Type 1 diabetes and measles, mumps and rubella childhood infections within the Italian Insulin-dependent Diabetes Registry.

AIMS: Several studies confirmed the growing rate of Type 1 diabetes mellitus in childhood coinciding with increasing diagnosis of viral infections. A study investigating the incidence of Type 1 diabetes during 1996-1997 showed a higher notification of viral infections in the Pavia District. The aim was to confirm these results. METHODS: This study evaluated the relationship between new cases of Type 1 diabetes and those of measles, mumps and rubella in 1996-2001, analysing data of newly-diagnosed Type 1 diabetes children, aged 0-14 years and enrolled into the RIDI (Italian Insulin-dependent Diabetes Registry) during the same years. Measles, rubella and mumps rates were calculated using as denominator the estimated 'population at risk', represented by the number of 0- to 14 year-old subjects who did not undergo the MMR (measles, mumps and rubella) vaccination. In order to investigate the association between Type 1 diabetes incidence and measles, rubella and mumps respectively, Spearman's rank correlation was used. RESULTS: The analysis of the whole Registries data did not at first show any statistical significance between age-standardized Type 1 diabetes incidence density and estimated rates of measles, mumps and rubella notifications. Excluding data from Sardinia Registry, a significant association was observed between Type 1 diabetes incidence and mumps (P = 0.034) and rubella (P = 0.014), respectively, while there was no statistical significance between the incidence of measles cases and diabetes rates (P = 0.269). CONCLUSIONS: According to our findings, mumps and rubella viral infections are associated with the onset of Type 1 diabetes. The statistical significance observed after exclusion of the Sardinian data suggests that other environmental factors may operate over populations with different genetic susceptibility.

Increased prevalence of proliferative retinopathy in patients with type 1 diabetes who are deficient in glucose-6-phosphate dehydrogenase.

AIMS/HYPOTHESIS: Impaired activity of the pentose phosphate pathway of glucose metabolism caused by hereditary deficiency of its key regulatory enzyme glucose-6-phosphate dehydrogenase (G6PD) has consequences that may worsen or attenuate the course of diabetic complications. Decreased availability of NADPH can predispose to oxidative stress and endothelial dysfunction, but can also limit the activity of the polyol pathway and cholesterol synthesis. Reduced availability of pentose phosphates for nucleic acid synthesis could impair cell proliferation. We sought to learn in which direction G6PD deficiency affects diabetic retinopathy. METHODS: We enrolled patients who were G6PD-deficient or -sufficient with type 1 diabetes of duration 15 years or longer for whom HbA(1c) records were available for at least the previous 3 years. Renal failure and smoking were exclusion criteria. For each participant seven standard field colour photographs were obtained of each eye, and retinopathy was graded in a masked fashion. RESULTS: The clinical characteristics of the 19 G6PD-deficient patients studied (age 42 ± 9 years, diabetes duration 24 ± 6 years, average HbA(1c) over 3 years 6.7 ± 0.8%) were similar to those of the 35 G6PD-sufficient patients. Almost 90% of patients in both groups had retinopathy; however, proliferative retinopathy was noted solely among G6PD-deficient patients (28%, p = 0.0036 vs G6PD-sufficient). The G6PD-deficient patients also showed a trend for increased frequency of microalbuminuria. CONCLUSIONS/INTERPRETATION: The data suggest that G6PD deficiency accelerates the microvascular complications of diabetes, and that among the consequences of G6PD deficiency those that can enhance the damage caused by diabetes outweigh those that could be protective.

Serum transforming growth factor ß1 during diabetes development in non-obese diabetic mice and humans.

Recent data show that regulatory cells with transforming growth factor (TGF)-ß1-dependent activity are able to restore self-tolerance in overtly diabetic non-obese diabetic (NOD) mice. Thus, TGF-ß1 seems to have a relevant role in protection from autoimmune diabetes. Our aim was to investigate the possible significance of serum TGF-ß1 measurement in the natural history of diabetes in NOD mice, as well as in children positive for at least one islet-related antibody. Serum TGF-ß1 (both total and active) was measured by enzyme-linked immunosorbent assay at monthly intervals in 26 NOD mice during the spontaneous development of diabetes and, on a yearly basis, in nine siblings of patients with type 1 diabetes (T1D) with a follow-up of 4 years. Diabetes appeared between the 12th week of age and the end of the study period (36 weeks) in 17 mice. TGF-ß1 serum level variations occurred in the prediabetic period in both NOD mice and humans and diabetes diagnosis followed a continuing reduction of active TGF-ß1 (aTGF-ß1) serum levels. In mice, aTGF-ß1 serum levels measured at 4 weeks of age correlated positively with severity of insulitis, and negatively with percentage of insulin-positive cells. Our findings suggest that in NOD mice serum TGF-ß1 levels during the natural history of the diabetes reflect the course of islet inflammation. The measurement of aTGF-ß1 in islet-related antibody-positive subjects may provide insights into the natural history of prediabetic phase of T1D.

Lower fasting blood glucose, glucose variability and nocturnal hypoglycaemia with glargine vs NPH basal insulin in subjects with Type 1 diabetes.

BACKGROUND AND AIMS: To compare switching from NPH insulin (NPH) to insulin glargine (glargine) with continuing NPH for changes in fasting blood glucose (FBG) in patients with Type 1 diabetes on basal-bolus therapy with insulin lispro as bolus insulin. Secondary objectives included self-monitoring blood glucose, mean daily blood glucose (MDBG) and mean amplitude glucose excursion (MAGE) values alongside changes in HbA(1c) and safety profiles. METHODS AND RESULTS: This was a 30-week, parallel, open-label, multicentre study. Seven-point profiles were used to calculate MDBG and MAGE. Hypoglycaemia and adverse events were recorded by participants. FBG improved significantly with both glargine (baseline-endpoint change: -28.0 mg/dL; 95% CI: -37.3, -18.7 mg/dL; p<0.001) and NPH (-9.8 mg/dL; 95% CI: -19.1, -0.5 mg/dL; p=0.0374). The improvement was significantly greater with glargine than NPH (mean difference: -18.2 mg/dL; 95% CI: -31.3, -5.2 mg/dL; p=0.0064). MDBG (-10.1 mg/dL; 95% CI: -18.1, -2.1 mg/dL; p=0.0126) and MAGE (-20.0 mg/dL; 95% CI: -34.5, -5.9 mg/dL; p=0.0056) decreased significantly with glargine, but not NPH although endpoint values were no different with the two insulins. Baseline to endpoint change in HbA(1c) was similar (-0.56 vs -0.56%) with no differences at endpoint. Overall hypoglycaemia was no different, but glargine reduced nocturnal hypoglycaemia ("serious episodes" with BG < 42 mg/dl, p=0.006) whereas NPH did not (p=0.123), although endpoint values were no different. CONCLUSION: Switching from NPH to glargine is well tolerated and results into lower FBG, and lower glucose variability while reducing nocturnal hypoglycaemia. These data provide a rationale for more aggressive titration to target with glargine in Type 1 diabetes.

Outcome of pregnancy in type 1 diabetic patients treated with insulin lispro or regular insulin: an Italian experience.

Some studies have shown that fetal outcome observed in patients using insulin lispro is much the same as in pregnant women using regular insulin. This study aims to analyze the Italian data emerging from a multinational, multicenter, retrospective study on mothers with type 1 diabetes mellitus before pregnancy, comparing those treated with insulin lispro for at least 3 months before and 3 months after conception with those treated with regular insulin. The data collected on pregnant women with diabetes attending 15 Italian centers from 1998 to 2001 included: HbA1c at conception and during the first and third trimesters, frequency of severe hypoglycemic episodes, spontaneous abortions, mode and time of delivery, fetal malformations and mortality. Seventy-two diabetic pregnancies treated with lispro and 298 treated with regular insulin were analyzed, revealing a trend towards fewer hypoglycemic episodes in the former, who also had a significantly greater reduction in HbA1c during the first trimester. The rate of congenital malformations was similar in the offspring of the two groups of women treated with insulin lispro or regular insulin. These findings suggest that insulin lispro could be useful for the treatment of hyperglycemia in type 1 diabetic pregnant women.

Can plasma glucose and HbA1c predict fetal growth in mothers with different glucose tolerance levels?

To assess whether HbA1c and plasma glucose predicts abnormal fetal growth, 758 pregnant women attending 5 Diabetic Centers were screened for gestational diabetes mellitus (GDM). On glucose challenge (GCT) at 24-27 weeks of gestation (g.w.), negative cases formed the normal control group (N1). Positive cases took an oral glucose tolerance test (OGTT): those found negative were classed as false positives screening test (N2); if they had an OGTT result at least as high as their normal glucose levels, they were classed as having one abnormal glucose value (OAV) at OGTT; two values as GDM. HbA1c was assayed on the day of GCT. We considered fetal macrosomia, large for gestational age (LGA), ponderal index and mean growth percentile. Mean age, pre-pregnancy BMI, fasting plasma glucose (FPG) and HbA1c were progressively higher from N1 to GDM patients. The newborn of N2 mothers were heavier than those with N1 or GDM. The mean growth percentile was significantly higher in N2 than in N1. More LGA babies were born to OAV than to N1 or N2 women. Macrosomia and ponderal index did not differ significantly in the four groups. At logistic regression only plasma glucose at GCT could predict LGA babies and a ponderal index above 2.85. At risk analysis, GDM and OAV significantly predicted LGA babies, and GDM a ponderal index >2.85. In conclusion, FPG at GCT could predict fetal overgrowth and plasma glucose >85mg/dl doubles the risk of LGA infants. HbA1c at 24-27g.w. does not predict fetal overgrowth. Mild alterations in glucose tolerance correlate with fetal overgrowth and needs monitoring and treatment.

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

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.

Incidence of type 1 diabetes in age groups above 15 years: facts, hypothesis and prospects for future epidemiologic research.

Although onset of type 1 diabetes can occur in adulthood, epidemiological data are scarce, limiting our potential to identify unknown determinants of the disease. Paucity of registries expanding the recruitment of incident cases up to adulthood, atypical clinical features of type 1 diabetes at onset, misclassification of type 1 as type 2 diabetes and little use of markers of ß-cell autoimmunity represents major obstacles in studying the risk of type 1 diabetes in adults. New strategies in study design, data collection and analyses may overcome these problems in the future. Population-based surveys and registries including adulthood; use of etiological rather than clinical criteria to define type 1 diabetes; availability of electronic health records as prescription data sources to avoid missing data; and application of proper statistical methods will be instrumental to gain better insight on the epidemiology and natural history of the disease.

High incidence rate of IDDM in Sardinia. Sardinian Collaborative Group for Epidemiology of IDDM.

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 less than 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.

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.

Markers of insulin resistance are strong risk factors for retinopathy incidence in type 1 diabetes.

OBJECTIVE: To determine the incidence of retinopathy and the relative importance of its risk factors in type 1 diabetes. RESEARCH DESIGN AND METHODS: This is a 7.3-year follow-up of 764 of 1,215 (63%) people with type 1 diabetes across Europe, aged 15-60 years at baseline with no retinopathy (the EURODIAB Prospective Complications Study). Retinal photographs were taken at baseline and follow-up and risk factors were assessed to a standard protocol. RESULTS: Retinopathy incidence was 56% (429/764, 95% CI 52-59%). Key risk factors included diabetes duration and glycemic control. We found no evidence of a threshold effect for HbA1c on retinopathy incidence. Univariate associations were observed between incidence and albumin excretion rate, cholesterol, triglyceride, fibrinogen, von Willebrand factor, gamma-glutamyltransferase, waist-to-hip ratio, and insulin dose. No associations were observed for blood pressure, cardiovascular disease, or smoking. Independent risk factors, as assessed by standardized regression effects, were HbA1C (1.93, P = 0.0001), duration (1.32, P = 0.008), waist-to-hip ratio (1.32, P = 0.01), and fasting triglyceride (1.24, P = 0.04). CONCLUSIONS: Retinopathy incidence in type 1 diabetes remains high. Key risk factors include diabetes duration and glycemic control, with no evidence of a threshold for the latter. Other independent risk factors, such as waist-to-hip ratio and triglyceride levels, both markers of insulin resistance, were strongly related to incidence.

The Sardinian Autoimmunity Study: 3. Studies on circulating antithyroid antibodies in Sardinian schoolchildren: relationship to goiter prevalence and thyroid function.

The relationship among iodine intake, goiter prevalence, and thyroid autoimmunity remains controversial. In the present article, we report the prevalence of antithyroid antibodies (ATA) in relation to iodine intake, frequency of goiter, and thyroid function in a large group of Sardinian schoolchildren living in areas with borderline iodine sufficiency, or mild to moderate iodine deficiency. A total of 8,040 schoolchildren (4,194 males, 3,846 females, ages 6-15 years) from 29 communities were examined between 1986-1994. Thyroid size was assessed by palpation, according to the Pan American Health Organization (PAHO) criteria. In all cases antimicrosomal (MAb) or antithyroid peroxidase antibodies (TPOAb) and thyrotropin (TSH) were assayed. Urinary iodine was determined in a subgroup of 820 children. ATA was detected in 235 (2.92%) sera (88 males, 2.12%; 147 females, 3.82%; chi2 = 20.41, p < 0.0001). ATA prevalence ranged between 0.0%-7.3% in the 29 communities without any geographical correlation with goiter prevalence and urinary iodine excretion. However, ATA was more frequently detected in goitrous children, especially in females. The presence of ATA was not age-dependent in males, whereas a significant increase of ATA was observed in females older than 11 years of age. Seventy-seven (0.96%) children showed borderline to slightly increased serum TSH (>5.2-32 mU/L). Increased serum TSH concentration was more frequently found in children with ATA, especially at higher titers. In summary, our study in Sardinian schoolchildren indicates: (1) ATA display geographical heterogeneity, which seems to be unrelated to goiter prevalence and/or to iodine supply; (2) ATA are more frequently detected in females older than 11 years of age, suggesting that puberty has a role in determining the predominance in females of thyroid autoimmunity; (3) although most goitrous children are ATA-negative, the prevalence of ATA is increased in children with enlarged glands; (4) ATA is associated with an increased prevalence of subclinical hypothyroidism.

Seasonality of birth in children (0-14 years) and young adults (0-29 years) with type 1 diabetes mellitus in Sardinia differs from that in the general population. The Sardinian Collaborative Group for Epidemiology of IDDM.

A cohort of 1,118 children (0-14 years) and 810 adolescents and young adults (15-29 years) with type 1 diabetes mellitus (DM) diagnosed in Sardinia between 1989 and 1998 were analyzed for seasonality of month of birth, and compared to the pattern registered in 314,084 live births. Patients with DM of both age groups had a statistically significant different seasonality pattern from the general population, revealing an increased birth rate during the summer months, a mirror image of the seasonality of onset of disease.

[IDDM-Sardinia Project: a study model on the etiopathogenesis of insulin-dependent diabetes mellitus and other autoimmune pathologies. Gruppi di studio IDDM-Sardegna]. / Il "progetto IDDM-Sardegna": un modello di studio sull'eziopatogenesi del diabete mellito insulino-dipedente e di altre patologie autoimmuni. "Gruppi di studio IDDM-Sardegna".

The "IDDM-Sardinia project" started in the beginning '90s and this main objective was, and still is, to clarify the epidemiological aspects of insulin-dependent diabetes mellitus in Sardinia, an island with a high incidence of the disease. Initially, the project included three main aims: 1) to continue monitoring the incidence of the disease and to design maps of geographical distribution of it in the island; 2) to study the pre-diabetes period, by assaying islet-related autoantibodies (ICA, GADA and IA-2icA), and to design models of prediction in a general population from a large cohort of 10,000 schoolchildren, and 3) to investigate the natural history of the disease by monitoring the appearance of islet-related autoantibodies in a cohort of 19,000 newborn. Most recently, new research lines branched from these main topics, and now the project is also investigating other autoimmune diseases, in particular coeliac disease and autoimmune thyroiditis. In this paper we still summarise and discuss the state-of-the-art of the whole project.

The "Sardinia-IDDM study": an attempt to unravel the cause of insulin-dependent diabetes mellitus in one of the countries with the highest incidence of the disease in the world.

Sardinia and Finland have the highest incidence of IDDM in the world. Thus, both regions represent ideal observatories for investigating the environmental, genetic and immunological factors, which have led to this dramatic increase. We have concentrated our efforts in Sardinia. Among several projects, there is the mapping of the Island for hot and cold spots for overt IDDM. In order to map the Island for pre-IDDM, we have collected and bled around 10,000 school children (age 6-14 years) and we are now in the process to enroll around 30,000 newborn. We report here our initial results, which show that progression to IDDM is accompanied in both cohorts by the presence of a combination of ICA with either GAD and IA-2 antibodies or both. This approach should lead to design reliable models of IDDM prediction in the general population, which will benefit an early insulin treatment and, hopefully, an effective prevention of the disease.