Elisabetta Pisu

A population-based prevalence survey of known diabetes mellitus in northern Italy based upon multiple independent sources of ascertainment.

SummaryThe aims of this survey were (1) to estimate the prevalence of known diabetes mellitus in 1988 in Casale Monferrato (Northern Italy); (2) to validate different data sources available in Italy; (3) to identify a population-based cohort of diabetic patients. Multiple independent data sources were used and the capture-recapture method was applied to estimate the completeness of ascertainment of the survey. The primary data source was the list of all patients attending the diabetic clinic or those referred by family physicians and paediatricians of the area. The secondary data sources were the list of hospital discharges, the prescriptions data source and the list of all people using reagent strips and insulin syringes. On 1 October 1988 (the cut-off date) 2,069 cases of known diabetes were identified. The estimated completeness of ascertainment of the survey was 91%. Prevalence of known diabetes, Type 1 (insulin-dependent), Type 2 (non-insulin-dependent) and insulin-treated diabetes were, respectively, 2.21% (95% CI 2.13–2.29), 0.80/1,000 (0.62–0.98) and 2.10% (2.01–2.19), 2.92/1,000 (2.57–3.27). A higher prevalence of Type 2 diabetes was observed in women (2.30%, 2.18–2.42) than in men (1.88%, 1.76–2.00). Age-specific prevalence of Type 2 diabetes increased with age. Computerized data sources routinely available in the Piedmont Region (hospital discharges and prescriptions data sources) showed a low completeness of ascertainment when considered together (65%, 1,338 of 2,069), indicating the need to involve the diabetic clinic and family physicians in the ascertainment of known diabetes. In conclusion, the prevalence of known diabetes in Italy was lower than in Northern Europe and the United States.

Insulin resistance in the aged: The role of the peripheral insulin receptors

In the healthy subject, glucose tolerance tends to decrease with age due to impaired insulin secretion and/or decreased peripheral insulin activity. An oral glucose (100 g) tolerance test was performed on 12 aged (70 +/- 4 yr) and 8 young (32 +/- 7 yr) subjects; these subjects underwent laparatomy for cholecystectomy or the management of abdominal diseases. Subcutaneous adipose tissue was removed during surgery and fat cells, prepared according to a personal modification of Rodbells method, were incubated in a medium containing monoiodo- and cold insulin to evaluate insulin binding and affinity constants. The results of the tolerance test pointed to an insulin resistant state i.e., impaired glucose tolerance coupled with normal plasma insulin, as previously shown also by us using other methods in the aged subject. The binding study demonstrates a distinct insulin receptor decrease in fat cells from the older subjects (185,000 +/- 19,200 as opposed to 310,000 +/- 12,000), without any change in affinity constants. The result indicates that insulin resistance in the aged may be attributed at least in part to a reduction in the number of insulin receptors on the target cells. This could be a consequence of aging itself, as proposed by other workers in the case of old fat rats.

Sex differences in incidence of IDDM in age-group 15-29 yr. Higher risk in males in Province of Turin, Italy.

Objective— To report the incidence of IDDM in the age-group 0–29 yr in the Province of Turin, Italy (951, 445 inhabitants 0–29 yr of age), over a 5-yr period (1984–1988) according to age, sex, and geographical region within the area and to identify any temporal trend. Research Design and Methods— The survey used as the primary data source the list of all patients attending diabetic clinics, and as secondary data source, used the list of hospital discharges for diabetes. Results— We identified 298 incident cases of IDDM in people 0–29 yr of age. Estimated completeness of ascertainment of the registry was 97%. Age-adjusted (world-standard) incidence rates were 7.40/100,000 (95% CI 6.28–8.71), 5.83 (4.95–6.86), and 6.70 (5.97–7.51), respectively, in the age-groups 0–14, 15–29, and 0–29 yr. Incidence was significantly higher in males than in females in the age-group 15–29 yr (7.36, 6.02–8.98, vs. 4.21, 3.12–5.56). An increasing incidence from rural areas to the greater Turin area (city and its industrial belt) was evident. No significant temporal trend during the study period was found, although year-to-year variability was evident, with the highest incidence in 1984. Conclusions— This study suggests a high male-to-female ratio of incidence of IDDM after 14 yr; either sex hormones or different exposure to environmental determinants could be involved.

Comparison of the metabolic effects of mixed meal and standard oral glucose tolerance test on glucose, insulin and C-peptide response in healthy, impaired glucose tolerance, mild and severe non-insulin-dependent diabetic subjects

Dietary constituents other than glucose can influence insulin secretion in non-insulin-dependent diabetes mellitus and administration of a standard mixed meal has been proposed as a more physiological test in regard to human diet for evaluating the patient both at the time of diagnosis and during follow-up. This study was carried out to compare the effects of a standard meal and the oral glucose tolerance test on glucose, insulin and C-peptide plasma levels in four groups of subjects: healthy controls, subjects with impaired glucose tolerance, patients with mild non-insulin-dependent diabetes, and non-insulin-dependent diabetic patients with secondary failure to oral agents. Plasma glucose values were significantly higher after the oral glucose tolerance test than after the mixed meal in all four groups of subjects. Plasma insulin and C-peptide values were similar during the two tests in all groups of subjects except in non-insulin-dependent diabetics with secondary failure (flattened curves). Insulin and C-peptide responses per unit rise in blood glucose were significantly higher after the oral glucose tolerance test than after the mixed meal both in mild non-insulin-dependent diabetics (P<0.05 andP<0.05) and in non-insulin-dependent diabetics in secondary failure (P<0.01 andP<0.05). There was significant correlation between oral glucose tolerance test and mixed meal glucose incremental areas (r=0.511,P<0.001). The diagnostic relevance of the test was evaluated by comparing the 120 min plasma glucose levels following mixed meal and oral glucose tolerance test: there was a significant correlation between the values in the two tests (r=0.956,P<0.001); the differences among the four groups were statistically significant and there was a partial overlap between healthy controls and impaired glucose tolerance patients: 93±3 versus 111±7 mg/dl for controls; 107±3 versus 161±5 mg/dl for impaired glucose tolerance patients; 204±11 versus 284±12 mg/dl for mild non-insulin-dependent diabetics; 309±9 versus 440±17 mg/dl for NID diabetics in secondary failure. The sensitivity of the test was 73% and specificity 100%. The mixed meal is proposed for clinical practice as a more physiological test than the standard oral glucose tolerance test for further characterization and longitudinal evaluation of patients with impaired glucose tolerance or non-insulin-dependent diabetes mellitus.

Incidence of IDDM during 1984-1986 in population aged less than 30 yr. Residents of Turin, Italy.

The goal of this study was to measure the incidence of insulin-dependentdiabetes mellitus (IDDM) during 1984–1986 in residents of Turin, Italy, aged <30 yr. The primary data source was the list of all subjects diagnosed with IDDM who attended diabetes clinics in Turin. Other data sources were the general register of death certificates, the list of hospital discharges, andthe computerized data base of insulin prescriptions. Eighty incident cases of IDDM were identified during the study in 1,130,284 person-yr for those <30 yr of age. Ageadjusted (world standard) incidence rates were 8.05, 8.10, and 6.96/100,000 in the age-groups 0–14, 0–19, and 0–29 yr, respectively. Estimated completeness of the primary data source compared with all other data sources was 91%, whereas the estimated completeness of ascertainment ofthe registry was 99%. Incidence rates of IDDM in northern Italy compare withthose of European countries with low-medium incidence. A population-based register is being established for the province of Turin (951,445 inhabitants aged 0–29 yr) for the collection of incident cases since 1984.

Uncoupling protein 2 G(-866)A polymorphism: a new gene polymorphism associated with C-reactive protein in type 2 diabetic patients C-reactive protein in type 2 diabetic patients

BackgroundThis study evaluated the relationship between the G(-866)A polymorphism of the uncoupling protein 2 (UCP2) gene and high-sensitivity C reactive protein (hs-CRP) plasma levels in diabetic patients.MethodsWe studied 383 unrelated people with type 2 diabetes aged 40-70 years. Anthropometry, fasting lipids, glucose, HbA1c, and hs-CRP were measured. Participants were genotyped for the G (-866)A polymorphism of the uncoupling protein 2 gene.ResultsHs-CRP (mg/L) increased progressively across the three genotype groups AA, AG, or GG, being respectively 3.0 ± 3.2, 3.6 ± 5.0, and 4.8 ± 5.3 (p for trend = 0.03). Since hs-CRP values were not significantly different between AA and AG genotype, these two groups were pooled for further analyses. Compared to participants with the AA/AG genotypes, homozygotes for the G allele (GG genotype) had significantly higher hs-CRP levels (4.8 ± 5.3 vs 3.5 ± 4.7 mg/L, p = 0.01) and a larger proportion (53.9% vs 46.1%, p = 0.013) of elevated hs-CRP (> 2 mg/L). This was not explained by major confounders such as age, gender, BMI, waist circumference, HbA1c, smoking, or medications use which were comparable in the two genotype groups.ConclusionsThe study shows for the first time, in type 2 diabetic patients, a significant association of hs-CRP levels with the G(-866)A polymorphism of UCP2 beyond the effect of major confounders.

Low-density lipoproteins are more electronegatively charged in type 1 than in type 2 diabetes mellitus

Multifactorial etiology is involved in premature atherosclerosis related to diabetes. Most of the mechanisms that are responsible for the etiology in diabetes have remained unsolved so far. Type 1 diabetes is associated with a favorable lipid pattern and with microangiopathy, which is not true for type 2 diabetes, which is related to dyslipidemia and macroangiopathy. The aim of this work was to evaluate the degree of LDL modification related to the types of diabetes. The question is whether the LDL could be differently modified since the pathogenesis of type 1 and type 2 diabetes is different. Thirtyone type 1 (19 male and 12 female) and thirty type 2 (18 male and 12 female) diabetic patients were included in this study. Isolated LDL was analyzed by capillary electrophoresis for diene conjugate content and for electronegativity. LDL from type 1 diabetes subjects showed the highest electrophoretic mobility (P=0.000). Instead, the diene conjugates contents were higher in the type 2 patients with HbA1c levels >8% (P=0.007). In conclusion, the increased diene content in type 2 diabetic subjects in poor glycemic control and the highest LDL mobility found in type 1 subjects show that the LDL undergoes different modifications. In type 2 patients, electronegative LDL are in a state of higher susceptibility to oxidation, whereas in type 1 subjects the finding of electronegative lipoproteins could provide an index of the relative atherogenicity of circulating LDL, especially as LDL has higher electrophoretic mobility than normal subjects.

Diurnal variations in insulin secretion and insulin sensitivity in aged subjects

SummaryGlucose tolerance tends to decrease in healthy aged subjects without family history of diabetes. Either reduced insulin secretion or insulin resistance may be responsible. Insulin secretion and insulin sensitivity were studied in 7 aged subjects (68–75 years) and 8 young controls (21–27 years). A 1-mg i.v. glucagon and a 5-U/m2 body area i.v. insulin test were run in each subject at 0700 and at 1900 on two different days to detect diurnal variations. An arginine test was also performed to evaluate pancreatic glucagon behavior. In the evening, young subjects presented a glucose tolerance impairment with significantly decreased plasma insulin levels, and a reduced hypoglycemic effect of exogenous insulin. Resistance to both endogenous and exogenous insulin in the aged was observed in the morning without significant morning/evening variations. Since the response to contra-insular hormones (GH in the insulin test, glucagon in the arginine test) was the same in both age groups, their role in the phenomenon could be ruled out. It is suggested that in the aged a stable reduction in number and/or a change in affinity of insulin receptors may occur. In addition, since again is seen to be associated with the disappearance of diurnal variations in glucose tolerance and insulin secretion and sensitivity, and since a reduction in the receptor level of young healthy subjects in the evening has been reported by some authors, it is suggested that aged subjects may be less able to modulate the binding of insulin to its peripheral receptors in the course of the day.

Insulin supplement in type 2 diabetic patients with secondary failure to oral agents ameliorates hepatic and peripheral insulin sensitivity but not insulin secretion

In order to investigate the mechanism of amelioration of metabolic abnormalities with supplementary doses of insulin, islet B‐cell function and insulin sensitivity were measured in 10 patients with Type 2 diabetes in secondary failure to oral agents. A small dose of ultralente insulin (0.26 ± 0.07 U kg‐ideal‐body‐weight−1) was added in the morning before breakfast. After 3 months insulin therapy and progressive improvement of metabolic control (HbA1 from 10.5 ± 0.4 to 9.0 ± 0.3 % at the end of insulin treatment, p < 0.001), basal C‐peptide and incremental area during an oral glucose tolerance test were unchanged. In vivo peripheral insulin sensitivity (euglycaemic clamp with insulin infusion of 40, 160, and 600 mU m−2 min−1, respectively) was significantly improved (glucose requirement: to 4.7 ± 1.0 from 3.0 ± 0.6 mg kg−1 min−1, p< 0.05 at first insulin level; to 10.8 ± 0.5 from 9.3 ± 0.7 mg kg−1 min−1, p<0.01 at second level; to 13.3 ± 0.6 from 11.8 ± 0.8 mg kg−1 min−1, p< 0.025 at third level). Basal hepatic glucose production was also significantly reduced (from 4.3 ± 0.4 to 3.3 ± 0.3 mg kg−1 min−1, p< 0.05), and residual glucose production further suppressed after insulin supplement (from 1.1 ± 0.4 to 0.3 ± 0.2 mg kg−1 min−1 after 120 min at 100 mU I−1 plasma insulin, p< 0.05). Specific insulin binding to mononuclear leucocytes was unchanged (from 3.1 ± 0.3 to 3.5 ± 0.3 %, NS).

Insulin secretion and insulin sensitivity defects are a common feature of mild, clinically homogeneous, recently diagnosed type II (Non-insulin-dependent) diabetics

SummaryAlteration in insulin secretion and reduced peripheral sensitivity to the hormone have been reported in type II diabetes. In this paper, a comparison is made of basal glucose production (3H-6 glucose), insulin secretion and insulin sensitivityin vivo (hyperglycemic clamp) andin vitro (binding to circulating monocytes) in 24 patients with recently diagnosed type II diabetes, matched for age and fasting glycemia and divided into non-obese (14 subjects) and moderately obese (10 subjects), and in 9 non-obese controls. The non-obese diabetics were slightly hyperinsulinemic during fasting (10.8±1.0vs 4.8±0.8 µU/ml in controls, p < 0.0005), with a significant reduction in early and late insulin secretion (14.0±1.5vs 20.8 ± 2.0 µU/ml, p<0.01 and 24.8±3.3vs 34.7±2.14 µU/ml, p<0.025). The insulin sensitivity index MCR/I was significantly reduced (2.30±0.32vs 4.14±0.40, p<0.005). Endogenous glucose production was significantly increased (107±10.2vs 84±3.7 mg/m2 per min, p<0.025) and displayed a positive correlation with fasting glycemia (r=0.51, p<0.05). Insulin binding to monocytes was significantly lower than in controls (2.36±0.22%vs 4.06±0.32%, p<0.0005). Moderately obese diabetics also were significantly hyperinsulinemic in the fasting state (18.1±2.8 µU/ml, p<0.0005vs controls) but, typically, lacked the early secretory phase (20.6±3.6 µU/mlvs baseline, n.s.). A similar increase of hepatic glucose production (107±11.2 mg/m2 per min, p<0.025vs controls, n.s.vs non-obese diabetics) and decrease of peripheral sensitivity to insulin (MCR/I=1.78±0.31, p<0.0005vs controls, n.s.vs non-obese diabetics) was found in moderately obsese diabetics, as well as a significant reduction of insulin binding to insolated monocytes (2.62±0.4% p<0.01vs controls, n.s.vs non-obese diabetics). These results confirm that common defects of both non-obese and moderately obese type II diabetics are: lack of early phase of glucose induced insulin secretion, increase in hepatic glucose production and decrease of peripheral insulin sensitivity together with reduction of insulin binding to circulating monocytes. The hypothesis of a unique defect as a cause of hyperglycemia in type II diabetes in early clinical phase is not borne out by the results of this study. Moderate obesity, even if able to reduce insulin sensitivity, seems to be less important in determining hyperglycemia.