IA-2 antibodies – a sensitive marker of IDDM with clinical onset in childhood and adolescence

Summary To study the relationship of IA-2 antibodies (IA-2A) to other autoantibodies and genetic risk markers in insulin-dependent diabetes mellitus (IDDM), 758 children and adolescents younger than 15 years of age (mean age 8.4 years) with newly diagnosed diabetes were analysed for IA-2A, GAD antibodies (GADA) and insulin autoantibodies (IAA) with radiobinding assays, for islet cell antibodies (ICA) with immunofluorescence and for HLA DR alleles by serology. IA-2A were detected in 85.9 % of cases with no association with gender or age. An overwhelming majority of the patients (71.3 %) tested positive for three or more antibodies, and 90.7 % for at least two. Fifty-four subjects (7.1 %) had one antibody detectable, whereas only 2.1 % of the patients tested negative for all four. A higher proportion of patients was positive for IA-2A and/or GADA than for ICA alone (95.5 vs 84.2 %, p < 0.001). The prevalence and level of IA-2A were increased in cases carrying HLA DR4/non-DR3 compared with other DR combinations. The results indicate that almost all patients with newly diagnosed childhood IDDM can be identified by screening with these four autoantibodies. The combination of IA-2A and/or GADA had a higher sensitivity for IDDM than ICA alone. The close association between IA-2A and HLA DR4, the strongest single allele predisposing to IDDM, suggests that IA-2A may be a more specific marker of beta-cell destruction than GADA, which have been shown to associate with the DR3 allele and thyroid autoimmunity. [Diabetologia (1998) 41: 424–429] Received: 20 August 1997 and in final revised form: 13 November 1997     

Coronary heart disease in young Type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors

Summary Fifty-nine Type 1 (insulin-dependent) diabetic patients with (group I) and 59 patients without nephropathy (group II) pair-matched according to sex (30 males and 29 females), age (33 years, range 15–48) and diabetes duration (19 years, range 6–42) were followed for a period of 10 years from about 5 years before to 5 years after onset of proteinuria. The cumulative incidence of coronary heart disease was estimated, and blood pressure and serum cholesterol were followed. Within six years after onset of proteinuria the cumulative incidence of coronary heart disease was increased eight-fold in group I (40%) compared with group II (5%), (p<0.001). Blood pressure was higher in group I compared with group II from before onset of proteinuria (135/86±17/9 mmHg vs 129/80±15/8 mmHg, p<0.001), and serum cholesterol elevated from onset of proteinuria in group I (6.3±1.2 mmol/l) vs. group II (5.5±1.0 mmol/l), (p<0.005). Patients in group I who developed coronary heart disease had similar age (36 years, range 21–51, vs 38 years, range 21–53), sex (50% males vs. 52% males), smoking frequency (50% vs 49%), diabetes duration (22 years, range 9–39, vs 24 years, range 10–42) and serum creatinine (110 mol/l, range 69–284, vs 108 mol, range 72–1024) compared with patients not developing coronary heart disease. However, the patients with coronary heart disease had higher blood pressure (135/87mmHg±16/9 vs 128/82±15/7, p<0.05) and serum cholesterol (7.3 mmol/l+ 1.2 vs 6.4 mmol/l±0.9, p<0.05) than patients without coronary heart disease. Thus, patients developing clinical nephropathy have a highly increased incidence of coronary heart disease compared with patients not developing nephropathy. Patients who developed coronary heart disease were characterized by higher blood pressure and serum cholesterol.     

Seasonality in clinical onset of Type 1 diabetes in Belgian patients above the age of 10 is restricted to HLA-DQ2/DQ8-negative males, which explains the male to female excess in incidence

Aims/hypothesis Type 1 diabetes arises from an interplay between environmental and genetic factors. The reported seasonality at diagnosis supports the hypothesis that currently unknown external triggers play a role in the onset of the disease. We investigated whether a seasonal pattern is observed at diagnosis in Belgian Type 1 diabetic patients, and if so whether seasonality varies according to age, sex and genetic risk, all known to affect the incidence of Type 1 diabetes.Methods The seasonal pattern at clinical diagnosis was assessed in 2176 islet antibody-positive diabetic patients aged 0 to 39 years diagnosed between 1989 and 2000. Additional stratification was performed for age, sex and HLA-DQ genotype.Results Overall, a significant seasonal pattern at clinical diagnosis of diabetes was observed (p<0.001). More subjects were diagnosed in the period of November to February (n=829) than during the period of June to September (n=619) characterised by higher averages of maximal daily temperature and daily hours of sunshine. However, the seasonal pattern was restricted to patients diagnosed above the age of 10 (0–9 years: p=0.398; 10–19 years: p<0.001; 20–29 years: p=0.003; 30–39 years: p=0.015). Since older age at diagnosis is associated with a male to female excess and a lower prevalence of the genetic accelerator HLA-DQ2/DQ8, we further stratified the patients aged 10 to 39 years (n=1675) according to HLA-DQ genotype and sex, and we found that the seasonal pattern was largely restricted to male subjects lacking DQ2/DQ8 (n=748; p<0.001 vs all others: n=927; p=0.031).Conclusions/interpretation In a subgroup of male patients diagnosed over the age of 10, the later stages of the subclinical disease process may be more driven by sex- and season-dependent external factors than in younger, female and genetically more susceptible subjects. These factors may explain the male to female excess in diabetes diagnosed in early adulthood.Abbreviations EURODIAB Europe and Diabetes - GADA glutamate decarboxylase antibodies - IA-2A insulinoma-associated protein 2 antibodies - IAA insulin autoantibodies - ICA islet cell cytoplasmic antibodies     

The HLA-D associations of Type 1 (insulin-dependent) diabetes in Punjabi Asians in the United Kingdom

Summary Type 1 (insulin-dependent) diabetes is less common in Asian Indians than in white Caucasoids. Forty-five Punjabi Asians with Type 1 diabetes and 96 racially matched control subjects were HLA-DR typed. DR3 was increased in diabetic patients vs control subjects (82% vs 38%, p<10^–5) with relative risk 7.7 and etiological fraction 0.72. DR4 was increased in diabetic patients vs control subjects (31% vs 7%, p<0.003) with relative risk 5.7 and etiological fraction 0.26. DR2 showed a negative association (relative risk 0.19, etiological fraction –0.28), as did DR7 (relative risk 0.21, etiological fraction –0.33). HLA-DQ-chain gene probing using restriction enzyme BamHI in 43 diabetic patients and 90 control subjects showed that the DR1-associated 6.2 and 3.2kb fragments were less common in diabetic patients than in the control subjects (12% vs 36%, p<0.02). A 12kb fragment was associated with DR4 in both diabetic patients and control subjects. DR3 is the major susceptibility factor for Type 1 diabetes in Punjabi Asians and DR4 is a second marker. Gene probing indicates that the same DR4 subset is associated with the condition as in white Caucasoids. DR1 and its associated DQ restriction fragments are reduced in Asian Type 1 diabetic patients making it unlikely that DR1 haplotypes carry a predisposing factor in this racial group. We conclude that the genetic component of Type 1 diabetes in Punjabis shows differences from that of the white Caucasoid population and that the lower frequency of DR4 in this population may contribute to the lower prevalence of Type 1 diabetes.     

Life table analysis of the risk of Type 1 (insulin-dependent) diabetes mellitus in siblings according to islet cell antibodies and HLA markers

Summary To determine whether genetic markers can improve the predictive value of islet cell antibodies for development of Type 1 (insulin-dependent) diabetes mellitus, 536 siblings aged 2–29 years were consecutively enrolled in a 8-year prospective survey. The risk of developing diabetes was estimated, using life-table methods, by years of follow-up and age, according to genetic factors (shared HLA-haplotypes, DR antigens, C4 allotypes) and islet cell antibody status. Fifteen siblings (2.8%) developed Type 1 diabetes during the study period (risk 4.4% after 8 years, 4% by age 22 years). DR3,4 heterozygosity identified higher risk (16% after 8 years, 12% by age 22 years, p <10^–5) than HLA-identity (10% and 7%, respectively, p <0.01); risks for DR3 or DR4 positive and for haplo-identical siblings were low (4%, 3% and 4.4%, respectively, NS). C4BQO also conferred significant risk (11% vs 3% in non-C4BQO siblings, p<0.01). The predictive value of genetic markers alone was poor (12% for DR3,4, 7% for HLA-identity, 9% for C4BQO) compared with that of islet cell antibody levels greater than 4 Juvenile Diabetes Foundation units (41%, risk 56% after 8 years, p <10^–7). HLA markers significantly contributed to risk prediction in combination with islet cell antibodies: islet cell antibody-positive DR3,4⁺ subjects had the highest risk (70% after 8 years, predictive value 58%, p <10^–7) compared with islet cell antibody-positive DR3,4^– (37% and 20%, respectively) and islet cell antibody-negative DR3,4⁺ (5% and 3.6%, respectively). Furthermore, islet cell antibody-positive DR3,4⁺ siblings progressed to diabetes at a younger age (risk 84% by age 22 years vs 20% in islet cell antibody-positive DR3,4^– siblings, p <0.005). Siblings with moderate islet cell antibody levels who carry the DR3,4 antigens have been identified as a subgroup with increased risk and more rapid progression to Type 1 diabetes.     

Increased Prevalence of Upper Gastrointestinal Symptoms in Long-term Type 1 Diabetes Mellitus

Using a validated postal questionnaire, we investigated the frequency of 24 gastrointestinal symptoms during the previous 3 months in a cohort of 110 young adult patients (54 males and 56 females, mean age 37.2 ± 4.7 years) with onset of Type 1 diabetes mellitus at <16 years of age. They were compared with 210 age- and sex-matched controls (104 males and 106 females). The main difference in the frequency of various symptoms between the two groups was a significant increase among the diabetic patients in upper gastrointestinal symptoms, such as loss of appetite (17.8% vs 3.6%, p < 0.001), early satiety (26.8% vs 6.1%, p < 0.001), nausea (22.7% vs 9.1%, p < 0.01) and vomiting (12.2% vs 3.0%, p < 0.01). No difference was noted in the frequency of symptoms from the lower gastrointestinal tract, apart from a significant increase in the feeling of incomplete defaecation (28.6% vs 17.0%, p < 0.04) in the diabetic patients. Patients with levels of haemoglobin A_1c in the highest quartile had significantly more gastrointestinal symptoms than other diabetic patients. Further, the prevalence of symptoms was higher in females than in males. In conclusion, long-term Type 1 diabetes is accompanied by a markedly increased frequency of upper gastrointestinal symptoms, mainly in females and patients with poor metabolic control.     

Association of IA-2 autoantibodies with HLA DR4 phenotypes in IDDM

Summary Insulin, glutamate decarboxylase (GAD) and the protein tyrosine phosphatase-like molecule IA-2 are major targets of humoral autoimmunity in insulin-dependent diabetes mellitus (IDDM). These autoantibodies are heterogeneous with respect to age and patient human leukocyte antigen (HLA) phenotype. We have previously demonstrated that GAD and IA-2 antibodies potentially identify different subsets of IDDM patients. The aim of this study was to determine whether GAD and IA-2 autoantibodies were associated with different HLA DR phenotypes. We studied 160 patients with IDDM onset before age 16 years. At disease onset serum was tested for GAD and IA-2 antibodies by immunoprecipitation of in vitro-translated³⁵S-methionine labelled recombinant proteins. IA-2 antibodies were significantly associated with HLA DR4: 67 (86 %) of 78 patients with HLA DR4 vs 31 (38 %) of 82 non-DR4 patients had IA-2 antibodies (p _c<0.0001) and IA-2 antibody levels were higher in patients with HLA DR4 (p _c<0.0001). In contrast, GAD antibodies were more prevalent (p _c<0.05) and antibody levels highest (p _c<0.01) in patients with HLA DR3 phenotypes. These data provide further evidence that, in IDDM, production and titre of major autoantibody specificities are associated with HLA class II alleles.     

Prevalence of hypertension in Type 1 (insulin-dependent) diabetes mellitus

Summary The prevalence of hypertension in a representative sample (n=10202) of the Danish general population aged 16–59 years was assessed to 4.4% based on three blood pressure readings. In Type 1 (insulin-dependent) diabetic patients of similar age (n=1703) the prevalence was determined in a similar way to 14.7% (p<0.00001). The excess prevalence in Type 1 diabetic patients was due to hypertension in patients with incipient and clinical nephropathy as the prevalence of hypertension among diabetic patients with normal urinary albumin excretion (essential hypertension) was 3.9%, similar to that observed in the general population. The patients with Type 1 diabetes and essential hypertension had higher systolic (146±19 vs 133±18 mmHg, p<0.00001) and diastolic blood pressure (87±12 vs 79±7mmHg, p<0.00001), but less changes in the eye background than patients with incipient nephropathy (urinary albumin excretion 30–300 mg/24 h) (p<0.03), indicating that the two groups were also different with respect to other microangiopathic lesions. Patients with essential hypertension were defined as having a normal urinary albumin excretion before and during antihypertensive treatment (if any). They were followed-up for a 58 (6–234) month period. We confirmed that hypertension is more common among Type 1 diabetic patients than in the general population and found the prevalence of essential hypertension similar in Type 1 diabetic patients to the non-diabetic population. This supports our hypothesis that hypertension is very unlikely to be the cause of diabetic nephropathy.     

IA-2 antibody prevalence and risk assessment of early insulin requirement in subjects presenting with type 2 diabetes (UKPDS 71)

Aims/hypothesis Established autoimmune markers of type 1 diabetes, including islet cell autoantibodies (ICA) and autoantibodies to glutamic acid decarboxylase (GADA) have been used to screen people presenting with type 2 diabetes for latent autoimmune diabetes in adults. We have examined the prevalence of autoantibodies to protein tyrosine phosphatase isoforms IA-2 (IA-2A) and IA-2/phogrin (IA-2A) in a cohort of adult UKPDS patients thought to have type 2 diabetes, and investigated the possible role of these autoantibodies in predicting requirement for insulin therapy.Methods IA-2A and IA-2A were measured by a validated radioimmunoassay with human recombinant autoantigens in 4,169 white Caucasian patients aged 25–65 years and newly diagnosed with type 2 diabetes. The clinical requirement for insulin therapy within 6 years was examined in 2,556 patients not randomised to insulin.Results IA-2A and IA-2A were present in 2.2 and 1.4%, respectively, of these patients. IA-2A were more prevalent in younger patients (p for trend <0.00001), more often associated with the HLA-DR4 allele (26.3 vs 8.0%, p<0.0001), and their presence increased the likelihood of insulin therapy requirement within 6 years from diagnosis [relative risk (95%CI) 12.2 (9.8–15.3)]. The presence of IA-2A together with GADA increased the relative risk of requiring insulin therapy from 5.4 (4.1–7.1) for GADA alone to 8.3 (3.7–18.8) and the corresponding positive predictive value from 33 to 50%.Conclusions/interpretation In type 2 diabetes, the presence of IA-2A is infrequent, associated with the HLA-DR4 haplotype, and highly predictive of future need for insulin therapy. The measurement of IA-2A does not provide additional information.An erratum to this article can be found at     

Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes

Aims/hypothesis Prevention trials in first-degree relatives of type 1 diabetic patients are hampered by large interindividual differences in progression rate to diabetes. We investigated whether specific combinations of immune and genetic markers can identify subgroups with more homogeneous progression to clinical onset.Methods Antibodies against islet cell cytoplasm (ICA), insulin (IAA), glutamate decarboxylase (GADA) and IA-2 protein (IA-2A) were measured in 790 non-diabetic control subjects and 4,589 first-degree relatives under age 40.Results On first sampling, 11.1% of the siblings presented at least one antibody type (p<0.001 vs other relatives). During follow-up (median 52 months) 43 subjects developed type 1 diabetes (31 siblings, ten offspring of a diabetic father, two offspring of a diabetic mother). Using Kaplan–Meier survival analysis and Cox regression, IA-2A conferred the highest 5-year diabetes risk (>50%) irrespective of the number of antibodies present. In initially IA-2A-positive relatives (n=58) progression to hyperglycaemia depended more on HLA DQ status than on type of kinship (84% progression in the presence of DQ2/DQ8 vs 32% in its absence; p<0.003). In IA-2A-negative relatives (n=4,531) 5-year progression to diabetes increased with the number of other antibodies (ICA, GADA and/or IAA) (p<0.001) but overall did not exceed 10% even for two or more antibodies. Among relatives initially positive for one or more antibody type other than IA-2A (n=315), there was significantly more progression to diabetes (overall still <10%) in carriers of DQ2 (p<0.001 vs no DQ2), regardless of DQ8 status.Conclusions/interpretation These observations suggest that the HLA-DQ-inferred risk of diabetes can proceed through two distinct pathways distinguished by IA-2A status. Combined positivity for DQ2/DQ8 and IA-2A defines a more homogeneous high-risk population for prevention trials than those used so far.Presented in part at the 38th Annual Meeting of the European Association for the Study of Diabetes, September 1–5, 2002, Budapest, Hungary.K. Decochez and I. Truyen contributed equally to the present work.     

IA-2-autoantibodies complement GAD65-autoantibodies in new-onset IDDM patients and help predict impending diabetes in their siblings

Summary IA-2 has been identified as an autoantigen that is recognized by immunoglobulins from insulin-dependent diabetic (IDDM) patients. Using a liquid phase radiobinding assay, we performed an IA-2-autoantibody (IA-2-Ab) assay in 474 IDDM patients and 482 non-diabetic control subjects aged 0–39 years. IA-2-Ab were detected in 58 % of the patients and 0.8 % of control subjects. Their prevalence in patients was lower than that of islet cell autoantibodies (ICA; 73 %) or glutamic acid decarboxylase (M_r 65 kDa)-autoantibodies (GAD₆₅-Ab; 82 %) but higher than that of insulin autoantibodies (IAA; 42 %). IA-2-Ab were more frequent in patients under age 20 years (70 %) than between 20 and 40 years (45 %; p < 0.001). In the whole IDDM group, 92 % of patients were positive for at least one of the three molecular assays, which is higher than the positivity for the ICA assay (73 %). Only 1 % was negative in the molecular assays and positive in the ICA assay. IA-2-Ab levels were positively correlated with ICA titres (p < 0.001) and HLA DQ A1^*0301 – DQ B1*0302 (p < 0.003) by multivariate analysis. In a group of 481 non-diabetic siblings (age 0–39 years) of IDDM patients only 7 were IA-2-Ab positive (1.5 %). All seven were under age 20 years and positive for at least two other autoantibodies and for DQ A1^*0301 – DQB1*0302. Four of these seven developed IDDM during the 6–70-month follow-up period. The positive predictive value of IA-2-Ab (57 %) was higher than that of ICA, GAD₆₅-Ab or IAA alone, or in combination (≤ 20 %) but these calculations are restricted by the relatively short observation period and the small number of cases. The only IA-2-Ab-negative case of pre-diabetes was also negative for IAA and GAD₆₅-Ab, while it was strongly positive for ICA. In conclusion, IA-2-Ab show a high diagnostic specificity for IDDM and are predictive markers of impending diabetes in siblings of patients. In combination with other molecular antibody assays they may replace ICA testing in future. Our data also indicate that other autoantibodies than IA-2-Ab, GAD₆₅-Ab and IAA contribute to ICA. [Diabetologia (1997) 40: 95–99] Received: 18 September 1996 and in revised form: 8 October 1996     

Immunological heterogeneity in Type I diabetes: presence of distinct autoantibody patterns in patients with acute onset and slowly progressive disease

Summary Type I diabetes mellitus may represent a heterogeneous disorder with a distinct pathogenesis in patients with young and adult onset of the disease. To investigate whether serological markers directed to different autoantigens have the potential to distinguish acute onset from slowly progressive Type I diabetes we analysed antibodies to tyrosine phosphatases IA-2/ICA512 (IA-2A) and IA-2β/phogrin (IA2βA), antibodies to GAD65 (GADA) and cytoplasmic islet cell antibodies (ICA) in a non-selected group of diabetic patients clinically classified as having Type I or Type II diabetes at diagnosis. Both IA-2A and IA-2βA were found to be positively associated with onset before the age of 20 years and the presentation of classical features of Type I diabetes. In Type I diabetes 56 % (112/200) of patients were positive for IA-2A and 38 % (76/200) for IA-2βA. In contrast, only 1 of 785 (0.1 %) patients with Type II diabetes had IA-2A and all of them were negative for IA-2βA (p < 0.001). Among the patients with Type II diabetes 7.6 % (n = 60) were ICA positive and 2.8 % (n = 22) had GADA suggesting the presence of slowly progressive Type I diabetes. GADA were found in 8 of 60 (13.3 %) ICA positive subjects which was lower than the percentage detected in patients with acute onset of diabetes (115/157 73.2 %) (p < 0.001). Blocking of double antibody positive sera showed that only 3 of 8 (37.5 %) patients with slowly progressive diabetes had ICA restricted to GAD or IA-2 whereas ICA were completely inhibited in 12 of 20 (60.0 %) patients with Type I diabetes. Among 193 patients with Type II diabetes available for follow-up, 35 % of ICA positives, 58 % of GADA positives and 60 % of those positive for both markers required insulin by 3 years. However, using strict criteria for the switch to insulin treatment the corresponding sensitivity of each marker was only low (9 %, 10 % and 5 %). We show that clinical subtypes of Type I diabetes are associated with distinct humoral autoimmunity. IA-2A and GADA were associated with classical features of Type I diabetes whereas GADA and an uncharacterized ICA subspecificity indicate slowly progressive disease. [Diabetologia (1998) 41: 891–897] Received: 15 January 1998 and in revised form: 10 April 1998     

Apolipoprotein(a) and cardiovascular disease in Type 2 (non-insulin-dependent) diabetic patients with and without diabetic nephropathy

Summary The relative mortality from cardiovascular disease is on average increased five-fold in Type 2 (non-insulin-dependent) diabetic patients with diabetic nephropathy compared to non-diabetic subjects. We assessed the possible contribution of dyslipidaemia in general and elevated serum apolipoprotein(a) (apo(a)) in particular. Type 2 diabetic patients with normo-, micro- and macroalbuminuria were compared with healthy subjects. Each group consisted of 37 subjects matched for age, sex and diabetes duration. Serum creatinine in the nephropathy group was 105 (54–740) mol/l. The prevalence of ischaemic heart disease (resting ECG, Minnesota, Rating Scale) was 57, 35, 19 and 2% in macro-, micro- and normoalbuminuric diabetic patients and healthy subjects, respectively. The prevalence of ischaemic heart disease was higher in all diabetic groups as compared to healthy subjects (p<0.05), and higher in macroalbuminuric as compared to normoalbuminuric diabetic patients (p<0.01). There was no significant difference between apo(a) in the four groups: 161 (10–1370), 191 (10–2080), 147 (10–942), 102 (10–1440) U/l (median (range)) in macro-, micro- and normoalbuminuric groups and healthy subjects. Serum total-cholesterol, HDL-cholesterol and LDL-cholesterol were not significantly different when comparing healthy subjects and each diabetic group. Apolipoprotein A-I was lower (p<0.05) in all diabetic groups as compared to healthy subjects (nephropathy vs healthy subjects): 1.50±0.25 vs 1.69±0.32 g/l (mean ± SD). Triglyceride was higher (p<0.05) in patients with nephropathy and microalbuminuria as compared to healthy subjects (nephropathy vs healthy subjects): 2.01 (0.66–14.7) vs 1.09 (0.41–2.75) mmol/l (median (range)). Apolipoprotein B was higher (p<0.02) in patients with nephropathy as compared to the other three groups (nephropathy vs healthy subjects): 1.54±0.47 vs 1.33±0.30 g/l. In conclusion, our case-control study has confirmed that Type 2 diabetic patients with increased urinary albumin excretion frequently suffer from dyslipidaemia and cardiovascular disease. However, our study revealed no significant elevation in serum concentration of apo(a) in patients with diabetic nephropathy, but numbers were small.     

Iron status in young Danes. Evaluation by serum ferritin and haemoglobin in a population survey of 634 individuals aged 14–23 yr

Abstract: Iron status was assessed by serum ferritin and haemoglobin in a population survey comprising 634 randomly selected urban Danes (312 males, 322 females) 14–23 yr old. At all ages, males had significantly higher serum ferritin and haemoglobin values than females. Males: median serum ferritin displayed a steady increase with age from 33 to 109 μg/l (r_s=0.53, p<0.0001). The prevalence of absent mobilizable body iron stores (serum ferritin <13 μg/l) was 3.5% at 16–17 yr of age, gradually declining to 0% at 22–23 yr. None of the males had iron deficiency anaemia (serum ferritin <13 μg/l and haemoglobin <129 g/l). Females: median ferritin values displayed a slight increase with age from 28 to 39 μg/l (r_s=0.19, p<0.001). The prevalence of absent iron stores was 12.5% at 16–17 yr of age, declining to 6.6% at 22–23 yr. The prevalence of iron deficiency anaemia (serum ferritin <13 μg/l and haemoglobin <121 g/l) was 4.7% at 16–17 yr of age, declining to 1.3% at 22–23 yr of age. Compared with surveys in other parts of Scandinavia, young Danes had slightly higher serum ferritin levels, and a lower prevalence of iron deficiency.     

Incidence and prevalence of Type 1 (insulin-dependent) diabetes in Estonia in 1988

Summary The objective of this study was to determine the incidence and prevalence of Type 1 (insulin-dependent) diabetes in Estonia in different sex and age groups. The data collection was based on a centralized retrospective registration of all cases of Type 1 diabetes nationwide using the records of all hospitals and polyclinics where diabetic patients are treated. In 1988, 35 new cases of Type 1 diabetes were diagnosed among children aged 0–14 years (10.3 per 100,000) and 131 among the population over 15 years. The highest incidence of Type 1 diabetes (39.9 per 100,000) was found in the age group 15–19 years. The total number of patients with Type 1 diabetes in Estonia was 2,719 in 1988. The overall prevalence was 1.72 per 1,000. It was highest in the age group 40–49 years (3.04 in males and 2.77 in females). In children under 15 years 204 cases of Type 1 diabetes were identified at the end of 1988. These data suggest that the risk of Type 1 diabetes in Estonia is not low, but is certainly not as high as in Finland where the population is ethnically and linguistically similar and where the highest incidence of Type 1 diabetes is found.     

Presence of very low density lipoprotein compositional abnormalities in Type 1 (insulin-dependent) diabetic patients; effects of blood glucose optimisation

Summary Plasma lipoprotein compositional abnormalities were investigated in eight normolipidaemic (plasma cholesterol <5.70 mmol/l; triglyceride <2.03 mmol/l) young male Type 1 (insulin-dependent) diabetic patients (before and after a short period of optimised blood glucose control) and in nine healthy control subjects, matched for sex, age and body mass index. Free and esterified cholesterol, triglyceride, phospholipids were assayed in all lipoprotein classes (VLDL, IDL, LDL) and in HDL subclasses (HDL2 and HDL3); apoB was measured only in very low density lipoproteins (VLDL). All VLDL constituents were increased in the diabetic group, the differences being more striking for apoB (6.0±1.1 mg/dl vs 2.0±0.1 mg/dl, p<0.02), free cholesterol (0.27±0.04 mmol/l vs 0.13±0.02 mmol/l, p<0.02) and esterified cholesterol (0.32±0.08 mmol/l vs 0.13±0.01 mmol/l, p<0.05). Also HDL subfractions showed differences between the two groups: all HDL2 constituents were increased, while in HDL3 only triglyceride was significantly increased (0.11±0.01 mmol/l vs 0.08±0.004 mmol/l, p<0.02). After two weeks of optimised blood glucose control all VLDL constituents were reduced and particularly: esterified cholesterol (–39%, p<0.02), free cholesterol (–37%, p<0.05), apoB (– 35%, p<0.05). Expressing each VLDL constituent as percent of the total lipoprotein mass, it was evident that the diabetic VLDL was rich in cholesterol both esterified (8.4±1.0% vs 5.4±0.5%, p<0.02) and free (8.5±0.7% vs 5.5±0.3%, p<0.001), apo B (5.1±0.6% vs 2.6±0.3%, p<0.001) and depleted in triglyceride (57.0±1.7% vs 64.1±1.7%, p<0.001). Two weeks of optimised blood glucose control were not able to correct the abnormal composition of VLDL. In conclusion, Type 1 (insulin-dependent) diabetic patients, although normolipidaemic, show an abnormal VLDL composition suggesting an increased prevalence of smaller and, possibly, more atherogenic VLDL particles. This abnormality is not corrected by a short period of blood glucose optimisation.     

Relationship between serum insulin autoantibodies,islet cell antibodies and Coxsackie-B4 and mumps virus-specific antibodies at the clinical manifestation of Type 1 (insulin-dependent) diabetes

Summary In order to elucidate the possible relationship between insulin autoantibodies (IAA), conventional (ICA-IgG) and complement-fixing (CF-ICA) islet cell antibodies and Coxsackie-B4 and mumps virus-specific antibodies (IgG, IgM and IgA classes), we studied 194 children and adolescents with newly diagnosed Type 1 (insulin-dependent) diabetes. Sixty-one (31.4%) of the subjects were IAA-positive at diagnosis and 73.8% (45/61) of these also had ICA-IgG compared to 51.1% (68/113, p<0.01) of IAA-negative children. CF-ICA showed no significant association with IAA. The levels of IAA were significantly higher in the patients with ICA-IgG compared to those without [5.9±1.6% (SEM) vs 2.5±0.3%, p<0.01]. The patients positive for IAA were younger at diagnosis than the IAA-negative ones; (7.1±0.5 vs 9.3±0.3 years, p<0.001) and this was also true for ICA-IgG-positive children (8.1±0.4 vs 9.4±0.5 years, p<0.05) in comparison to ICA-IgG-negative subjects. No significant associations were found between IAA or ICA on the one hand and a positive family history of Type 1 diabetes or metabolic derangements at diagnosis on the other. Subjects negative for ICA were more frequently positive for mumps virus specific IgG antibodies than the ICA-positive patients (50/80 vs 53/111, p<0.05), and Coxsackie-B4 virus-specific IgA antibodies were more common in the CF-ICA-negative than the CF-ICA-positive children (53/111 vs 29/80, p<0.05). There was no association between the IAA levels and Coxsackie-B4 or mumps virus specific antibodies. However, patients with serological evidence of a recent mumps infection (n=13) had higher IAA levels than the other children (4.4±7.7% vs 2.8±1.4%, p<0.02). Our data suggest a positive association between IAA and ICA-IgG, supporting the view that IAA are like ICA serological markers of autoimmune B cell damage. The inverse associations between autoantibodies and age and between ICA and viral antibodies support the hypothesis that autoimmune mechanisms may play a more crucial role in younger patients contracting Type 1 diabetes while environmental factors may be more important in older ones.     

Incidence and Prevalence of Type 1 Diabetes in Children and Adolescents in Benghazi,Libya

The mean annual incidence rates of Type 1 diabetes mellitus in Arab children and adolescents in Benghazi, Libya were assessed as based on prospective registration of patients during the period 1981–1990. Results showed an annual incidence (per 100 000) of 7.0 (6.0–8.2) (males 6.3(5.0–7.9) females 7.8(6.3–9.7)) in 0–14 year olds and 8.8(7.8–10.0) (males 8.3(6.9–10.0), females 9.2(7.7–11.0)) in 0–19 year olds. There were no significant differences between males and females or between season of onset. The commonest age of onset was 15–19 years. Annual variations were significant in the 0–14 years age group (p < 0.001) and non-significant in the 0–19 years age group. In 1981 the age adjusted prevalence rates of Type 1 patients (per 100 000) were 23.5 (17.1–31.5) (males 21.2(13.1–32.3), females 25.9(16.8–38.3)) in 0–14 year olds and 36.2(29.1–45.1) (males 31.4(22.2–43.2), females 41.0(30.2–54.5)) in 0–19 year olds. In 1990 the prevalence rates had increased to 37.3(30.5–45.5) (males 40.7(30.8–53.3), females 33.8 (24.6–45.3)) in 0–14 year olds and 59.5(51.6–58.5) (males 60.3(49.3–73.6), females 58.6 (47.7–72.1)) in 0–19 year olds. Increase in prevalence rates was significant in both sexes and in both age groups (p < 0.001). Increase in prevalence rates in girls in 1981 and in boys in 1990 were not significant. It is concluded that Type 1 diabetes is a common chronic disease of children and adolescents in Benghazi, Libya.     

A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population

Summary A cross-sectional multicentre study of randomly selected diabetic patients was performed using a standardised questionnaire and examination, to establish the prevalence of peripheral neuropathy in patients attending 118 hospital diabetes clinics in the UK. Vibration perception threshold was performed in two centres to compare with the clinical scoring systems. A total of 6487 diabetic patients were studied, 53.9% male, median age 59 years (range 18– 90 years), 37.4% Type 1 (insulin-dependent) diabetes mellitus, with a median duration of diabetes 8 years (0–62 years). The overall prevalence of neuropathy was 28.5% (27.4– 29.6 %) (95 % confidence interval) in this population. The prevalence in Type 1 diabetic patients was 22.7% (21.0– 24.4 %) and in Type 2 (non-insulin-dependent) diabetic patients it was 32.1 % (30.6–33.6 %). The prevalence of diabetic peripheral neuropathy increased with age, from 5% (3.1– 6.9 %) in the 20–29 year age group to 44.2 % (41.1–47.3 %) in the 70–79 year age group. Neuropathy was associated with duration of diabetes, and was present in 20.8 % (19.1–22.5 %) of patients with diabetes duration less than 5 years and in 36.8 % (34.9–38.7 %) of those with diabetes duration greater than 10 years. Mean vibration perception threshold measured at the great toe was 21.1±13.5 SD volts and correlated with the neuropathy disability score, r=0.8 p<0.001. In conclusion, diabetic peripheral neuropathy is a common complication associated with diabetes. It increases with both age and duration of diabetes, until it is present in more than 50% of Type 2 diabetic patients aged over 60 years. An increased awareness of the high prevalence of peripheral neuropathy, especially in older patients, should result in improved screening programmes in order to reduce the high incidence of neuropathic diabetic foot ulceration.     

Change in patients’ body weight after 12 months of treatment with glimepiride or glibenclamide in Type 2 diabetes: a multicentre retrolective cohort study

Aims/hypothesis Our study compared the effects of glimepiride or glibenclamide treatment on body weight over 12 months of treatment in patients with Type 2 diabetes in routine outpatient practice.Methods This new retrospective study design used data from physicians in a restricted manner (retrolective). Data from case report forms from 520 patients from 91 randomly selected centres were assessed and covariance analysis performed.Results The influence of practice and patient characteristics on treatment assignment was low, reflecting the design of randomised controlled trials. Mean weight loss and reduction in body mass index from baseline to study endpoint were greater with glimepiride than with glibenclamide (–2.04±3.99 kg vs –0.58±3.65 kg, p<0.001; –0.71±1.38 kg/m² vs –0.20±1.28 kg/m², p<0.001). Duration of treatment at baseline influenced treatment outcome, but propensity score, sex, age and fasting blood glucose at baseline did not. Both glimepiride and glibenclamide led to decreases in fasting blood glucose (–2.43±0.24 mmol/l vs –3.03±0.24 mmol/l; p<0.001 vs baseline) and HbA_1c (–1.23±0.09% vs –1.26±0.09%; p<0.001 vs baseline). Both treatments were associated with a decrease in serum total cholesterol and low density lipoprotein cholesterol. Triglycerides were lower in the glibenclamide group and high density lipoprotein cholesterol was higher in the glimepiride group only.Conclusions/interpretation Initial treatment of Type 2 diabetes with glimepiride was associated with a significantly greater decrease in body weight and body mass index than treatment with glibenclamide, while providing equivalent glycaemic control.Abbreviations FBG Fasting blood glucose - SU sulphonylurea - UKPDS United Kingdom Prospective Diabetes Study