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  1. 1. What is Diabetes? • The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both.The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs. (K.G.M.M. Alberti et al, 1998)
  2. 2. • DM consists of a group of disorders characterized by hyperglycemia; altered metabolism of Lipids, carbohydrates, and proteins and an increased risk of complications from vascular disease.
  3. 3. Prevalence of diabetes in Pakistan • Cross-sectional survey conducted earlier in the rural and urban areas of all the four provinces of Pakistan. Newly diagnosed diabetes was 5.1% in men and 6.8% in women in urban areas and 5.0% in men and 4.8% in women in rural areas ( F. Jawad et al,2006) • Prevalence of diabetes is high ranging from 7.6 to 11% in Pakistan (R. Hakeem et al ,2010)
  4. 4. Global Prevalence • The prevalence of diabetes for all age-groups worldwide was estimated to be 2.8% in 2000 and 4.4% in 2030. (SARAHWILD et,al 2004)
  5. 5. Cause: • Genetic Susceptibility • Autoimmune Destruction of Beta Cells (Alexandra E. Butler et al, 2004) • Environmental Factors • Viruses and infections • Obesity and Physical Inactivity • Insulin Resistance (NIH Publication No. 09–3873, November 2008)
  6. 6. • AbnormalGlucose Production by the Liver • Metabolic Syndrome Cell Signaling and Regulation Beta Cell Dysfunction deficit in -cell mass, increased -cell apoptosis, and impaired insulin secretion. • Endocrinopathies. (AMERICAN DIABETESASSOCIATION,2006) • Drug- or chemical-induced diabetes. • Diseases of the exocrine pancreas.
  7. 7. • Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus and deafness • Uncommon forms of immune-mediated diabetes. (Expert Committee on the Diagnosis and Classification of Diabetes,2006)
  8. 8. Types of diabetes The three main types of diabetes are • Type 1 diabetes • Type 2 diabetes
  9. 9. Type 1 Diabetes • Type 1 indicates the processes of beta-cell destruction that may ultimately lead to diabetes mellitus in which ‘insulin is required for survival’ to prevent the development of ketoacidosis, coma and death. • Type 1 is usually characterized by the presence of anti-GAD, islet cell or insulin antibodies which identify the autoimmune processes that lead to beta-cell destruction. (K.G.M.M. Alberti et al, 1998)
  10. 10. Type 1
  11. 11. Type 2 Diabetes • Type 2 is the most common form of diabetes and is characterized by disorders of insulin action and insulin secretion, either of which may be the predominant feature. Both are usually present at the time that this form of diabetes is clinically manifest. (K.G.M.M. Alberti et al, 1998)
  12. 12. Pathophysiology • Several pathogenetic processes are involved in the development of diabetes.These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that result in resistance to insulin action.The abnormalities of carbohydrate, fat and protein metabolism are due to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin. (KahnSE et al, 2000)
  13. 13. • Diabetes mellitus type 2 (formerly noninsulin- dependent diabetes mellitus (NIDDM) or adult- onset diabetes) is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency Virtually all forms of DM result from a decrease in the circulating concentration of insulin (insulin deficiency) and a decrease in the response of peripheral tissues to insulin (insulin resistance). • These abnormalities lead to alterations in the metabolis of carbohydrates, lipids, ketones, and amino acids , the central feature of the syndrome is hyperglycemia.
  14. 14. • Insulin lowers the concentration of glucose in blood by inhibiting hepatic glucose production and by stimulating the uptake and metabolism of glucose by muscle and adipose tissue. • These two important effects occur at different concentrations of insulin. Glucose production is inhibited half maximally by an insulin concentration of about 20 μunits/mL, whereas glucose utilization is stimulated half maximally at about 50 μunits/mL.
  15. 15. • Lack of GIP amplification of the latephase plasma insulin response to glucose seems to be a consequence of diabetes mellitus, characterizing most, if not all, forms of diabetes.1 beta-cell dysfunction and insulin resistance are two central, interrelated defects in the pathophysiology of type 2 diabetes (T.VILSBØLL et al, 2003)
  16. 16. • Type 2 diabetes is a progressive disease and that this progression is due to declining beta-cell function. (The American Journal of Medicine ,2000) • Proinsulin is a precursor of mature insulin and C- peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights aboutT2D pathophysiology. (Rona J. Strawbridge et al ,2003)
  17. 17. Diabetes Research & Wellness Foundation
  18. 18. Role of insulin in glucose regulation • Insulin lowers the concentration of glucose in blood by inhibiting hepatic glucose production and by stimulating the uptake and metabolism of glucose by muscle and adipose tissue ( Goodman and Gillman’s Pharmacology)
  19. 19. REGULATION OF GLUCOSE TRANSPORT • Stimulation of glucose transport into muscle and adipose tissue is a key response to insulin. Glucose enters cells by facilitated diffusion through one of a family of five glucose transporters, GLUTs 1–5, that mediate Na+- independent facilitated diffusion of glucose into cells
  20. 20. • Insulin stimulates glucose transport by promoting translocation of intracellular vesicles that contain the GLUT4 and GLUT1 glucose transporters to the plasma membrane .The transporters return to the intracellular pool on removal of insulin
  21. 21. Symptoms • Polyuria , polydipsia, and unexplained weight loss) and a random plasma glucose concentration of greater than 200 mg/dL , a fasting plasma glucose concentration of greater than 126 mL/dL or a plasma glucose concentration of greater than 200 mg/dL 2 hours after the ingestion of an oral glucose load. (K.G.M.M.Alberti et al, 1998)
  22. 22. • In its most severe forms, ketoacidosis or a non-ketotic hyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death occur. (K.G.M.M. Alberti et al, 1998)
  23. 23. Complications 5 • Diabetic cardiovascular disease (Dongjuan wang et al, 2013) • Insulin resistance • Beta-cell defect • Metabolic syndrome These are the pathologic problems leading to hyperglycemia • Heart attack • Stroke • Cardiovascular death ( Collins FM. Et al, 2013 )
  24. 24. • Oxidative stress causes diabetic complications that are undefined. • Elevated FFA result in the generation of ROS and RNS, leading to increased oxidative stress. In the absence of an appropriate compensatory response from the endogenous antioxidant network, the system becomes overwhelmed (redox imbalance), leading to the activation of stress-sensitive signaling pathways, such as NF- B, p38 MAPK, JNK/SAPK, PKC, AGE/RAGE (JOSEPH L.et al, 2002)
  25. 25. Current treatment • Sulfonylureas • Insulin secretagogues • Biguanides • Alpha-glucosidase inhibitors • Thiazolidinediones • Insulin ( Collins FM. Et al, 2013 )
  26. 26. Possible targets for diabetes type 2 • Adenosine 58- monophosphate-activated protein kinase (AMPK) now appears to be a metabolic master switch, phosphorylating key target proteins (W.W.WINDER et al.2013) • Several G protein-coupled receptors (GPCRs) expressed in islet β-cells are known to be involved in the regulation of islet function (Bo Ahrén et al 2009)
  27. 27. • Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for β-cell dysfunction ( Michael Stumvoll et al, 2013)
  28. 28. • Genes have been identified so far: genes for calpain 10, potassium inward-rectifier 6·2, peroxisome proliferator-activated receptor γ, insulin receptor substrate-1 ( Michael Stumvoll et al, 2013)
  29. 29. Current targets (David E. Moller et al, 2001)
  30. 30. (David E. Moller et al, 2001)
  31. 31. Enhancing glucose-stimulated insulin secretion (David E. Moller et al, 2001)
  32. 32. Targeting the insulin signalling pathway (David E. Moller et al, 2001)
  33. 33. AMP-activated kinase and acetyl- CoA carboxylase (David E. Moller et al, 2001)
  34. 34. Need • Patients with diabetes have CVD-related mortality that is 2 to 4 times higher than in non- diabetics. • Despite all the new treatments that have emerged in the last 20 years, diabetes sufferers remain challenged in effectively managing their disease over the long term and some drugs lose efficacy as the disease progresses.Oral drugs eventually fail to control blood glucose, and insulin injections become unavoidable.
  35. 35. • The challenge will be to advance these agents while meeting the demands of patients for better-tolerated drugs, optimal efficacy, and safety in the face of heightened testing requirements to assess CV risk.
  36. 36. • Metformin was approved by the US food and drug administration (FDA) in 1994. Preferred first-line drug for the treatment of type 2 diabetes. • Additional agents are often prescribed in combination with metformin.
  37. 37. • Alpha-glucosidase inhibitors; various novel insulins with rapid onset of action or long duration of effect; thiazolidinediones (tzds); meglitinides; glucagon-like peptide-1 receptor agonists (GLP-1 RA); and dipeptidyl peptidase-4 (DPP-4) inhibitors.
  38. 38. • Rosiglitazone/avandia published in 2007 raised concerns about cv safety • Rosiglitazone had an increased risk of myocardial infarction and a borderline increased risk of death from cv events. • Taking insulin glargine had no effect (negative or positive) on the risk of a heart attack or stroke.
  39. 39. • Treatment of diabetes requires a multi- faceted approach and there are no “one-size- fits- all” solutions. • Some of the newer drugs such as glp-1 ra, dpp-4 inhibitors, and sodium-glucose cotransporter 2 (sglt2) inhibitors may have favourable CV effects.
  40. 40. • Novel drug class is oral inhibitors of sglt2, the protein responsible for at least 90 per cent of the glucose reabsorption in the kidney. • Sglt2 compounds have also shown significant blood pressure-lowering effects, but it remains uncertain whether these benefits will reduce CV events.
  41. 41. • Dapagliflozin was approved for use in europe, becoming the first sglt2 entrant to gain regulatory approval for type 2 diabetes. • Reductions in weight and blood pressure. • Dapagliflozin was denied approval by the fda in early 2012 due to concerns over apparent bladder and breast cancer risks.
  42. 42. • Other novel drug classes in development for type 2 diabetes are G-protein-coupled receptor (GPCR) agonists and interleukin-1- receptor (IL-1) antagonists. GPCRs are cell surface receptors that mediate a variety of important cellular signals related to control of blood pressure and blood glucose.
  43. 43. New targets • Aldosterone and MR signaling represent an ideal candidate pathway linking early promoters of diabetes, especially overnutrition and obesity, to vascular insulin resistance, dysfunction, and disease (Shawn B. Bender et, al 2013 )
  44. 44. • Preserve b-cell function and the impact on clinical care and outcomes (Judith E et, al 2013) • An increased b-cell workload (insulin resistance) is a risk factor forT2DM, most individuals adaptively increase insulin and IAPP expression and secretion without b-cell failure. (Safia Costes et, al 2013)
  45. 45. • Several nonpeptide, except DPP-4 inhibitors, binding G protein-coupled receptors (GPCRs) have been deorphanized recently and are currently being evaluated as candidate GLP-1 secretagogues forT2DM (Xiaoyun Zhu et al , 2013)
  46. 46. (Xiaoyun Zhu et al , 2013)
  47. 47. • A characteristic feature of type 2 diabetes is delayed wound healing, which increases the risk of recurrent infections, tissue necrosis, and limb amputation. • Diabetes impairs resolution of wound healingstimulating resolution with proresolving lipid mediators could be a novel approach to treating chronic, nonhealing wounds in patients with diabetes (YunanTang et, al 2013 )
  48. 48. • Damage to mitochondrial DNA (mtDNA), may result in Glucotoxicity due to metabolic oversupply (Martin Picard et al, 2013)
  49. 49. (Martin Picard et al, 2013)
  50. 50. • Brown adipose tissue (BAT) as therapeutic strategies for preventing and treating obesity and type 2 diabetes 20 (Harold Sacks et, al 2013) • Islet transplantation as a treatment (R. Paul Robertson et, al 2004)
  51. 51. (R. Paul Robertson et, al 2004)
  52. 52. • Renoprotective Agents (Macaulay Onuigbo et al ,2013)
  53. 53. • Blood pressure as targets for treatment, the efficacy of blocking the renin-angiotensin system (RAS) pathway, (EBERHARD RITZ et, al 2011) • Postprandial hyperglycemia is a direct and independent risk factor for cardiovascular disease (CVD)Correcting the postprandial hyperglycemia may form part of the strategy for the prevention and management of CVDs in diabetes (Antonio Cerielloet et,al 2005)
  54. 54. • The acute phase of insulin release is a major determinant of the efficiency of glucose clearance, • cAMP potentiates both acute-phase and sustained-phase insulin secretion and provides a therapeutic target to restore glucose control. (Kelly A. Kaihara et,al 2013)
  55. 55. • Oleanolic acid (OA), improves insulin response, preserves functionality and survival of b-cells, and protects against diabetes complications. (Jose M. Castellano et,al 2013) • Vascular endothelial growth factor (VEGF) are revolutionizing the treatment of diabetic retinopathy (DR) and diabetic macular edema (DME). (Paul M.Titchenell et, al 2013)
  56. 56. • Inhibition of hepatic glycogen phosphorylase is a promising treatment strategy for attenuating hyperglycemia , glycogen phosphorylase inhibition aimed at attenuating hyperglycaemia is unlikely to negatively impact muscle metabolic and functional capacity. (David J. Baker et, al 2005) • Pharmacological inhibition of hepatic glycogen phosphorylase has the potential to be an effective therapeutic strategy for the treatment of type 2 diabetes
  57. 57. • A novel peptide has been named ‘irisin’ acts on the cells of white adipose tissue. Irisin increases total energy expenditure and, in certain animal models, prolongs life expectancy, reduces body weight, and mitigates diet-induced insulin resistance, thus reducing obesity and insulin resistance (Fabian Sanchis et, al 2012)
  58. 58. • Use of antioxidants may be very important in preventing activation of oxidative stress (JOSEPH L et,al 2012)
  59. 59. Molecular targets • Reducing islet cell oxidative stress is a potential target of human type 2 diabetes therapy. (Silvia Del Guerra et,al 2005) • Nitrotyrosine and 8-hydroxy-2- deoxyguanosine concentrations, markers of oxidative stress, were significantly higher in type 2 diabetic than control islets, and they were correlated with the degree of glucose- stimulated insulin release impairment
  60. 60. Plants having hypoglycemic activity (Nidhi Aggarwal et al , 2011)
  61. 61. • Eugenia jambolana (EJ) commonly known as Jaman • Lawsonia alba Lam commonly known as henna is a perennial plant of the family Lythraceae, henna leaves (mehendi) • Momordica charantia • Morus alba (synonyms Morus alba Linn) (MA) known aswhite mulberry • Nigella sativa Linn. (NS), known as black cumin Kalonji • Trigonella foenum graecum Linn. (TF) commonly known as methi (M. SAEEDARAYNEetal, 2007)
  62. 62. Plant having hypoglycemic activity Botanical name : Allium cepa Family : (Liliaceae) Common name :Onion • Allium cepa has some anti-diabetic that b may be due to the antioxidant properties of its essential oil components, which can signify its anti-diabetic and antihyperlipidaemic activity (DK Patel et,al 2012)
  63. 63. Why this plant…!!! • Hypoglycaemic and hypolipidaemic activity • Antioxidative activity (Ozougwu et al , 2011)
  64. 64. Methods 1. Streptozotocin-induceddiabetes 2. Alloxan-induced diabetes 3. Virus-induced diabetes 4. Pancreatectomy in dogs 5. Growth hormone-induced diabetes 6. Corticosteroid-induced diabetes 7. Insulin deficiency due to insulin antibodies HansGerhard Vogel 3rd edition
  65. 65. Streptozotocin Induced Diabetic Aim : This is apropos to investigate the antioxidative effect of allium cepa essential oil in streptozotocin induced diabetic albino rats (Neveen Abou El-Soud et,al 2010)
  66. 66. Materials • Essential oil of red onion (0.05%) will be prepared and isolate it according to Harborne (Harborne JB et, al 1984) • Streptozotocin (STZ) will be purchased from ABC company Pakistan • Chloroform, Methyl alcohol, ether will be purchased from GHK chemicals
  67. 67. Animals: • Thirty male albino rats weighing 150-200g will be obtained from UOS animal house • Rats will be caged under controlled temperature 20-24°C and 12 h light/dark cycle.They will be fed with standard laboratory chow and water ad libitum.
  68. 68. Induction of Diabetes • Rats will be kept on fasting prior to streptozotocin injection. • On the day of administration, STZ will be freshly dissolved in 50 Mm sodium citrate (pH 4.5) solution containing 150 mM NaCl and subcutaneous injection will be given at the dosage of 60 mg/kg b.w. • Blood glucose concentration will be checked by the glucose oxidase method (Trinder P. Et, al 1969) after 3 days of STZ injection.The animals with glucose concentration exceeding 200 mg /dl will be considered diabetic.
  69. 69. Rats will be divided into 3 groups 10 rats in each • Group: group I: normal control rats • Group II: diabetic control rats • Group III: diabetic rats received onion essential oil (100 mg/kg b.W. Orally) • The dose will be chosen according to its LD50 (the medium 50 lethal doses after acute toxicity).
  70. 70. Groups FBG (mg/dl) Serum insulin (µu/ml) I Normal control II Diabetic control III Onion essential oil control (100 mg/kg b.W. Orally)
  71. 71. Samples Collection • After 21 days from the beginning of the experiment • Rats will be fasted for 12 hours • Then blood samples will collected • Blood will be collected retro-orbitally from the inner canthus of the eye under ether anaesthesia using capillary tubes containing sodium fluoride (MadwayW et, al 1969)
  72. 72. • Serum and plasma will be separated and centrifuged at 3000 rpm for 5 minutes. • The serum and plasma will be separated for measurement of glucose, insulin, cholesterol, triglycerides, HDL, LDL, nitric oxide and tbars in different study groups.
  73. 73. ALLOXAN-INDUCED DIABETES (Ozougwu et al ,2011)
  74. 74. Animal Model • Sixty three (63) adult white wistar strain albino rats (R. norvegicus) weighing 200 to 250g, bred in the animal house of the Faculty of Pharmacology UOS will be used for the study. • They will be fed ad labium with 30% crude protein (Guinea feed) commercial feed. • They will be allowed to acclimatize under standard photoperiodic condition in a clean rat cage Research Laboratory. • All animals will be maintained under the standard laboratory condition for temperature (26 ± 20C) and light (12 hours day length) and allowed free access to food and water.
  75. 75. Preparation of Plant Extracts • The methods of Habib MY et al 2005 and Battu GR et al, 2005 will be used. • Fresh health plant of A. cepa (2000 g) will be washed, cut into small pieces and homogenized in a warring blender. • The resulting mixture will be soaked in 2L of distilled water. • The mixture will be allowed to stand for twenty four hours with intermittent shaking.
  76. 76. • Following filtration, the filtrates will be heated to dryness in a water bath and the weight of the crude extract will be determined. • The extract will be kept in refrigerator (40 C) thereafter. • The extract will be reconstituted in normal saline (0.85% NaCl) at a concentration of 1g/ml before administration.
  77. 77. Induction of Diabetes Mellitus • The methods of Osinubi AA et al , 2006 and Battu GR et al , 2007 will be used to induce diabetes in the rats. • 150 mg of alloxan per kg body weight of rat will be administered intraperitoneally after overnight fast (access to only water) of twelve hours to make them more susceptible to developing diabetes. • Rats with serum glucose levels between (250 – 400 mg/dl) after two weeks will be considered diabetic and used for the experiment.
  78. 78. Experimental Design • The study will be carried out on alloxan- induced diabetic rats for six weeks. • The animals will be fasted for sixteen hours before each experiment and blood sample collected from the eye of the rats. • All parameters assessed will be determined before the extract treatments of the animals (initials) and subsequently will be evaluated weekly for six weeks. • The experimental design will be three by three Latin square design using 63 rats divided into two major groups
  79. 79. • Group I: nine non diabetic rats (non diabetic control) • Group II: fifty four alloxan induced diabetic rats. • Group I rats were divided into 3 subgroups (Ia, Ib, Ic) of 3 rats each in different cages and receives 1.0ml of normal saline intraperitoneally daily. • Group II (fifty - four alloxan induced diabetic rats) will be divided into 2 subgroups (IIa , IIb). Subgroups IIa, (twenty seven rats) will be divided into 3 replicates (IIa1, IIa2, IIa3).
  80. 80. • Each replicate will have three rats and received 200 mg/kg, 250 mg/kg or 300 mg/kg of A. cepa aqueous extracts intraperitoneally daily respectively. • The subgroups IIb will be diabetic control (twenty- seven rats) and will be divided into 3 replicates (IId1, IId2 and IId3) each replicate will have three rats and will be administered 2.5mg/kg/, 3.8mg/kg and 5.0mg/kg of standard antidiabetic drug (glibenclamide) daily for six weeks
  81. 81. Parameters • Determination of Blood Glucose • Determinations ofTotal Serum • Cholesterolose Level Determination • Determination ofTotal Lipids in Serum
  82. 82. INSULIN DEFICIENCY DUETO INSULIN ANTIBODIES: • Bovine insulin, will be dissolved in acidified water (pH 3.0) and incorporated in a water-oil emulsion based on complete Freund’s adjuvant or a mixture of paraffin oil and lanolin. • A dose of 1 mg insulin will be injected in divided doses subcutaneously to male guinea pigs weighing 300–400 gm.
  83. 83. • Injections will be given at monthly intervals and the guinea pigs will be bled by cardiac puncture twoWeeks after the second and subsequent doses of antigen. • It is possible to get 10 ml blood from every animal once a month. Intravenous injection of 0.25–1.0 ml guinea pig antiinsulin serum to rats will induce a dose-dependent increase of blood glucose reaching values up to 300 mg%.
  84. 84. • This effect is unique to guinea pig anti-insulin serum and is due to neutralization by insulin antibodies of endogenous insulin secreted by the injected animal. In this way a state of insulin deficiency will be induced. • It persists as long as antibodies capable of reacting with insulin remain in the circulation. Slow rate intravenous infusion or intraperitoneal injection prolongs the effect for more than a few hours. • However, large doses and prolonged administration accompanied by ketonemia, ketonuria, glucosuria, and acidosis will proove to be fatal to the animals. • After lower doses, the diabetic syndrome will be reversible after a few hours (Moloney and Coval 1955; Wright 1968).
  85. 85. References : • Alexandra E. Et al 2010, Diabetes Due to a Progressive Defect in _-Cell Mass in RatsTransgenic for Human Islet Amyloid Polypeptide (HIP Rat)A New Model forType 2 Diabetes Expert Rev Clin Pharmacol. 2010;3(2):209-229. • Antonio Ceriello et al, 2005 Perspectives in Diabetes Postprandial Hyperglycemia and Diabetes Complications Is It Time toTreat?, Diabetes 54:1–7, 2005 • Bo Ahrén et al, 2009 Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes , Nature Reviews Drug Discovery 8, 369-385 (May 2009) | doi:10.1038/nrd2782 • Collins FM. Et al 2013 , Current treatment approaches to type 2 diabetes mellitus: successes and shortcomings. Am J Manag Care. 2002 Oct;8(16 Suppl):S460-71.
  86. 86. • David E. Moller et al , 2001, New drug targets for type 2 diabetes and the metabolic syndrome NATURE |VOL 414 | 13 DECEMBER 2001 | www.nature.com • David J. Baker et al, 2005, Glycogen Phosphorylase Inhibition inType 2 DiabetesTherapyA Systematic Evaluation of Metabolic and Functional Effects in Rat Skeletal Muscle,Diabetes 54: 2453–2459, 2005
  87. 87. • Development of New Diabetes Drugs - Implications for Clinical Practice Journal for Clinical Studies Volume 5 Issue 1 • DK Patel et al,2012, Natural medicines from plant source used for therapy of diabetes mellitus:An overview of its pharmacological aspects , DK Patel et al./Asian Pacific Journal ofTropical Disease (2012)239- 250 • EBERHARD RITZ, MD et al, 2011, Limitations and FutureTreatment Options inType 2 DiabetesWith Renal Impairment, DIABETESCARE,VOLUME 34, SUPPLEMENT 2, MAY 2011
  88. 88. • Fabian Sanchis-Gomar et al, 2012, Irisin: A new potential hormonal target for the treatment of obesity and type 2 diabetes, Journal of Diabetes 4 (2012) 196 196 a • Harold Sacks et al, 2013 , Anatomical Locations of Human Brown AdiposeTissue Functional Relevance and Implications in Obesity andType 2 Diabetes, Diabetes 62:1783–1790, 2013 • Jose M. Castellano et al, 2013, Biochemical Basis of the AntidiabeticActivity of Oleanolic Acid and Related PentacyclicTriterpenes, Diabetes 62:1791–1799, 2013
  89. 89. • JOSEPH L. EVANS et al, 2012 , Oxidative Stress and Stress-Activated Signaling Pathways: A Unifying Hypothesis ofType 2 Diabetes Endocrine Reviews 23(5):599–622 Printed in U.S.A.Copyright © 2002 by The Endocrine Society • Judith E et al 2013 , Diabetes Research: A Perspective From the National Institute of Diabetes and Digestive and Kidney Diseases, DIABETES,VOL. 62, FEBRUARY 2013 • K.G.M.M.Alberti et al,1998, Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications Part 1: Diagnosis and Classification of Diabetes Mellitus Provisional Report of aWHO Consultation , Diabet. Med. 15: 539–553 (1998) • K.G.M.M.Alberti, Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications Part 1: Diagnosis and Classification of Diabetes Mellitus Provisional Report of a WHO Consultation
  90. 90. • Kelly A. Kaihara et al, 2013, b-Cell–Specific Protein Kinase A Activation Enhances the Efficiency of Glucose Control by Increasing Acute-Phase Insulin Secretion, DIABETES,VOL. 62, MAY 2013 • M. SAEED ARAYNEetal, 2007, INVITRO HYPOGLYCEMIC ACTIVITY OF METHANOLIC EXTRACT OF SOME INDIGENOUS PLANTS, Pak. J. Pharm. Sci., 2007, Vol.20(4), 261-268 • Macaulay Onuigbo et al, 2013, Renoprotection and the Bardoxolone Methyl Story – IsThis the Right Way Forward? A NovelView of Renoprotection in CKDTrials: A New Classification Scheme for Renoprotective Agents, Nephron Extra 2013;3:36–49
  91. 91. • Martin Picard , et al 2013 , Linking the Metabolic State and Mitochondrial DNA in Chronic Disease, Health, and Aging ,DIABETES,VOL. 62, MARCH 2013 • Michael Stumvoll et al,Type 2 diabetes: principles of pathogenesis and therapyThe Lancet,Volume 365, Issue 9467, Pages 1333-1346 • National Diabetes Information Clearinghouse (NDIC) ,A service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) • NidhiAggarwal et al , 2011,A Review of Recent Investigations on Medicinal Herbs Possessing Anti- Diabetic Properties Aggarwal and Shishu, J Nutrition DisorderTher 2011, 1:1 • OZOUGWU, J. C.et,al 2012,ANTI-DIABETIC EFFECTS OF ALLIUMCEPA (ONIONS)AQUEOUS EXTRACTSONALLOXAN-INDUCED DIABETIC RATTUS NOVERGICUS. Pharmacologyonline 1: 270-281 (2011)Ozougwu et al.
  92. 92. • Paul M.Titchenell et, al 2013 Using the Past to Inform the Future: Anti-VEGFTherapy as a Road Map to Develop NovelTherapies for Diabetic Retinopathy, Diabetes 62:1808–1815, 2013 • R. Hakeem1, et al 9 2010, Diabetes in Pakistan: Epidemiology, Determinants and Prevention, Journal of Diabetology, June 2010; 3:4 • R. Paul Robertson et al , 2013, IsletTransplantation as aTreatment for Diabetes — AWork in Progress, N Engl J Med 2004;350:694-705.
  93. 93. • R. Paul Robertson et al, 2013, Perspectives in Diabetes GlucoseToxicity in _-Cells:Type 2 Diabetes, Good Radicals Gone Bad, and the Glutathione Connection, DIABETES, VOL. 52, MARCH 2003 • Rona J. Strawbridge, DIABETES,VOL. 60, OCTOBER 2011 Genome-Wide Association Identifies Nine CommonVariants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology ofType 2 Diabetes. diabetes.diabetesjournals.org, Diabetes 60:2624–2634, 2011 • S. E. Kahn,The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology ofType 2 diabetes, Diabetologia (2003) 46:3–19 DOI 10.1007/s00125-002-1009-0
  94. 94. • Safia Costes et al , 2013 , b-Cell Failure inType 2 Diabetes: A Case of AskingToo Much ofToo Few? DIABETES, VOL. 62, FEBRUARY 2013 • SARAH WILD, MB BCHIR, PHD et , al 2004, Global Prevalence of Diabetes Estimates for the year 2000 and projections for 2030, DIABETES CARE,VOLUME 27, NUMBER 5, MAY 2004 • Shawn B. Bender et al 2013, Mineralocorticoid Receptor–Mediated Vascular Insulin Resistance An Early Contributor to Diabetes-Related Vascular Disease? ,DIABETES, VOL. 62, FEBRUARY 2013
  95. 95. • Silvia Del Guerra et al, 2005, Functional and Molecular Defects of Pancreatic Islets in HumanType 2 Diabetes, DIABETES,VOL. 54, MARCH 2005 • T.VILSBØLL, (2003,)The Pathophysiology of Diabetes Involves a DefectiveAmplification of the Late-Phase Insulin Response to Glucose by Glucose-Dependent Insulinotropic Polypeptide—Regardless of Etiology and Phenotype ,The Journal of Clinical Endocrinology & Metabolism 88(10):4897–4903 • YunanTang et al 2013, ProresolutionTherapy for theTreatment of Delayed Healing of DiabeticWounds , DIABETES,VOL. 62, FEBRUARY 2013