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In three groups of patients with insulin-dependent diabetes following total (n=5) or partial (n=5) pancreatectomy or chronic pancreatitis (n=7) and in a group of idiopathic diabetics, ketogenic capacity following insulin withdrawal and during a 24-h fast was studied. Basal glucagon values were significantly increased in all diabetic groups with no significant intergroup differences. Basal ketone body values and their increase during starvation and insulin withdrawal were high and not different in totally pancreatectomized and primary diabetics, both showing unmeasurable C-peptide levels. On the contrary, ketogenesis was reduced in partially pancreatectomized and in pancreatitis diabetics with persistent levels of C-peptide. Our data confirmed the persistence of immunoreactive glucagon after pancreatectomy and demonstrated that ketogenesis is not suppressed in pancreatectomized diabetics and depends above all on residual B-cell function. A possible ketogenic effect of extra-pancreatic glucagon-like substances cannot be excluded. [ABSTRACT FROM AUTHOR]

The influence of age on plasma growth hormone (HGH) and cortisol response to i.v. insulin (0.1 U/kg of body weight) was evaluated in 32 healthy subjects whose ages ranged between 20 and 4 years. A significant reduction in HGH response to insulin was observed with aging. In the young (20-34 years), middle-aged (35-49 years), and elderly (53-84 years) groups, average hgh peaks were 46.53±7.37, 29.95±5.35, and 14.31 ±2.39 ng/ml while average HGH areas were 2.911±0.484, 1.654±0.316, and 0.699±0.149 μg-min, respectively. Since insulin's hypoglycemic effect became less rapid with aging, this could, in part, explain the progressive decline in the HGH response to insulin. This phenomenon may also be attributed to histological changes occurring in the pituitary with aging. Moreover, cortisol response was similar in all three age groups. These findings suggest that, while HGH response to insulin is correlated with age, adrenal response does not show any important modifications with aging. [ABSTRACT FROM PUBLISHER]

The affects of chronic alcohol consumption on plasma branched chain amino acids and alanine concentrations were evaluated, and basal blood concentrations of these amino acids were determined after chronic ethanol intake and following a withdrawal period in 30 admitted alcoholics. After ethanol intake, alcoholics showed increased branched chain amino acid concentrations; the blood alanine concentrations were depressed after the withdrawal period. To evaluate the effect of ethanol on diurnal variations of these amino acids in the blood, a group of these patients underwent two isocaloric diets with and without wine. The diet with alcohol induced a sustained increase of branched chain amino acids persisting even after the postprandial phase with a decrease of alanine as compared to the diet without [ABSTRACT FROM AUTHOR]

Objective: Vasculoprotective endothelial progenitor cells (EPCs) are regulated by stromal-derived factor-1alpha (SDF-1alpha) and are reduced in type 2 diabetes. Because SDF-1alpha is a substrate of dipeptidyl-peptidase-4 (DPP-4), we investigated whether the DPP-4 inhibitor sitagliptin modulates EPC levels in type 2 diabetic patients.Research Design and Methods: This was a controlled, nonrandomized clinical trial comparing 4-week sitagliptin (n = 16) versus no additional treatment (n = 16) in addition to metformin and/or secretagogues in type 2 diabetic patients. We determined circulating EPC levels and plasma concentrations of SDF-1alpha, monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and nitrites/nitrates.Results: There was no difference in clinical baseline data between the sitagliptin and control arms. After 4 weeks, as compared with control subjects, patients receiving sitagliptin showed a significant increase in EPCs and SDF-1alpha and a decrease in MCP-1.Conclusions: Sitagliptin increases circulating EPCs in type 2 diabetic patients with concomitant upregulation of SDF-1alpha. This ancillary effect of DPP-4 inhibition might have potential favorable cardiovascular implications. [ABSTRACT FROM AUTHOR]

Metformin has been proposed as a potential drug treatment to reduce liver steatosis. Therefore, the study of the effects of in vivo metformin administration, on hepatic fat metabolism in the isolated perfused liver is of great interest. We have studied the effects of in vivo metformin treatment of rats with experimentally induced overweight, hyperglycemia and hypertriglyceridemia, on plasma hormone and metabolite concentrations, as well as on triglyceride and ketone body output by the isolated perfused livers. Sprague–Dawley rats were fed ad libitum with a high lipid diet for 10 weeks. Then, one rat group was treated for 7 days with 350 μg/kg of BW of metformin per day, whereas the control group received only water. Thereafter, the livers were excised and perfused in vitro under controlled conditions. The hypertriglyceridemic rats had a greater body weight, as well as greater plasma glucose, insulin and triglyceride concentrations, than the control rats fed ordinary chow. In vivo metformin treatment decreased plasma glucose, insulin and triglyceride concentrations. With respect to the overweight, hyperglycemic, hypertriglyceridemic, untreated control rats, the cumulative (i.e. over 3 h of perfusion) triglyceride output by the perfused livers was decreased by >60%, whereas total ketone body (i.e. the sum of 3-hydroxybutyrate and acetoacetate) output was increased by >100% ( p < 0.01 for both). In conclusion, the in vivo treatment with metformin of rats with diet-induced overweight and hypertriglyceridemia is capable to re-address hepatic fatty acid metabolism from lipogenesis toward fat oxidation and ketone body production, either directly or through a reduction of insulin concentrations. [ABSTRACT FROM AUTHOR]

Presents a study which investigated the effects of retinal and peripheral vascular complications on circulating progenitor cells in type 2 diabetic patients. Research design and methods; Analysis of peripheral blood progenitor cells for surface antigen expression; Technique used in confirming the enhanced endothelial differentiation of circulating progenitors.

A response from the authors of the article "Polypharmacy in elderly people with diabetes admitted to hospital" in the November 2015 issue is presented.

A response from the authors of the article "Intensive Structured Self-Monitoring of Blood Glucose and Glycemic Control in Noninsulin-Treated Type 2 Diabetes: The PRISMA Randomize Trial" published in the journal in 2013 is presented.

Abstract: Aims: Severe hypoglycemia can be dramatic in diabetic patients, but its long-term outcome is unknown. We aimed to describe clinical characteristics of type 2 diabetic patients hospitalized for iatrogenic hypoglycemia, and find predictors of long-term mortality, with a special regard to anti-hyperglycemic regimens. Methods: We retrospectively analyzed 126 episodes of severe hypoglycemia in type 2 diabetic patients. We collected data on the event (coma, pre-hospital fall, glucose level, duration of hypoglycemia), concomitant risk factors, diabetic complications and chronic comorbidities. We divided patients according to the use of insulin or oral agents (OHAs). In-hospital outcomes were acute coronary syndrome (ACS) and duration of hospitalization. We finally assessed long-term mortality. Results: Hypoglycemia due to OHA was associated with higher prevalence of coma and longer duration than hypoglycemia due to insulin. OHA use was also associated with a longer hospital stay, but no increase in the incidence of ACS. Overall mortality after a 2-year median follow-up was 42.1%. Despite the apparent worse presentation of hypoglycemic episodes associated with OHA use, this did not lead to an increased long-term mortality. Conclusions: Severe iatrogenic hypoglycemia in OHA-treated patients has a worse presentation, but is not associated with a higher long-term mortality than in insulin-treated patients. [Copyright &y& Elsevier]

Abstract: The expanding diabetic epidemic and the high risk of cardiovascular events in diabetic patients suggest that screening heart disease in this population is an important issue. Nonetheless, the advisability of large-scale screening in asymptomatic individuals with diabetes is debated, because available techniques are expensive and have suboptimal diagnostic accuracy. Moreover, all diabetic patients should be treated aggressively as if they all had a positive screening test, because diabetes could be considered a coronary risk equivalent. In this article, we underline the importance of an early diagnosis of coronary artery disease and heart failure in diabetic patients, suggesting that positive screening tests have significant implications in clinical management. [Copyright &y& Elsevier]

Objective: To evaluate the accuracy of a new subcutaneous glucose sensor (Glucoday; A. Menarini Diagnostics) compared with venous blood glucose measurement in type 1 and type 2 diabetic patients.Research Design: A multicenter study was performed in 70 diabetic patients. A microdialysis fiber was inserted subcutaneously into the periumbelical region and perfused with a buffer solution. Glucose concentrations in the dialysate were then measured every 3 min by the glucose sensor over a 24-h period, during which nine venous blood samples were also collected throughout the day.Results: Both the insertion of the fiber and the wearing of the device were well tolerated by the patients. Subcutaneous glucose levels were well correlated with venous glucose measurements (r = 0.9, P < 0.001) over a wide range (40-400 mg/dl) for up to 24 h, with a single-point calibration. An analysis of 381 data pairs showed a linear relationship between the GlucoDay and serial venous blood glucose levels, and 97% of the data fell in the A and B regions of the error grid analysis. Percentage bias between the GlucoDay and the blood venous levels was -2.0% in the hypoglycemic range (<70 mg/dl), 6.9% in the euglycemic range (70-180 mg/dl), and 11.2% in the hyperglycemic range (>180 mg/dl).Conclusions: The GlucoDay system demonstrated high reliability and reported values that closely agreed with venous blood glucose measurements. The system was well tolerated and thus constitutes a relatively easy method to monitor glucose excursions in diabetic patients. [ABSTRACT FROM AUTHOR]

Aim: Polypharmacy in older diabetics can have detrimental effects linked to poor adherence and the risk of drug interaction or more serious/frequent side effects. The aim of this study was to identify the characteristics associated with polypharmacy in a cohort of elderly diabetic patients being treated with oral hypoglycemic agents. Methods: The study population consisted of 1342 diabetic patients consecutively enrolled in 57 diabetes centers in Italy participating in the METABOLIC Study. Patients meeting the following inclusion criteria were enrolled: diagnosis of type 2 diabetes mellitus, age ≥65 years, and receiving oral antidiabetic treatment. Data concerning diabetes duration and complications, the medications the patients were taking, and the number of hypoglycemic events were registered. Multidimensional impairment was assessed using the Multidimensional Prognostic Index. Results: The mean age of the participants was 73.3 ± 5.5 years. Polypharmacy, defined as being prescribed contemporaneously at least five drugs, was found in 57.1 % of the study population. According to a multivariable logistic model, the female gender was significantly associated with polypharmacy, as were living in Northern Italian regions, diabetes duration longer than 4 years, and having a body mass index ≥30 kg/m. Comorbidities, diabetes complications, a better cognitive performance on the Short Portable Mental Status Questionnaire, and being malnourished/at risk of malnourishment according to the mini nutritional assessment were associated with polypharmacy. Conclusions: Polypharmacy, a condition that may lead to many potential detrimental outcomes in older diabetic subjects, was significantly associated with some risk factors that may be useful to identify subjects at risk. [ABSTRACT FROM AUTHOR]

Self-monitoring of blood glucose (SMBG) is a core component of diabetes management. However, the International Diabetes Federation recommends that SMBG be performed in a structured manner and that the data are accurately interpreted and used to take appropriate therapeutic actions. We designed a study to evaluate the impact of structured SMBG on glycemic control in non-insulin-treated type 2 diabetes (T2DM) patients. The Prospective, Randomized Trial on Intensive SMBG Management Added Value in Non-insulin-Treated T2DM Patients (PRISMA) is a 12-month, prospective, multicenter, open, parallel group, randomized, and controlled trial to evaluate the added value of an intensive, structured SMBG regimen in T2DM patients treated with oral agents and/or diet. One thousand patients (500 per arm) will be enrolled at 39 clinical sites in Italy. Eligible patients will be randomized to the intensive structured monitoring (ISM) group or the active control (AC) group, with a glycosylated hemoglobin (HbA1c) target of <7.0%. Intervention will comprise (1) structured SMBG (4-point daily glucose profiles on 3 days per week [ISM]; discretionary, unstructured SMBG [AC]); (2) comprehensive patient education (both groups); and (3) clinician's adjustment of diabetes medications using an algorithm targeting SMBG levels, HbA1c and hypoglycemia (ISM) or HbA1c and hypoglycemia (AC). The intervention and trial design build upon previous research by emphasizing appropriate and collaborative use of SMBG by both patients and physicians. Utilization of per protocol and intent-to-treat analyses facilitates assessment of the intervention. Inclusion of multiple dependent variables allows us to assess the broader impact of the intervention, including changes in patient and physician attitudes and behaviors. ClinicalTrials.gov (NCT00643474). [ABSTRACT FROM AUTHOR]

Objective: We aimed to evaluate the added value of intensive self-monitoring of blood glucose (SMBG), structured in timing and frequency, in noninsulin-treated patients with type 2 diabetes.Research Design and Methods: The 12-month, randomized, clinical trial enrolled 1,024 patients with noninsulin-treated type 2 diabetes (median baseline HbA1c, 7.3% [IQR, 6.9-7.8%]) at 39 diabetes clinics in Italy. After standardized education, 501 patients were randomized to intensive structured monitoring (ISM) with 4-point glycemic profiles (fasting, preprandial, 2-h postprandial, and postabsorptive measurements) performed 3 days/week; 523 patients were randomized to active control (AC) with 4-point glycemic profiles performed at baseline and at 6 and 12 months. Two primary end points were tested in hierarchical order: HbA1c change at 12 months and percentage of patients at risk target for low and high blood glucose index.Results: Intent-to-treat analysis showed greater HbA1c reductions over 12 months in ISM (-0.39%) than in AC patients (-0.27%), with a between-group difference of -0.12% (95% CI, -0.210 to -0.024; P=0.013). In the per-protocol analysis, the between-group difference was -0.21% (-0.331 to -0.089; P=0.0007). More ISM than AC patients achieved clinically meaningful reductions in HbA1c (>0.3, >0.4, or >0.5%) at study end (P<0.025). The proportion of patients reaching/maintaining the risk target at month 12 was similar in ISM (74.6%) and AC (70.1%) patients (P=0.131). At visits 2, 3, and 4, diabetes medications were changed more often in ISM than in AC patients (P<0.001).Conclusions: Use of structured SMBG improves glycemic control and provides guidance in prescribing diabetes medications in patients with relatively well-controlled noninsulin-treated type 2 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Aims: The hyperglycemic hyperosmolar syndrome (HHS) is a life-threatening diabetic complication. We aimed to portrait the short and long term outcome after a HHS episode and to describe features associated with increased early mortality. Methods: We collected data from consecutive HHS cases, defined based on rigorous glucose and osmolality criteria. We retrieved anthropometric measures, history of diabetes, other cardiovascular risk factors and chronic co-morbidity. Clinical and biochemical parameters were recorded at admission, after 24h and at discharge. We assessed incidence of complications, as well as short (≤30 days) and long term mortality. Results: Patients were about 80-year old. Fifty-one cases were included, characterized by severe hyperglycemia (55.5mosm/L) and hyperosmolality (385mosm/L). Thirty-three percent developed at least one complication. Short term mortality was 16%; lower Glasgow Coma Scale, higher plasma glucose and mild acidosis were predictive of short term mortality. The long term mortality (median follow-up 1.27 years) was not significantly different from historical mortality data after hypoglycemic coma. Conclusion: In this study, early mortality of HHS was 16% and some clinical features at presentation were predictive of an adverse short term outcome. Long term survival after a HHS episode did not appear to be severely impaired. [Copyright &y& Elsevier]

OBJECTIVE --Reduction of bone marrow-derived circulating progenitor cells has been proposed as a novel mechanism of cardiovascular disease in type 2 diabetes. The present study was designed to describe the extent and potential mechanisms of progenitor cell reduction during the natural history of type 2 diabetes. RESEARCH DESIGN AND METHODS-- We identified 425 individuals, divided into seven categories according to carbohydrate metabolism status (normal glucose tolerance [NGT], impaired fasting glucose, impaired glucose tolerance [IGT], and newly diagnosed type 2 diabetes) and diabetes duration (0-9, 10-19, and ≥20 years). These categories were examined as ideally describing the natural history of type 2 diabetes development and progression. We measured CD34+ and CD34+KDR+ progenitor cells by flow cytometry. We also evaluated progenitor cells in 20 coupled bone marrow and peripheral blood samples and examined progenitor cell apoptosis in 34 subjects. RESULTS -- In comparison to NGT, CD34+ cells were significantly reduced in IGT and had a first nadir in newly diagnosed type 2 diabetes and a second nadir after 20 years of diabetes. Statistical adjustment for possible confounders confirmed that CD34+ cell counts are deeply reduced at time of diagnosis, that they partially recover during the subsequent 0-19 years, and that they dip again after ≥20 years. A similar, but less consistent, trend was detected for CD34+KDR+ cells. Peripheral blood CD34+ cells were directly correlated with bone marrow CD34+ cells and inversely correlated with CD34+ cell apoptosis. CONCLUSIONS-- Circulating progenitor cell reduction marks the clinical onset of type 2 diabetes. Both defective mobilization and increased apoptosis may account for this phenomenon. While a partial recovery occurs during subsequent years, bone marrow reserve seems exhausted in the long term. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Metabolic syndrome (MetS) associates with endothelial dysfunction and a high risk of cardiovascular events and death. Circulating progenitor cells have been shown to contribute to endothelial homeostasis and repair . We aimed to test whether progenitor cell count is an independent event predictor and modifies cardiovascular risk associated with MetS. Methods: On the basis of the expression of CD34, CD133 and KDR, 6 phenotypes of progenitor cells were counted using flow cytometry in 214 subjects with and without MetS. We recorded classical risk factors and MetS components, cumulative risk estimates, and high-sensitive C-reactive protein. Subjects were followed-up for a median of 34 months to collect total events, cardiovascular events and all-cause mortality. Results: In the Cox proportional hazards regression analyses, we found that, unlike other phenotypes, reduced CD34+ cells predicted cardiovascular and total events and death, independently of all potential confounders. Remarkably, a low CD34+ cell count significantly increased the risk associated with MetS, as shown by synergy indexes. Conclusion: The level of circulating CD34+ cells is a novel independent risk biomarker and modulates outcomes in the MetS, suggesting that generic progenitor cells have a role in disease development or progression over the long-term. [Copyright &y& Elsevier]

Nitric oxide (NO) is a key regulatory molecule with wide vascular, cellular, and metabolic effects. Insulin affects NO synthesis in vitro. No data exist on the acute effect of insulin on NO kinetics in vivo. By employing a precursor-product tracer method in humans, we have directly estimated the acute effect of insulin on intravascular NOx (i.e., the NO oxidation products) fractional (FSR) and absolute (ASR) synthesis rates in vivo. Nine healthy male volunteers were infused iv with L-[15N2-guanidino]-arginine ([15N2]arginine) for 6 h. Timed measurements of 15NOx and [15Nx]arginine enrichments in whole blood were performed in the first 3 h in the fasting state and then following a 3-h euglycemic-hyperinsulinemic clamp (with plasma insulin raised to ≈1,000 pmol/l). In the last 60 min of each experimental period, at ≈steady-state arginine enrichment, a linear increase of 15NOx enrichment (mean r = 0.9) was detected in both experimental periods. In the fasting state, NOx FSR was 27.4 ± 4.3%/day, whereas ASR was 0.97 ± 0.36 mmol/day, accounting for 0.69 ± 0.27% of arginine flux. Following hyperinsulinemia, both FSR and ASR of NO,, increased (FSR by ≈50%, to 42.4 ± 6.7%/day, P < 0.005; ASR by ≈25%, to 1.22 ± 0.41 mmol/day, P = 0.002), despite a ≈20-30% decrease of arginine flux and concentration. The fraction of arginine flux used for NOx synthesis was doubled, to 1.13 ± 0.35% (P < 0.003). In conclusion, whole body NOx synthesis can be directly measured over a short observation time with stable isotope methods in humans. Insulin acutely stimulates NOx synthesis from arginine. [ABSTRACT FROM AUTHOR]

Abstract: Insulin can generate oxygen free radicals. Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, exert a powerful antioxidant effect. The present study aimed to clarify the mechanisms through which insulin generates free radicals and to assess whether pravastatin modulates such effects. In cultured skin fibroblasts from human volunteers exposed to high insulin concentration, either in the presence or in the absence of pravastatin, insulin induced translocation of the p47phox subunit of NAD(P)H oxidase from the cytosol to the membrane and generation of radical oxygen species through a PKC δ-dependent mechanism. The insulin-induced translocation of p47phox was PKC δ dependent and attenuated by pravastatin, but independent of the activation of Akt and Rac1. Insulin-induced Akt phosphorylation was increased by pravastatin and ERK1/2 phosphorylation attenuated. The present study demonstrates a novel mechanism by which insulin stimulates the generation of free radicals in human fibroblasts, ex vivo. It involves phosphatidylinositol 3-kinase, PKC δ, and p47phox translocation and promotes ERK1/2 phosphorylation. Pravastatin inhibited radical oxygen species production by inhibiting PKC δ. These observations offer a robust explanation for the positive effects of pravastatin treatment in patients with insulin resistance syndrome. [Copyright &y& Elsevier]

Microalbuminuria is a risk factor for renal and cardiovascular disease. A role for insulin resistance in the pathogenesis of microalbuminuria has been suggested but is still unproven. In this case-control, cross-sectional study, we compared glucose disposal rate (GDR), measured by hyperinsulinemic-euglycemic clamp, in 50 pairs of matched type 2 diabetic patients with micro- or normoalbuminuria (main study) and in 29 matched pairs of diabetic patients with macro- or microalbuminuria (substudy). In the main study, GDR was approximately 25% lower in micro- than in normoalbuminuric patients (5.20 +/- 1.91 vs. 6.86 +/- 2.88 mg . kg(-1) . min(-1), P < 0.05) and was independently associated with microalbuminuria (P = 0.002), with each 1 mg . kg(-1) . min(-1) decrease predicting approximately 40% increased prevalence (odds ratio 1.37 [95% CI 1.14-1.70]). Microalbuminuria was threefold more frequent in patients with GDR < or =7.50 +/- 2.56 mg . kg(-1) . min(-1) than in those with higher GDR (60% vs. 20%, P < 0.005). In the substudy, GDR in macro- and microalbuminuric patients was comparable (5.52 +/- 2.56 vs. 5.16 +/- 1.61 mg . kg(-1) . min(-1)) and independent of macroalbuminuria. GDR was significantly correlated with urinary albumin excretion rate in the main study (P = 0.004) but not in the substudy (P = 0.60). In type 2 diabetes, more severe insulin resistance is independently associated with microalbuminuria. Longitudinal studies are needed to clarify the role of insulin resistance in the pathogenesis of microalbuminuria and related complications. [ABSTRACT FROM AUTHOR]