by macroalbuminuria proceeding to loss of glomerular filtration rate (GFR) and probable end stage renal failure. A study conducted on diabetic patients in USA demonstrated that the patients had increased urine albumin secretion and high systolic pressure as compared to nondiabetic subjects. Currently, almost half of the individuals with renal disease attempting to go for renal replacement therapy in USA are type 2 diabetic.22 An Indian study from 2009 to 2011 demonstrated that microalbuminuria was elevated in population with uncontrolled hyperglycemia and even led to increased serum creatinine level indicating a renal damage with high significance (p 0.0001).23 Persistent proteinuria and albuminuria also lead to renal tubule dysfunction due to epithelial damage by continuous passage of plasma protein. This condition results in tubulointerstitial fibrosis followed by irreversible kidney damage. Serum cystatin C, a protease inhibitor, is completely filtered through glomerulus and almost completely catabolized by the tubular epithelium. A study on 70 diabetic and 20 control subjects in 2013 demonstrated that serum cystatin C level was significantly elevated in diabetic patients as compared to control population and was positively correlated with urine albumin and creatinine secretion.24 Diabetic nephropathy is also characterized, at molecular level, by the excessive deposition of the proteins of extracellular matrix (ECM) in basement membrane and mesangium of the basement membrane and renal tubulointerstitium due to increased production of reactive oxygen species (ROS) and increased expression of TGF-b while a decreased expression of matrix metalloproteinases (MMP). This is followed by an increase in thickness of glomerular basement membrane. Physiological changes include glomerulosclerosis and tubulointerstitial fibrosis too. Biochemical changes thus follows are decreased creatinine clearance and microalbuminuria.25 3.4. Pulmonary defects Despite the fact that pulmonary functions are neglected in diabetic patients, they have been found to encounter various respiratory problems. The most common problem associated has been the deposition of non-enzymatically glycosylated collagen in the lung parenchyma and chest walls increasing the stiffness of lungs thus reducing its expansion. The lung muscle strength also decreases based on neuropathic changes affecting respiratory muscles. Obesity has been related to increased leptin level and T2D (insulin resistance) and high leptin in obese-diabetic subjects has been significantly associated with ailments such as obstructive sleep apnea, asthma, chronic obstructive pulmonary disorder (COPD) and lung Please cite this article in press as: Kumar A, et al., Diabetes mellitus type 2: One monster eating all, Apollo Medicine (2014), http://dx.doi.org/10.1016/j.apme.2014.01.009
  5. 5. 4 a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1 e6 Table 1 e Type 2 diabetes related complications, markers and related pathology. Diabetes related complications Cardiovascular disorders Diabetic retinopathy Diabetic nephropathy Pulmonary defects Diabetic neuropathy Hepatic dysfunction Diagnostic markers Lipid accumulation in hepatocytes, elevated liver enzymes. cancer.26 It has been reported that diabetic subjects with poor glycemic control have lower forced expiratory volume in 1 s (FEV1) and forced vital capacity as compared to the normal subjects.26 The histo-pathological examination of lungs of diabetic subjects has evidence of thickened alveolar, epithelial and capillary basal lamina. Pulmonary vascular damage has been related to diabetic microangiopathy.26 Indian scientists have also found a negative correlation between lung function and glycemia with reduction of FEV1 and forced vital capacity (FVC) in a study involving forty diabetic patients.27,28 Another Indian study involving sixty type 2 diabetic and sixty control individuals exhibited the reduction in all pulmonary parameters in diabetic individuals as compared to the control ones29 (Table 1). 3.5. Related pathology Hypertriglyceridemia, hypercholesterolemia, circulating rAGE. Increased PLA2, VEGF, COX-2, macular edema, retinal exudate. High glycated albumin, increased serum cystatin C, high serum creatinine, low GFR. Reduction in PFTs, elasticity, parenchymal aberrations etc. Reduction in serum TNF-a. Diabetic neuropathy Diabetic peripheral neuropathy (DPN) is one of the major effects of uncontrolled hyperglycemia affecting almost 50% of diabetic patients not receiving proper diagnosis and treatments. It can be seen as distal, symmetric and sensorimotor neuropathy. Around 30% of the patients exhibit painful neuropathy while the rest experience numbness and loss of sensation. The disease is clinically determined by poor gait and balance (with large sensory fibers) and abnormal heat and cold sensation (with small sensory fibers). Patients also complain of chronic pain and very often perceived symptoms are tingling, itching and “pin needle poking sensation”, walking on hot coal, bee stinging etc. The chronic pain experienced can be described as hyperesthesias (increased sensitivity to touch), allodynia (pain from normal stimuli) and hyperalgesia (increased sensitivity to painful stimuli). The advanced stage affects the limbs and commonly leads to diabetic foot (foot ulceration). International Association for the Study of Pain has defined the diabetic neuropathic pain as “a pain arising as a direct consequence of abnormalities in peripheral somatosensory system in people with diabetes”.30,31 A recent study conducted on DPN patients and control subjects has shown a positive correlation between serum TNF-a and DPN.32 References Arterial stiffness, atherosclerosis, LVH, hypertension etc. 8,9,11,12 Ocular arterial stiffness, permanent blindness. 17,18,21 Glomerulosclerosis, end stage renal disease. 22e25 COPD, obstructive sleep apnea, lung cancer. Pain, numbness, hyperesthesia, allodynia, hyperalgesia, severe lower limb infections. NAFLD, cirrhosis, HCC. 26e29 30e33 34e36 Diabetic foot infection (DFI) is the most common result of peripheral neuropathy, starting with a neuropathic ulceration. Vascular insufficiency and diminished neutrophil function augment the DPN resulting in infection. Most DFIs are associated with aerobic gram-positive cocci especially staphylococci and aerobic gram negative bacilli as common copathogens.37 The most common organisms colonizing the infected area are Staphylococcus aureus and beta-hemolyzing streptococci. Apart from the above stated, Escherichia coli, Klebsiella and Methicillin Resistant Staphylococcus aureus (MRSA) are common inhabitant.33 3.6. Hepatic dysfunction Type 2 diabetes has begun to be recognized as an important factor for the development of non-alcohol fatty liver disease (NAFLD) and chronic liver diseases. Nonalcoholic steatohepatitis (NASH), the most severe form of NAFLD, is a chronic necro-inflammatory condition resulting in fibrosis, cirrhosis and finally to hepatocellular carcinoma (HCC). In a large cohort study it was found that T2DM doubled the risk of NAFLD and HCC.34 Insulin resistance increases peripheral lipolysis leading to accumulation of free fatty acids in liver resulting in NAFLD.34 In another human cohort study conducted between 1994 and 2006, it was concluded that subjects with diabetes had higher risk of developing serious hepatic disorder compared to control subjects. Diabetes was found to pose a greater risk than hypertension, dyslipidemia and obesity.35,38 A vast medline literature study has revealed an elevation of liver enzyme alanine aminotransferase (ALT) very commonly in T2DM patients while uncommon in normal subjects. The survey shows a high incidence of development of liver diseases in patients with type 2 diabetes.36 3.7. Other complications 3.7.1. Post-surgical infection Type 2 diabetes mellitus is also considered a major risk factor for surgical site infections (SSI). In a review case study of 195 selected patients who underwent spinal arthrodesis, 30 were Please cite this article in press as: Kumar A, et al., Diabetes mellitus type 2: One monster eating all, Apollo Medicine (2014), http://dx.doi.org/10.1016/j.apme.2014.01.009
  6. 6. a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1 e6 diabetic and the rest non-diabetic. The review of the case record found that 30% of diabetic subjects developed SSI while it was only 11% for non-diabetic subjects with the similar arthrodesis, thus providing evidence that T2DM elevates the risk of SSI with spinal surgeries.39 A recent published study also supports the finding that uncontrolled blood glucose before surgery increased the risk of SSI.40 3.7.2. Genito-urinary infections Diabetes mellitus type 2 has been a well-known risk factor for vulvovaginitis in females and balanitis in males, the most common urinary tract infections (UTI) reported. Hyperglycemia and glycosuria, the two most common symptoms of T2D represent the favorable factors for the growth of Candida albicans at vaginal epithelium, since hyperglycemia may interfere with normal host-defence mechanism and also helps the growth of the pathogenic candida.41,42 In one of the study conducted in UK using the General Practice Research Database (GPRD), it was concluded that T2D increases the risk of UTI by 60% as compared to the non-diabetic subjects. It was also concluded from one of the database survey that T2D increased the risk of vulvovaginitis by 2 folds and balanitis by 3 folds.43,44 Type 2 diabetes mellitus also predisposes females with a rare fungal infection of mucormycosis in pouch of douglas, as reported recently for a patient in Kolkata, India.45 3.7.3. Tuberculosis In a recent large population based cohort study, it was found that type 2 diabetes significantly increased risk of development of tuberculosis (TB). Diabetes also increased the risk of relapse of the disease after successful completion of treatments for TB and also high bacillary load in sputum. The study was significant for the young diabetics.46 Diabetes patients are shown to have lower circulating neutrophils and activated macrophages and there was a negative correlation found between the increased HbA1c and phagocytic activity and that the controlled glucose level improved the phagocytic activity.47 In another meta-analysis based review covering research articles based on association of T2DM and TB, it was observed that diabetes led to a 3-fold increase in the risk of developing active TB.48 This study too emphasized on the higher risk in young subjects. The study also pointed to the observations that diabetic mice infected with Mycobacterium Tuberculosis had higher bacterial load than the control populations. The diabetic mice had low levels of IFN-g and IL-12 and Th1 responsiveness towards TB which play a crucial role in controlling TB. In humans too, hyperinsulinemia resulted in a decrease in Th1 cell and reduction in essential protective cytokines too. It also pointed that level of HbA1c and IFN-g had a negative correlation.48 4. Summary Diabetes is one of the very few diseases adversely affecting almost all the organs. This review has focused on various complications arising from type 2 diabetes primarily emphasizing on cardiovascular diseases, neuropathy, retinopathy, pulmonary defects. Diabetes can be said to be a syndrome which exhibits various different organ-related dysfunctions. 5 Organ dysfunction significantly affects the quality of life and has been the major cause of diabetic morbidity. Diabetic subjects are also susceptible to various serious and different infections which respond poorly to the available antibiotic treatments. Post-surgical infections have been a major feature of uncontrolled blood glucose prior to surgical procedure. The number of diabetes patients projected by WHO and CDC should be considered a serious event. Lifestyle modifications can result in a significant reduction in the incidence of diabetes. Conflicts of interest All authors have none to declare. Acknowledgments Authors are thankful to Department of Biotechnology, National Institute of Technology (NIT), Raipur (CG), India and Department of Biochemistry, Patna University, Patna, Bihar, India for providing facility, space and resources for this work. references 1. WHO. Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia. Report of a WHO/IDF Consultation. 2006:1e46. 2. www.who.int/diabetes/action_online/basics/en/index1.html. 3. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2011 Jan;34(1):S62eS69. 4. CDC. Diabetes report card. Division of Diabetes Translation. 2012:1e14. 5. Taylor SI. Deconstructing type 2 diabetes. Cell. 1999;97:9e12. 6. Kaku K. Pathophysiology of type 2 diabetes and its treatment policy. J Jpn Med Assoc. 2010;53(1):41e46. 7. American Diabetes Association. Standards of medical care in diabetes e 2013. Diabetes Care. 2013;36(1):S11eS66. 8. Murea M, Ma L, Freedman BI. Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications. Rev Diabet Stud. 2012;9(1):6e22. 9. Goldin A, Beckman JA, Schmidt AM. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114:597e605. 10. Zieman SJ, Kass DA. Advanced glycation end product crosslinking: pathophysiologic role and therapeutic target in cardiovascular disease. Congest Heart Fail. 2004;10:144e151. 11. Barlovic DP, Paavonen AS, Jandeleit-Dahm KAM. RAGE biology, atherosclerosis and diabetes. Clin Sci. 2011;121:43e55. 12. Selvin E, Halushka MK, Rawlings AM, et al. sRAGE and risk of diabetes, cardiovascular disease, and death. Diabetes. 2013;62:2116e2121. 13. Mohan V, Sandeep S, Deepa M, et al. A diabetes risk score helps identify metabolic syndrome and cardiovascular risk in Indians e the Chennai Urban Rural Epidemiology Study (CURES-38). Diabetes Obes Metab. 2007;9(3):337e343. 14. Sandeep S, Gokulakrishnan K, Deepa M, et al. Insulin resistance is associated with increased cardiovascular risk in Asian Indians with normal glucose tolerance e the Chennai Urban Rural Epidemiology Study (CURES-66). J Assoc Physicians India. 2011;59:480e484. Please cite this article in press as: Kumar A, et al., Diabetes mellitus type 2: One monster eating all, Apollo Medicine (2014), http://dx.doi.org/10.1016/j.apme.2014.01.009
  7. 7. 6 a p o l l o m e d i c i n e x x x ( 2 0 1 4 ) 1 e6 15. Ramachandran A, Murugesan N, Snehalatha C, et al. Insulin resistance and clustering of cardiometabolic risk factors in urban teenagers in southern India. Diabetes Care. 2007;30:1828e1833. 16. Pappachan JM, Varughese GI, Sriraman R, et al. Diabetic cardiomyopathy: pathophysiology, diagnostic evaluation and management. World J Diabetes. 2013;4(5):177e189. 17. Ly A, Scheerer MF, Zukunft S, et al. Retinal proteome alterations in a mouse model of type 2 diabetes. Diabetologia. 2013. 18. Lupo G, Motta C, Giurdanella G, et al. Role of phospholipases A2 in diabetic retinopathy: in vitro and in vivo studies. Biochem Pharmacol. 2013;13:00580e00587. 19. Ramachandran A, Snehalatha C, Vijay V, et al. Diabetic retinopathy at the time of diagnosis of NIDDM in south Indian subjects. Diabetes Res Clin Pract. 1996;32:111e114. 20. Rema M, Pradeepa R. Diabetic retinopathy: an Indian perspective. Indian J Med Res. 2007;125(3):297e310. 21. Idiculla J, Nithyanandam S, Joseph M. Serum lipids and diabetic retinopathy: a cross-sectional study. Indian J Endocrinol Metab. 2012;16(2):S492eS494. 22. Kramer HJ, Nguyen QD, Curhan G, et al. Renal insufficiency in absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA. 2003;289:3273e3277. 23. Kondaveeti SB, Kumaraswamy D, Mishra S, et al. Evaluation of glycated albumin and microalbuminuria as early risk markers of nephropathy in type 2 diabetes mellitus. J Clin Diagn Res. 2013;7(7):1280e1283. 24. Assal HS, Tawfeek S, Rasheed EA, et al. Serum cystatin C and tubular urinary enzymes as biomarkers of renal dysfunction in type 2 diabetes mellitus. Clin Med Insights Endocrinol Diabetes. 2013;6:7e13. 25. Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol. 2003;14:1358e1373. 26. Pitocco D, Fuso L, Conte EG, et al. The diabetic lung e a new target organ? Rev Diabet Stud. 2012;9(1):23e35. 27. Dharwadkar AR, Dharwadkar AA, Banu G, et al. Reduction in lung functions in type-2 diabetes in Indian population: correlation with glycemic status. Indian J Physiol Pharmacol. 2011;55(2):170e175. 28. Aparna. Pulmonary function tests in type 2 diabetics and non-diabetic people e a comparative study. J Clin Diagn Res. 2013;7(8):1606e1608. 29. Shah SH, Sonawane P, Nahar P, et al. Pulmonary function tests in type 2 diabetes mellitus and their association with glycemic control and duration of the disease. Lung India. 2013;30(2):108e112. 30. Farmer KL, Li C, Dobrowsky RT. Diabetic peripheral neuropathy: should a chaperone accompany our therapeutic approach? Pharmacol Rev. 2012;64(4):880e900. 31. Vinik AI, Casellini CM. Guidelines in the management of diabetic nerve pain: clinical utility of pregabalin. Diabetes Metab Syndr Obes. 2013;6:57e78. 32. Hussain G, Rizvi SA, Singhal S, et al. 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Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infec Dis. 2012;54(12):132e173. Porepa L, Ray JG, Romeu PS, et al. Newly diagnosed diabetes mellitus as a risk factor for serious liver disease. Can Med Ass J. 2010;182(11):E526eE531. Chen S, Anderson MV, Cheng WK. Diabetes associated with increased surgical site infections in spinal arthrodesis. Clin Orthop Relat Res. 2009;467:1670e1673. Hikata T, Iwanami A, Hosogane N, et al. High preoperative hemoglobin A1c is a risk factor for surgical site infection after posterior thoracic and lumbar spinal instrumentation surgery. J Orthop Sci. 2013 [Epub ahead of print]. Johnsson KM, Ptaszynska A, Schmitz B, et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27(5):479e484. Johnsson KM, Ptaszynska A, Schmitz B, et al. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complications. 2013;27(5):473e478. Hirji I, Guo Z, Andersson SW, et al. Incidence of urinary tract infection among patients with type 2 diabetes in the UK General Practice Research Database (GPRD). J Diabetes Complications. 2012;26:513e516. Hirji I, Andersson SW, Guo Z, et al. Incidence of genital infection among patients with type 2 diabetes in the UK General Practice Research Database. J Diabetes Complications. 2012;26:501e505. Mondal PK, Mondal SK, Mondal TK, et al. Mucormycosis of pouch of douglas in a diabetic woman. J Glob Infect Dis. 2012;4(3):172e174. Kuo MC, Lin SH, Lin CH, Mao IC, Chang SJ, Hsieh. Type 2 diabetes: an independent risk factor for tuberculosis: a nationwide population based study. PLoS ONE. 2013;8(11):e78924. Jepsen DF. The double burden. Dan Med J. 2013;60(7):B4673. Jeon CY, Murray MB. Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies. PLoS Med. 2008;5(7):e152. Please cite this article in press as: Kumar A, et al., Diabetes mellitus type 2: One monster eating all, Apollo Medicine (2014), http://dx.doi.org/10.1016/j.apme.2014.01.009
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