Bengt Littorin

Male predominance of type 1 (insulin-dependent) diabetes mellitus in young adults : results from a 5-year prospective nationwide study of the 15-34 year age group in Sweden

SummaryThe incidence of diabetes mellitus in Sweden in the 15–34 year age group was prospectively studied on a nationwide basis, beginning 1 January 1983. A total of 1,214 male and 720 female cases of newly-diagnosed (excluding gestational) diabetes were reported over a 5-year period. This corresponds to an incidence of 20.5 per 100,000/year in male subjects and 12.7 per 100,000/year in female subjects. Most cases were classified as Type 1 (insulin-dependent) diabetes, with an incidence of 15.9 in males and 8.6 in females. The incidence of Type 1 diabetes decreased gradually with age, while the incidence of Type 2 (non-insulin-dependent) diabetes increased. A male predominance was found in all age groups, with a male-to-female ratio of 1.8∶1 for Type 1 diabetes and 1.3∶1 for Type 2 diabetes. Maximum blood glucose concentration at diagnosis was significantly higher in males than in females in both Type 1 and Type 2 diabetic subjects. In contrast, the percent desirable weight was significantly higher in females, both in Type 1 and Type 2 diabetic subjects. The difference in diabetes incidence therefore cannot be attributed to any methodological error. The present finding of a marked male predominance after puberty in Type 1 diabetes in an ethnically quite homogeneous population supports the hypothesis that environmental risk factors and life-style are important for the development of the disease.

Negative association between type 1 diabetes and HLA DQB1*0602-DQA1*0102 is attenuated with age at onset

HLA-associated relative risks of type 1 (insulin-dependent) diabetes mellitus were analysed in population-based Swedish patients and controls aged 0-34 years. The age dependence of HLA-associated relative risks was assessed by likelihood ratio tests of regression parameters in separate logistic regression models for each HLA category. The analyses demonstrated an attenuation with increasing age at onset in the relative risk for the positively associated DQB1*0201-A1*0502/B1*0302-A1*0301 (DQ2/8) genotype (P = 0.02) and the negatively associated DQB1*0602-A1*0102 (DQ6.2) haplotype (P = 0.004). At birth, DQ6.2-positive individuals had an estimated relative risk of 0.03, but this increased to 1.1 at age 35 years. Relative risks for individuals with DQ genotype 8/8 or 8/X or DQ genotype 2/2 or 2/X, where X is any DQ haplotype other than 2, 8 or 6.2, were not significantly age-dependent. An exploratory analysis of DQ haplotypes other than 2, 8 and 6.2 suggested that the risk of type 1 diabetes increases with age for DQB1*0604-A1*0102 (DQ6.4) and that the peak risk for the negatively associated DQB1*0301-A1*0501 haplotype is at age 18 years. There was also weak evidence that the risk for DQB1*0303-A1*0301 (DQ9), which has a positive association in the Japanese population, may decrease with age. We speculate that HLA-DQ alleles have a significant effect on the rate of beta cell destruction, which is accelerated in DQ2/8-positive individuals and inhibited, but not completely blocked, in DQ6.2-positive individuals.

Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1 diabetes on clinical grounds

Differentiation between Type 1 and Type 2 diabetes in adults is difficult at diagnosis. In this study we tested the hypothesis that autoantibodies at diagnosis are predictive for insulin treatment within 3 years in patients initially not classified as Type 1 diabetes.

Difficulties in Classifying Diabetes at Presentation in the Young Adult

All newly diagnosed diabetic patients in Sweden aged 15–34 years have been registered since 1983. In this study the clinical characteristics initially and after 2.5‐3 years were evaluated by a questionnaire to the patients physician and by non‐fasting C‐peptide. The study comprised patients registered 1983‐84, and for 281 patients (37%), complete information was obtained. At diagnosis 75% were classified as Type 1, 19% as Type 2, and 6% as secondary diabetes or as uncertain by their physician. Twenty patients (7.1%) were reported to have ketoacidosis. Seventy‐five percent were treated with insulin, 7% with oral hypoglycaemic agents (OHG), and 18% with diet alone. At follow‐up 71% were classified as Type 1, 21% as Type 2, and 8% as secondary or uncertain while treatment was 82% insulin, 8% OHG, and 9% diet. During the follow‐up period 42% of the initially non‐insulin‐treated patients were put on insulin whereas only a few stopped insulin treatment. Patients treated with diet or OHG at follow‐up were older, had higher percent desirable weight, and lower blood glucose at diagnosis than patients treated with insulin. All except one patient had measurable random C‐peptide at follow‐up and mean values were for patients treated with insulin 0.55, OHG 1.41 and diet alone 1.29 nmol I−1. Random blood glucose results were similar. In conclusion the majority of newly diagnosed patients in the age group 15–34 years have the characteristics of Type 1 diabetes and Type 2 diabetes is rare before 25–30 years of age. Patients with biochemically mild hyperglycaemia are difficult to classify and there is a need for new guidelines for classification of diabetes which include aetiopathogenetic aspects.

Appearance of islet cell autoantibodies after clinical diagnosis of diabetes mellitus.

Islet cell antibodies (ICA) and glutamic acid decarboxylase antibodies (GAD65Ab) are often present at diagnosis of insulin dependent diabetes mellitus (type I diabetes) and are supposed to decline in level and frequency during the first years of disease. We have analysed ICA and GAD65Ab at onset and after one year in 395 population based randomly selected 15-34 year old patients newly diagnosed with diabetes mellitus, to study how these autoantibodies persist, disappear and appear and their relation to C-peptide levels. Of the 395 samples 212 (54%) were positive for ICA, 250 (63%) were positive for GAD65Ab and 170 (43%) were positive for both. At follow up after one year, 27/183 (15%) of the ICA negative patients and 25/145 (17%) of the GAD65Ab negative patients had converted to positivity. Among the 103 patients negative for both ICA and GAD65Ab, 16 turned positive for one or both antibodies after one year. Patients converting to positivity for one or the other antibody after one year, had lower C-peptide levels after one year than patients who initially were and remained negative, supporting the hypothesis that these patients have a genuine type I diabetes. In conclusion, newly diagnosed patients may be negative for autoantibodies at diagnosis but develop these antibodies later on during the disease.

Patient administrative system as a tool to validate the ascertainment in the diabetes incidence study in Sweden (DISS)

The aim of this study was to evaluate the degree of ascertainment in a nationwide prospective registration of incident cases of diabetes mellitus in the age group 15-34 years (The Diabetes Incidence Study in Sweden (DISS)). Incident cases of diabetes mellitus in DISS during a five year period were compared with inpatients, with the diagnosis of diabetes mellitus, registered in a routine computer-based administrative register. The Patient Administrative System-Inpatient Care (PAS-IC). To clarify this issue the two-sample capture-recapture phenomena was employed in the two southernmost counties in Sweden, Malmöhus and Kristianstad, covering 9.2% of the total of 2.3 million people aged 15-34 years in Sweden. The results showed that the ascertainment level in DISS was 0.86 for insulin dependent diabetes mellitus (IDDM). Hence, the DISS registry is a valid tool to monitor the incidence of IDDM in young (15-34 years) adult subjects.

Combinations of beta cell specific autoantibodies at diagnosis of diabetes in young adults reflects different courses of beta cell damage

To explore the natural course of beta cell function in recent onset diabetes, a subgroup (n=157) of all incident cases (n=879) 15-34 years old, 1992-1993 in Sweden, and with posi-tivity for at least one autoantibody of islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA) or tyrosine phosphatase antibodies (IA-2A) were followed prospectively for the first four years with annual analysis of C-peptide. The aim was to relate the course of beta cell function, measured as C-peptide, in early diabetes with the presence of different islet autoantibodies at diagnosis. We found that patients positive for ICA alone (n=11) had significantly higher C-peptide levels both at diagnosis and during the first three years compared with the other patients (n=146; p=0.022, p<0.001, p=0.004 and p=0.0022). Patients positive for GADA alone or in combination with other antibodies (n=125) had significantly lower C-peptide during the first three years after diagnosis compared with the other patients (n=32, p<0.001, p=0.0011 and p=0.0136). Patients with two or three autoantibodies had C-peptide levels similar to levels found in patients positive only for GADA. However, after four years, there were no significant differences between any of the groups of different autoantibody combinations. At diagnosis, 55% (86/157) of the patients had C-peptide levels above the lower normal range of 0.25 nmol/1, but the frequency of patients with beta cell function above this level decreased after two years to 41% (65/157; p=0.035) and after four years to 22% (35/157; p=0.0041). It is concluded that young adult diabetic patients positive only for ICA at diagnosis have a better preserved beta cell function with higher levels of C-peptide during the first three years compared with patients positive for GADA alone or in combinations with other autoantibodies.

Ketoacidosis in young adults is not related to the islet antibodies at the diagnosis of Type 1 diabetes mellitus – a nationwide study

Aims To test the hypothesis that there is lower prevalence of islet antibodies in subjects with newly diagnosed Type 1 diabetes mellitus in young adulthood than in children is associated with less severe diabetes at time of diagnosis.

Increasing body mass index at diagnosis of diabetes in young adult people during 1983-1999 in the Diabetes Incidence Study in Sweden (DISS)

Abstract.  Littorin B, Nyström L, Gullberg B, Råstam L, Östman J, Arnqvist HJ, Björk E, Blohmé G, Bolinder J, Eriksson JW, Scherstén B, Sundkvist G (University of Malmö/Lund, Malmö/Lund; Umeå University, Umeå; University Hospital, Uppsala; Söder Hospital, Stockholm; Huddinge Hospital, Huddinge; Faculty of Health Sciences, University of Linköping, Linköping and University Hospital, Umeå; Malmö University Hospital, Malmö, Sweden). Increasing body mass index at diagnosis of diabetes in young adult people during 1983–1999 in the Diabetes Incidence Study in Sweden (DISS). J Intern Med 2003; 254: 251–256.

Increased mortality in diabetes during the first 10 years of the disease. A population-based study (DISS) in Swedish adults 15-34 years old at diagnosis: EARLY MORTALITY IN DIABETES

Abstract. Wibell L, Nyström L, Östman J, Arnqvist H, Blohmé G, Lithner F, Littorin B, Sundkvist G (Uppsala University Hospital, Uppsala; Umeå University, Umeå; Huddinge Hospital, Stockholm; Linköping University Hospital, Linköping; Sahlgrenska Hospital, Gothenburg; University of Lund; and Malmö University Hospital, Malmö, Sweden). Increased mortality in diabetes during the first 10 years of the disease. A population‐based study (DISS) in Swedish adults 15–34 years old at diagnosis. J Intern Med 2001; 249: 263–270.