A critical requirement for orderly epidemiologic, genetic and clinical research, and indeed for the management of diabetes mellitus and other forms of glucose intolerance is an appropriate classification system. Furthermore, a hallmark in the process of understanding the etiology of a disease and studying its natural history is the ability to identify and differentiate its various forms and place them into a rational etiopathologic framework.
While there have been a number of sets of nomenclature and diagnostic criteria proposed for diabetes, no systematic categorization existed until the mid 1960s . Now diabetes mellitus is recognized as being a syndrome, a collection of disorders that have hyperglycemia and glucose intolerance as their hallmark, due either to insulin deficiency or to impaired effectiveness of insulin’s action, or to a combination of these.
Historical perspective and current classifications
In 1965, an Expert Committee on Diabetes Mellitus published the first World Health Organization (WHO) report on diabetes classification . The report includes one of the first attempts at international consensus on a classification. They decided to classify diabetes: “… based on the age of recognized onset, which seemed to be the only reliable means of classification for universal use.”
The report also recognized certain specific types of diabetes including brittle, insulin-resistant, gestational, pancreatic, endocrine, and iatrogenic diabetes. Since then, several pathogenic mechanisms have been described and long-term studies have shown different courses and outcomes of different types of diabetes.
A revised classification of glucose intolerance, was formulated by the National Diabetes Data Group (NDDG) . This was amended and adopted in the second report of the WHO Expert Committee in 1980  and in a modified form in 1985. The 1980 Expert Committee proposed two major classes of diabetes mellitus and named them insulin-dependent diabetes mellitus (IDDM) or type 1, and non-insulin-dependent diabetes mellitus (NIDDM) or type 2 . In the 1985 Study Group Report, the terms type 1 and type 2 were omitted, but the classes IDDM and NIDDM were retained and a new class of malnutrition-related diabetes mellitus (MRDM) was introduced . The 1985 WHO classification was essentially based on clinical descriptions, with a specific focus on the pharmacologic management of patients (i.e., insulin-dependent, non-insulin-dependent, gestational). The question as to whether certain clinical forms of diabetes (such as the so-called “tropical diabetes”) had been given adequate priority to correct hierarchic order that was raised many years before probably led to the introduction of MRDM, although more precise epidemiologic data and a better assessment were needed, and called for.
Both the 1980 and 1985 reports included other types of diabetes and impaired glucose tolerance (IGT) as well as gestational diabetes mellitus (GDM). The 1985 classification was widely accepted and used internationally, and represented a compromise between clinical and etiological classifications.
Furthermore, it permitted classification of individual patients in a clinically useful manner even when the specific etiology was unknown. The 2011 American Diabetes Association (ADA)  classifications or staging of diabetes still include clinical descriptive criteria but a complementary classification according to etiology is recommended by both organizations.
In 1999, the WHO incorporated an approach developed by Kuzuya and Matsuda , which clearly separated the criteria related to etiology from those related to the degree of deficiency of insulin or insulin action, and defined each patient on the basis of these two sets of criteria (Figure 1.1). It is now well established that diabetes may progress through several clinical stages during its natural history, quite independent of its etiology. The clinical staging reflects this and, indeed, individuals may move from one stage to another stage in both directions (Figure 1.1). Even if there is no information concerning the underlying etiology, persons with diabetes or those who are developing the disease can be categorized by stage according to clinical characteristics.
The current classification allows for various degrees of hyperglycemia in individuals irrespective of the disease process.These are glycemic stages ranging from normoglycemia (normal glucose tolerance) to hyperglycemia where insulin is required for survival. All individuals with the disease can be categorized according to clinical stage . The stage of glycemia may change over time depending on the extent of the underlying disease processes. As shown in Figure 1.1, the disease process may be present but may not have progressed far enough to cause hyperglycemia. The etiological classification is possible as the defect or process which may lead to diabetes may be identified at any stage in the development of diabetes, even at the stage of normoglycemia. As an example, the presence of islet cell antibodies (ICA) and/or antibodies to glutamic acid decarboxylase (anti-GAD)  in a normoglycemic individual indicates the autoimmune process, which underlies type 1 diabetes, is present, although the individual may or may not ultimately develop diabetes [7.9]. For type 2 diabetes, there are few useful highly specific indicators, though the presence of risk factors such as obesity indicates the likelihood of developing type 2 diabetes. Hopefully, future research will reveal some specific markers of the type 2 diabetes disease process.
The same disease process can cause various degrees of impaired glucose metabolism such as impaired fasting glycemia (IFG) and impaired glucose tolerance (IGT) without fulfilling the criteria for the diagnosis of diabetes . Weight reduction, exercise and/or oral hypoglycemic therapy can achieve satisfactory glycemic control in some persons with type 2 diabetes. These persons, therefore, do not require insulin initially but may do so much later in their course as β-cell function deteriorates. Some persons require insulin for adequate glycemic control at an earlier stage in type 2 diabetes but could survive without it. By definition these persons have some residual insulin secretion. Patients with extensive β-cell destruction (minimal residual insulin secretion) do require insulin for survival and this is the hallmark of type 1 diabetes [7,9].
The classification by etiological type (Table 1.1) results from improved understanding of the causes of diabetes, although this is still far from complete, particularly for type 1 diabetes.
The terms “insulin-dependent diabetes mellitus,” “noninsulin-dependent diabetes mellitus” and their acronyms “IDDM” and “NIDDM” have been removed from classifications. These terms were very confusing and frequently resulted in misclassification, as patients were classified on the basis of their treatment, and indeed their age, rather than on pathogenesis. In the current classification, the terms “type 1” and “type 2” are retained (using Arabic rather than Roman numerals) .
Type 1 includes those cases attributable to an autoimmune process (although the basic precipitating cause of this process is still unknown), as well as those with β-cell destruction for which neither an etiology nor a pathogenesis is known (idiopathic). Those forms of β-cell destruction or failure to which specific causes can be assigned (e.g. cystic fibrosis, mitochondrial defects) are not included in this type of diabetes. These issues are discussed in greater detail later.
Type 2 includes the common major form of diabetes which results from defect(s) in insulin secretion and/or from insulin resistance, and often a combination of both. Malnutrition related diabetes (MRDM) is no longer part of the WHO classification . Of its two subtypes, protein-deficient pancreatic diabetes (PDPD or PDDM) needs more studies for a better definition. The other former subtype of MRDM, fibrocalculous pancreatic diabetes (FCPD), is now classified as a disease of the exocrine pancreas labeled “fibrocalculous pancreatopathy,” which may lead to diabetes.
Impaired glucose tolerance (IGT) and impaired fasting glycemia (IFG) are classified as stages of impaired glucose regulation, since they can be observed in any hyperglycemic disorder.
Gestational diabetes is a state of glucose intolerance first recognized during pregnancy which usually resolves after delivery but is associated with later increased long-term risk of type 2 diabetes. It encompasses the groups formerly classified as gestational impaired glucose tolerance (GIGT) and gestational diabetes mellitus (GDM) .
- World Health Organization (WHO): Diabetes Mellitus. Report of a WHO Expert Committee. Technical Report Series 310. Geneva: WHO, 1965.
- National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979;28:1039–1057.
- World Health Organization: WHO Expert Committee on Diabetes Mellitus. Second report. Technical Report Series 646. Geneva: WHO, 1980.
- World Health Organization: Diabetes mellitus. Report of a WHO Study Group. Technical Report Series 727. Geneva: WHO, 1985, p. 727.
- American Diabetes Association (ADA): Diagnosis and classification of diabetes mellitius. Diabetes Care 2011;34(S1):S62–69.
- Kuzuya T, Matsuda A: Classification of diabetes on the basis of etiologies versus degree of insulin deficiency. Diabetes Care 1997;20:219–220.
- World Health Organization: Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications. Part 1: Diagnosis and Classification of Diabetes Mellitus.Geneva:WHO, 1999. Report No.WHO/NCD/NCS/99.2.
- Tuomi T, Groop L, Zimmet P, et al.: Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin dependent onset of disease. Diabetes 1993;42:359–362.
- Atkinson M, Maclaren N: The pathogenesis of insulin-dependent diabetes mellitus. New England Journal of Medicine 1994;331:1428–1436.
- McLarty D, Atharde I, Bottazzo G, et al.: Islet cell antibodies are not specifically associated with insulin-dependent diabetes in Tanzanian Africans. Diabetes Research and Clinical Practice 1990;9:219–224.
- Ahrén B, Corrigan C: Intermittant need for insulin in a subgroup of diabetic patients in Tanzania. Diabetic Medicine 1984;2:262–264.
- Billings LK, Florez JC: The genetics of type 2 diabetes: what have we learned from GWAS? Annals of the New York Academy of Sciences 2010;1212:59–77.
- Kissebah A, Vydelingum N, Murray R, et al.: Relation of body fat distribution to metabolic complications of obesity. Journal of Clinical Endocrinology & Metabolism 1982;54:254–260.
- Harris MI, Klein R, Welborn TA, Knuiman MW: Onset of NIDDM occurs at least 4–7 yr before clinical diagnosis. Diabetes Care 1992; 15:815–819.
- Gill GV, Mbanya JC, Ramaiya KL, Tesfaye S: A sub-Saharan African perspective of diabetes. Diabetologia 2009;52:8–16.
- Sobngwi E, Mauvais-Jarvis F, Vexiau P, et al.: Diabetes in Africans. Part 2: Ketosis-prone atypical diabetes mellitus. Diabetes & Metabolism 2002;28:5–12.
- Banerji M, Chaiken R, Huey H, et al.: GAD antibody negative NIDDM in adult black subjects with diabetic ketoacidosis and increased frequency of HLA DR3 and DR4. Flatbush diabetes. Diabetes 1994;13:741–745.
- Meigs JB, Shrader P, Sullivan LM, et al.: Genotype score in addition to common risk factors for prediction of type 2 diabetes. New England Journal of Medicine 2008;359:2208–2219.
- Hattersley A, Bruining J, Shield J, et al.: ISPAD Clinical Practice Consensus Guidelines 2006–2007. The diagnosis and management of monogenic diabetes in children. Pediatric Diabetes 2006;7:352–360.
- Vionnet N, Stoffel M, Takeda J, et al.: Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature 1992;356:721–722.
- Murphy R, Ellard S, Hattersley AT: Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nature Clinical Practice Endocrinology and Metabolism 2008;4:200–213.
- Spyer G, Macleod KM, Shepherd M, et al.: Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabetic Medicine 2009;26:14–18.
- Stride A, Vaxillaire M, Tuomi T, et al.: The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia 2002;45:427–435.
- Hattersley A, Bruining J, Shield J, et al.: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatric Diabetes 2009;10(Suppl 12):33–42.
- Iafusco D, Stazi MA, Cotichini R, et al.: Permanent diabetes mellitus in the first year of life. Diabetologia 2002;45:798–804.
- Ellard S, Flanagan SE, Girard CA, et al.: Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. American Journal of Human Genetics 2007;81:375–382.
- Rigoli L, Di Bella C: Wolfram syndrome 1 and Wolfram syndrome 2. Current Opinion in Pediatrics 2012;24:512–517.
- Maassen JA, Kadowaki T: Maternally inherited diabetes and deafness: a new diabetes subtype. Diabetologia 1996;39:375–382.
- Robbins DC, Shoelson SE, Rubenstein AH, Tager HS: Familial hyperproinsulinemia. Two cohorts secreting indistinguishable type II intermediates of proinsulin conversion. Journal of Clinical Investigation 1984;73:714–719.
- Haneda M, Polonsky KS, Bergenstal RM, et al.: Familial hyperinsulinemia due to a structurally abnormal insulin. Definition of an emerging new clinical syndrome. New England Journal of Medicine 1984;310:1288–1294.
- Johns DR: Seminars in medicine of the Beth Israel Hospital, Boston. Mitochondrial DNA and disease. New England Journal of Medicine 1995;333:638–644.
- Semple RK, Savage DB, Cochran EK, et al.: Genetic syndromes of severe insulin resistance. Endocrine Reviews 2011;32:498–514.
- Gullo L, Pezzilli R, Morselli-Labate AM: Diabetes and the risk of pancreatic cancer. New England Journal of Medicine 1994;331: 81–84.
- Permert J, Larsson J, Westermark GT, et al.: Islet amyloid polypeptide in patients with pancreatic cancer and diabetes. New England Journal of Medicine 1994;330:313–318.
- Utzschneider KM, Kowdley KV: Hereditary hemochromatosis and diabetes mellitus: implications for clinical practice. Nature Reviews Endocrinology 2010;6:26–33.
- Yajnik CS, Shelgikar KM, Naik SS, et al.: The ketoacidosis-resistance in fibro-calculous-pancreatic-diabetes. Diabetes Research and Clinical Practice 1992;15:149–156.
- Krejs GJ,Orci L,Conlon JM, et al.: Somatostatinoma syndrome. Biochemical, morphologic and clinical features. New England Journal of Medicine 1979;301:285–292.
- Pandit MK, Burke J, Gustafson AB, et al.: Drug-induced disorders of glucose tolerance. Annals of Internal Medicine 1993;118: 529–540.
- Miller LV, Stokes JD, Silpipat C: Diabetes mellitus and autonomic dysfunction after vacor rodenticide ingestion. Diabetes Care 1978; 1:73–76.
- Assan R, Perronne C,Assan D, et al.: Pentamidine-induced derangements of glucose homeostasis. Diabetes Care 1995;18:47–55.
- Madziarska K: New-onset posttransplant diabetes mellitus begins in the dialysis period. Journal of Renal Nutrition 2012;22:162–165.
- Drachenberg CB, Klassen DK, Weir MR, et al.: Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. Transplantation 1999;68:396–402.
- Penfornis A, Kury-Paulin S: Immunosuppressive drug-induced diabetes. Diabetes & Metabolism 2006;32:539–546.
- Fabris P, Betterle C, Floreani A, et al.: Development of type 1 diabetes mellitus during interferon alfa therapy for chronic HCV hepatitis. Lancet 1992;340:548.
- Sattar N, Preiss D, Murray HM, et al.: Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735–742.
- Preiss D, Seshasai SR, Welsh P, et al.: Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011;305:2556–2564.
- Wang KL, Liu CJ, Chao TF, et al.: Statins, risk of diabetes, and implications on outcomes in the general population. Journal of the American College of Cardiology 2012;60(14):1231–1238.
- Guo JJ, Keck PE, Jr,, Corey-Lisle PK, et al.: Risk of diabetes mellitus associated with atypical antipsychotic use among patients with bipolar disorder: a retrospective, population-based, case-control study. Journal of Clinical Psychiatry 2006;67:1055–1061.
- Kalra S, Kalra B, Agrawal N, Unnikrishnan A: Understanding diabetes in patients with HIV/AIDS. Diabetology and Metabolic Syndrome 2011;3:2.
- De Wit S, Sabin CA, Weber R, et al.: Incidence and risk factors for new-onset diabetes in HIV-infected patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. Diabetes Care 2008;31:1224–1229.
- Fleischman A, Johnsen S, Systrom DM, et al.: Effects of a nucleoside reverse transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults. American Journal of Physiology—Endocrinology and Metabolism 2007;292: E1666–1673.
- Lansang MC, Hustak LK: Glucocorticoid-induced diabetes and adrenal suppression: how to detect and manage them. Cleveland Clinical Journal of Medicine 2011;78:748–756.
- Rhen T, Cidlowski JA: Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. New England Journal of Medicine 2005;353:1711–1723.
- van Raalte DH, Nofrate V, Bunck MC, et al.:Acute and 2-week exposure to prednisolone impair different aspects of beta-cell function in healthymen. European Journal of Endocrinology 2010;162:729–735.
- Forrest JM, Menser MA, Burgess JA: High frequency of diabetes mellitus in young adults with congenital rubella. Lancet 1971; 2:332–334.
- King ML, Bidwell D, Shaikh A, et al.: Coxsackie-B-virus-specific IgM responses in children with insulin-dependent (juvenile-onset; type I) diabetes mellitus. Lancet 1983;1(8339):1397–1399.
- Karjalainen J, Knip M, Hyoty H, et al.: Relationship between serum insulin antibodies, islet cell antibodies and Coxsackie-B4 and mumps virus-specific antibodies at the clinical manifestation of Type I (insulin-dependent) diabetes. Diabetologia 1988;31: 146–152.
- Pak C, Eun H-M, McArthur R, Yoon J: Association of cytomegalovirus infection with autoimmune type 1 diabetes. Lancet 1988;II:1–4.
- Hirata Y, Ishizu H, Ouchi N, et al.: Insulin autoimmunity in a case of spontaneous hypoglycaemia. Journal of the Japan Diabetes Society 1970;13:312–320.
- Solimena M, De Camilli P: Autoimmunity to glutamic acid decarboxylase (GAD) in Stiff-Man syndrome and insulin-dependent diabetes mellitus. Trends in Neuroscience 1991;14:452–457.
- Flier JS: Lilly Lecture: syndromes of insulin resistance: from patient to gene and back again. Diabetes 1992;41:1207–1219.
- Khan C, Baird K, Flier JS, Jarret D: Effects of autoantibodies to the insulin receptor on isolated adipocytes. Studies of insulin binding and insulin action. Journal of Clinical Investigation 1977;60:1094–1106.
- Tsokos GC, Gorden P, Antonovych T, et al.: Lupus nephritis and other autoimmune features in patients with diabetes mellitus due to autoantibody to insulin receptors. Annals of Internal Medicine 1985;102:176–181.
- Moran A, Brunzell C, Cohen RC, et al.: Clinical care guidelines for cystic fibrosis-related diabetes: a position statement of the American Diabetes Association and a clinical practice guideline of the Cystic Fibrosis Foundation, endorsed by the Pediatric Endocrine Society. Diabetes Care 2010;33:2697–2708.
- Azzopardi P, Brown AD, Zimmet P, et al.: Type 2 diabetes in young Indigenous Australians in rural and remote areas: diagnosis, screening, management and prevention. Medical Journal of Australia 2012;197:32–36.
- Pozzilli P,Guglielmi C:Double diabetes: a mixture of type 1 and type 2 diabetes in youth. Endocrine Development 2009;14:151–166.
- Craig ME, Hattersley A, Donaghue KC: Definition, epidemiology and classification. In:Hanas R,Donaghue KC, Klingensmith G, et al. (eds.) Global IDF/ISPAD Guideline for Diabetes in Childhood and Adolescence. Brussels: International Diabetes Federation, 2011.
- Craig ME, Hattersley A, Donaghue KC: Definition, epidemiology and classification of diabetes in children and adolescents. Pediatric Diabetes 2009;10(Suppl 12):3–12.
- World Health Organization: Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia. Report of a WHO/IDF consultation. Geneva: WHO, 2006.
- Peterson KP, Pavlovich JG, Goldstein D, et al.: What is hemoglobin A1c? An analysis of glycated hemoglobins by electrospray ionization mass spectrometry. Clinical Chemistry 1988;44:1951–1958.
- Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine 1993;329:977–986.
- UKPDS (UK Prospective Diabetes Study Group): Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853.
- Little RR, Rohlfing CL, Sacks DB: Status of hemoglobin A1c measurement and goals for improvement: from chaos to order for improving diabetes care. Clinical Chemistry 2011;57:205–214.
- Colagiuri S, Lee CM, Wong TY, et al.: Glycemic thresholds for diabetes-specific retinopathy: implications for diagnostic criteria for diabetes. Diabetes Care 2011;34:145–150.
- Khaw KT, Wareham N, Bingham S, et al.: Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Annals of Internal Medicine 2004;141:413–420.
- Stratton IM, Adler AI, Neil HA, et al.: Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405–412.
- Sacks DB: A1C versus glucose testing: a comparison. Diabetes Care 2011;34:518–523.
- World Health Organization: Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitius. Abbreviated report of a WHO consultation. Geneva: WHO, 2011.
- International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32:1327–1334.
- Christensen DL, Witte DR, Kaduka L, et al.: Moving to an A1C-based diagnosis of diabetes has a different impact on prevalence in different ethnic groups. Diabetes Care 2010;33:580–582.
- Metzger BE, Lowe LP, Dyer AR, et al.: Hyperglycemia and adverse pregnancy outcomes. New England Journal of Medicine 2008;358: 1991–2002.
- Metzger BE, Gabbe SG, Persson B, et al.: International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676–682.
- Santaguida PL, Balion C, Hunt D, et al.: Diagnosis, prognosis, and treatment of impaired glucose tolerance and impaired fasting glucose. Evidence Report/Technology Assessment (Summary) 2005; 1–11.
- Unwin N, Shaw J, Zimmet P, Alberti KG: Impaired glucose tolerance and impaired fasting glycaemia: the current status on definition and intervention. Diabetic Medicine 2002;19:708–723.
- Shaw JE, Zimmet PZ, Hodge AM, et al.: Impaired fasting glucose: how low should it go? Diabetes Care 2000;23:34–39.
- Gabir MM, Hanson RL, Dabelea D, et al.: Plasma glucose and prediction of microvascular disease and mortality: evaluation of 1997 American Diabetes Association and 1999 World Health Organization criteria for diagnosis of diabetes. Diabetes Care 2000;23:1113–1118.
- Ford ES, Zhao G, Li C: Pre-diabetes and the risk for cardiovascular disease: a systematic review of the evidence. Journal of the American College of Cardiology 2010;55:1310–1317.
- The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26:3160–3167.
- American Diabetes Association: Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 1997;20:1183–1197.