Printer Friendly

Is diabetes mellitus a continuous spectrum?

Historically, diabetes mellitus has been classified into 2 clinical types: type 1 diabetes (T1D) [3] and type 2 diabetes (T2D) (1, 2). The diagnosis of T1D vs T2D is usually made on the basis of such criteria as age at onset, abruptness of hyperglycemic symptoms, presence of ketosis, degree of obesity, and perceived need for insulin replacement. T1D patients were historically defined by diagnosis in childhood or young adulthood (before the age of 35 years). In contrast, T2D was believed to occur primarily in adults and has historically been considered nonautoimmune in nature. The age distinction between the 2 diseases has proved to be problematic, however, with the identification of "pediatric type 2 diabetes patients" (3-5), "adult type 1" diabetes patients (6), and patients demonstrating characteristics of both T1D and T2D, leading some researchers to coin the terms "type 1.5 diabetes" and "double diabetes" (7-9). In recent years, many notable discoveries have made further assaults on the current scheme of diabetes classification. Evidence to support the concept of immune system involvement in T2D, with both similarities to and differences from the pathogenesis of T1D, is accumulating (10, 11). In this review, we discuss some of these similarities and differences between T1D and T2D and then propose our resolution to the current classification dilemma.

Pathogenesis

In the pancreas of T1D patients, the immune system selectively destroys [beta] cells in a process known as insulin's (12). Recently, immune cells have also been demonstrated to infiltrate the pancreata of T2D patients (10-14). In T1D, an autoimmune reaction characterizes the insulitis, whereas a more "autoinflammatory" infiltrate appears to characterize the insulitis associated with T2D (10-14). Moreover, islet-reactive T cells responding to multiple islet proteins have been found in both T1D patients (15-18) and phenotypic T2D patients with and without islet autoantibodies, the historical hallmark of islet autoimmunity (19-22). Potential differences between T1D patients and autoimmune phenotypic T2D patients in the islet proteins recognized by T cells have been identified, hinting at potentially different pathogenic mechanisms (21). These studies suggest that T-cell-mediated islet damage may be a component of more than just classic T1D. Recently, we demonstrated in phenotypic T2D patients that the presence of islet-reactive T cells identified patients with a more severe [beta]-cell lesion, compared with assessing islet autoantibodies alone (23). This result thus indicated a potential link between the presence of islet-reactive T cells in T2D patients and [beta]-cell destruction.

Islet autoantibodies have historically been relied upon as indicators of the presence of islet autoimmunity in diabetes patients. The most common islet autoantibodies, which are islet cell autoantibodies (ICAs), glutamic acid decarboxylase (GAD) autoantibodies, insulinoma-associated antigen 2 (IA-2) autoantibodies, and insulin autoantibodies, are found in childhood T1D patients, and many of these patients demonstrate positivity for multiple islet autoantibodies. In fact, positivity for an increasing number of islet autoantibodies is associated with a progressively greater risk of developing T1D (24-28). In contrast, singular positivity for either ICAs or GAD autoantibodies is characteristic of autoimmune T2D patients (9, 19, 20, 29). For phenotypic T2D patients, GAD autoantibodies and ICAs are much more common than insulin, IA-2, and zinc transporter 8 (ZnT8) autoantibodies (8, 9, 29, 30). IA-2 autoantibodies, however, are more common in Japanese autoimmune T2D patients (29). Wenzlau et al. (31) detected ZnT8 autoantibodies in up to 80% of new-onset T1D patients, compared with < 2% of controls, < 3% of T2D patients, and up to 20% of patients with other autoimmune diseases. Because the islet autoantibodies used to categorize and identify T2D patients are islet autoantibodies that were originally identified in T1D patients, there may be other islet autoantibodies specific to autoimmunity in phenotypic T2D that have not yet been identified. Such antibodies might classify such patients more accurately or differently. In support of this concept, Seissler et al. (32) demonstrated that GAD and IA-2 autoantibodies could block ICA staining in approximately 60% of sera from T1D patients but in a much lower percentage of sera from autoimmune T2D patients.

Pathophysiology

A greater rate of decline in C-peptide has been reported in adult T1D patients than in adult T2D patients (29, 33, 34); differences between T1D and T2D patients in insulin secretion have also been reported (35). Increased body weight, central obesity, hypertension, and dyslipidemia are indicative of the metabolic syndrome that has been associated with both T1D and T2D (36, 37). Insulin resistance, an integral part of the pathophysiology of T2D, is affected by many variables, including age, body mass index, ethnicity, physical activity, and medications. When insulin resistance is assessed by the homeostasis model and corrected for body mass index, autoimmune and nonautoimmune T2D patients show no difference in insulin resistance (38). Insulin resistance has also been recognized in T1D and is associated with progression to disease in people at risk for T1D (39-42). Interleukin-1 [beta] has been hypothesized to be both a component in the development of insulin resistance and the driving force in disease development, for both T1D and T2D (10-13, 43-45). In fact, interleukin-1 [beta] is increased in the circulation and the pancreatic islets during progression from obesity to T2D (45) and is a proinflammatory cytokine acting during the autoimmune process of T1D (43, 44). The improvement in T2D patients observed with the administration of an interleukin-1 receptor antagonist (46) further emphasizes the importance of understanding the immune components in the development of T1D and T2D so that potential treatment targets may be identified.

Genetics

On the genetics front, there are similarities and differences between autoimmune T1D and T2D patients, as well as differences between autoimmune and nonautoimmune T2D patients. The HLA-DR2 and DQ[beta]1 * 0602 phenotype that has been associated with protection against childhood T1D does not appear to confer protection against adult autoimmune T2D (37). Compared with nonautoimmune T2D patients, autoimmune T2D patients are reportedly more commonly positive for HLA-DR3 and -DR4 and their associated DQ[beta]1 alleles 0201 and 0302, which are haplotypes strongly linked to a predisposition to childhood T1D (29, 30, 47). Other non-HLA genetic differences between T1D and T2D are seen in the MICA [4] (MHC class I polypeptide-related sequence A) gene (48, 49) and an allelic polymorphism within the promoter region of the TNF (tumor necrosis factor) gene (the TNF2 allele) (50). Recent genomewide association studies have demonstrated a link between the polymorphisms in the SLC30A10 (solute carrier family 30, member 10; also known as ZNT8) gene and T2D, although ZnT8 autoantibodies are rarely detected in phenotypic T2D (51-53) but are common in T1D patients. A family history of diabetes has been identified for both T1D and T2D as a risk factor for the development of diabetes (54), with the risk of developing diabetes increasing with the number of affected relatives (54-56). Therefore, differences at the genetic level may help account for not only the differences seen in pathogenic mechanisms but also similarities that may drive the development of the diabetes disease process.

Proposal and Conclusions

We propose that diabetes mellitus encompasses a spectrum of diseases with immune system involvement. At one end of the spectrum are patients with classic childhood T1D encompassing autoimmune-mediated destruction of [beta] cells. At the other end of the spectrum is age-related deterioration of glucose tolerance. In the middle is T1D with a disease onset in early adulthood (twenties and thirties), followed by autoimmune phenotypic T2D patients and nonimmune phenotypic T2D patients (Fig. 1). The differences between T1D and T2D patients in autoantibody and T-cell recognition of islet proteins suggest important differences between the 2 diabetes subgroups in the disease process; however, the results of immune system involvement in [beta]-cell destruction may be similar. The observed similarities and differences in etiologies and the prevalences of the subgroups along the spectrum of diabetes disease are areas of much-needed research. We propose that the schema for separating patients into T1D and T2D on the basis of phenotypic characteristics be discarded and that a new framework that encompasses the spectrum of diabetes disease be used instead. We recommend that the new disease distinctions be based on immune system involvement in the destruction of [beta] cells. As efficacious and safe treatments that block the deleterious effects of the immune system on pancreatic [beta] cells become available, the use of such agents will dramatically change how providers treat patients with diabetes.

[FIGURE 1 OMITTED]

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.

Role of Sponsor: The funding organizations played no role in the design of study, choice of enrolled patients, review and interpretation of data, or preparation or approval of manuscript.

References

(1.) Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997;20: 1183-97.

(2.) McCance DR, Hanson RL, Pettitt DF, Bennett PH, Hadden DR, Knowler WC. Diagnosing diabetes mellitus: Do we need new criteria? Diabetologia 1997;40:247-55.

(3.) Zeitler P. Considerations regarding the diagnosis and treatment of childhood type 2 diabetes. Postgrad Med 2010;122:89-97.

(4.) Mohamadi A, Cooke DW. Type 2 diabetes mellitus in children and adolescents. Adolesc Med State Art Rev 2010;21:103-19.

(5.) Pinhas-Hamiel O, Zeitler P Clinical presentation and treatment of type 2 diabetes in children. Pediatr Diabetes 2007;8(Suppl 9):16-27.

(6.) Lohmann T, Seissler J, Verlohren H-J, Schroder S, Rotger J, Dahn K, et al. Distinct genetic and immunological features in patients with onset of IDDM before and after age 40. Diabetes Care 1997;20:524-9.

(7.) Libman IM, Sun K, Foley TP, Becker DJ. Thyroid autoimmunity in children with features of both type 1 and type 2 diabetes. Pediatr Diabetes 2008;9:266-71.

(8.) Cervin C, Lyssenko V, Bakhtadze E, Lindholm E, Nilsson P, Tuomi T, et al. Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes. Diabetes 2008;57:1433-7.

(9.) Juneja R, Hirsch IB, Naik RG, Brooks-Worrell B, Greenbaum CJ, Palmer JP. Islet cell antibodies and glutamic acid decarboxylase antibodies but not the clinical phenotype help to identify type 1V2 diabetes in patients presenting with type 2 diabetes. Metabolism 2001;50:1008-13.

(10.) Ehses JA, Ellingsgaard H, Boni-Schnetzler M, Donath MY. Pancreatic islet inflammation in type 2 diabetes: from a and [beta] cell compensation to dysfunction. Arch Physiol Biochem 2009;115: 240-7.

(11.) Donath MY, Schumann DM, Faulenbach M, Ell ingsgaard H, Perren A, Ehses JA. Islet inflammation in type 2 diabetes. Diabetes Care 2008;31: S161-4.

(12.) Richardson SJ, Wilcox A, Bone AJ, Morgan NJ, Foulis AK. Immunopathology of the human pancreas in type-I diabetes. Semin Immunopathol [Epub ahead of print 2010 Apr 28].

(13.) Donath MY, Boni-Schnetzler M, Ellingsgaard H, Ehses JA. Islet inflammation impairs the pancreatic [beta]-cell in type 2 diabetes. Physiology 2009; 24:325-31.

(14.) Boni-Schnetzler M, Ehses JA, Faulenbach M, Donath MY. Insulitis in type 2 diabetes. Diabetes Obes Metab 2008;10(Suppl 4):201-4.

(15.) Brooks-Worrell BM, Starkebaum GA, Greenbaum C, Palmer JP. Peripheral blood mononuclear cells of insulin-dependent diabetic patients respond to multiple islet cell proteins. J Immunol 1996;157: 5668-74.

(16.) Brooks-Worrell B, Gersuk VH, Greenbaum C, Palmer JPP. Intermolecular antigen spreading occurs during the preclinical period of human type 1 diabetes. J Immunol 2001;166:5265-70.

(17.) Roep BO, Kallan AA, Duinkerken G, Arden SD, Hutton JC, Bruining GJ, DeVries RRP. T-cell reactivity to beta-cell membrane antigens associated with beta-cell destruction in IDDM. Diabetes 1995;44:278-83.

(18.) Roep BO. T-cell responses to autoantigens in IDDM. The search for the Holy Grail. Diabetes 1996;45:1147-56.

(19.) Mayer A, Fabien N, Gutowski MC, Dubois V, Gebuhrer L, Bienvenu J, et al. Contrasting cellular and humoral autoimmunity associated with latent autoimmune diabetes in adults. Eur J Endocrinol 2007;157:53-61.

(20.) Zavala AV, Fabiano de Bruno LE, Cardoso AI, Mota AH, Capucchio M, Poskus E, et al. Cellular and humoural autoimmunity markers in type 2 (non-insulin-dependent) diabetic patients with secondary drug failure. Diabetologia 1992;35: 1159-64.

(21.) Brooks-Worrell BM, Juneja R, Minokadeh A, Greenbaum CJ, Palmer JP. Cellular immune responses to human islet proteins in antibodypositive type 2 diabetic patients. Diabetes 1999; 48:983-8.

(22.) Ismail H, Wotring M, Kimmie C, Au L, Palmer JP, Brooks-Worrell B. "T cell-positive antibody-negative" phenotypic type 2 patients, a unique subgroup of autoimmune diabetes [Abstract]. Diabetes 2007;56:A325.

(23.) Goel A, Chiu H, Felton J, Palmer JP, Brooks-Worrell B. T-cell responses to islet antigens improves detection of autoimmune diabetes and identifies patients with more severe [beta]-cell lesions in phenotypic type 2 diabetes. Diabetes 2007;56: 2110-5.

(24.) Verge CF, Gianani R, Kawasaki I, Yu LP, Pietropaolo F, Chase HP, Eisenbarth GS. Number of autoantibodies (against insulin, GAD or ICA512/IA2) rather than particular autoantibody specificities determines risk of type 1 diabetes. J Autoimmun 1996;9:379-83.

(25.) Naserke HE, Ziegler A-G, Lampasona V, Bonifacio E. Early development and spreading of autoantibodies to epitopes of IA-2 and their association with progression to type 1 diabetes. J Immunol 1998;161:6963-9.

(26.) Kawasaki E, Yu L, Rewers MJ, Hutton JC, Eisenbarth GS. Definition of multiple ICA512/phogrin autoantibody epitopes and detection of intramolecular epitope spreading in relatives of patients with type 1 diabetes. Diabetes 1998;47:733-42.

(27.) Palmer JP. Predicting IDDM. Use of humoral immune markers. Diabetes Rev 1993;1:104-15.

(28.) Greenbaum CJ, Brooks-Worrell BM, Palmer JP, Lernmark A. Autoimmunity and prediction of insulin dependent diabetes mellitus. In: Marshal SM, Home PD, eds. Diabetes annual/8. Amsterdam: Elsevier; 1994. p 21-9.

(29.) Hosszufalusi N, Yatay A, Rajczy K, Prohaszka Z, Pozsonyi E, Horvath L, et al. Similar genetic features and different islet cell autoantibody pattern of latent autoimmune diabetes in adults (LADA) compared with adult-onset type 1 diabetes with rapid progression. Diabetes Care 2003;26:452-7.

(30.) Murao S, Kondo S, Ohashi J, Fujii Y, Shimizu I, Fujiyama M, et al. Anti-thyroid peroxidase antibody, IA-2 antibody, and fasting C-peptide levels predict beta cell failure in patients with latent autoimmune diabetes in adults (LADA)--a 5-year follow-up of the Ehime study. Diabetes Res Clin Pract 2008;80:114-21.

(31.) Wenzlau JM, Moua O, Sarkar SA, Yu L, Rewers M, Eisenbarth GS, et al. SIC30A8 is a major target of humoral autoimmunity in type 1 diabetes and a predictive marker in prediabetes. Ann N Y Acad Sci 2008;1150:256-9.

(32.) Seissler J, de Sonnaville JJJ, Morgenthaler NG, Steinbrenner H, Glawe D, Khoo-Morgenthaler UY, et al. Immunological heterogeneity in type I diabetes: presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease. Diabetologia 1998;41: 891-7.

(33.) Borg H, Gottsater A, Fernlund P, Sundkvist G. A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult onset diabetes. Diabetes 2002;51:1754-62.

(34.) Torn C, Landin-Olsson M, Lernmark A, Palmer JP, Arnqvist HJ, Blohme G, et al. Prognostic factors for the course of beta cell function in autoimmune diabetes. J Clin Endocrinol Metab 2000;85: 4619-23.

(35.) Gottsater A, Landin-Olsson M, Fernlund P, Lernmark A, Sundkvist G. Beta cell function in relation to islet cell antibodies during the first 3 yr after clinical diagnosis of diabetes in type II diabetic patients. Diabetes Care 1993;16:902-10.

(36.) Zinman B, Kahn SE, Hafner SM, O'Neill MC, Heise MA, Freed MI, and ADOPT Study Group. Pheno typic characteristics of GAD antibody-positive recently diagnosed patients with type 2 diabetes in North America and Europe. Diabetes 2004;53: 3193-200.

(37.) Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A, et al. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 1999;48:150-7.

(38.) Chiu HK, Tsai EC, Juneja R, Stoever J, Brooks Worrell B, Goel A, Palmer JP. Equivalent insulin resistance in latent autoimmune diabetes in adults (LADA) and type 2 diabetes patients. Diabetes Res Clin Pract 2007;77:237-44.

(39.) Pang TTL, Narendran P. Addressing insulin resistance in type 1 diabetes. Diabet Med 2008;25: 1015-24.

(40.) Fourlanos S, Narendran P, Byrnes GB, Colman PG, Harrison LC. Insulin resistance is a risk factor for progression to type 1 diabetes. Diabetologia 2004;47:1661-7.

(41.) Xu P, Cuthbertson D, Greenbaum C, Palmer JP, Krischer JP, for the Diabetes Prevention Trial-Type 1 Study Group. Role of insulin resistance in predicting progression to type 1 diabetes. Diabetes Care 2007;30:2314-20.

(42.) Bingley PJ, Mahon JL, Gale EAM, for the European Nicotinamide Diabetes Intervention Trial (ENDIT) Group. Insulin resistance and progression to type 1 diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT). Diabetes Care 2008;31:146-50.

(43.) Mandrup-Poulsen T. The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia 1996;39: 1005-29.

(44.) Mandrup-Poulsen T, Pickersgill L, Donath MY. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat Rev Endocrinol 2010;6:158-66.

(45.) Maedler K, Dharmadhikari G, Schumann DM, Sterling J. Interleukin-1 beta targeted therapy for type 2 diabetes. Expert Opin Biol Ther 2009;9: 1177-88.

(46.) Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Selfert B, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 2007;356:1517-26.

(47.) Gleichmann H, Zorcher B, Greulich B, Gries FA, Henrichs HR, Betrams J, Kolb H. Correlation of islet cell antibodies and HLA-DR phenotypes with diabetes mellitus in adults. Diabetologia 1984; 27(Suppl):90-2.

(48.) Torn C, Gupta M, Zake LN, Sanjeevi CB, Landin Olsson M. Heterozygosity for MICA5.0/MICA5.1 and HLA-DR3-DQ2/DR4-DQ8 are independent genetic risk factors for latent autoimmune diabetes in adults. Hum Immunol 2003;64:902-9.

(49.) Sanjeevi CB, Gambelunghe G, Falorni A, Shtauvere-Brameus A, Kanungo A. Genetics of latent autoimmune diabetes in adults. Ann N Y Acad Sci 2002;958:107-11.

(50.) Vatay A, Rajczy K, Pozsonyi E, Hosszufalusi N, Prohaszka Z, Fust G, et al. Differences in the genetic background of latent autoimmune diabetes in adults (LADA) and type 1 diabetes mellitus. Immunol Lett 2002;84:109-15.

(51.) Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 2007;445:881-5.

(52.) Scott JL, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 2007;316:1341-5.

(53.) Boesgaard TW, Zilinskaite J, Vanttinen M, Laakso M, Jansson PA, Hammarstedt A, et al. The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients--the EUGENE2 study. Diabetologia 2008;51:816-20.

(54.) Meigs JB, Cupples LA, Wilson PW. Parental transmission of type 2 diabetes: the Framingham Offspring Study. Diabetes 2000;49:2201-7.

(55.) Grill V, Persson P-G, Carlsson S, Norman A, Alvarsson M, Ostensson CG, et al. Family history of diabetes in middle-aged Swedish men is a gender unrelated factor which associates with insulinopenia in newly diagnosed diabetes subjects. Diabetologia 1999;42:15-23.

(56.) Bonifacio E, Hummel M, Walter M, Schmid S, Ziegler AG. IDDM1 and multiple family history of type 1 diabetes combine to identify neonates at high risk for type 1 diabetes. Diabetes Care 2004; 27:2695-700.

Barbara Brooks-Worrell [1,2] * and Jerry P. Palmer [1,2]

[1] Department of Medicine, DVA Puget Sound Health Care System, Seattle, WA;

[2] Department of Medicine, University of Washington, Seattle, WA.

[3] Nonstandard abbreviations: T1D, type 1 diabetes; T2D, type 2 diabetes; ICA, islet cell autoantibody; GAD, glutamic acid decarboxylase; IA-2, insulinoma associated antigen 2; ZnT8, zinc transporter 8.

[4] Human genes: MICA, MHC class I polypeptide-related sequence A; TNF, tumor necrosis factor; SLC30A10 (also known as ZNT8), solute carrier family 30, member 10.

* Address correspondence to this author at: 1660 S. Columbian Way (111), DVA Puget Sound Health Care System, Seattle WA 98108. Fax 206-764-2615; e-mail bbrooks@u.washington.edu.

Received September 13, 2010; accepted October 26, 2010.

Previously published online at DOI: 10.1373/clinchem.2010.148270
COPYRIGHT 2011 American Association for Clinical Chemistry, Inc.
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2011 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Brooks-Worrell, Barbara; Palmer, Jerry P.
Publication:Clinical Chemistry
Date:Feb 1, 2011
Words:3363
Previous Article:Unexpected hemoglobin [A.sub.1c] results.
Next Article:Therapeutic approaches to target inflammation in type 2 diabetes.

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters