Metabolic risk profiles in diabetes stratified according to age at onset, islet autoimmunity and fasting C-peptide

Published:October 05, 2017DOI:


      • Method for stratifying diabetes into groups with differences in cardiometabolic risk is proposed.
      • Age at onset is not useful in stratifying diabetes into these groups.
      • Fasting C-peptide and GADab define groups with relevant differences in cardiometabolic risk.
      • Groups are defined as insulin deficient diabetes, LADA and type 2 diabetes mellitus.



      Islet autoimmunity, age at onset and time to insulin treatment are often used to define subgroups of diabetes. However, the latter criterion is not clinical useful. Here, we examined whether an unbiased stratification of diabetes according to age at onset, fasting C-peptide and GAD autoantibodies (GADab) defines groups with differences in glycaemic control and markers of cardiometabolic risk.

      Design and methods

      A cohort of 4374 adults with relatively newly diagnosed diabetes referred to a Danish hospital during 1997–2012 was stratified according to age at onset above or below 30 years, fasting C-peptide above or below 300 pmol/l (CPEPhigh or CPEPlow), and presence or absence of GADab (GADpos or GADneg). HbA1c, BMI, blood pressure (BP), lipid profile, alanine aminotransferase (ALT) and creatinine were evaluated.


      GADab were present in 13% of the cohort. Age at onset was not associated with major differences between groups. Patients with insulin deficient diabetes (CPEPlow; n = 503) had higher HbA1c but otherwise lower cardiometabolic risk (lower BMI, BP, LDL, triacylglycerol, and ALT, and higher HDL) than both patients with latent autoimmune diabetes of adults (LADA defined as GADposCPEPhigh; n = 327) and patients with type 2 diabetes (GADnegCPEPhigh; n = 3544). Patients with LADA defined an intermediate group with higher HbA1c but otherwise lower cardiometabolic risk than patients with type 2 diabetes.


      Our results demonstrate that fasting C-peptide and GADab status, but not age at onset, define groups of patients with diabetes with clinically relevant differences in glycaemic control and cardiometabolic risk.


      To read this article in full you will need to make a payment


        • Hawa M.I.
        • et al.
        Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: Action LADA 7.
        Diabetes Care. 2013; 36: 908-913
        • Fourlanos S.
        • et al.
        Latent autoimmune diabetes in adults (LADA) should be less latent.
        Diabetologia. 2005; 48: 2206-2212
        • Leslie R.D.
        • et al.
        Diabetes classification: grey zones, sound and smoke: Action LADA 1.
        Diabetes Metab Res Rev. 2008; 24: 511-519
        • Naik R.G.
        • Brooks-Worrell B.M.
        • Palmer J.P.
        Latent autoimmune diabetes in adults.
        J Clin Endocrinol Metab. 2009; 94: 4635-4644
        • Tuomi T.
        • et al.
        Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies.
        Diabetes. 1999; 48: 150-157
        • Grant S.F.
        • Hakonarson H.
        • Schwartz S.
        Can the genetics of type 1 and type 2 diabetes shed light on the genetics of latent autoimmune diabetes in adults?.
        Endocr Rev. 2010; 31: 183-193
        • Carlsson S.
        • Midthjell K.
        • Grill V.
        Influence of family history of diabetes on incidence and prevalence of latent autoimmune diabetes of the adult: results from the Nord-Trondelag Health Study.
        Diabetes Care. 2007; 30: 3040-3045
        • Hawa M.I.
        • et al.
        Metabolic syndrome and autoimmune diabetes: action LADA 3.
        Diabetes Care. 2009; 32: 160-164
        • Carlsson S.
        • et al.
        Age, overweight and physical inactivity increase the risk of latent autoimmune diabetes in adults: results from the Nord-Trondelag health study.
        Diabetologia. 2007; 50: 55-58
        • Mishra R.
        • et al.
        Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes.
        BMC Med. 2017; 15: 88
        • Lukacs K.
        • et al.
        The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by obesity: a meta-analysis and an individual study.
        Diabetologia. 2012; 55: 689-693
        • Gorus F.K.
        • et al.
        Twenty-year progression rate to clinical onset according to autoantibody profile, age, and HLA-DQ genotype in a registry-based group of children and adults with a first-degree relative with type 1 diabetes.
        Diabetes Care. 2017; 40: 1065-1072
        • Brophy S.
        • et al.
        Time to insulin initiation cannot be used in defining latent autoimmune diabetes in adults.
        Diabetes Care. 2008; 31: 439-441
        • Gale E.A.
        Latent autoimmune diabetes in adults: a guide for the perplexed.
        Diabetologia. 2005; 48: 2195-2199
        • Tfayli H.
        • et al.
        Phenotypic type 2 diabetes in obese youth: insulin sensitivity and secretion in islet cell antibody-negative versus -positive patients.
        Diabetes. 2009; 58: 738-744
        • Gilliam L.K.
        • et al.
        Autoimmunity and clinical course in children with type 1, type 2, and type 1.5 diabetes.
        J Autoimmun. 2005; 25: 244-250
        • Jones A.G.
        • Hattersley A.T.
        The clinical utility of C-peptide measurement in the care of patients with diabetes.
        Diabet Med. 2013; 30: 803-817
        • Li X.
        • et al.
        Variation of C peptide decay rate in diabetic patients with positive glutamic acid decarboxylase antibody: better discrimination with initial fasting C peptide.
        BMC Endocr Disord. 2013; 13: 10
        • Thunander M.
        • et al.
        Levels of C-peptide, body mass index and age, and their usefulness in classification of diabetes in relation to autoimmunity, in adults with newly diagnosed diabetes in Kronoberg, Sweden.
        Eur J Endocrinol. 2012; 166: 1021-1029
        • Brophy S.
        • et al.
        Interventions for latent autoimmune diabetes (LADA) in adults.
        Cochrane Database Syst Rev. 2007; : CD006165
        • Zinman B.
        • et al.
        Phenotypic characteristics of GAD antibody-positive recently diagnosed patients with type 2 diabetes in North America and Europe.
        Diabetes. 2004; 53: 3193-3200
        • Mollo A.
        • et al.
        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: 446-451
        • Buzzetti R.
        • et al.
        High titer of autoantibodies to GAD identifies a specific phenotype of adult-onset autoimmune diabetes.
        Diabetes Care. 2007; 30: 932-938
        • Olsson L.
        • et al.
        Mortality in adult-onset autoimmune diabetes is associated with poor glycemic control: results from the HUNT Study.
        Diabetes Care. 2013; 36: 3971-3978
        • Rosario P.W.
        • et al.
        Comparison of clinical and laboratory characteristics between adult-onset type 1 diabetes and latent autoimmune diabetes in adults.
        Diabetes Care. 2005; 28: 1803-1804
        • Andersen C.D.
        • et al.
        Worse glycaemic control in LADA patients than in those with type 2 diabetes, despite a longer time on insulin therapy.
        Diabetologia. 2013; 56: 252-258
        • Davies H.
        • et al.
        Latent autoimmune diabetes in adults (LADA) in South Wales: incidence and characterization.
        Diabet Med. 2008; 25: 1354-1357
        • Groop L.
        New approaches beyond genetics: towards precision medicine in diabetes.
        Diabetologia. 2016; 59: 2495-2496
        • Skyler J.S.
        • et al.
        Differentiation of diabetes by pathophysiology, natural history, and prognosis.
        Diabetes. 2017; 66: 241-255
        • Hother-Nielsen O.
        • et al.
        Classification of newly diagnosed diabetic patients as insulin-requiring or non-insulin-requiring based on clinical and biochemical variables.
        Diabetes Care. 1988; 11: 531-537
        • Toivonen E.
        • et al.
        Two-site time-resolved immunofluorometric assay of human insulin.
        Clin Chem. 1986; 32: 637-640
        • Harrell F.E.
        Regression modeling strategies: with applications to linear models, logistic and ordinal regression, and survival analysis (2 edn).
        2nd ed. Springer, Heidelberg2015
        • Hosszufalusi N.
        • 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: 452-457
        • Al-Majdoub M.
        • et al.
        Metabolite profiling of LADA challenges the view of a metabolically distinct subtype.
        Diabetes. 2017; 66: 806-814
        • Sorgjerd E.P.
        • et al.
        Presence of anti-GAD in a non-diabetic population of adults; time dynamics and clinical influence: results from the HUNT study.
        BMJ Open Diabetes Res Care. 2015; 3: e000076
        • Radtke M.A.
        • et al.
        Heterogeneity of patients with latent autoimmune diabetes in adults: linkage to autoimmunity is apparent only in those with perceived need for insulin treatment: results from the Nord-Trondelag Health (HUNT) study.
        Diabetes Care. 2009; 32: 245-250
        • Bakhtadze E.
        • et al.
        Common variants in the TCF7L2 gene help to differentiate autoimmune from non-autoimmune diabetes in young (15–34 years) but not in middle-aged (40–59 years) diabetic patients.
        Diabetologia. 2008; 51: 2224-2232
        • Rolandsson O.
        • Palmer J.P.
        Latent autoimmune diabetes in adults (LADA) is dead: long live autoimmune diabetes!.
        Diabetologia. 2010; 53: 1250-1253
        • Maruyama T.
        • et al.
        Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus.
        J Clin Endocrinol Metab. 2008; 93: 2115-2121
        • Kobayashi T.
        • et al.
        Small doses of subcutaneous insulin as a strategy for preventing slowly progressive beta-cell failure in islet cell antibody-positive patients with clinical features of NIDDM.
        Diabetes. 1996; 45: 622-626
        • Gjessing H.J.
        • et al.
        Fasting plasma C-peptide, glucagon stimulated plasma C-peptide, and urinary C-peptide in relation to clinical type of diabetes.
        Diabetologia. 1989; 32: 305-311
        • Landin-Olsson M.
        • et al.
        Islet cell antibodies and fasting C-peptide predict insulin requirement at diagnosis of diabetes mellitus.
        Diabetologia. 1990; 33: 561-568
        • Irvine W.J.
        • et al.
        Clinical and pathogenic significance of pancreatic-islet-cell antibodies in diabetics treated with oral hypoglycaemic agents.
        Lancet. 1977; 1: 1025-1027
        • Caprio S.
        Development of type 2 diabetes mellitus in the obese adolescent: a growing challenge.
        Endocr Pract. 2012; 18: 791-795
        • Wing R.R.
        • et al.
        Intensive lifestyle intervention in type 2 diabetes.
        N Engl J Med. 2013; 369: 2358-2359