Sergio Muntoni

Comparison of the Seasonal Pattern in the Clinical Onset of IDDM in Finland and Sardinia

OBJECTIVE To examine the seasonal pattern for the clinical onset of IDDM in Finland and Sardinia, two areas where the incidence of IDDM is the highest in the world, and to determine the effect of climate and temperature on the clinical onset of IDDM. RESEARCH DESIGN AND METHODS Analysis of seasonality for the diagnosis of IDDM was based on 1,405 cases in Finland and 425 cases in Sardinia diagnosed at ≤14 years of age from 1989 to 1992. The average annual incidence of IDDM was 36.4/100,000 in Finland and 34.4/100,000 in Sardinia. Seasonal patterns were estimated presenting the data as short Fourier series up to three harmonics together with a possible linear trend. Likelihood ratio tests and Akaikes information criterion were used to determine the number of harmonics necessary to model the seasonal pattern. Seasonal patterns in both countries were compared between sexes and between the three 5-year age-groups, each controlling for the others effect. RESULTS In both countries, a significant seasonal pattern during a calendar year was found for the sexes combined and for two age-groups (0–9 and 10–14 years). In Sardinia, two distinct cycles were found in the younger age-group, with a decreased incidence during May through August and an increased incidence during the autumn months. Two cycles were apparent in the older age-group, with the nadir occurring during June through September. In Finland, one cycle was found in the younger age-group, with a decreased incidence in June. In the older age-group, there were two distinct cycles, with a decreased incidence in June and in the September through December period. CONCLUSIONS Differences between Finland and Sardinia in the seasonal pattern for the incidence of newly diagnosed IDDM cannot be explained by differences in climate, temperature, a longer warm period in Sardinia, or other climatic phenomena. The results do not provide evidence in favor of a specific viral etiology of IDDM. It may be suggested that there are triggering events at certain times, but they are likely to be unspecinc. Nevertheless, why the incidence of IDDM in these two populations is equally high despite differences in climate, environment, and genetic background remains an unsolved question.

Serum lipoproteins and cancer

BACKGROUND AND AIMS In haematological and solid tumours the blood lipoprotein profile has been reported to be altered; while decreased levels of total cholesterol and increased values of triglycerides have been observed. The mechanism and meaning of these changes are, however, not fully understood. The aim of the present study was to determine relationships between cancer progression and serum lipoproteins. METHODS AND RESULTS We performed a case-control study. We included cancer patients admitted to the 1st Division of Medical Oncology, Businco Hospital of Cagliari, Italy, between 1984 and 1998; 519 patients with any type of solid tumours and 928 healthy controls. We considered total cholesterol (C), high-density lipoprotein (HDL)-C, low-density lipoprotein (LDL)-C, triglycerides and apolipoprotein A-1; other parameters examined were glycaemia, insulinaemia, body mass index (BMI), homeostasis model assessment-estimated insulin resistance (HOMA-IR), C reactive protein (CRP) and tumour necrosis factor-alpha (TNF-alpha). In the cancer group HDL-C and apolipoprotein A-1 were lower (p<0.05) and triglycerides were higher (p<0.05) than in controls; HDL-C (mg/dl) females: 48 vs. 64; males, 40 vs. 52; Apo-A-1 (mg/dl) females: 125 vs. 173; males, 120 vs. 152; triglycerides (mg/dl) females: 133 vs. 96; males, 152 vs. 117. Glucose (mg/dl) was lower in the cancer group (p<0.05); females, 72.3 vs. 80.0; males, 75.7 vs. 78.4. CONCLUSION Using multivariate analysis we were able to rule out cardiovascular and inflammatory diseases as causes of low HDL-C, and also demonstrate that these alterations can be shown as a specific consequence of the presence of a malignant tumour with a diagnostic and prognostic significance.

Serum lipoprotein profile in the Mediterranean variant of glucose-6-phosphate dehydrogenase deficiency

Sardinian males with erythrocyte glucose-6-phosphate dehydrogenase (G-6-PD) deficiency have lower serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB), compared to normals. Since the enzyme deficiency is expressed also in nucleated cells, we studied cholesterol (C) and DNA synthesis and LDL-receptor expression in freshly isolated circulating mononuclear cells from normal and G-6-PD-deficient Sardinians. Synthesis of C (as 14C-acetate incorporation) and of DNA (as 3H-thymidine incorporation) was clearly reduced, both in basal state and after PHA stimulation, in G-6-PD-deficient cells compared to normal cells. On the other hand, no clear influence of G-6-PD deficiency on LDL-receptor expression could be demonstrated. The Mediterranean variant of G-6-PD deficiency is characterized, whatever the metabolic mechanism may be, by a serum lipoprotein pattern of reduced atherogenicity.

Steadily high IDDM incidence over 4 years in Sardinia.

OBJECTIVE To verify whether the high incidence of insulin-dependent diabetes mellitus (IDDM) in Sardinia is an epidemic outbreak or a steady phenomenon. RESEARCH DESIGN AND METHODS All newly diagnosed cases of IDDM with onset in patients 0–29 years of age between 1 January 1989 and 31 December 1992 among residents in Sardinia were obtained from the Sardinian IDDM Incidence Registry. The local IDDM patient association (Associazione Diabete Infantile Giovanile) served as the secondary and independent source. RESULTS The completeness of ascertainment was 91%. The age-standardized mean annual incidence of IDDM (per 100,000) was 34.4 in the 0- to 14-year-old age-group and 26.2 in the entire 0- to 29-year-old range, respectively. Men-to-women ratios were 1.38 and 1.55, respectively. Seasonal variation in incidence was observed, with a peak in fall and winter and a nadir in summer. CONCLUSIONS Sardinia has a very high and steady IDDM incidence rate, which is up to fivefold that of other Italian regions and Mediterranean countries and approaches the Finnish top rate in the world. Interaction between the genetic peculiarity of Sardinians and still unidentified powerful environmental agents is likely to account for the phenomenon.

Inhibition of fatty acid oxidation by biguanides: implications for metabolic physiopathology.

Publisher Summary This chapter discusses inhibition of fatty acid oxidation by biguanides and describes its implications for metabolic physiopathology. Biguanides exert their metabolic effects through a single basic mechanism, namely, inhibition of fatty acid oxidation. This mechanism has no connection with the inhibition of oxidative phosphorylation that is rather a toxic effect produced by concentrations too high with respect to the sensitivity of the treated animal, a factor that varies from species to species. Biguanides increase glucose utilization through the Embden–Meyerhof–Krebs pathway, with consequent increase both in the activity of the Cori cycle and in CO2 production from glucose. Biguanides do not inhibit gluconeogenesis indiscriminately; by depressing fatty acid oxidation they exert an inhibitory effect only when pyruvate carboxylase, activated by acetyl-CoA, is the rate-limiting step of gluconeogenesis. Glucose uptake and oxidation in muscle, hindered by increased fatty acid oxidation, are stimulated by biguanides. Hyperinsulinemia, secondary to peripheral insulin-resistance is normalized by biguanides that are capable of abolishing the signal for hypersecretion.

New insights into the epidemiology of Type 1 diabetes in Mediterranean countries

In Mediterranean countries, the incidence (per 100 000 per year) of Type 1 diabetes in children aged under 15 years shows wide variation from country to country, ranging from 2.45 in Macedonia to 34.4 in Sardinia. By interacting with environmental factors such as diet, toxins or viral infections, the HLA plus non‐HLA genes of susceptibility or resistance to Type 1 diabetes so far identified are the strongest determinants of the disease as far as incidence, age at onset and sex ratio are concerned. The distribution of these genes in the Mediterranean region is still not completely known.

Epidemiological Association between Some Dietary Habits and the Increasing Incidence of Type 1 Diabetes Worldwide

Background/Aims: The variation in incidence of type 1 diabetes (T1D) worldwide is genetically based. However, its increasing incidence is environmentally determined. Our aim was to describe the role of nutritional habits and of gene-nutrient interactions in the rising incidence of TID. Methods: We did an ecological study in the 37 world areas were a 3% yearly increase of T1D incidence had been reported, and we calculated through the FAO’s Food Balance Sheets the per caput daily supply of milk, meat and cereals from 1961 to 2000 and its correlation with the TID incidence. Results: The supply of milk and cereals remained almost unchanged, whereas that of meat increased by over 31%. The absolute mean TID increase (number of cases per 100,000 per year) was + 0.32. A significant positive correlation with supply of milk was present from 1961 to 2000, while that with meat and cereals became significant in 1983 and 2000. Conclusion: Our ecological analysis indicates that nutritional factors, and in particular meat consumption, play a role in the incidence of T1D and its increase worldwide. Further experimental and case-control studies are warranted in order to assess the gene-nutrient interactions.

Results of a five-year community-based programme for cardiovascular disease prevention: The ATS-Sardegna Campaign

The objective of this study was to evaluate the effects of the ATS-Sardegna Campaign on lifestyle and cardiovascular disease (CVD) risk factors in the Sardinian population. The Campaign was a community-based public health action programme funded by the Sardinian Government with a view to prevent CVD and promote healthy behaviour. It was also part of the Targeted Project FAT.MA. of the Italian National Research Council (CNR), with the main purpose of evaluating the effects of this public health initiative after a five- year intervention. The evaluation was effected with three parallel procedures: individual interviews with 1486 randomly chosen people; assessment of eating patterns through a food-frequency questionnaire; measurement of the mean levels of the major CVD risk factors in 1729 randomly chosen subjects (1044 in the calendar year 1992, and 685 in 1995, two and five years, respectively, after the beginning of the Campaign). Overall, we recorded a favourable trend in eating habits in both sexes; a significant decrease in LDL-cholesterol in males, and in systolic and diastolic blood pressure in both sexes; a non- significant decrease in prevalence of smokers among males and increase among females. The ATS-Sardegna Campaign was the first CVD prevention programme in Italy to have attained reduction in the risk profile of an entire region at the lowest ever borne cost.

Cow's milk consumption and IDDM incidence in Sardinia.

M arked geographical differences in the incidence of insulin-dependent diabetes mellitus (IDDM), with a south-north gradient, have been reported in past years (1) and confirmed recently by the EURODIAB ACE Study (2). Sound evidence exists that IDDM incidence rates have been rising in several countries over the last decades (3). This phenomenon points to environmental factors capable of converting genetic susceptibility for IDDM into overt disease. Among these factors, cows milk consumption early in life is associated with increased risk for IDDM in the following years (4). Moreover, positive correlation between cows milk mean consumption per person and IDDM incidence in various countries has been described (5,6). Sardinia, a large Mediterranean island with a geographically well-defined and ethnically homogeneous population (7), has been shown to have a very high (8) and rising (9,10) IDDM incidence rate, which is now 30.2 per 100,000/year. This is the second highest rate in Europe after Finland (2). Sardinia also has a very high (3.08%) prevalence of positive islet cell antibodies (ICA) in schoolchildren, again the second highest after Finland (11). Here we report data on cows milk consumption and IDDM incidence in Sardinia compared with a number of geographical areas to detect a possible correlation between the two variables. Data on IDDM incidence (per 100,000/year) in children 0-14 years of age in various European countries or regions and Israel in the 2-year period from 1989 to 1990 were derived from the EURODIAB ACE Study (2). Data on fluid cows milk consumption per person/year between 1975 and 1990 in the same countries were obtained from the Italian National Institute of Statistics in Rome (12). Available data on both variables concerned 17 regions. For each region, the mean annual variation rate (%) over the 15-year period was calculated. In no region did this rate exceed ±4.5%; in Sardinia the rate was 1.22%. Therefore, mean annual consumption over the 15-year period was used for statistical analysis. IDDM incidence rates and cows milk consumption in individual countries fit a linear regression model with an r2 of 0.44 (Table 1). In this model, Sardinia lies considerably far from the regression line, its actual IDDM incidence (30.2) being three times higher than the incidence predicted by milk consumption (10.35). Hence, this makes a good 19.85 residual, which is by far the highest one among the 17 regions considered. Therefore, in this study, Sardinia represents the most considerable exception to the association between the two variables, much the same as it does to the one between IDDM incidence and latitude (2,8). Among the variables that can account for latitude-related, cross-country differences in IDDM risk, diet, temperature, cultural practices, viral infections, and genetic factors must be considered (1). In this regard, cows milk consumption early in life has been implicated as a possible primer of the autoimmune re-

Gene-Nutrient Interactions in G6PD-Deficient Subjects – Implications for Cardiovascular Disease Susceptibility

Background/Aims: The enzyme glucose-6-phosphate dehydrogenase (G6PD) is the principal source of reducing equivalents, necessary for regenerating reduced glutathione through NADPH in order to protect cells from oxidative damage, and whichin erythrocytes produces hemolysis. When fava beans are ingested by G6PD-deficient subjects (gene-nutrient interaction), or some oxidant drugs are assumed (gene-drug interactions), a life-threatening hemolysis can occur. However, the same defect results in lower cardiovascular disease (CVD) risk. Methods: Physiopathological, clinical and mortality studies of CVD risk in relation with G6PD deficiency have been surveyed. Results: CVD risk in men was lowered in the G6PD-deficient state, and was associated with reduced levels of plasma low-density lipoprotein cholesterol (LDL-C) compared to the normal condition (p < 0.05). Both cholesterol and DNA synthesis in circulating mononuclear cells from G6PD-deficient men were likewise reduced (p = 0.05). Conclusions: Since NADPH is a necessary cofactor for the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA R), G6PD deficiency appears to be a naturally occurring model of HMG-CoA R restraint, whose consequences are similar to those produced on the same enzyme by statins. G6PD deficiency therefore results in protection against CVD, despite an increased susceptibility to oxidative stress.