Biomedical subjects
Publications and source records attributed to S Del Prato.
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AIMS: The potential importance of postprandial glucose (PPG) control in the development of complications in Type 2 diabetes is much debated. The recent American Diabetes Association (ADA) consensus statement discussed the role of postprandial hyperglycaemia in the pathogenesis of diabetic complications and concluded that the relationship between PPG excursions and the well-established risk factors for cardiovascular disease (CVD) should be further examined. Using the ADA statement as a starting point and including the more recent American College of Endocrinology guidelines on glycaemic control, a panel of experts in diabetes met to review the role of PPG within the context of the overall metabolic syndrome, in the development of complications in Type 2 diabetes. RESULTS: Post-prandial hyperglycaemia is a risk indicator for micro- and macrovascular complications, not only in patients with Type 2 diabetes but also in those with impaired glucose tolerance. In addition, the metabolic syndrome confers an increased risk of CVD morbidity and mortality. The debate focused on the relative contributions of postprandial hyperglycaemia, the metabolic syndrome and, in particular, raised triglyceride levels in the postprandial state, to the development of cardiovascular complications of diabetes. CONCLUSIONS: The panel recommended that in the prevention and management of microvascular complications of Type 2 diabetes, targeting both chronic and acute glucose fluctuations is necessary. Lowering the macrovascular risk also requires control of (postprandial) triglyceride levels and other components of the metabolic syndrome.
Haptoglobin (Hp) is a glycoprotein involved in the acute phase response to inflammation. Our previous findings indicate that Hp mRNA and protein are present in the adipose tissue of rodents and that Hp gene expression is up-regulated in obese models. The aim of the present study was to establish whether Hp could be considered a marker of obesity in humans. In 312 subjects, serum Hp was correlated directly with body mass index (BMI), leptin, C-reactive protein (CRP), and age. In a multivariate stepwise regression analysis, BMI and CRP were independent determinants of serum Hp in females, with BMI having the strongest effect. CRP and age were independent determinants of serum Hp in males, although explaining only a modest percentage of the total variability. Serum Hp was positively associated with body fat, as assessed by dual-energy x-ray absorptiometry, both in female and in male groups. The level of significance improved when serum Hp was analyzed against fat mass adjusted for lean mass. Finally, Northern and Western blot analyses performed in biopsies of sc abdominal fat from 20 obese individuals showed the presence of Hp mRNA and protein in the human adipose tissue. In conclusion, serum Hp constitutes a novel marker of adiposity in humans, and the adipose tissue likely contributes to determine its levels.
AIMS/HYPOTHESIS: This study was done to measure the effect of Na+ intake on blood pressure and albuminuria, in relation with insulin sensitivity and kidney haemodynamics, in Type 2 diabetic patients with and without microalbuminuria. METHODS: Type 2 diabetic patients, 20 with microalbuminuria, 21 without, spent two consecutive 7-day periods, one on a high (250 mmol), the other on a low-Na+ (20 mmol) diet. Body weight, 24-h blood pressure and albuminuria were measured at the end of each period. At the end of high-Na+ diet insulin sensitivity (euglycaemic insulin clamp; 2 mU.kg(-1).min(-1)) and kidney haemodynamics were measured in nine patients from each group. RESULTS: Switching from low to high-Na+ diet resulted in an increase in blood pressure (7.4+/-4.7 mmHg; p<0.001), body weight (1.9+/-0.4 kg; p<0.05) and albuminuria [from 80 (31-183) microg/min to 101 (27-965) microg/min; p<0.01) in patients with microalbuminuria. No changes occurred in patients without microalbuminuria. Patients with microalbuminuria also had greater intraglomerular pressure (44+/-1 mmHg vs 36+/-1; p<0.001), calculated from glomerular filtration rate, renal plasma flow, plasma protein concentration and the relationship between pressure and natriuresis. In these patients insulin sensitivity was lower (5.16+/-49 vs 7.36+/-0.63 mg.kg(-1).min(-1); p=0.007). Urinary albumin excretion (r=0.40; p=0.009) and insulin sensitivity (r=-0.59; p=0.01) were correlated with intraglomerular pressure. CONCLUSION/INTERPRETATION: High salt intake increases blood pressure and albuminuria in Type 2 diabetic patients with microalbuminuria. These responses are associated with insulin resistance and increased glomerular pressure. Insulin resistance could contribute to greater salt sensitivity, increased glomerular pressure and albuminuria.
Peroxisome proliferator-activated receptors (PPARs) are a subgroup of the superfamily of nuclear receptors, with three distinct main types: alpha, beta and gamma (subdivided into gamma(1) and gamma(2)). Recently, the presence of PPARgamma has been reported in human islets. Whether other PPAR types can be found in human islets, how islet PPARgamma mRNA expression is regulated by the metabolic milieu, their role in insulin secretion, and the effects of a PPARgamma agonist are not known. In this study, human pancreatic islets were prepared by collagenase digestion and density gradient purification from nonobese adult donors. The presence of PPAR mRNAs was assessed by RT-PCR, and the effect was evaluated of exposure for up to 24 h to either 22.2 mmol/l glucose and/or 0.25, 0.5, or 1.0 mmol/l long-chain fatty acid mixture (oleate to palmitate, 2:1). PPARbeta and, to a greater extent, total PPARgamma and PPARgamma(2) mRNAs were expressed in human islets, whereas PPARalpha mRNA was not detected. Compared with human adipose tissue, PPARgamma mRNA was expressed at lower levels in the islets, and PPARbeta at similar levels. The expression of PPARgamma(2) mRNA was not affected by exposure to 22.2 mmol/l glucose, whereas it decreased markedly and time-dependently after exposure to progressively higher free fatty acids (FFA). This latter effect was not affected by the concomitant presence of high glucose. Exposure to FFA caused inhibition of insulin mRNA expression, glucose-stimulated insulin release, and reduction of islet insulin content. The PPARgamma agonists rosiglitazone and 15-deoxy-Delta-(12,14)prostaglandin J(2) prevented the cytostatic effect of FFA as well as the FFA-induced changes of PPAR and insulin mRNA expression. In conclusion, this study shows that PPARgamma mRNA is expressed in human pancreatic islets, with predominance of PPARgamma(2); exposure to FFA downregulates PPARgamma(2) and insulin mRNA expression and inhibits glucose-stimulated insulin secretion; exposure to PPARgamma agonists can prevent these effects.
AIMS/HYPOTHESIS: To verify whether individual susceptibility to diabetic nephropathy resides in an intrinsic difference in Protein Kinase C (PKC) activity. METHODS: We compared the effect of different glucose concentrations on PKC activity, PKC isoform expression and diacylglycerol (DAG) content in cultured fibroblasts from 14 Type 1 diabetic patients who developed nephropathy with those in cells from 14 patients without nephropathy. We recruited 14 normal subjects as control patients. Forearm skin fibroblasts were cultured in either normal (5 mmol/l) or high (20 mmol/l) glucose concentrations. RESULTS: In normal glucose, in situ PKC activity was higher in Type 1 patients with nephropathy (10.1+/-1.4 pmol/min/mg protein; p<0.01) than in those without (6.8+/-0.8) and the normal control subjects (6.3+/-0.5). This difference was due to increased concentrations of PKCalpha isoform in the membrane fraction of fibroblasts from patients with nephropathy. DAG content was also higher in cells from Type 1 patients with nephropathy. Incubation in high glucose concentration caused a further increase in PKC activity and DAG content in quiescent fibroblasts from patients with diabetic nephropathy, with no significant changes in cells from diabetic patients without nephropathy and normal control subjects. CONCLUSION/INTERPRETATION: Differences in PKC activation could contribute to the individual susceptibility to renal damage in Type 1 diabetic patients.
Cardiovascular diseases represent, today, the principal cause of mortality in the general population, especially in subjects with type 2 diabetes mellitus. In these patients the risk of death from cardiovascular diseases is equal to that of non-diabetic subjects with a previous episode of myocardial infarction. Many factors concur to determine such high risk. Hyperglycaemia contributes to the increase in morbidity and cardiovascular mortality associated with diabetes mellitus. Hyperglycaemia acts as a multiplier of cardiovascular risk due to frequent association of multiple risk factors in diabetic patients. Therefore, effective treatment requires a more complete assessment of quantitative and qualitative aspects of glycemic control as well as all components of the diabetic syndrome or, more commonly, metabolic syndrome.
Six-month efficacy of benfluorex (Mediator) (150-450 mg/day) was assessed in a double-blind multicenter study vs. placebo or metformin hydrochloride (850-2550 mg/day). After a 2-month run-in period of strict dieting, 722 type 2 diabetic patients were randomized (1:2:2) to receive placebo (n=144), benfluorex (n=294) or metformin (n=284). After a 5-week dose-finding phase, the efficacy of benfluorex was compared with that of placebo (test for difference, main analysis) and metformin (non-inferiority test, secondary analysis) during a 6-month fixed-dose treatment. At entry after strict dieting, there was no difference between groups for HbA(1C) (placebo, 7.4%+/-1.5%; benfluorex, 7.7%+/-1.6%; metformin, 7.8%+/-1.6%) and fasting plasma glucose (FPG; placebo, 9.7+/-2.3 mmol/l; benfluorex, 10.0+/-2.0 mmol/l; metformin, 10.2+/-2.5 mmol/l). At the end of the dose-finding phase, mean doses were 2.71 tablets/day for placebo group, 2.65 tablets/day for benfluorex (397.5 mg/day) and 2.50 tablets/day for metformin (2125 mg/day). At the end of treatment, HbA(1C) level decreased by 0.60% ( p<0.001) in benfluorex patients while it increased by 0.50% ( p<0.001) with placebo (intent-to-treat analysis). The mean endpoint difference was -0.86% (SE, 0.17%; p<0.001). Mean endpoint difference in HbA(1C) between benfluorex and metformin was 0.28% (SE, 0.12%) [90% CI, 0.07 to 0.48] (non-inferiority test, p=0.037). Treatment with benfluorex was well tolerated; 39% of these patients reported one or more emergent adverse events (compared to 38% on placebo and 43% on metformin) and only two patients suffered a treatment-related, serious adverse event. This study demonstrates that benfluorex: (1) significantly reduces HbA1C and fasting plasma glucose when compared to placebo; (2) has a good safety profile; and (3) has relatively lower potency compared to metformin, although the non-inferiority test (equivalence limit for HbA(1C) of 0.5%) was significant.
In order to evaluate the prevalence of gestational diabetes mellitus (GDM) and the presence of risk factors for GDM, we conducted a retrospective study of a cohort of Italian women. In addition, we compared universal versus selective screening to validate the ADA's recommendations in our population. From June 1st, 1995 to December 31st, 2001, universal screening for GDM was performed in 3950 women. The glucose challenge test (GCT) was positive (GCT+) in 1389 cases (35.2%). The 1-h glucose level after GCT enabled us to diagnose GDM directly in 24 pregnant women. Oral glucose tolerance test (OGTT) was performed in 1221 GCT+ women (144 cases with GCT+ dropped out) and GDM was diagnosed in 284 (23.2%) of them. OGTT was also performed in 391 randomly chosen, women from the GCT negative (GCT-) group. In this last group 25 (6.3%) women had GDM. Thus, the total number of subjects with GDM was 333 out of 3806 with a prevalence of 8.74% in the entire cohort. Assuming that the rate of GDM observed in the random sample of GCT- women is applicable to the whole group of 2561 GCT- women, then 161 GCT- patients could also have GDM. This will further increase the estimated prevalence for the whole cohort up to 12.3% (i.e. 469 out of 3806 pregnant women). There were 236 (5.6%) women with a low risk for GDM (normal weight, age less than 25 years and without a family history of diabetes). In this group we found 34 cases and five cases with positive screening test and GDM, respectively. Thus, if we excluded low risk women from the screening test, as suggested by ADA recommendations, only five women with GDM would have been missed. However, about 95% of our population were at medium or high risk for GDM and, therefore, would have been screened. The rate of GDM was significantly higher in women with a positive history of diabetes, increasing age, previous pregnancies, pre-pregnancy overweight and short stature. After logistic regression analysis, GDM diagnosis was significantly correlated with age (P<0.0001), pre-pregnancy BMI (P<0.0001), weight gain (P<0.0001) and family history of diabetes (P<0.01).
Insulin resistance, defined as the inability of insulin to exert a normal biological action at the level of its target tissues, is one of the principal pathogenetic defects of type 2 diabetes. Metformin, the most widely-prescribed insulin-sensitizing agent in current clinical use, improves blood glucose control mainly by improving insulin-mediated suppression of hepatic glucose production, and by enhancing insulin-stimulated glucose disposal in skeletal muscle. Experimental studies show that metformin-mediated improvements in insulin sensitivity may be associated with several mechanisms, including increased insulin receptor tyrosine kinase activity, enhanced glycogen synthesis, and an increase in the recruitment and activity of GLUT4 glucose transporters. In adipose tissue, metformin promotes the re-esterification of free fatty acids and inhibits lipolysis, which may indirectly improve insulin sensitivity through reduced lipotoxicity. The improved glycaemia with metformin is not associated with increased circulating levels of insulin, and the risk of hypoglycaemia with metformin is minimal. The therapeutic profile of metformin supports its use for the control of blood glucose, in diabetic patients and for the prevention of diabetes in subjects with impaired glucose tolerance. Moreover, the improvement by metformin of cardiovascular risk factors associated with the dysmetabolic syndrome may account for the significant improvements in macrovascular outcomes observed in the UK Prospective Diabetes Study.
OBJECTIVE: Chinese hamster ovary (CHO) cells transfected with human engineered insulin receptor (IR) cDNA to mutate Cys 860 to Ser (CHO-IR(C860S)) showed a defective insulin internalization without affecting insulin binding and IR autophosphorylation. Moreover, this mutation reduces insulin receptor substrate (IRS)-1 tyrosine phosphorylation and insulin-induced metabolic and mitogenic effects. Altogether, these observations support a role of the extracellular domain of IR beta-subunit in insulin and receptor intracellular targeting as well as in insulin signaling. DESIGN AND METHODS: This study assesses in more details the effect of IR(C860S) mutation on the trafficking of the insulin-IR complex. In particular, IR internalization, phosphorylation, dissociation and recycling, as well as insulin degradation and retroendocytosis have been investigated in CHO cells overexpressing either wild type (CHO-IR(WT)) or mutated IRs. RESULTS: the C860S mutation significantly decreases IR internalization both insulin stimulated and constitutive. In spite of a similar dissociation of internalized insulin-IR complex, recycling of internalized IR was significantly faster (half life (t(1/2)): 21 min vs 40 min, P<0.001) and more extensive (P<0.01) for IR(C860S) than for IR(WT). On the other hand, insulin degradation and retroendocytosis were superimposable in both cell lines. As expected, insulin-induced phosphorylation was similar in both IRs, however dephosphorylation was much more rapid and was greater (P<0.01) in CHO-IR(WT) as compared with CHO-IR(C860S) cells. CONCLUSIONS: Transmembrane and intracellular domain of IR seem to be determinants for IR internalization. Now we report that Cys 860 in the IR beta-subunit ectodomain may be of relevance in ensuring a proper internalization and intracellular trafficking of the insulin-IR complex.
BACKGROUND: The relationships between lipid levels and atherosclerotic lesions of carotid arteries in kidney graft recipients are still unclear. METHODS: We evaluated carotid morphology in 53 recipients of functioning renal transplantation, and studied the relationship of carotid artery wall lesions with relevant clinical and laboratory risk factors for cardiovascular disease. The patients were on stable, cyclosporine-based immunosuppressive therapy. RESULTS: The main clinical characteristics of patients were: age, 46.5 +/- 10.1 years; males/females, 40/13; body mass index, 25.8 +/- 4.4 kg/m2; duration of transplantation, 43 +/- 52 months. Ultrasonographic scanning of carotid arteries showed the presence of lesions (intimal-media thickness and/or plaque) in 28 patients (52.8%). These recipients differed from patients without carotid lesions in terms of age (50.4 +/- 9.0 vs 42.2 +/- 9.7 years, p < 0.01) and duration of pre-transplant dialysis (4.6 +/- 3.4 vs 2.3 +/- 1.9 years, p < 0.01), whereas no statistically significant difference was observed as for total cholesterol (230 +/- 44 vs 235 +/- 35 mg/dl), LDL-cholesterol (142 +/- 32 vs 143 +/- 30 mg/dl), HDL-cholesterol (52 +/- 12 vs 58 +/- 20 mg/dl) and triglycerides (178 +/- 94 vs 167 +/- 89 mg/dl). The percentage of post-transplant diabetes was 3-fold higher in patients with carotid lesions (25 vs 8%). No difference was observed as for the following parameters: body mass index, duration of transplantation, fibrinogen levels, DDimer concentrations, reactive C-protein values, prevalence of hypertension, percentage of smokers vs non-smokers. CONCLUSIONS: The present study supports the view that carotid artery lesions in kidney graft recipients on stable, cyclosporine-based immunosuppressive therapy may not be related to circulating lipid values.
AIMS/HYPOTHESIS: A loss of early-phase insulin response is common in Type II diabetic patients and in people with impaired glucose metabolism. It is hypothesized that this alteration is not simply a marker for the risk of developing diabetes, rather it is a an important pathogenetic mechanism causing excessive postprandial hyperglycaemia. METHODS: Relevant literature on the epidemiology, physiopathology, and therapeutic intervention related to loss of early insulin secretion and postprandial hyperglycaemia has been analysed. RESULTS: In response to intravenous glucose, insulin secretion is biphasic. This behaviour translates as a rapid release of insulin into the blood stream in response to the ingestion of carbohydrates or a mixed meal. The rapid increase in portal insulin concentration and the avid binding of the hormone to its receptor on liver cell membranes, account for a prompt suppression of endogenous glucose production and reduction of the rate of increase in plasma glucose concentrations. This has been supported by experimental studies carried out in both animals and humans: the selective abolition of early insulin secretion in healthy subjects results in impaired glucose tolerance, excessive glucose excursions, and possible hampering of the thermic effects of ingested carbohydrates. In non-diabetic subjects, the loss of early insulin secretion is a determinant for developing diabetes. The critical role of the early-phase insulin response in determining postprandial hyperglycaemia, is supported by an amelioration of glucose tolerance by restoring the acute rise in plasma insulin concentrations after the ingestion of both glucose and a mixed meal. This amelioration in plasma glucose profile can prevent late hyperglycaemia and hyperinsulinaemia. CONCLUSION/INTERPRETATION: Therapeutic approaches aimed at restoring a physiological pattern of insulin secretion could prove effective in reducing postprandial glucose excursions particularly in the early stage of Type II diabetes.
This study retrospectively evaluated two groups of pregnant women. Group A women (n=1,338) were universally screened for gestational diabetes mellitus (GDM) and GDM patients were intensively treated. In Group B (n=4,035), screening was performed only in women at high risk for GDM and treatment was conventional. This study confirms the validity of a cost-effective screening program for the diagnosis of GDM and that selective screening may be an option only in a situation where healthcare resources are very scarce and/or universal screening of any kind is not feasible. Once the diagnosis of GDM has been made, metabolic management with an intensive approach is important to reduce maternal and fetal morbidity. Diagnosis of GDM and intensive treatment represent a cost for the public health system, but permit a significant monetary savings in terms of costs linked to maternal and neonatal morbidity.
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OBJECTIVES: To test the effectiveness of a combined approach to an early diagnosis of neuro-osteoarthropathy (NOA) of the diabetic foot, we studied a group of outpatients with active NOA, presenting for the first time to our Diabetic Foot Clinic in 1998, by means of an integrated approach designed to assess bone turnover. PATIENTS AND METHODS: Fifteen consecutive diabetic patients (five Type 1 and ten Type 2 diabetic individuals, age 61.9+/-12.2 years, diabetes duration 18.7+/-8.9 years, HbA(1c) 8.4+/-1.5%) with active NOA (Group 1) were compared to nine diabetic patients with chronic stable NOA (Group 2), 14 neuropathic diabetic patients without NOA (Group 3), 13 non-neuropathic diabetic patients (Group 4) and 15 healthy controls (Group 5). Determination of serum carboxy-terminal collagen telopeptide (ICTP), bone alkaline phosphatase isoenzyme (B-ALP), osteocalcin (BGP) concentrations, as well as urinary excretion of deoxypyridinoline (DPD) were obtained in all individuals for assessment of bone reabsorption and new bone formation. Moreover in all individuals quantitative ultrasound (QUS) of the calcaneal bone was performed and mass density of lumbar spine and femur bone was determined by dual-energy X-ray absorptiometry (DEXA). RESULTS: QUS was significantly lower in the active NOA patients as compared with other groups (P<0.01), while ICTP was higher in both NOA groups (P<0.01). Urinary DPD was higher in the neuropathic non-NOA group (P<0.01) than the other groups, and osteocalcin was higher in healthy controls compared to diabetic patients without NOA. QUS and ICTP were inversely correlated (r=0.44, P=0.000). QUS in the active NOA group was significantly (P<0.01) lower in the affected compared to the unaffected foot. CONCLUSION: Our results indicate a possible role for an integrated approach to the diagnosis and monitoring of NOA involving the diabetic foot. DPD may identify patients at-risk for NOA, ICTP could be tested as a marker for NOA in asymptomatic cases. Finally, QUS of the calcaneal bone may be useful in discriminating active versus quiescent phases.
In the context of the EU funded Telematic Management of Insulin-Dependent Diabetes Mellitus (T-IDDM) project, we have designed, developed and evaluated a telemedicine system for insulin dependent diabetic patients management. The system relies on the integration of two modules, a Patient Unit (PU) and a Medical Unit (MU), able to communicate over the Internet and the Public Switched Telephone Network. Using the PU, patients are allowed to automatically download their monitoring data from the blood glucose monitoring device, and to send them to the hospital data-base; moreover, they are supported in their every day self monitoring activity. The MU provides physicians with a set of tools for data visualization, data analysis and decision support, and allows them to send messages and/or therapeutic advice to the patients. The T-IDDM service has been evaluated through the application of a formal methodology, and has been used by European patients and physicians for about 18 months. The results obtained during the project demonstration, even if obtained on a pilot study of 12 subjects, show the feasibility of the T-IDDM telemedicine service, and seem to substantiate the hypothesis that the use of the system could present an advantage in the management of insulin dependent diabetic patients, by improving communications and, potentially, clinical outcomes.