BLDE University Journal of Health Sciences

: 2020  |  Volume : 5  |  Issue : 1  |  Page : 8--14

Mechanism of diabetic nephropathy and traditional drugs for management

Shabnam Ansari 
 Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi, India

Correspondence Address:
Dr. Shabnam Ansari
Department of Biotechnology, Faculty of Natural Sciences, Jamia Millia Islamia, New Delhi


Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus which affects the kidneys. Recent reports of increasing prevalence of diabetes around the globe suggested that that the prevalence of DN will be doubled by 2025. There is an extremely high risk of progression of DN to end-stage renal disease and cardiovascular morbidity and mortality. Control of sugar levels, blood pressure control via renin–angiotensin–aldosterone system inhibition, and regular monitoring of renal functions have remained the principle of the management for DN for a long time. As conventional drugs cannot fulfill all the clinical needs due to accessibility, clinical efficacy, and safety issues, the need for novel inexpensive traditional drugs from Unani medicine to improve DN treatment and reduce the risk of complications has become urgent. Several herbal and mineral drugs have been mentioned in the old Unani books for the treatment of similar conditions stipulating DN. Through this article, an uttermost effort has been put to rememorize the mechanism of development of DN and available Unani drugs so that effect and mechanism of these drugs could be evidenced in the treatment of DN in future.

How to cite this article:
Ansari S. Mechanism of diabetic nephropathy and traditional drugs for management.BLDE Univ J Health Sci 2020;5:8-14

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Ansari S. Mechanism of diabetic nephropathy and traditional drugs for management. BLDE Univ J Health Sci [serial online] 2020 [cited 2021 Jun 16 ];5:8-14
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Diabetes mellitus (DM) is one of the most serious diseases affecting millions across the world. DM and its comorbidities have remained the fourth-largest cause of morbidity and mortality in the developed world.[1] Approximately 382 million people are affected worldwide. Reports have suggested that the prevalence may increase to 592 million by 2035.[2] India is considered as the diabetic capital of the world because of its ever-increasing population with diabetes, with an estimated number of 65.1 million adult diabetics.[3] In India, approximately 52% of adults are not aware of their diabetic status. Epidemiologic surveys have reported that the prevalence of diabetes is comparatively higher in urban than in rural areas.[4] DM is a large group of disorders characterized by hyperglycemia and disturbed metabolism of carbohydrates, proteins, and lipids.[5] Although pancreatic β-cells and hormone insulin are central in the etiology of DM, the pathogenic mechanisms by which high blood glucose levels arise differ widely. DM is mainly classified into three main types, namely Type 1, Type 2, and gestational diabetes, all of which are caused by a complex interaction of environmental factors, genetics, and lifestyle habits. Type 1 diabetes is characterized by insulin deficiency or a genetic abnormality that leads to defective insulin release, while as Type 2 and gestational diabetes depict insulin resistance as their underlying etiology. All categories of DM are characterized by the development of diabetes-specific microvascular complications in the eyes, kidneys, and peripheral nervous system and macrovascular complications in arteries that supply the heart, brain, and lower extremities. As a result of microvascular complications, diabetes is the leading cause of chronic kidney disease (CKD), blindness, and a variety of debilitating nerve pathologies. Diabetic patients are also at a much higher risk of stroke, myocardial infarction, and lower limb amputation. Although diabetic complications comprise a heterogeneous group of diseases, diabetic nephropathy (DN) is the most prevalent form.[6]

The present paper is primarily focused on DN. DN is one of the most serious microvascular complications of DM and a leading cause of end-stage renal disease (ESRD) across the world.[7] It is a chronic disease that mainly targets glomerular and tubular cells resulting in the loss of renal function and integrity. About 20%–30% of Type 1 and 30%–40% of Type 2 diabetic patients develop nephropathy.[8],[9] Clinically, DN is manifested by a progressive reduction of glomerular filtration rate, persistent proteinuria, and renal dysfunction. The most striking characteristics of DN include specific renal structural and functional aberrations, glomerular hyperfiltration and hypertrophy, glomerular basement membrane thickening (BMT), mesangial expansion, and accumulation of extracellular matrix (ECM) proteins.

 Mechanism of Nephropathy in Diabetes Mellitus

The DN has multifactorial etiologies. hypertension, hyperglycemia, dyslipidemia, genetic factor, obesity, inflammation, and oxidative stress, and other metabolic disorders have been reported to contribute to the initiation and progression of DN.[10] Upstream to all factors, hyperglycemia is the major driving force for the development of DN. Downstream of the all factors, chronic renal microinflammation and subsequent ECM accumulation, is the important pathway for the progression of DN. Persistent hyperglycemia-induced advanced glycation end product (AGE) formation contributes significantly to the development of DN. AGEs modify the structure and function of intracellular as well as extracellular proteins, which stimulate the production of reactive oxygen species (ROS). ROS favors an increase in the expression and accumulation of ECM proteins in glomerular and mesangial cells.[11],[12] Similarly, increased production of sorbitol through the polyol pathway also plays a significant role in the development of DN. Sorbitol has been liked to trigger osmotic stress, activation of protein kinase C (PKC), production of AGEs, and formation of ROS in diabetic kidneys.[13] In addition, hemodynamic pathways involving the renin–angiotensin system (RAS) and nitric oxide (NO) system activates the proliferation of renal cells and the expression of cytokines or growth factors, which directly or indirectly contribute to the renal damage in diabetes patients.[14] Activation of PKC pathway is another important factor in the etiology of DN. Both metabolic and hemodynamic factors activate PKC and act as a stimulus for the expression of several cytokines and growth factors.[15] The direct action on renal cells or indirectly by stimulating other factors, cytokines and growth factors produce renal damage and thereby affect renal function.[16],[17]

Inflammatory pathways have also been suggested to play a critical part in the pathogenesis of DN beside metabolic and hemodynamic factors.[16],[18] The most convenient evidence concerning the involvement of inflammation in DN comes from the fact that patients with DM and overt nephropathy exhibit the increased levels of acute-phase markers of inflammation, including interleukin-1 beta (IL-1 β), IL-6, tumor necrosis factor-alpha (TNF-α), and fibrinogen.[19] The key mediators of inflammation pathways in DN include transcription factors, pro-inflammatory cytokines, adhesion molecules, chemokines, toll-like receptors, NO, and profibrotic proteins.

Nuclear factor-kappa B (NF-κB), an important transcription factor, regulates the expression of various genes involved in inflammation and ECM turnover such as growth factors, inflammatory cytokines, chemokines, and cell adhesion molecules (CAMs).[20] NF-κB is expressed by almost all cells of the body, including adipocytes, skeletal muscles, macrophages, leukocytes, and intrinsic renal cells. Normally, the majority of NF-κB is present as a heterodimer of p65 (RELA)/p50 proteins and is inhibited by inhibitory κB (IκB) proteins, which inactivate NF-κB by trapping it in the cytoplasm. Phosphorylation and proteasomal degradation of IκB leads to the activation of the NF-κB complex, which then translocates into the nucleus and induces the expression of downstream effector genes. NF-κB is activated by various cell stress-associated stimuli including hyperglycemia, oxidative stress, cytokines, and obesity.[21] NF-κB has been implicated in the development of insulin resistance,[22],[23] and DN.[24] In diabetic kidney, NF-κB activation leads to the increased expression of pro-inflammatory cytokines such as IL-1 β, IL-6, and TNF-α; growth factors such as vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and cytoplasmic transmembrane growth factor (CTGF); chemokines such as chemokine ligand 2; and CAMs such as intercellular CAM 1.[24],[25],[26],[27],[28] Pro-inflammatory cytokines, chemokines, and CAMs cause the infiltration and accumulation of macrophages, monocytes, and leukocytes into the renal tissue and thus initiate an inflammatory cascade, which, in turn, lead to structural and hemodynamic abnormalities in renal tissue.[19],[29],[30],[31] TNF-α has been implicated in the promotion of local oxidative stress,[32] increasing protein permeability,[33] and the induction of renal cell loss.[34] On the other hand, growth factors, such as TGF-β, VEGF and CTGF, stimulate the expression and accumulation of ECM proteins including laminin, fibronectin, and collagen-IV in mesangial cells, thus causing structural abnormalities in nephrons.[35],[36] Suppression of NF-κB activation by various agents, such as 1,25-dihydroxyvitamin D3,[37] thiazolidinediones,[38] curcumin,[39] and cilostazol,[40] has shown promising protective effects against DN in both human subjects and animal models, suggesting the importance of NF-κB as a potential therapeutic target of DN.

ROS such as hydroxyl radical, hypochlorous acid, and superoxide radical also significantly contribute to renal injury in DM. In the diabetic kidney, ROS generation is stimulated by a number of factors including high glucose level, AGEs, growth factors, and cytokines.[41],[42] The effects of ROS in renal cells include damage of cellular macromolecules, mesangial cell proliferation, expression of growth factors, ECM accumulation, and induction of epithelial–mesenchymal transition.[41],[42],[43]

 Available Drugs in Modern Medicine

Most of the conventional drugs employed for DN are directed against hyperglycemia and hypertension. However, these drugs have shown only limited success against DN. Antihyperglycemic drugs such as sulfonylureas (e.g., glibenclamide), biguanides (e.g., metformin), thiazolidinediones (e.g., rosiglitazone), and alpha-glucosidase inhibitors (e.g., acarbose) have been commonly utilized. These drugs act selectively to modulate a specific pathological pathway [44],[45] and control blood glucose at normal levels. Even though these drugs may be valuable in the management of DM, they have certain limitations due to undesirable side effects associated with them such as hypoglycemia, secondary failure, weight gain, liver toxicity, skin allergy, and inability to arrest pancreas degeneration.[46],[47],[48] Moreover, these therapies only partially compensate for secondary target organ derangement seen in diabetics.[49] These antihyperglycemic drugs have lost their role as a stand-alone treatment for DN because of their limited clinical efficacy, prevention of course and associated comorbidities of the disease, and the associated adverse effects. Antihypertensive drugs have been employed in the treatment of DN to reduce proteinuria and renal damage. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockade (ARB) delayed the increase in albuminuria. In type 2 diabetes, ACE inhibitors and ARBs have shown to reduce the risk of DN.[50],[51],[52] However, again, these are often associated with substantial toxicity. In addition, anti-inflammatory agents such as NF-κB inhibitors, TNF-α blocking agents, IL-1 receptor antagonists, monoclonal antibodies against TGF-β, and IL-6 blockers have also shown their potentials in protecting kidneys from damage through inflammatory mediators in variousin vivo studies of DM as well as in clinical trials.[37],[38],[39],[40],[53],[54] Although they are much effective in attenuating renal dysfunction in diabetic patients, many populations are not able to use such agents because of their higher costs.[55] Moreover, since DN is a disorder of multiple etiologies involving numerous pathways, consumption of a drug which acts on only one molecular target is not sufficient to treat DN. Besides, the drugs with multiple pharmacological effects would be ideal to use for treatment. Hence, it is highly desirable to find therapeutic agents that could prevent the initiation as well as the progression of DN through multifactorial pathways and do not produce side effects unlike modern drugs. All these issues have led the experts to search for safe, effective, and economic alternative treatment strategies that are preventive, quite effective, and less toxic.

 Treatment With Traditional Drugs

Plants are the basic source of drugs for traditional and alternative medicine systems that have been in existence for thousands of years. Till now, herbal and traditional systems continue to play an essential role in providing health care at all levels. Old data of the World Health Organization (WHO) project that approximately 80% of the world's population from developing countries count solely on traditional medicines (mostly derived from plants) for their primary health care.[56],[57] Plant products also play an important role in health care for the remaining 20% in developing countries and for those in industrialized countries as well.[58] Medicinal plants and the compounds obtained from them are being looked up for the treatment of DM and its secondary complications. Many conventional drugs have been derived from medicinal plants, such as metformin and curcumin. The committee for the WHO on diabetes has recommended that traditional medicine must be further investigated for their antihyperglycemic effect.[59] Therefore, contrary to the modern synthetic drugs, herbal or traditional medicine has emerged as a promising alternative to the lowest degree of toxicities and negligible side effects. India has an extensive flora and fauna area enriched with a large number of medicinal and aromatic plants. Hence, there is a huge potential for investigating such traditionally important medicinal plants to elucidate their potential therapeutic applications. Unani medicine is also one of the oldest traditional and herbal systems of medicines, which treats various diseases and ailments with drugs of mostly 90% herbal and rest with mineral and animal origin. The practice, research, and education of Unani medicine are governed through the Ministry of AYUSH, government of India. The present study is a step in this direction to outline those traditional herbal and Unani drugs which could be utilized in the treatment of DN [Table 1].{Table 1}


DM is a noncommunicable disease of global healthcare burden with approximately 400 million people affected worldwide and expected to be around 600 million by the year 2035. It is the fourth leading cause of mortality throughout the world. The diabetes-induced disease burden is increasing in every country due to the prevalence of obesity, emotional stress, unhealthy lifestyles, lack of screening strategies and their proper implementation, reluctant population, and awareness.

DN remains one of the most common etiologies for the development of CKD and end-stage renal failure worldwide. Experimental studies have explored the pathophysiology of DN which led to the availability of range of potential novel therapies. DN not necessarily develops in all the diabetics. However, the main modifiable risks are hypertension, glycaemic control, and dyslipidaemia. DN is a multistage condition that makes several years to develop ESRD. Incipient nephropathy is the veryfirst presence of low but microamounts of urine albumin, referred to as microalbuminuria (persistent albuminuria at level 30–299 mg/24 h). Overt nephropathy or macroalbuminuria (persistent albuminuria at level ≥300 mg/24 h) develops after many years in type 1 diabetes but may be present at the time of diagnosis of type 2 diabetes. Macroalbuminuria patients are more likely to develop ESRD. Various guidelines have suggested screening with a spot urine albumin/creatinine ratio (normal >30 mg/g creatinine) from eitherfirst morning (preferred) or random specimens along with an assessment of kidney function test. Novel strategies to slow down the progression of different types of pathway to renal damage have emerged. However, arresting the progression of DN remains a major challenge. Glycemic management, blood pressure control, and the RAS inhibitors are used primarily for the treatment for DN and have been evidenced in reducing the risk and progression of the disease. However, novel potential therapies are the requisite for the patients who are intolerant to conventional therapies and those patients with deteriorating renal function with normoalbuminuria.

India is the fourth country with the highest number of people suffering from DM. Due to restricted resources and deficient systematic treatment strategies in rural areas of India, traditional drugs from Indian system of medicine (AYUSH) can be investigated as novel potential therapeutic agents to prevent the risks and progression of DN. Various herbal and mineral origin drugs have been cited in the literature of Unani medicine to be beneficial in the treatment of DN. Unani drugs such as giloy, ginger, horse gram, Indian horse-chestnut, Indian olibanum, Indian rhubarb, isabgol/psyllium husk, Levant cotton, maidenhair fern, muskmelon, opium, pistachio, pomegranate, quince, rose, turmeric, watermelon, Arabic gum, asafoetida, black asphalt, black henbane, black piper, and celery are mentioned in Unani classics for the treatment of albuminuria. Thus, these drugs plausibly could be a better candidate to study for their efficacy and ascertaining them under the canvas of mechanism of development of DN.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.



1Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: Estimates and projections to the year 2010. Diabet Med 1997;14 Suppl 5:S1-85.
2International Diabetes Federation. IDF Diabetes Atlas. 6th ed. Brussels, Belgium: International Diabetes Federation; 2013.
3The World Factbook, Central Intelligence Agency; 2013. Available from: [Last accessed on 2013 Jul 26].
4Bajaj S. RSSDI clinical practice recommendations for the management of type 2 diabetes mellitus 2017. Int J Diabetes Dev Ctries 2018;38:1-15.
5Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539-53.
6Ritz E, Zeng XX, Rychlík I. Clinical manifestation and natural history of diabetic nephropathy. Contrib Nephrol 2011;170:19-27.
7Reutens AT, Atkins RC. Epidemiology of diabetic nephropathy. Contrib Nephrol 2011;170:1-7.
8Yokoyama H, Okudaira M, Otani T, Sato A, Miura J, Takaike H, et al. Higher incidence of diabetic nephropathy in type 2 than in type 1 diabetes in early-onset diabetes in Japan. Kidney Int 2000;58:302-11.
9Devi DP, George J. Diabetic nephropathy: Prescription trends in tertiary care. Indian J Pharm Sci 2008;70:374-8.
10Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001;414:813-20.
11Soulis-Liparota T, Cooper ME, Dunlop M, Jerums G. The relative roles of advanced glycation, oxidation and aldose reductase inhibition in the development of experimental diabetic nephropathy in the Sprague-Dawley rat. Diabetologia 1995;38:387-94.
12Yamagishi S, Matsui T. Advanced glycation end products, oxidative stress and diabetic nephropathy. Oxid Med Cell Longev 2010;3:101-8.
13Lee AY, Chung SS. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J 1999;13:23-30.
14Ziyadeh FN, Wolf G. Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev 2008;4:39-45.
15Hempel A, Maasch C, Heintze U, Lindschau C, Dietz R, Luft FC, et al. High glucose concentrations increase endothelial cell permeability via activation of protein kinase C alpha. Circ Res 1997;81:363-71.
16Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, García-Pérez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol 2011;7:327-40.
17Border WA, Noble NA. Cytokines in kidney disease: The role of transforming growth factor-beta. Am J Kidney Dis 1993;22:105-13.
18Luis-Rodríguez D, Martínez-Castelao A, Górriz JL, De-Álvaro F, Navarro-González JF. Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy. World J Diabetes 2012;3:7-18.
19Dalla Vestra M, Mussap M, Gallina P, Bruseghin M, Cernigoi AM, Saller A, et al. Acute-phase markers of inflammation and glomerular structure in patients with type 2 diabetes. J Am Soc Nephrol 2005;16 Suppl 1:S78-82.
20Karin M, Greten FR. NF-kappaB: Linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 2005;5:749-59.
21Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci (Lond) 2013;124:139-52.
22Hommelberg PP, Plat J, Langen RC, Schols AM, Mensink RP. Fatty acid-induced NF-kappaB activation and insulin resistance in skeletal muscle are chain length dependent. Am J Physiol Endocrinol Metab 2009;296:E114-20.
23Shah PK. Innate immune pathway links obesity to insulin resistance. Circ Res 2007;100:1531-3.
24Mezzano S, Aros C, Droguett A, Burgos ME, Ardiles L, Flores C, et al. NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy. Nephrol Dial Transplant 2004;19:2505-12.
25Fitzgerald DC, Meade KG, McEvoy AN, Lillis L, Murphy EP, MacHugh DE, et al. Tumour necrosis factor-alpha (TNF-alpha) increases nuclear factor kappaB (NFkappaB) activity in and interleukin-8 (IL-8) release from bovine mammary epithelial cells. Vet Immunol Immunopathol 2007;116:59-68.
26Nam JS, Cho MH, Lee GT, Park JS, Ahn CW, Cha BS, et al. The activation of NF-kappaB and AP-1 in peripheral blood mononuclear cells isolated from patients with diabetic nephropathy. Diabetes Res Clin Pract 2008;81:25-32.
27Hasegawa G, Nakano K, Kondo M. Role of TNF and IL-1 in the development of diabetic nephropathy. Nefrologia 1995;5:1-4.
28Yang B, Hodgkinson A, Oates PJ, Millward BA, Demaine AG. High glucose induction of DNA-binding activity of the transcription factor NF?B in patients with diabetic nephropathy. Biochim Biophys Acta Mol Basis Dis 2008;1782:295-302.
29Baud L, Ardaillou R. Tumor necrosis factor in renal injury. Miner Electrolyte Metab 1995;21:336-41.
30Shelbaya S, Amer H, Seddik S, Allah AA, Sabry IM, Mohamed T, et al. Study of the role of interleukin-6 and highly sensitive C-reactive protein in diabetic nephropathy in type 1 diabetic patients. Eur Rev Med Pharmacol Sci 2012;16:176-82.
31Pfeilschifter J, Pignat W, Vosbeck K, Märki F. Interleukin 1 and tumor necrosis factor synergistically stimulate prostaglandin synthesis and phospholipase A2 release from rat renal mesangial cells. Biochem Biophys Res Commun 1989;159:385-94.
32Koike N, Takamura T, Kaneko S. Induction of reactive oxygen species from isolated rat glomeruli by protein kinase C activation and TNF-alpha stimulation, and effects of a phosphodiesterase inhibitor. Life Sci 2007;80:1721-8.
33McCarthy ET, Sharma R, Sharma M, Li JZ, Ge XL, Dileepan KN, et al. TNF-alpha increases albumin permeability of isolated rat glomeruli through the generation of superoxide. J Am Soc Nephrol 1998;9:433-8.
34Boyle JJ, Weissberg PL, Bennett MR. Tumor necrosis factor-alpha promotes macrophage-induced vascular smooth muscle cell apoptosis by direct and autocrine mechanisms. Arterioscler Thromb Vasc Biol 2003;23:1553-8.
35Yamagishi N, Nakayama K, Wakatsuki T, Hatayama T. Characteristic changes of stress protein expression in streptozotocin-induced diabetic rats. Life Sci 2001;69:2603-9.
36Park IS, Kiyomoto H, Abboud SL, Abboud HE. Expression of transforming growth factor-beta and type IV collagen in early streptozotocin-induced diabetes. Diabetes 1997;46:473-80.
37Zhang Z, Yuan W, Sun L, Szeto FL, Wong KE, Li X, et al. 1,25-Dihydroxyvitamin D3 targeting of NF-kappaB suppresses high glucose-induced MCP-1 expression in mesangial cells. Kidney Int 2007;72:193-201.
38Ohga S, Shikata K, Yozai K, Okada S, Ogawa D, Usui H, et al. Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-kappaB activation. Am J Physiol Renal Physiol 2007;292:F1141-50.
39Soetikno V, Sari FR, Veeraveedu PT, Thandavarayan RA, Harima M, Sukumaran V, et al. Curcumin ameliorates macrophage infiltration by inhibiting NF-κB activation and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy. Nutr Metab (Lond) 2011;8:35.
40Lee WC, Chen HC, Wang CY, Lin PY, Ou TT, Chen CC, et al. Cilostazol ameliorates nephropathy in type 1 diabetic rats involving improvement in oxidative stress and regulation of TGF-Beta and NF-kappaB. Biosci Biotechnol Biochem 2010;74:1355-61.
41Noh H, Ha H. Reactive oxygen species and oxidative stress. Contrib Nephrol 2011;170:102-12.
42Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 2008;57:1446-54.
43Elmarakby AA, Sullivan JC. Relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy. Cardiovasc Ther 2012;30:49-59.
44Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology. 5th ed. London: Churchill Livingstone; 2003.
45Krentz AJ, Ferner RE, Bailey CJ. Comparative tolerability profiles of oral antidiabetic agents. Drug Saf 1994;11:223-41.
46Chen ZC, Zhang SL, Yan L, Wu MC, Chen LH, Ji LN. Association between side effects of oral anti-diabetic drugs and self-reported mental health and quality of life among patients with type 2 diabetes. Zhonghua Yi Xue Za Zhi 2011;91:229-33.
47Asplund K, Wiholm BE, Lithner F. Glibenclamide-associated hypoglycaemia: A report on 57 cases. Diabetologia 1983;24:412-7.
48Harrower AD. Comparison of efficacy, secondary failure rate, and complications of sulfonylureas. J Diabetes Complications 1994;8:201-3.
49Taylor R, Agius L. The biochemistry of diabetes. Biochem J 1988;250:625-40.
50Lindholm LH, Ibsen H, Dahlöf B, Devereux RB, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet 2002;359:1004-10.
51Kvetny J, Gregersen G, Pedersen RS. Randomized placebo-controlled trial of perindopril in normotensive, normoalbuminuric patients with type 1 diabetes mellitus. QJM 2001;94:89-94.
52Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1998;128:982-8.
53Gupta-Ganguli M, Cox K, Means B, Gerling I, Solomon SS. Does therapy with anti-TNF-alpha improve glucose tolerance and control in patients with type 2 diabetes? Diabetes Care 2011;34:e121.
54Ziyadeh FN, Hoffman BB, Han DC, Iglesias-De La Cruz MC, Hong SW, Isono M, et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A 2000;97:8015-20.
55Valesini G, Iannuccelli C, Marocchi E, Pascoli L, Scalzi V, Di Franco M. Biological and clinical effects of anti-TNFalpha treatment. Autoimmun Rev 2007;7:35-41.
56Payyappallimana U. Role of Traditional Medicine in Primary Health Care: An Overview of Perspectives and Challenges. Yokohama J Soc Sci 2010;14:723-45.
57Baharvand-Ahmadi B, Bahmani M, Tajeddini P, Naghdi N, Rafieian-Kopaei M. An ethno-medicinal study of medicinal plants used for the treatment of diabetes. J Nephropathol 2016;5:44-50.
58Chivian E, Medicines from natural sources, Biodiversity: Its Importance to Human Health, Interim Executive Summary, Center for Health and the Global Environment. Boston: Harvard Medical School; 2002. p. 20.
59World Health Organization, Expert Committee Diabetes Mellitus, Technical Report Second Series. Geneva: World Health Organization; 1980.
60Aksarai J. Commentry to brief the Canon. Vol. 2. Lucknow: Matba Munshi Nawal Kishore; 1918. p. 590-92.
61Samarqandi N. book of causes and manifestations. In: Kbiruddin H, editor. Commentry of the book. New Delhi: Aijaz Publishing House; 2007. p. 17-20, 29-36.
62Jurjani AH. Zakhira khwarjim shahi. In: Khan HH, Translated. Part 6, Vol 2. Lucknow: Munshi Nawal Kishore Press; 1903. p. 502-5, 540-41.
63Khan A. Ikseere Azam. In: Kbiruddin H, translated. New Delhi: Aijaz Publishing House; 2010. p. 685-91, 705-9.
64Chou ST, Peng HY, Hsu JC, Lin CC, Shih Y. Achillea millefolium L. essential oil inhibits LPS-induced oxidative stress and nitric oxide production in RAW 264.7 Macrophages. Int J Mol Sci 2013;14:12978-93.
65Zolghadri Y, Fazeli M, Kooshki M, Shomali T, Karimaghayee N, Dehghani M. Achillea millefolium L. Hydro- Alcoholic Extract Protects Pancreatic Cells by Down Regulating IL- 1β and iNOS Gene Expression in Diabetic Rats. Int J Mol Cell Med 2014;3:255-62.
66Conforti F, Loizzo MR, Statti GA, Menichini F. Comparative radical scavenging and antidiabetic activities of methanolic extract and fractions from Achillea ligustica ALL. Biol Pharm Bull 2005;28:1791-4.
67Sangita S, Manju M, Anil S, Vikram T. Hypoglycaemic and hypocholesterolimic efficacy of horse chestnut (Aesculus indica) using Rat Models. J Clin Nutr Diet 2016;1:1-6.
68Suter A, Bommer S, Rechner J. Treatment of patients with venous insufficiency with fresh plant horse chestnut seed extract: A review of 5 clinical studies. Adv Ther 2006;23:179-90.
69Mumtaj M, Khan MA, Altamash B, Aijaz H. Nutritional value and oil content of Indian horse chestnut seed. Glob J Sci Front Res 2010;10:17-9.
70Dilipkumar P, Harpreet S, Manoj K. A preliminary study on the in vitro antioxidant activity of seeds of Aesculus indica and barks of Populus euphratica. Int J Pharm Pharm Sci 2012;4:249-50.
71Uniyal SK, Singh KN, Jamwal P, Lal B. Traditional use of medicinal plants among the tribal communities of Chhota Bhangal, Western Himalaya. J Ethnobiol Ethnomed 2006;2:14.
72Balakumar P, Arora MK, Ganti SS, Reddy J, Singh M. Recent advances in pharmacotherapy for diabetic nephropathy: Current perspectives and future directions. Pharmacol Res 2009;60:24-32.