Diabetes mellitus classification

Abstracts

A correta classificação do diabete melito (DM) permite o tratamento mais adequado e compreende quatro categorias: DM tipo 1; DM tipo 2; Outros tipos e Diabete Gestacional. Em alguns casos, pode ocorrer sobreposição de quadros, principalmente no DM que inicia no adulto jovem ou que se apresenta inicialmente com cetoacidose, intermediários ao DM 1 e DM 2. Assim, acréscimos ao sistema de classificação clássico têm sido propostos, avaliando a presença de autoimunidade (anticorpos) e a função de célula β (peptídeo-C) para definir mais precisamente os subtipos. O objetivo desta revisão foi de analisar o desempenho desses índices diagnósticos para a classificação do DM e descrever os subtipos em detalhe. Os anticorpos contra o pâncreas evidenciam a autoimunidade, sendo o anticorpo contra insulina o mais acurado antes dos 5 anos de idade e o anti-descarboxilase do ácido glutâmico para início da doença acima dos 20 anos, é esse o teste que permanece positivo por mais tempo. Já a medida do peptídeo-C avalia a reserva pancreática de insulina, e os métodos de estímulo mais usados são a medida após refeição ou após glucagon endovenoso. Valores de peptídeo-C < 1,5 ng/ml definem o paciente com função pancreática ausente, e acima desse valor, com função preservada. Combinando-se a presença de anticorpos (A+) dirigidos ao pâncreas e a sua capacidade secretória de insulina (β+), pode-se subdividir a classificação do DM em tipo 1A (A+β-) e 1B (A+ β-); e o DM tipo 2 em subgrupos de DM 2A (A+β+) e DM 2B (A-β+), o que permite uma classificação e tratamento mais precisos, além de abrir os horizontes para o entendimento da patogênese do DM.

Diabete melito; ácido glutâmico; carboxi-líases; peptídeo C

CLINICAL UPDATE

Diabetes mellitus classification

Jorge de Faria Maraschin; Nádia Murussi; Vanessa Witter; Sandra Pinho Silveiro

Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS - Brazil

Mailing address

ABSTRACT

The right classification for diabetes mellitus (DM) allows a more adequate treatment and comprises four categories: type 1 DM, type 2 DM, other types, and gestational diabetes. In some cases, there might be a superposition of situations, especially with regard to the DM that initiates in the young adult or is initially presented with diabetic ketoacidosis intermediately to type 1 and 2 DM. Thus, additions to the classic classification system have been proposed as assessing the presence of autoimmunity (antibody) and b cell function (C-peptide) to precisely define the subtypes. The aim of this literature review was to analyze these diagnostic indexes’ performance in the DM classification and to describe subtypes with details. The antibodies against pancreas confirm autoimmunity, and the antibody against insulin is more accurate before 5 years old, while the anti-glutamic acid decarboxylase is more accurate after 20 years old, a test which remains positive for a longer period. The measurement of C-peptide evaluates the pancreatic insulin reserve, and the most largely used methods of stimulation are the measurement after meals or after intravenous glucagon. C-peptide values < 1.5 ng/ml define a patient with absent pancreatic function and, above this value, patients with preserved function. When the presence of antibodies (A+) directed to the pancreas is combined to its insulin secretion capability (β+), it is possible to subdivide DM’s classification in type 1A (A+β-) and 1B (A+β-); and type 2A (A+β+) and 2B (A-β+), which allows a more precise classification and treatment besides opening horizons for the understanding of DM pathogenesis.

Key words: Diabetes mellitus/classification; glutamic acid; carboxy-lyases; C-peptide.

Diabetes mellitus (DM) is a common disease which is considered epidemic by World Health Organization (WHO). Estimative for world prevalence is around 4.0%^1,2 and, in Brazil, around 7.6%, as shown in the last evaluation³. Its incidence in adults and adolescents have been alarmingly rising in developed countries with estimatives for an increase of 60% in the adult population with more than 30 years old in 2025¹, as the higher prevalence would be present in 45 to 64 years-old adults^1,2.

The right classification for DM type allows a precocious adequate treatment, with higher rate of success concerning the obtainment of a safe glycemic control, which reduces microvascular complications in patients with type 1 or type 2 DM^4,5. Although randomized clinical trials have not shown reduction in cardiovascular outcomes during intensified glycemic control studies, the long term follow-up of patients have shown a decrease in the risk of macrovascular disease⁶. Currently, the American Diabetes Association (ADA) and the American Heart Association (AHA) recommend that the target range for HbA1c be in general < 7% (ADA: B level and AHA: A level). Less rigorous target ranges have been suggested for individuals with history of severe hypoglycemia, limited expectation of life, advance-staged micro or macrovascular disease and important comorbidities (ADA: C level and AHA: C level).

New DM classification was redefined in an ADA’s publication in 1997⁷ and of WHO in 2006⁸. Updated national and international directions recommend DM’s classification in four categories: type 1 DM (DM1), type 2 (DM2), other types and gestational diabetes⁹ (Chart 1).

DM1 is responsible for approximately 5 to 10% of all DM cases, and is subdivided in type 1A, type 1B and Latent Autoimmune Diabetes of the Adult (LADA). In general, DM1 is disclosed before 30 years old, but may attain individuals of all age groups. There is a destruction of pancreatic b-cells, and its treatment requires insulin for hindering diabetic ketoacidosis³. In DM 1A, β-cells destruction is of autoimmune cause (90% of cases) and in DM 1B there are no known causes (idiopathic). LADA is a type of DM1 in which autoimmune β-cells destruction also happens, but it is much slower and comprises older individuals (older than 30 years old). its phenotype is peculiar, for patients are not obese, had DM diagnosed in age compatible with type 2 DM, are initially controlled by oral agents, but they present signs of progressive β-cell’s function loss⁹ and eventually need insulin after at least six months post-DM diagnosis⁹. DM 1B was initially described in Africans and Asians⁷. However, this type have been assessed and described with more details in other populations, which brought out a new nomenclature: ketosis-prone DM¹⁰, a type of DM that would be intermediate to type 1 and 2. These cases would differ from LADA for being initially manifested as ketoacidosis, while proper LADA requires insulin six months after diagnosis. An additional observation describes the presence of antibodies in children and adolescents that are not dependent on insulin initially, but present DM2 profile. In these cases, as following LADA terminology for adults, the right classification would be "LADY" (Latent Autoimmune Diabetes in Youth), but a longer period of follow-up is still necessary for defining such cases’ development, besides the fact that this nomenclature is not official¹¹.

DM2 is responsible for more than 90% of DM cases, has no autoimmune component, and is unleashed generally after 30 years old in individuals with positive family history. The initial treatment usually involves diet and oral hypoglycemic agents with no need for insulin. When necessary, insulin can be added to treatment, but this usually happens, at least, five years after the diagnosis configuring a initial state of non insulin requiring diabetes, the opposite of type 1 DM^6,7.

In the "other DM type" category, the Maturity Onset Diabetes of the Young (MODY) is highlighted, a subtype that attains individuals younger than 25 years old, non-obese, and which is characterized by a deficiency in insulin secretion but does not provoke dependence on it. It also presents dominant autossomic inheritance, thus involving many generation of one sole family^7,12. There are six subtypes of MODY, which are qualified according to the identified genetic mutation: MODY 1 (mutation in the hepatic transcription factors gene, HNF-4α); MODY 2 (mutation in the glycokinasis gene); MODY 3 (mutation in the HNF-1α gene); MODY 4 (mutation in the insulin promoter factor, also known as IPF); MODY 5 (HNF-1β) and MODY 6 (mutation in Neuro-D1 gene). The more common types are MODY 2 and 3, and the others are very rare¹².

Unlikely MODY, that typically represents a pattern of monogenic DM, DM2 brings a polygenic inheritance that has not been completely defined yet. DM2’s pathogenesis is complex and comprises the interaction between genetics and environment factors, especially obesity due to sedentary life and to excessive food intake. With regard to DM2’s genetic aspects, some genes, such as calpain-10, PPARγ2 and Kir6.2, have been confirmed, but it is necessary to go forward in the elucidation of these and other genes’ roles¹³. Although DM1 participate in the autoimmune 1A subtype, it is a heterogeneous disease and many patterns of monogenic inheritance (associated with autoimmune polyendocrinopathy) have already been defined. Nonetheless, the majority of the genes that promote genetic susceptibility in type 1 are still to be identified.

Despite the fact that this classification defines this and other categories through peculiar characteristics, there might be a superposition of clinical situations, mainly concerning DM that develops in the young adult. Sometimes it is difficult to distinguish a subtype from another based solely on clinical data, especially DM1 MODY and DM2 of precocious initiation, which is becoming more and more frequent due to an increase in obesity and metabolic syndrome prevalence among occidental societies. Besides, some types of DM identified in the last decades, which are intermediate to type 1 and 2, do not comply with ADA and WHO’s classifications, for there are particularities in their natural history, as well as the necessity of insulin treatment. The aforementioned DM propense to ketosis is an example¹¹.

For that reason, complementary schemes for classification have been proposed with the involvement of autoimmunity (antibodies) and of β-cells function indexes (C-peptide) capable of not only defining more specific pathogenesis and nomenclature, but also suggesting more adequate methods of treatment. The Ab classification (A=antibodies and β=islet function) has been proposed with the purpose of complementing the traditional ADA classification for the types of diabetes which have propensity to ketosis, but without being contradictory to it. The presence of antibodies is defined as "A+" while the preservation of pancreatic function is defined as "β+". ADA’s classification or DM1 cases is maintained in two subgroups (type 1A and 1B, with and without antibodies, respectively, and both without insulin production), and this subdivision is applied to DM2, which implies having insulin reserve with or without antibodies.

This proposal is based on the recognition of DM heterogeneous syndrome, which have been identified and followed in cohorts. Through the comparison between other classifications, it has shown to be more accurate and predictive of important outcomes, such as glycemic control and dependence on insulin, as well as a good indicator of new causes for β-cell dysfunction, with molecular and biochemical profile already described¹¹.

The objective of this literature review is to assess the performance of the indexes that evaluate autoimmunity and insulin secretion with the purpose of putting DM into classification and describing in details the subtypes that were generated by such classification.

The role of pancreatic antibodies

Autoimmunity against pancreatic islets was described in 1965, but the presence of antibodies (AB) against islets (the islet-cell cytoplasm antibodies; ICA) was first demonstrated in 1974¹⁴. Following, the existence of many other antibodies was identified: islet cell surface antibody (ISCA); insulin auto-antibodies (IAA); and insulinoma like antigen-2 (IA-2). The different types of antibodies directed to the pancreas as well as their role in the diagnosis of patients with DM1 will be herein described (Chart 2)¹⁶.

The presence of antibodies indicates a DM of autoimmune etiology and, thus, type 1 classic, which is called type 1A. Many methods were created, in international collaborations, to measure the diverse antibodies and to standardize it^17,18. As there is no international standard for the islet-cell antibody and also a lack of studies with consistent and reproducible results, its use is limited to research¹⁴. The islet-cell antibodies, the anti-glutamic acid decarboxylase and the insulinoma like antigen-2 were subject for trials based on recombinant proteins, which may be marked with radioactive iodine, allowing the development of reproducible and precise trials that are already standardized according to the criteria recommended by WHO¹⁷. The sensibility and specificity for the diagnosis of DM1 are presented in Chart 2.

The islet-cell antibodies, initially described in 1974¹³, were the first ones to be used, but their laboratorial standardizing happened only in 1986¹⁹. Their reaction occurs against all components of pancreatic islet^14,15. There are several other pancreatic islet antibodies and many are still to be recognized. However, the anti-glutamic acid decarboxylase, anti-insulin, anti-islet and AI-2 have more utility in the clinical practice²⁰.

The islet-cell antibodies are efficient markers of DM1. Their sensibility varies from 70 to 90%^16,17. However, the capability of predicting risk for DM1 decreases significantly in individuals with symptoms manifestation in advanced ages, mainly after 20 years old^21,22. These antibodies are present during the pre-diabetes phase and in the beginning of the disease establishment, but their titles drop rapidly right away^21,23. Their presence is associated with a rapid loss of β-cell function²¹ and with the prediction of insulin necessity in patients initially diagnosed with DM2^21,23,24.

Anti-insulin antibodies are present in approximately 50% of patients recently diagnosed with DM1, and they are reckoned by means of a radioimmune trial of simple liquid phase²⁵. It shows 50 to 70% of sensibility in the DM1 diagnosis. In general, the younger is the patient in the beginning of the disease, the bigger is its positivity²⁶. It consists of a efficient marker for pre-clinical disease in children especially those who are less than 5 years old, for it predicts DM risk in children better than in adults^22,27.

The anti-glutamic acid decarboxylase antibody was initially described as a protein of 64 kilodaltons^14,28. There are two isoforms²⁹: one denominated 65 (expressed in β-cells) and other denominated 67 (in the brain). The function of glutamic acid decarboxylase enzyme consists of producing the inhibitory neurotransmitter GABA and, in the pancreatic β-cell, adenosine triphosphate (ATP)²⁹. Anti-glutamic acid decarboxylase antibody’s sensibility for DM1 diagnosis is between 75 and 85%³⁰. There is a great difference in its sensibility concerning genre³¹ and age of DM diagnosis³⁰. For females, its sensibility is around 80% and does not vary with age. For males, the sensibility of approximately 50 to 60% before 10 years old and between 75 and 90% after this age^30,31. Specificity reaches 99% and the sensibility is considered as better than anti-islets and anti-insulin in adults^30,32. The anti-glutamic acid decarboxylase is the most durable antibody, for it may still be positive after 15 of the establishment of DM³³. In first-grade relatives, its positivity varies from 6 to 8%, similarly to the risk of DM1 development during life³⁰. It is more positive in sons of fathers than in sons of mothers that are carriers of DM1³⁴. In Diabetes Prevention Trial (DPT-1)³⁵, this antibody was the most sensitive marker for the detection of multiple antibodies. However, it is known that no antibody predicts solely and satisfactorily the risk of DM1 development, which is related to the number of antibodies present during the autoimmune evolution process^35-38. The risk of DM development in first grade relatives carriers of DM1 was 39 to 68% after three and five years, respectively, when two antibodies were present. The presence of three antibodies shows a 100% risk within five years³⁶.

IA-2, also known as ICA-512, is a protein expressed in the neuroendocrine tissue and that is present in pancreatic a and b-cell. The most accurate measure trials are radioimmune trials³⁹. Their sensibility for DM1 diagnosis varies from 60 to 70%. Positivity decreases according to the disease’s duration, and is higher in patients diagnosed with DM before 10 years old.

In short, antibodies are autoimmunity markers and their presence means type 1 diabetes. In children with DM1 there is positivity for the presence of antibodies in 90% of the cases. Anti-insulin antibody is present in younger individuals, especially those who were diagnosed with DM before 5 years old, and it is considered the best marker of the disease in this age group.

The anti-glutamic acid decarboxylase shows a better performance in individuals that had manifestation of the disease after 20 years old. It is also the one that remains positive during longer periods (10 to 15 years of disease), and is often chosen for LADA diagnosis. Positivity of antibodies predicts the insulin necessity and their solicitation is indicated in cases of diagnostic doubt, that occur mainly when DM is established after 30 years old (Figure 1).

The role of C-peptide

C-peptide levels (CPEP) have been employed as b-cell function indexes, considered as an auxiliary exam in classification of DM type and for the initial choice of treatment⁴⁰. Preservation of endogenous secretion is correlated to a precise glycemic control^41-45, reduction of DM chronicle complications and of hypoglycemic episodes^41,46. CPEP presents as advantage the fact that, unlikely insulin, it is not degraded by the liver, but is exclusively eliminated by the kidney and has a 30-minute half-life⁴⁷. Besides that, exogenous insulin interferes with endogenous insulin dosage, while CPEP does not suffer this intervention.

The two-chain insulin structure was first described in 1955⁴⁸ and, in 1967, the existence of a biosynthetic precursor was documented: the proinsulin⁴⁹. The CPEP is a subproduct of proinsulin degradation and is co-secreted with the insulin by the pancreatic β-cell. Inside the pancreatic islet, proinsulin suffers cleavage, generating insulin and CPEP as final products, which are liberated in the portal circulation in equimole concentrations (Figure 2)⁵⁰.

CPEP consists of a small molecule that may suffer cleavage from proteolytic enzymes and, therefore, the plasma must be soon separated (within less than two hours), which should be carried out during the first freeze month. World strategies for the standardization of CPEP measurement are being currently considered^46,51.

One of the most important aspects, which have not been well established yet, concerns the glycemic homeostasis conditions under which CPEP must be measured⁵². Hyperglycemia may increase (by direct stimulation of glycemia) or decrease (by glucotoxicity) the β-cell response to the test, as well as hypoglycemia may inhibit the β-cell response^52,53. For that reason, CPEP measure must be made in the absence of hyper or hypoglycemia, as the ideal glycemia would be between 70 and 200 mg/dl.

CPEP measure may be made in the basal or stimulated by endovenous, intramuscular or subcutaneous glucagon; oral or endovenous amino acids, oral or endovenous glucose; and by mix diet^54-57. The two most used stimulations are endovenous glucagon and the mix diet test, as the latter is strongly recommended by ADA.

The patient is characterized with DM1 when presents CPEP values inferior to 1.8 ng/dl after 1 mg of endogenous glucagon⁵⁸, and inferior to 1.5 ng/dl after the mix diet test⁴⁵. Some authors suggest that the basal value alone would be sufficient to characterize the patient, and a study have shown that the random CPEP value (1.5 ng/ml cut-point) measured at any time would be more sensitive⁵⁹. A classical Denmarkian study indicated that a basal value inferior to 0.9 ng/ml could already be able to indicate insulin dependence⁴⁷. Many authors do not take into account the duration time effect of DM in CPEP levels, once several other studies that followed diabetic patients have showed that the β-cell function decreases together with the duration of DM, and is faster in patients with a bad glycemic control^41,45,60,61. As the decreasing rate varies, one single measure is enough for the diagnosis in new cases, but not to evaluate its decrease and, thus, repeated measurements are recommended^46,60,62.

In summary, the CPEP measure appears to be a good marker for the β-cell function and must be made with glycemia between 70 and 200 mg/dl. Stimulation with mix diet is recommended by ADA, but the test performed with endovenous glucagon 1 mg is simpler and equally effective. Stimulated values that are inferior to 1.5 ng/ml define the DM1 patients, while the superior values define the DM2 patients (Figure 1).

Critical analysis of classification schemes

DM is defined as a heterogeneous group of metabolic diseases, and its correct classification must be based on physiopathological principles and be helpful in the choice of the treatment^7,8. However, current sudies^63,64 show that the available classification scheme does not truly reflect all the involved mechanisms. Some DM subtypes have been described in the last decades. In 2002, the name "Ketosis-prone diabetes" was created, which would correspond to a subtype that is intermediate to type 1 and 2¹⁰. Initially, the case was described in Africans and Afro-Americans, but in the past few years American, European, Japanese and other populations have presented this subtype^63-65.

It is known that DM2, in stress situations such as severe infections and cardiovascular diseases, may present with ketoacidosis. In contrast, the ketosis-prone diabetes manifests initially with ketoacidosis symptoms without apparent causes, as the name says. Finally, the non-ketosis-prone diabetes is the classic DM2, which does not cause dependence on insulin.

There are four different classifications for ketosis-prone diabetes. The ADA’s scheme⁷, other scheme modified from ADA’s classification⁶⁵, the scheme based on body mass index (BMI)⁶⁶ and the one that assesses the presence of autoimmunity and the β-cell function, called Aβ⁶⁴.

According to ADA’s classification, the presence of ketoacidosis characterizes the person as a DM1 patient, and it is considered subtype 1A if there are any positive immunologic markers against β-cell, and type 1B (idiopathic) if they are absent.

The modified ADA’s classification⁶⁵ divides patients into three groups. Type 1 has positive immunologic markers against b-cells. Those that do not present antibodies are divided into two subgroups: dependent and independent on insulin, a classification based on the necessity of insulin at long term. In general, type 1A and insulin-dependent diabetes have clinical characteristics of DM1 with low b-cell function, while the insulin-dependent types have clinical characteristics of DM2 with preserved b-cell function⁶⁵.

The scheme based on BMI⁶⁶ characterize the patients as thin (BMI < 28 kg/m²) or obese (BMI > 28 kg/m²). The thin patients present DM1 with low β-cell function characteristics, and the obese patients present DM2 with preserved β-cell function characteristics.

The classification Aβ⁶⁴ is based on the presence of autoimmunity markers against pâncreas (A+ ou A-) and associated with the analysis of the β-cell function (β+ ou β-). There are four groups: type 1ª DM, with positive autoimmunity and absence of β-cell function (A+β-); type 1B DM, without autoimmunity and absence of β-cell function (A-β-). These first subtypes are comprised in ADA’s classification. Additionally, two more subtypes are described as branches of DM2: DM2 with autoimmunity and preserved β-cell function (A+β+), and DM2B, without autoimmunity and maintained β-cell function (A-β+). The fluxogram indicates how to identify these subtypes (Figure 1).

A+β- and A-β- patients are immunologically and genetically different from one another, but they present DM1 clinical characteristics with low β-cell function. A-β+ and A+β+ patients are immunologically and genetically different, but with DM2 clinical characteristics and preserved b-cell function⁶⁴. Therefore, there are important differences in phenotypes and in natural history of subtypes that remain unexplained in ADA’s classification, in which both β- subtypes would be DM1 and both β+ subtypes would be DM2. As confirming it, after assessing the histocompatibility system, susceptible alleles were acknowledged as more frequent in both A+ subgroups than in A- subgroups. Resistance alleles, on the other hand, were found to be more frequent in β+ subgroups⁶⁷. The inheritance of specific alleles may be considered as a marker of the pancreatic function evolution, determining the necessity of insulin and identifying candidates for immunomodulatory therapy.

A recent study⁶³ compared the diagnostic accuracy of the four classification items of ketosis-prone diabetes. The Ab classification, with a 99.4% sensitivity, 95.9% specificity, 97.1% positive predictive value, 99.2% negative predictive value and a 0.972 area under the receiver operating characteristic curve (ROC), was statistically superior to the other three classifications for DM. Although this data are not definitive and further studies on diverse races are necessary for the confirmation of such findings, the magnitude of the differences with regard to other means of classification in current use suggests that it may be adopted as an effective, relatively simple and precise method for DM classification, complementing ADA and WHO’s classifications.

To sum up, the Aβ classification, which allows for the presence or absence of antibodies (A+ or A-) and the β-cell function (β+ or β-), defines the presence of diabetes mellitus type 1A, 1B, 2A and 2B. These classifications maintain the already recognized DM1 subtypes, and extend them to other ethnicities. It also permits to identify type 2 patients that are initially insulin-dependent and later on may renounce its use, DM2B (A-β+) and also make notice the patients who have initially preserved pancreatic function, but may evolve to insulin dependence (A+β+), hence with periodic pancreatic function reviews needed.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

This study was funded by FIPE.

Study Association

This article is part of the thesis of master submitted by Jorge de Faria Maraschin, from Universidade Federal do Rio Grande do Sul.

References

• 1. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998; 21: 292-6.
• 2. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004; 27: 1047-53.
• 3. Gross JL, Silveiro SP, Camargo JL, Reichelt AJ, Azevedo MJ. Diabetes melito: diagnóstico, classificação e avaliação do controle glicêmico. Arq Bras Endocrinol Metab. 2002; 46: 16-26.
• 4. Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T. Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care. 2005; 28: 164-76.
• 5. Campagnolo N, Murussi N, Silveiro SP. Diabete melito. In: von Exe Colerta, Capp E. (orgs.). Ginecologia no consultório. São Paulo: Artmed; 2008. p. 519-41.
• 6. Skyler JS, Bergenstal R, Bonow RO, Buse J, Deedwania P, Gale EA, et al. Position Statement. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA Diabetes Trials: a position statement of the American Diabetes Association and a Scientific statement of the American College of Cardiology; Foundation and the American Heart Association. Diabetes Care. 2009; 32: 187-92.
• 7. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997; 20: 1183-97.
• ⁸
  World Health Organization Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia : Report of a WHO/IDF consultation. Geneva: WHO; 2006.
• 9. American Diabetes Association. Position Statement. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2009; 32: S62-S67.
• 10. Balasubramanyam A, Nalini R, Hampe CS, Maldonado M. Syndromes of ketosis-prone diabetes mellitus. Endocr Rev. 2008; 29: 292-302.
• 11. Reinehr T, Schober E, Wiegand S, Thon A, Holl R, DPV-Wiss Study Group. Beta-cell autoantibodies in children with type 2 diabetes mellitus: subgroup or misclassification? Arch Dis Child. 2006; 91: 473-7.
• 12. Campagnolo N, Dallapicola PF, Murussi N, Canani LH, Gross JL, Silveiro SP. Aspectos clínicos e moleculares do Maturity Onset Diabetes of the Young (MODY). Revista do Hospital de Clínicas de Porto Alegre. 2005; 24: 51-9.
• 13. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Williams textbook of endocrinology. 11th ed. Philadelphia: Saunders Elsevier; 2008. p. 1329-89.
• 14. Eisenbarth GS, Polonsky KS, Buse JB. Type 1 diabetes mellitus. In: Williams textbook of endocrinology. 11th ed. Philadelphia: Saunders Elsevier; 2008. p. 1391-416.
• 15. Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 1990; 347: 151-6.
• 16. Lan MS, Wasserfall C, Maclaren NK, Notkins AL IA-2. A transmembrane protein of the protein tyrosine phosphatase family, is a major autoantigen in insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA. 1996; 93: 6367-70.
• 17. Mire-Sluis AR, Das RG, Lernmark Å. The World Health Organization International collaborative study for islet cell antibodies. Diabetologia. 2000; 43: 1282-92.
• 18. Bingley PJ, Bonifacio E, Mueller PW: Diabetes antibody standardization program: first assay proficiency evaluation. Diabetes. 2003; 52: 1128-36.
• 19. Bottazzo GF, Gleichmann H. Immunology and diabetes workshops: report of the first international workshop on the standardisation of cytoplasmic islet cell antibodies. Diabetologia. 1986; 29: 125-6.
• 20. Winter WE, Harris N, Schatz D. Immunological markers in the diagnosis and prediction of autoimmune Type 1a diabetes. Clin Diabetes. 2002; 20: 183-91.
• 21. Marner B, Agner T, Binder C, Lernmark Å, Nerup J, Mandrup-Poulsen T. Increased reduction in fasting C-peptide is associated with islet cell antibodies in Type 1 (insulin-dependent) diabetic patients. Diabetologia. 1985; 28: 875-80.
• 22. Landin-Olsson M, Karlsson FA, Lernmark A, Sundkvist G. Islet cell and thyrogastric antibodies in 633 consecutive 15-to 34-yr-old patients in the Diabetes Incidence Study in Sweden. Diabetes. 1992; 41: 1022-7.
• 23. Schiffrin A, Ciampi A, Hendricks L, Rozen R, Weitzner G. Evidence for different clinical subtypes of type 1 diabetes mellitus: a prospective study. Diabet Res Clin Pract. 1994; 23: 95-102.
• 24. Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, et al. for UK Prospective Diabetes Study (UKPDS) Group UKPDS 25. Autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet. 1997; 350: 1288-93.
• 25. Ziegler AG. The Fourth International Workshop on the Standardisation of Insulin Autoantibody Measurement. Diabetologia. 1990; 33: 683-9.
• 26. Eisenbarth GS, Jackson RA, Pugliese A. Insulin autoimmunity: the rate limiting factor in pre-type I diabetes. J Autoimmun. 1992; 5: 241-6.
• 27. Knip M: Natural course of preclinical type 1 diabetes. Horm Res. 2002; 57: 6-11.
• 28. Karlsen AE, Hagopian WA, Grubin CE, Dube S, Disteche CM, Adler DA, et al. Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10. Proc Natl Acad Sci. 1991; 88: 8337-41.
• 29. Bu DF. Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene. Proc Natl Acad Sci. 1992; 89: 2115-9.
• 30. Vandewalle CL, Falorni A, Svanholm S, Lernmark A, Pipeleers DG, Gorus FK. High diagnostic sensitivity of glutamate decarboxylase autoantibodies in insulin-dependent diabetes mellitus with clinical onset between age 20 and 40 years. The Belgian Diabetes Registry. J Clin Endocrinol Metab. 1995; 80: 846-51.
• 31. Verge CF, Howard NJ, Rowley MJ, Mackay IR, Zimmet PZ, Egan M, et al. Anti-glutamate decarboxylase and other antibodies at the onset of childhood IDDM: a population-based study. Diabetologia. 1994; 37: 1113-20.
• 32. Aanstoot HJ, Sigurdsson E, Jaffe M, Shi Y, Christgau S, Grobbee D, et al. Value of antibodies to GAD65 combined with islet cell cytoplasmic antibodies for predicting IDDM in a childhood population. Diabetologia. 1994; 37: 917-24.
• 33. Maraschin JF. Acurácia diagnóstica do anticorpo anti-descarboxilase do ácido glutâmico (anti-GAD) como marcador de auto-imunidade no diabete melito. [Dissertação]. Porto Alegre: Universidade Federal do Rio Grande do Sul; 2007.
• 34. Ziegler AG, Hummel M, Schenker M, Bonifacio E. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study. Diabetes. 1999; 48: 460-8.
• 35. Krischer JP, Cuthbertson DD, Yu L, Orban T, Maclaren N, Jackson R, et al. Screening strategies for the identification of multiple antibody-positive relatives of individuals with type 1 diabetes. J Clin Endocrinol Metab. 2003; 88: 103-8.
• 36. Verge CF. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes. 1996; 45: 926-33.
• 37. Bingley PJ, Bonifacio E, Williams AJK, Genovese S, Bottazzo GF, Gale EAM. Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. Diabetes. 1997; 46: 1701-10.
• 38. Achenbach P, Warncke K, Reiter J, Naserke HE, Williams AJ, Bingley PJ, et al. Stratification of type 1 diabetes risk on the basis of islet autoantibody characteristics. Diabetes. 2004; 53: 384-92.
• 39. Leslie RD, Atkinson MA, Notkins AL. Autoantigens IA-2 and GAD in Type I (insulin-dependent) diabetes. Diabetologia. 1999; 42: 3-14.
• 40. Polonsky KS, Licinio-Paixao J, Given BD, Pugh W, Rue P, Galloway J, et al. Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients. J Clin Invest. 1986; 77: 98-105.
• 41. The DCCT Research Group: Effect of intensive therapy on residual β-cell function in patients with type I diabetes in the Diabetes Control and Complications Trial. Ann Intern Med. 1998; 128: 517-23.
• 42. Nakanishi K, Kobayashi T, Miyashita H, Ohkubo M, Sugimoto T, Murase T, et al. Relationships among islet cell antibodies, residual β-cell function, and metabolic control in patients with insulin-dependent diabetes mellitus of long duration: use of a sensitive C-peptide radioimmunoassay. Metabolism. 1990; 39: 925-30.
• 43. Sjoberg S, Gunnarsson R, Gjotterberg M, Lefvert AK, Persson A, Osterman J. Residual insulin production, glycaemic control and prevalence of microvascular lesions and polyneuropathy in long-term type 1 (insulindependent) diabetes mellitus. Diabetologia. 1987; 30: 208-13.
• 44. Sjoberg S, Gjotterberg M, Berglund L, Moller E, Osterman J. Residual C-peptide excretion is associated with a better long-term glycemic control and slower progress of retinopathy in type 1 (insulin-dependent) diabetes mellitus. J Diabet Complications. 1991; 1: 18-22.
• 45. The DCCT Research Group: Effects of age, duration and treatment of insulin-dependent diabetes mellitus on residual beta-cell function: observations during eligibility testing for the Diabetes Control and Complications Trial (DCCT). J Clin Endocrinol Metab. 1987; 65: 30-6.
• 46. Palmer JP, Fleming AG, Greenbaum CJ, Herold KC, Jansa LD, Kolb H, et al. C-Peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve ß-cell function: ADA Workshop Report. Diabetes. 2004; 53: 250-64.
• 47. Faber OK, Kehlet H, Madsbad S, Binder C. Kinetics of human C-peptide in man. Diabetes. 1978; 27 (Suppl. 1): 207-9.
• 48. Ryle AP, Sanger F, Smith LF, Kitai R. The dissulphide bonds of insulin. Biochem J. 1955; 60: 541-56.
• 49. Steiner DF, Cunningham D, Spigelman L, Aten B. Insulin biosynthesis: evidence for a precursor. Science. 1967; 157: 697-700.
• 50. Rubenstein AH, Clark JL, Melani F, Steiner DF. Secretion of proinsulin, C-peptide by pancreatic cells and its circulation in blood. Nature. 1969; 224: 697-9.
• 51. Little RR, Rohlfing CL, Tennill AL, Madsen RW, Polonsky KS, Myers GL, et al. Standardization of C-peptide measurements. Clin Chem. 2008; 54: 1023-6.
• 52. Madsbad S, Sauerbrey N, Moller-Jensen B, Krarup T, Kuhl C. Outcome of the glucagon test depends upon the prevailing blood glucose concentration in type I (insulin-dependent) diabetic patients. Acta Med Scand. 1987; 222: 71-4.
• 53. Ronnemaa T. Practical aspects in performing the glucagon test in the measurement of C-peptide secretion in diabetic patients. Scand J Clin Lab Invest. 1986; 46: 345-9.
• 54. Menchini M, Meschi F, Lambiase R, Puzzovio M, Del Guercio MJ, Chiumello G. C-peptide response to arginine stimulation in diabetic children. J Pediatr. 1980; 96: 362-6.
• 55. Scheen AJ, Castillo MJ, Lefebvre PJ. Assessment of residual insulin secretion in diabetic patients using the intravenous glucagon stimulatory test: methodological aspects and clinical applications. Diabetes Metab. 1996; 22: 397-406.
• 56. Sjoberg S, Gunnarsson R, Ostman J. Residual C-peptide production in type I diabetes mellitus: a comparison of different methods of assessment and influence on glucose control. Acta Med Scand. 1983; 214: 231-7.
• 57. Heinze E, Beischer W, Keller L, Winkler G, Teller WM, Pfeiffer EF. C-peptide secretion during the remission phase of juvenile diabetes. Diabetes. 1978; 27: 670-6.
• 58. Hother-Nielsen O, Faber O, Sorensen NS, Beck-Nielsen H. Classification of newly diagnosed diabetic patients as insulin requiring or non-insulin-requiring based on clinical and biochemical variables. Diabetes Care. 1988; 11: 531-7.
• 59. Berger B, Stenstrom G, Sundkvist G. Random C-peptide in the classification of diabetes. Scand J Clin Lab Invest. 2000; 60: 687-3.
• 60. Zangeneh F, Arora PS, Dyck PJ, Bekris L, Lernmark A, Achenbach SJ, et al. Effects of duration of type 2 diabetes mellitus on insulin secretion. Endocr Pract. 2006; 12: 388-93.
• 61. Niskanen L, Karjalainen J, Siitonen O, Uusitupa M. Metabolic evolution of type 2 diabetes: a 10-year follow-up from the time of diagnosis. J Intern Med. 1994; 236: 263-70.
• 62. Brandenburg D. History and diagnostic significance of C-Peptide. Exp Diabetes Res. 2008; 2008: 576862.
• 63. Balasubramanyam A, Garza G, Rodriguez L, Hampe CS, Gaur L, Lernmark A, et al. Accuracy and predictive value of classification schemes for ketosis-prone diabetes. Diabetes Care. 2006; 29: 2575-9.
• 64. Maldonado M, Hampe CS, Gaur L, D'Amico S, Iyer D, Hammerle LP, et al. Ketosis-prone diabetes: dissection of a heterogeneous syndrome using an immunogenetic and ß-cell functional classification: prospective analysis and clinical outcomes. J Clin Endocrinol Metab. 2003; 88: 5090-8.
• 65. Mauvais-Jarvis F, Sobngwi E, Porcher R, Riveline JP, Kevorkian JP, Vaisse C, et al. Ketosis-prone type 2 diabetes inpatients of sub-Saharan African origin: clinical pathophysiology and natural history of b-cell dysfunction and insulin resistance. Diabetes. 2004; 53: 645-53.
• 66. Umpierrez GE, Woo W, Hagopian WA, Isaacs SD, Palmer JP, Gaur LK, et al. Immunogenetic analysis suggests different pathogenesis for obese and lean African-Americans with diabetic ketoacidosis. Diabetes Care. 1999; 22: 1517-23.

Publication Dates

• Publication in this collection
  10 Sept 2010
• Date of issue
  Aug 2010

History

• Received
  13 Oct 2008
• Reviewed
  16 Feb 2009
• Accepted
  06 May 2009