Autoimmune insulitis in patients with type 2 diabetes mellitus
A randomized clinical trial in hospitalized patients

Czech version

Authors: Emil Martinka; Mariana Rončáková; Michaela Mišaníková; Arash Davani
Authors‘ workplace: Národný endokrinologický a diabetologický ústav, n. o., Ľubochňa, Slovenská republika
Published in: Vnitř Lék 2016; 62(7-8): 521-533
Category: Original Contributions

Overview

Background:
It is not always easy to classify diabetes (DM) diagnosed in adults, with a significant group of patients initially classified and treated for type 2 diabetes mellitus (DM2T) presenting signs indicating the presence of autoimmune insulitis (AI), which is characteristic of type 1 diabetes mellitus (DM1T), or latent autoimmune diabetes mellitus in adults (LADA).

Goal:
Identify the proportion of patients entered with DM2T who present AI signs, and the number of patients of that proportion, who at the same time present low insulin secretion, and what clinical and laboratory manifestations could be used to differentiate between these patients.

Cohort and methods:
A randomized clinical trial with a pre-determined set of assessed parameters for n = 625 patients, who were hospitalized during the first 6 months of 2016 at the National Endocrinology and Diabetology Institute (NEDU), Lubochna. Apart from the standard parameters, C-peptide (CP) and autoantibodies to glutamic acid decarboxylase (GADA) were examined for each patient. GADA positive (GADA⁺) patients were compared to GADA negative (GADA^-) patients in the following parameters: gender, age, age at the time of diagnosing DM, duration of DM, HbA_1c, incidence of hypoglycemia, lipidogram, fasting C-peptide levels, BMI, waist circumference, incidence of hypoglycemias, presence of microvascular and macrovascular complications, treatment of diabetes and incidence of other endocrinopathies. GADA⁺ with low CP were subsequently compared to GADA⁺ patients with normal CP.

Results:
Of 625 patients originally classified and treated as DM2T, 13 % were GADA⁺. 31 % of them had low CP (< 0.2 nmol/l) and 28 % had CP levels within the intermediary range (0.2–0.4 nmol/l). Females made up a larger proportion of GADA⁺ patients, with a lower BMI, smaller waist circumference, lower CP, higher HDL cholesterol levels, a greater incidence of hypoglycemias and lower total daily dose of insulin. GADA⁺ patients with low CP differed from GADA⁺ patients with normal CP in higher HDL cholesterol levels, lower triglyceride levels and earlier need of insulin therapy. The testing for GADA and CP levels with regard to the other relevant characteristics led to re-classification, or more precisely adding of DM1T/LADA (as the main, or parallel cause of DM) for 2.9 % of all the patients included and a clinically significant proportion of AI could be assumed in 6.1 % of the patients.

Summary:
The results of our study show that the pathogenesis of DM in patients initially diagnosed and registered with DM2T and with concurrent presence of GADA includes mechanisms characteristic of both DM2T (insulin resistance) and DM1T (autoimmune insulitis) acting in parallel, with different intensity, in differing proportions and time sequence as a fluid continuum, which also accounts for the differences between individual patients. The characteristics highlighting the presence and role of AI based on our results include high titre of GADA⁺, low CP levels, early need of insulin therapy, presence of thyroid disorder, higher HDL cholesterol levels and lower triglyceride levels. The characteristics highlighting the dominance of mechanisms characteristic of DM2T (insulin resistance) included higher BMI and waist circumference values, normal CP levels, low HDL cholesterol levels, higher triglyceride levels, higher blood pressure and borderline titre of GADA.

Key words:
autoimmune diabetes mellitus – C-peptide – GADA – HDL-cholesterol – classification

Sources

1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010; 33(Suppl 1): S62-S69.

2. Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part I. Diagnosis and classifiction of diabetes mellitus – Provisional report of WHO consultation. Diabet Med 1998; 15(7): 539–553.

3. Djekic K, Mouzeyan A, Ipp E. Latent autoimmune diabetes of adults is phenotypically similar to type 1 diabetes in a minority population. J Clin Endocrinol Metab 2012; 97(3): E409-E413.

4. Fourlanos S, Perry C, Stein MS et al. A clinical screening tool identifies autoimmune diabetes in adults. Diabetes Care 2006; 29(5): 970–975.

5. Gale EA. Latent autoimmune diabetes in adults: a guide for the perplexed. Diabetologia 2005; 48(11): 2195–2199.

6. Guglielmi C, Palermo A, Pozzilli P. Latent autoimmune diabetes in the adults (LADA) in Asia: from pathogenesis and epidemiology to therapy. Diabetes Metab Res Rev 2012; 28(Suppl 2): 2S40–2S46.

7. Banerjee S, Bytyci F. Latent Autoimmune Diabetes of Adulthood (LADA): A Commonly Misdiagnosed Condition as Type II Diabetes Mellitus. Medicine Journal 2016; 3(1): 1–5.

8. Hawa MI, Kolb H, Schloot N et al. Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: action LADA 7. Diabetes Care 2013; 36(4): 908–913.

9. Huang G, Xiang Y, Pan L et al. Zinc transporter 8 autoantibody (ZnT8A) could help differentiate latent autoimmune diabetes in adults (LADA) from phenotypic type 2 diabetes mellitus. Diabetes Metab Res Rev 2013; 29(5): 363–368.

10. Itariu BK, Stulnig TM. Autoimmune Aspects of Type 2 Diabetes Mellitus – A Mini-Review. Gerontology 2014; 60(3): 189–196.

11. Laakso M, Voutilainen E, Sarlund H et al. Inverse relationship of serum HDL and HDL2 cholesterol to C-peptide level in middle-aged insulin-treated diabetics. Metabolism 1985; 34(8): 715–720.

12. Leslie RDG, Williams R, Pozzilli P. Clinical review: type 1 diabetes and latent autoimmune diabetes in adults: one end of the rainbow. J Clin Endocrinol Metab 2006; 91(5): 1654–1659.

13. Leslie RD, Kolb H, Schloot NC et al. Diabetes classification: grey zones, sound and smoke: Action LADA 1. Diabetes Metab Res Rev 2008; 24(7): 511–519.

14. Lohmann T, Kellner K, Verlohren HJ et al. Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA). Diabetologia 2001; 44(8): 1005–1010.

15. Liu L, Li X, Xiang,G et al. Latent autoimmune diabetes in adults with low-titer GAD antibodies: similar disease progression with type 2 diabetes: a nationwide, multicenter prospective study (LADA China Study 3). Diabetes Care 2015; 38(1): 16–21.

16. Martinka E. Úskalia klasifikácie diabetes mellitus zo začiatkom v dospelom veku. Lufema: Bratislava 1999.

17. Migdalis IN, Iliopoulou V, Kalogeropoulou K et al. Correlation between high density lipoprotein cholesterol and C-peptide in sulfonylurea-treated diabetic patients. J Med 1989; 20(5–6): 349–355.

18. Mollo A, Hernandez M, Marsal JR et al. [Action LADA 8]. Latent autoimmune diabetes in adults is perched between type 1 and type 2: evidence from adults in one region of Spain. Diabetes Metab Res Rev 2013; 29(6): 446–451. Erratum in Diabetes Metab Res Rev 2013; 29(8):693.

19. Palmer JP, Hampe CS, Chiu H et al. Is latent autoimmune diabetes in adults distinct from type 1 diabetes or just type 1 diabetes at an older age? Diabetes 2005; 54(Suppl 2): 2S62–2S67.

20. Pietropaolo M, Barinas-Mitchell E, Pietropaolo SL et al: Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes. Diabetes 2000; 49(1): 32–38.

21. Pettersen E, Skorpen F, Kvaløy K et al. Genetic heterogeneity in latent autoimmune diabetes is linked to various degrees of autoimmune activity: results from the Nord-Trøndelag Health Study. Diabetes 2010; 59(1): 302–310.

22. Redondo MJ. LADA Time for a New Definition. Diabetes 2013; 62(2): 339–340.

23. Reghina AD, Florea S, Constantin M et al. The Impact of Thyroid Autoimmunity on the Clinical and Diabetes Parameters of Patients with Latent Autoimmune Diabetes in Adults. Exp Clin Endokinol Diabetes 2015; 123(9): 543–547.

24. Rolandsson O, Palmer JP. Latent autoimmune diabetes in adults (LADA) is dead: long live autoimmune diabetes! Diabetologia 2010; 53(7): 1250–1253.

25. Sachdeva N, Paul M, Badal D et al. Preproinsulin specific CD8+ T cells in subjects with latent autoimmune diabetes show lower frequency and different pathophysiological characteristics than those with type 1 diabetes. Clin Immunol 2015; 157(1): 78–90.

26. Shields BM, Peters JL, Cooper Ch et al. Can clinical features be used to differentiate type 1 from type 2 diabetes? A systematic review of the literature. BMJ Open 2015; 5(11): e009088. Dostupné z DOI: <http://dx.doi.org/10.1136/bmjopen-2015–009088>.

27. Thunander M, Petersson C, Jonzon K et al. Incidence of type 1 and type 2 diabetes in adults and children in Kronoberg, Sweden. Diabetes Res Clin Pract 2008; 82(2): 247–255.

28. Tiittanen M, Huupponen JT, Knip M et al. Insulin treatment in patients with type 1 diabetes induces upregulation of regulatory T-cell markers in peripheral blood mononuclear cells stimulated with insulin in vitro. Diabetes 2006; 55(12): 3446–3454.

29. Tuomi T, Carlsson A, Li H et al. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 1999; 48(1): 150–157.

30. Tuomi T, Groop LC, Zimmet PZ 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(2): 359–362.

31. Turner R, Stratton I, Horton V et al. [UK Prospective Diabetes Study Group]. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylasefor prediction of insulin requirementin type 2 diabetes. Lancet 1997; 350(9087): 1288–1293.

32. Zampetti S, Capizzi M, Spoletini M et al. [NIRAD Study Group]. GADA Titer-Related Risk for Organ-Specific Autoimmunity in LADA Subjects Subdivided according to Gender (NIRAD Study 6). J Clin Endocrinol Metab 2012; 97(10): 3759–3765.