Marco Songini

Zinc Transporter 8 Antibodies Complement GAD and IA-2 Antibodies in the Identification and Characterization of Adult-Onset Autoimmune Diabetes: Non Insulin Requiring Autoimmune Diabetes (NIRAD) 4

OBJECTIVE Zinc transporter 8 (ZnT8) is an islet β-cell secretory granule membrane protein recently identified as an autoantibody antigen in type 1 diabetes. The aim of this study was to determine the prevalence and role of antibodies to ZnT8 (ZnT8As) in adult-onset diabetes. RESEARCH DESIGN AND METHODS ZnT8As were measured by a radioimmunoprecipitation assay using recombinant ZnT8 COOH-terminal or NH2-terminal proteins in 193 patients with adult-onset autoimmune diabetes having antibodies to either GAD (GADAs) or IA-2 (IA-2As) and in 1,056 antibody-negative patients with type 2 diabetes from the Non Insulin Requiring Autoimmune Diabetes (NIRAD) study. RESULTS ZnT8As-COOH were detected in 18.6% patients with autoimmune diabetes and 1.4% with type 2 diabetes. ZnT8As-NH2 were rare. ZnT8As were associated with younger age and a high GADA titer. The use of GADAs, IA-2As, and ZnT8As in combination allowed a stratification of clinical phenotype, with younger age of onset of diabetes and characteristics of more severe insulin deficiency (higher fasting glucose and A1C, lower BMI, total cholesterol, and triglycerides) in patients with all three markers, with progressive attenuation in patients with two, one, and no antibodies (all Ptrend < 0.001). Autoantibody titers, association with high-risk HLA genotypes, and prevalence of thyroid peroxidase antibodies followed the same trend (all P < 0.001). CONCLUSIONS ZnT8As are detectable in a proportion of patients with adult-onset autoimmune diabetes and seem to be a valuable marker to differentiate clinical phenotypes.

High Incidence Rate of IDDM in Sardinia

OBJECTIVE To provide reliable data on the incidence of IDDM in Sardinia and contribute to a better understanding of its geographical variability throughout Europe. RESEARCH DESIGN AND METHODS All newly diagnosed cases of IDDM with onset < 30 yr of age between 1 January 1989 and 31 December 1990 among residents in Sardinia were recorded. Primary ascertainment was based on notification by all Sardinian hospitals, outpatient clinics, family doctors, and pediatricians. The local IDDM patient association served as the secondary and independent source. RESULTS The completeness of ascertainment was 92.8%. The annual incidence rate of IDDM (per 100,000) over the 2-yr period was 30.7 in the 0–14–yr-old age-group and 24.1 in the entire 0–29–yr-old range, respectively, with no significant differences between the two groups. Male/female ratios were 1.25 and 1.55, respectively. No significant seasonal variation in incidence was observed. CONCLUSIONS Sardinia appears to have the second-highest IDDM incidence rate in Europe after Finland, and the island contradicts the generally accepted rule of a south-to-north incidence gradient.

Different risk factors of microangiopathy in patients with Type I diabetes mellitus of short versus long duration. The EURODIAB IDDM Complications Study

Aims/hypothesis. To identify factors associated with early development of and late protection from microvascular complications in subjects with Type I (insulin-dependent) diabetes mellitus.¶Methods. The frequency of microvascular complications and their relation to risk factors were studied in 300 Type I diabetic subjects with short duration of disease ( ≤ 5 years) compared with 1062 subjects with long duration ( ≥ 14 years). Microvascular disease was defined as the presence of either retinopathy (assessed from centrally-graded retinal photographs) or urinary albumin excretion rate of more than 20 μg/min.¶Resu1ts. The prevalence of microvascular disease was 25 % in the short duration group. In the long duration group 18 % had no evidence of microvascular complications. In the short duration group factors associated with early development of complications were cigarette smoking and a family history of hypertension. Subjects free of microvascular complications in spite of long duration of diabetes had better glycaemic control, lower blood pressure, better lipid profile and lower von Willebrand factor levels.¶Conclusion/interpretation. At the early stages of Type I diabetes, cigarette smoking and genetic susceptibility to hypertension are important risk factors for microvascular complications. At a later stage, additional risk factors are poorer glycaemic control, higher blood pressure, and an unfavourable lipid profile possibly associated with endothelial dysfunction. Many of these factors are amenable to long-term intervention which should be started as soon as possible in the course of the disease. [Diabetologia (2000) 43: 348–355]

Dyschromatopsia in diabetes mellitus and its relation to metabolic control.

In 102 insulin-dependent diabetic patients without retinopathy and with visual acuity 20/20, the Farnsworth-Munsell 100-Hue test was performed, and glycosylated hemoglobin (GlHb) levels were determined. In 70% of the patients, a dyschromatopsia in the yellow-blue axis (tritanopia) was found. No correlation existed between duration of diabetes and tritanopia. On the other hand, the degree of this visual defect was positively correlated with GlHb levels. Thus, dyschromatopsia might be associated with poor metabolic control. It is suggested that dyschromatopsia is a consequence of hypoxia at the neuroepithelial level. The high levels of GlHb could be a contributory cause of hypoxia by reduction of both oxygen release capacity and erythrocyte deformability.

More than 20 years of registration of type 1 diabetes in Sardinian children: temporal variations of incidence with age, period of diagnosis, and year of birth.

We analyzed Sardinian registry data to assess time trends in incidence rates (IRs) of type 1 diabetes during the period 1989–2009 (2,371 case subjects 0–14 years of age). Poisson regression models were used to estimate the effects of sex, age, period of diagnosis, and birth cohorts. IR was 44.8 cases/100,000 person-years (95% CI 43.1–46.7). The annual increase was 2.12% (1.45–2.80; test for linear trend, P < 0.001). For boys, the increasing trend was evident up to 5 years of age and for girls up to 8 years of age. Compared with the 1989–1994 birth cohort, the relative risk increased from 0.78 (0.61–1.10) in 1974–1979 to 1.62 (1.18–2.23) in 2004–2009. The increase over period was less striking, with a tendency to regress in more recent years. The best-fitting model for boys included age and a linear time trend, and for girls age and nonlinear effects of calendar period and birth cohort. In conclusion, incidence increased over time, and the increase tended to level off in more recent years by calendar period but not by birth cohort, with some evidence of a stronger increase among girls than boys. Should the increase be attributable to the effects of some perinatal environmental factor, this would mean that such a factor has started affecting females before males.

Human herpes virus-8 infection among pregnant women and their children: Results from the sardinia-IDDM study 2

Marked variations exist in the distribution of human herpesvirus 8 (HHV-8) infection in different geographical and socioeconomic settings, mirroring variations in incidence rates of classic Kaposi’s sarcoma (KS). Thus, HHV-8 infection is more frequent in Italy than in the United States 1–3 and, within Italy, in Sardinia and Sicily, 2 regions with high incidence rates of classic KS, than in the northern part of the country, where classic KS is less frequent. 3–6 In Western countries, HHV-8 infection is usually acquired after adolescence ( i.e., at the beginning of sexual activity), whereas in Africa it occurs commonly in childhood, with prevalence reaching relatively high levels before the age of sexual activity.7 This finding indicates that transmission modes other than sexual intercourse may be important for HHV-8 acquisition also in Western countries, possibly through vertical and/or horizontal transmission. 8,9

High GADA titer increases the risk of insulin requirement in LADA patients: a 7-year follow-up (NIRAD study 7)

OBJECTIVE The aim of this study was to determine whether glutamic acid decarboxylase antibody (GADA) titer and other clinical parameters could define the risk of progression to insulin therapy in latent autoimmune diabetes in adults (LADA) patients during a 7-year follow-up. METHODS This study involved 220 LADA and 430 type 2 diabetes subjects followed up for 7 years from the time of GADA screening to evaluate their progression toward insulin therapy. Kaplan-Meier curves and multivariate logistic regression analysis were performed to identify the markers capable of influencing this progression. RESULTS During the follow-up, the drop out was 4% in both groups. A total of 119 (56.1%) out of 212 LADA patients required insulin during the 7 years of follow-up. The Kaplan-Meier plots showed that 74/104 (71.1%) of high GADA titer required insulin compared with 45/108 (41.6%) of low GADA titer and with 86/412 (20.9%) of type 2 diabetes (P<0.0001 for both). A BMI of ≤25 kg/m2 and IA-2IC and zinc transporter 8 (ZnT8) positivity were also shown as the markers of faster progression (P<0.0001 for both). The proportion of LADA patients requiring insulin was significantly higher in the group of subjects treated also with sulfonylurea in the first year from diagnosis compared with those treated with diet and/or insulin sensitizers (P<0.001). The multivariate analysis confirmed that the presence of high GADA titer was a significant predictor of insulin requirement (P<0.0001, OR=6.95). CONCLUSIONS High GADA titer, BMI ≤ 25, ZnT8 and IA-2IC positivity and sulfonylurea treatment, in the first year from diagnosis, significantly increase the progression toward insulin requirement in LADA patients.

Blue eyes as a risk factor for type 1 diabetes

A high frequency of blue eyes and fair skin are reported in northern European Caucasians with type 1 diabetes (T1D). Also there is an inverse relationship between latitude and T1D incidence. We determined whether iris colour and skin pigmentation are risk factors in a Caucasian population living in two Mediterranean regions located at the same latitude with higher ultraviolet B irradiance, but with different T1D incidence.

Bayesian approach to study the temporal trend and the geographical variation in the risk of type 1 diabetes. The Sardinian Conscript Type 1 Diabetes Registry

Background:  A previous analysis of the Sardinian Conscript Type 1 Diabetes Registry indicated an abrupt increase in the risk for type 1 diabetes (T1D) among Sardinian male cohorts starting from the 1946 one.

Type 1 diabetes in Sardinia: facts and hypotheses in the context of worldwide epidemiological data

Abstract Type 1 diabetes (T1D) results from an autoimmune destruction of insulin-producing beta cells that requires lifelong insulin treatment. While significant advances have been achieved in treatment, prevention of complications and quality of life in diabetic people, the identification of environmental triggers of the disease is far more complex. The island of Sardinia has the second highest incidence of T1D in the world (45/100,000), right after Finland (64.2/100,000). The genetic background as well as the environment of the island’s inhabitants makes it an ideal region for investigating environmental, immunological and genetic factors related to the etiopathogenesis of T1D. Several epidemiological studies, conducted over the years, have shown that exposures to important known environmental risk factors have changed over time, including nutritional factors, pollution, chemicals, toxins and infectious diseases in early life. These environmental risk factors might be involved in T1D pathogenesis, as they might initiate autoimmunity or accelerate and precipitate an already ongoing beta cell destruction. In terms of environmental factors, Sardinia is also particular in terms of the incidence of infection with Mycobacterium avium paratuberculosis (MAP) that recent studies have linked to T1D in the Sardinian population. Furthermore, the unique geochemical profile of Sardinia, with its particular density of heavy metals, leads to the assumption that exposure of the Sardinian population to heavy metals could also affect T1D incidence. These factors lead us to hypothesize that T1D incidence in Sardinia may be affected by the exposure to multifactorial agents, such as MAP, common viruses and heavy metals.