General introduction to diabetes mellitus

Its very important topic in periodontology as Diabetes Mellitus has high impact on periodontium. So before going into details how it act on periodontium, we have to know what it is and how it is detected in blood. Here is the vast knowledge on diabetes mellitus

1. DIABETES MELLITUS GENERAL INTRODUCTION

2. CONTENTS Introduction History Epidemiology Classification Type 1 DM Type 2 DM Gestational DM Pre-diabetes Complications: Acute & chronic: the Proposed mechanisms Diagnostic criteria’s: Laboratory tests Management Conclusion References

3. "Diabetes " and “Mellitus” are derived from Greek . “ Diabetes” denotes "a passer through; a siphon" whereas the "Mellitus" denotes "sweet". It is thought that the Greeks named it so due to the excessive amounts of urine produced by diabetics attracted flies and bees. Insulin deficiency in turn leads to chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism. INTRODUCTION Diabetes Mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia resulting from defects of insulin secretion and/or increased cellular resistance to insulin

4. HISTORY Diabetes mellitus has been known since antiquity, its treatments were known since the Middle Ages, and the elucidation of its pathogenesis occurred mainly in the 20th century. The discovery of the role of the pancreas in diabetes was made by Joseph Von Mering and Oskar Minkowski in 1889. In 1910 , Sir Edward Albert Sharpey -Schafer of Edinburgh in Scotland suggested that diabetics lacked a single chemical which was normally produced by the pancreas. Name of this chemical was later proposed to be I nsulin by Himsworth , 1936.

5. In 1921 , Frederick Grant Banting and Charles Herbert Best repeated the work of Von Mering and Minkowski but went a step further and managed to show that they could reverse the induced diabetes in dogs by giving them an extract from the pancreatic islets of Langerhans of healthy dogs . These scientists proceeded on to isolate insulin from bovine pancreases at the University of Toronto in Canada, thereby leading to the availability of an effective treatment of diabetes mellitus, with the first clinical patient being treated in 1922

6. The distinction between what is now known as type I and type II diabetes was made by Sir Harold Percival (Harry ) Himsworth in 1935 O ther landmark discoveries followed viz ; identification of sulfonylureas in 1942 The radioimmunoassay for insulin, as discovered by Rosalyn Yallow and Solomon Berson Identification of thiazolidinediones as effective antidiabetics in the 1990s

7. EPIDEMIOLOGY A pproximately 285 million people worldwide (6.6%) in the 20–79 year age group have diabetes in 2010 and by 2030, 438 million people (7.8%) of the adult population, is expected to have diabetes. India leads the world with largest number of diabetic subjects earning the dubious distinction of being termed the “diabetes capital of the world”

8. CLASSIFICATION OF DIABETES MELLITUS American Diabetes Association in 2001

9. TYPE 1 DIABETES MELLITUS

10. Type 1 diabetes is one of the most frequent chronic childhood diseases. According to the American Diabetes Association , this form is present in the 5–10% of patients with diabetes. Peak incidence occurs during puberty, around 10–12 years of age in girls and 12–14 years of age in boys.

11. Markers of autoimmune destruction have been identified and can be used for diagnosis or risk assessment. These include antibodies to islet cells and to insulin, glutamic acid decarboxylase and tyrosine phosphatase IA-2 and IA-2b. Type 1 diabetes has a genetic predisposition with strong human leukocyte antigen associations. Monozygous twins have a concordance for type1 diabetes of 30–50%. These patients are also prone to other autoimmune disorders.

12. PATHOGENESIS OF TYPE 1 DM

13. ETIOLOGY

14. CLINICAL FEATURES W eight loss Polyurea Polydypsia Polyphagia C onstipation fatigue Cramps B lurred vision, and Candidiasis Long lasting type 1 DM patients may susceptible to microvascular complications and macrovascular disease

15. RISK FACTORS

16. TYPE 2 DIABETES MELLITUS

17. Type 2 diabetes has a stronger genetic component than type 1, with a concordance rate of up to 90% in identical twins. In addition to genetic risk factors, acquired or environmental factors play a major role; foremost among these is obesity . Increased consumption of more energy dense , nutrient-poor foods with high levels of sugar and saturated fats, combined with reduced physical activity, have led to obesity rates that have risen three-fold or more since 1980 in some areas of North America, the UK, Eastern Europe, the Middle East, the Pacific Islands, Australia and China.

18. “Non–insulin dependent diabetes” Have altered insulin production however, autoimmune destruction of β-cells does not occur and patients retain the capacity for some insulin production The incidence of ketoacidosis is very low. B ut ketoacidosis can occur in association with the stress of another illness such as an infection Type 2 Diabetes

19. In many patients, especially early in the disease, insulin production is increased, resulting in hyperinsulinemia . As the condition progresses, insulin production often decreases and patients have a relative insulin deficiency in association with peripheral insulin resistance. The primary abnormality is insulin resistance and the β -cell dysfunction arises from the prolonged, increased secretory demand placed on them by the insulin resistance. They can remain undiagnosed for many years because the hyperglycemia appears gradually and many times without symptoms.

20. INSULIN RESISTANCE Insulin resistance is a state in which a given concentration of insulin produces a less-than-expected biological effect. Insulin resistance has also been arbitrarily defined as the requirement of 200 or more units of insulin per day to attain G lycemic control and to prevent ketosis . The pathogenesis of type 2 diabetes involves abnormalities in both insulin action and secretion.

21. NORMAL INSULIN SIGNALLING PATHWAY

22. CAUSES OF INSULIN RESISTANCE Combinations of defects: Obesity is associated mainly with post receptor abnormality and is also associated with a decreased number of insulin receptors. Obesity is the most common cause of insulin resistance. Aging: This may cause insulin resistance through a decreased production of GLUT-4 transporters. Increased production of insulin antagonists :  A number of disorders are associated with increased production of insulin antagonists, such as - -Cushing syndrome -Acromegaly -Stress states, such as trauma, surgery, diabetes ketoacidosis , severe infection, uremia, and liver cirrhosis.

23. Medications: include glucocorticoids (Cushing syndrome), cyclosporine, niacin, and protease inhibitors. Human immunodeficiency virus (HIV):  Protease inhibitor – associated lipodystrophy is a recognized entity. Nucleoside analogues have also been implicated in the development of insulin resistance. Insulin treatment : Low titer IgG anti-insulin antibody levels are present in most patients who receive insulin. Enhanced destruction of insulin at the site of subcutaneous injection has also been implicated.

24. PATHOGENESIS OF TYPE 2 DM

25. ETIOLOGY OF TYPE 2 DM

26. CLINICAL FEATURES Carries a high risk of large vessel atherosclerosis commonly associated with hypertension, hyperlipidaemia and obesity. Most patients with type 2 diabetes die from cardiovascular complications and end stage renal disease. Geographical variation can contribute in the magnitude of the problems and to overall morbidity and mortality.

27. RISK FACTORS

28. OBESITY & TYPE 2 DM There is a close association between BMI and risk of developing T2D , the relative risk of T2D increasing with Body Mass Index (BMI). The normal BMI is under 25 kg/m2, whereas a BMI between 25 and 30 kg/m2 is defined as overweight , and a BMI of over 30 kg/m2 is defined as obese . Adipose tissue plays an important role in the development of insulin resistance. Elevated circulating levels of free fatty acids (FFA) derived from adipocytes contribute to insulin resistance by inhibiting glucose uptake, glycogen synthesis, and glycolysis and by increasing hepatic glucose production.

29. ‘ Diabesity ’

30. GESTATIONAL DIABETES

31. Women with gestational diabetes mellitus have an increased frequency of: H ypertensive disorders I ncreases the risk for foetal congenital abnormalities Stillbirth Macrosomia Hypoglycemia Jaundice R espiratory distress syndrome Polycythemia and H ypocalcemia

32. PRE-DIABETES

33. ACUTE COMPLICATIONS

34. DIABETIC KETOACIDOSIS P rimarily results from insulin deficiency result in subsequent glucagon and counter-regulatory hormone excess from lack of suppression from insulin.

35. PATHOGENESIS The situation is complicated by the fact that in this more catabolic state there is breakdown of proteins to form new amino acids that in turn are used to build glucose The risk of DKA increases with any increased stress state. In a so-called ‘‘stressed state,’’ there is a relative abundance of epinephrine and cortisol. In a stressed state, such as infection, myocardial infarction, intoxication, pregnancy, or stroke there is an increased demand for insulin , but a diminished supply by the stress put on the pancreas .

36. Insulin is normally the most important regulator in production and utilization of ketones . It inhibit lipolysis and oxidation of FFA. The fruity breath odour of ketone further suggest the diagnosis of DKA

37. Elevated blood glucose shifts water into the extracellular compartment. and osmotic diuresis occurs G lycosuria and P olyuria result Water losses are typically greater than electrolyte losses, and thus there is an increased serum osmolality Polydypsia

38. SYMPTOMS Nausea Vomiting abdominal pain respiratory insufficiency

39. HYPERGLYCEMIC HYPEROSMOLAR STATE T he second most common life-threatening form of decompensated DM. The greatest risk is for elderly people, particularly those bedridden or dependent on others for their daily care. Infection is a common precipitating event, as is poor compliance with insulin therapy. Various drugs that alter carbohydrate metabolism, such as corticosteroids, sympathomimetic agents, β -adrenergic blockers, and excessive use of diuretics in the elderly may also precipitate the development of hyperglycemic hyperosmolar state. Mortality rate is around 15%. Most deaths occur in the first 2 days of hospitalization; thereafter, a significant decrease in morbidity and mortality is seen.

40. SYMPTOMS W eakness Polyuria Polydipsia Weight loss M ental confusion L ethargy and Coma Some patients present with focal neurological signs ( hemiparesis or hemianopsia ) and seizures TREATMENT Vigorous hydration E lectrolyte replacement S mall amounts of insulin

41. HYPOGLYCEMIA Common problem in diabetic patients and in the seriously ill patient because of the combination of medical conditions and the use of multiple medications, particularly insulin. More likely to be encountered in the dental office. Many hypoglycemic episodes are never brought to medical attention because they are treated at home. However, severe hypoglycemia is a life-threatening event, and must be managed immediately. In some diabetic patients, especially those whose glucose levels are tightly controlled, the patient’s physiological response to decreasing blood glucose levels becomes diminished over time. This phenomenon is known as hypoglycemia unawareness.

42. CLASSIC/CHRONIC COMPLICATIONS

43. Diabetes has been classically associated with a group of microvascular and macrovascular complications Microvascular complications

44. 6 th complication: PERIODONTITIS H. Loe , 1993

45. PROPOSED MECHANISMS

46. 1) INCREASED POLYOL PATHWAY Glucose Glucose alcohol (Sorbitol) Aldose reductase C ellular dysfunction

47. REACTIVE OXYGEN SPECIES? D efined as highly reactive oxygen- centered chemical species containing one or two unpaired electrons. The unpaired electron containing chemical species can also be called “free radicals .” ROS are generated by a variety of sources from our environment and by physiological cellular functions (e.g. neutrophil phagocytosis and mitochondrial cell respiration ). Include free radicals (e.g. superoxide and hydroxyl radicals ), nonradical oxygen species [e.g. hydrogen peroxide (H2O2)] and reactive lipids and carbohydrates. In diabetes, reactive oxygen species are the major player in the pathology of microvascular complications. Pathological condition causing diabetic complications is an overproduction of superoxide by the mitochondrial electron transport chain.

48. 2) ACTIVATION OF PKC PATHWAY DAG and PKC are important intracellular signalling molecules that can regulate many vascular functions. Intracellular hyperglycemia increases the formation of DAG leading to activation of PKC pathway Thus , PKC activation involving several isoforms is likely to be responsible for some of the pathologies in DR, nephropathy and cardiovascular disease.

49. 3) ADVANCED GLYCATION END PRODUCTS (AGEs) AGEs are proteins or lipids that become glycated as a result of exposure to sugars. Constitute a heterogenous group of molecules formed by the non-enzymatic reaction of reducing sugars, ascorbate and other carbohydrates with amino acids, lipids peroxidation as well. Although this process take place continuously within the body during aging, it is extremely accelerated in DIABETES.

50. Early stage Intermediate stage Late stage glucose protein Schiff base Amadori product Dicarbonyl compounds Advanced glycation end product aminoguanidine - Maillard Reaction

51. AGEs in collagen C ollagen cross-linking H ighly stable collagen macromolecules (AGE-modified collagen) R esistance to normal enzymatic degradation and tissue turn over. In blood vessels accumulates Thickening the vessel wall and narrowing the lumen Covalently cross-links with circulating low density lipoprotein Atherosclerosis B asement membrane of small blood vessels Increases basement membrane thickness Normal homeostatic transport across the membrane.

52. AGEs have major effects at the cellular level. A receptor for AGEs known as RAGE (receptor for AGE) has been identified on the surface of endothelial cells, neurons , smooth muscle cells, and monocytes/macrophages AGEs are chemotactic for monocytes. Change in the monocyte/macrophage phenotype Increased production of proinflammatory cytokines Chronic inflammatory process in atheroma formation

53. 4) INCREASED FLUX THROUGH HEXOSAMINE PATHWAY In a normal glucose condition, only a small fraction (approximately 1–3%) of glucose is metabolized through the hexosamine pathway. Elevation of intracellular glucose levels can cause an increased flux through the hexosamine pathway which generates Fructose-6-Phosphate. Fructose-6-Phosphate glucosamine-6-phosphate End-product: uridine diphosphate N- acetylglucosamine (UDP- GlcNAc ), which is a substrate for the subsequent O-linked GlcNAc alter the function of glycosylation of protein glutamine fructose-6-phosphate aminotransferase (GFAT)

54. 5) INCREASED OXIDATIVE STRESS Oxidative stress occurs when the production of reactive oxygen species (ROS) exceeds the capability of antioxidant systems. There is substantial evidence showing that ROS production is increased in endothelial cells, kidney, retina either exposed to hyperglycemia . These compounds may activate all four of the pathways described. Antioxidant therapies have been applied in animal experiments, such as vitamin C, vitamin E and α - lipoic acids. All of them have showed improved biological and pathological changes, and prevented or slowed the progression of diabetic complications.

55. DIAGNOSTIC CRITERIA LABORATORY TESTS

56. BLOOD INVESTIGATIONS In 1998 , the WHO adopted the diagnostic parameters for diabetes established by the American Diabetes Association.

57. ORAL GLUCOSE TOLERANCE TEST The criterion for a diagnosis of diabetes with this test is a two-hour blood glucose level of 200 mg/dl or higher. Prediabetes is diagnosed if the two-hour blood glucose level is 140–199 mg/dl.

58. (mg/dl) Time in minutes Concentration in mg/dl

59. Diabetic vs Normal curve

60. EVALUATION OF GLYCEMIC CONTROL HbA1C: Glycated Haemoglobin HbA1c is used to monitor the patient’s overall glycemic control .

61. HbA1C Test: U sed to measure glycohemoglobin levels and provides an estimate of the average blood glucose level over the preceding 30 to 90-day period It is not recommended for diagnosis because there is not a gold standard assay for the HbA1c and because many countries do not have ready access to the test.

62. DIAGNOSIS OF GESTATIONAL DM At least 6 weeks after the pregnancy ends, the woman should receive an oral glucose tolerance test and be reclassified as having diabetes, normal glucose tolerance, impaired.

63. 2. URINE ANALYSIS DETECTION OF GLUCOSURIA Benedict’s & Fehling’s test This involves testing the urine with the Benedict’s reagent. Results indicate the person having diabetes based on the colour formation. Light colour = normal Parrot green colour = >120 mg/dl Dark yellow colour = >180mg/dl Reddish brown colour = +++ > 250 mg/dl Brown colour = ++++ > 350 mg/dl

64. Diasticks (detection of glucosuria ) These are strips that used to indicate the person having diabetes mellitus or not. These strips tested with urine and based on the color change only diagnosis the diabetes mellitus. DETECTION OF KETONURIA Qualitative detection of ketone bodies can be accomplished by nitroprusside tests, Rothera’s test etc. Ketone bodies may be present in a normal subject as a result of simple prolonged fasting.

65. DETECTION OF MICROALBUMINURIA May be defined as an albumin excretion rate intermediate between normality (2.5-25 mg/day) and macroalbuminuria ( 250 mg/day). The small increase in urinary albumin excretion is not detected by simple albumin stick tests and requires confirmation by careful quantization in a 24 hour urine specimen. The importance of micro- albuminuria in the diabetic patient is that it is a signal of early reversible renal damage.

66. 3 . GLUCOMETERS These meters are also involving in diagnosing the diabetes mellitus. Within the fraction of seconds these will give results about blood glucose levels.

67. MANAGEMENT

68. The goals of therapy for Type 1 or Type 2 DM are to: E liminate symptoms related to hyperglycemia . R educe or eliminate the long-term micro vascular and macro vascular complications of DM . A llow the patient to achieve as normal a lifestyle as possible.

69. TREATMENT Drug treatment for diabetes Non drug treatment for diabetes

70. DRUG TREATMENT Anti-diabetic drugs treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of I nsulin , Exenatide , and Pramlintide , all are administered orally and are thus also called oral hypoglycemic agents or oral anti hyperglycemic agents . T ype 1 DM : Insulin is used which must be injected or inhaled. T ype 2 DM : agents which increase the amount of insulin secreted by the pancreas, agents which increase the sensitivity of target organs to insulin and agents which decrease the rate at which glucose is absorbed from the gastrointestinal tract.

71. INSULIN Insulin is usually given subcutaneously, either by injections or by an insulin pump. In acute care settings, insulin may also be given intravenously. There are several types of insulin, characterized by the rate which they are metabolized by the body. Insulin is essential for the treatment of type 1 diabetes. For many years it was assumed, as an act of faith, that normalizing plasma glucose would prevent diabetic complications. The diabetes control and complications trial ( A merican D iabetes A ssociation , 1993 ) showed that this faith was well placed: type1 diabetic patients were randomly allocated to intensive or conventional management.

72. INSULIN SENSITIZERS Sulfonylureas F irst widely used oral hypoglycemic medications. They are insulin secretagogues , triggering insulin release by direct action on the KATP channel of the pancreatic beta cells . Meglitinides H elp the pancreas produce insulin and are often called "short-acting secretagogues ." Their mode of action is original, affecting channels. By closing the potassium channels of the pancreatic β cells , they open the calcium channels, hence enhancing insulin secretion. Eg : Repaglinide , Nateglinide

73. Biguanides R educe hepatic glucose output and increase uptake of glucose by the periphery, including skeletal muscle. Although it must be used with caution in patients with impaired liver or kidney function, it has become the most commonly used agent for type 2 diabetes in children and teenagers. Eg : Metformin, Phenformin , Buformin . Thiazolidinediones (TZDs ) A lso known as " glitazones ," bind to PPAR γ, a type of nuclear regulatory proteins involved in transcription of genes regulating glucose and fat metabolism. The PPREs influence insulin sensitive genes, which enhance production of mRNAs of insulin dependent enzymes. The final result is better use of glucose by the cells. Eg : Rosiglitazone, Pioglitazone, Troglitazone .

74. E. Alpha-Glucosidase Inhibitors A re "diabetes pills" but not technically hypoglycemic agents because they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small intestine, so that glucose from the starch of a meal enters the bloodstream more slowly, and can be matched more effectively by an impaired insulin response or sensitivity. These delays carbohydrates adsorption , reducing the postprandial increase in blood glucose. Eg : Miglitol , Acarbose

75. NEWLY APPROVED AGENTS FOR DIABETES PEPTIDE ANALOGS Incretin Mimetics Incretions are insulin secretagogues . The two main candidate molecules that fulfill criteria for being an incretion are Glucagons -like peptide-1 (GLP-1) and Gastric inhibitory peptide (aqua glucose-dependent Insulin tropic peptide or GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4). B. Glucagon-Like Peptide (GLP) Analogs And Agonists GLP agonists bind to a membrane GLP receptor. As a consequence of this, insulin release from the pancreatic β cells is increased. Exenatide , Liraglutide . I njected subcutaneously in a dose of 5 or 10 µg twice daily, given within 1 h before meals

76. C. Gastric Inhibitory Peptide (GIP) Analogs : DPP-4 Inhibitors Dipeptidyl peptidase-4 (DPP-4) inhibitors increase blood concentration of the incretin GLP-1 (glucagon-like peptide-1) by inhibiting its degradation by dipeptidyl peptidase-4 (DPP-4). Vildagliptin , Sitagliptin AMYLIN ANALOGUES Approved by the FDA in 2005, is an antihyperglycemic drug for use in diabetic patients who are also being treated with insulin . Amylin analogues slow gastric emptying and suppress glucagons . Injection of amylin decreases post-prandial glucose elevations and decreases cellular oxidative stress. Like insulin, it is administered by subcutaneous injection. Pramlintide The FDA requires that the package insert for pramlintide carry a “black box warning”, clearly identifying the high risk for hypoglycemia .

77. MANAGEMENT OF TYPE 1 DM ISLET CELL TRANSPLANTATION Largiadèr et al were the first to report insulin independence following islet cell allotransplantation in a patient with type 1 DM in 1980 I s a minimally invasive procedure, wide application of this procedure for the treatment of type 1 diabetes is limited by the dependence on multiple donors and the requirement for potent long-term immunotherapy.

78. STEM CELL THERAPY- Stem cell therapy is one of the most promising treatments for the near future. It is expected that this kind of therapy can ameliorate or even reverse some diseases. To promote regeneration and/or preservation of β cell mass.

79. NON DRUG TREATMENT Life style changes which are used to controlling diabetes Life style change is defined as the way of living which has been altered by variety manner. Life style have seven principles of good diabetes care: • Learn as much as you can about diabetes • Get regular care for diabetes • Learn how to control your diabetes • Take care of your diabetic ABC’s • Monitor your diabetic ABC’s • Prevent long term diabetes problems • Get checked for long term problems and treat them

80. Exercise It is an important in helping to prevent diabetes and is having vital role of our treatment. Some good qualities of exercise: 1 . It helps in losing weight 2 . It can reduce blood glucose levels and keep it low for several hours afterwards 3 . Exercise can reduce cholesterol and blood pressure 4 . Exercise helps reduce stress 5 . Exercise makes the tissues in your body more sensitive to the effects of insulin. This allows insulin to push more glucose out of the blood stream into the cells, which will reduce the level of glucose in our blood .

81. Diet The diet recommends places an emphasis on foods that are higher in fiber and low in fat . High fiber , low fat diet can make body more sensitive to insulin. Diet also involves weight loss which is another way to increase diabetic patient’s body sensitivity to the effects of insulin.

82. CONCLUSION The considered view is that the diabetes therapy should focus on delaying progression of the disease. Treatment options are supposed to be directed at the known pathogenetic disturbances of the disease. The realization that DM is a “metabolic curse” should be a trigger for desire to seek understanding of the biochemical and molecular basis of this metabolic disorder. Such an understanding will inform efforts to elucidate more effective management interventions against diabetes mellitus.

83. REFERENCES Habtamu Wondifraw Baynest ; Classification, Pathophysiology, Diagnosis and Management of Diabetes Mellitus; J Diabetes Metab ; Volume 6 , Issue 5 M.N. Piero , G.M. Nzaro , J.M. Njagi ; Diabetes mellitus – a devastating metabolic disorder; Asian Journal of Biomedical and Pharmaceutical Sciences; 4(40) 2014,1-7. K.Harikumar , B. Kishore Kumar, G.J.Hemalatha , M.Bharath Kumar, Steven Fransis Saky Lado ; A Review on Diabetes Mellitus; international journal of novel trends in pharmaceutical sciences; volume 5, number 3, jun 2015. Gretchen Perilli , Christine Saraceni , Michael N. Daniels, Aakif Ahmad; Diabetic Ketoacidosis: A Review and Update; Curr Emerg Hosp Med Rep (2013) 1:10–17 W Todd Cade; Diabetes-Related Microvascular and Macrovascular Diseases in the Physical Therapy Setting; Journal of American Physical Therapy Assocoation ; Volume 88 Number 11 Abdullah S Al- Goblan , Mohammed A Al- Alfi , Muhammad Z Khan; Mechanism linking diabetes mellitus and obesity; Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy; 2014

84. Brian L. Mealey and Thomas W. Oate ; Diabetes Mellitus and Periodontal Diseases; Journal of Periodontology; August 2006 Brian L. Mealey &Alan J. Moritz; Hormonal influences: effects of diabetes mellitus and endogenous female sex steroid hormones on the periodontium; Periodontology 2000, Vol. 32, 2003, 59–81 Varun Parkash Singh, Anjana Bali, Nirmal Singh, and Amteshwar Singh Jaggi ; Advanced Glycation End Products and Diabetic Complications; Korean J Physiol Pharmacol Vol 18: 1－ 14, February, 2014 Internet sources