Search

Aims To investigate the relationship between single therapeutic interventions and indicators of glycemic control in the PRISMA trial, a large study comparing the effects of intensive structured SMBG (ISM) vs. active control (AC) in non-insulin-treated type 2 diabetes (T2D). Methods Information was collected at four time points, corresponding to months 3, 6, 9, and 12 and visits 2, 3, 4, and 5, respectively. Data on therapeutic interventions, HbA1c levels and the number of hypoglycemic episodes at each visit were analyzed. Results Intensification of drug therapy occurred in 20.3% vs. 15.6%, and no change in 71.8% vs. 78.7% of visits for the ISM and AC groups, respectively. On the other hand, de-intensification and redistribution of drugs and/or drug dose occurred in a similar proportion of visits. Intensification of drug therapy in both groups was associated with significant reductions in HbA1c vs. the previous visit, while de-intensification of therapy led to a significant increase in HbA1c in the AC group only. Conclusions. Our data strongly support that structured SMBG has clinical value in reducing HbA1c in non-insulin-treated T2D and suggest that this clinical benefit may be mediated by more appropriate and timely changes in drug therapy.

Background: To evaluate whether structured self-monitoring of blood glucose (SMBG) is associated with changes in diabetes-specific quality of life (DSQoL) and locus of control (LOC) in patients with noninsulin-treated type 2 diabetes (T2DM). Study Design and Methods: In this analysis of the PRISMA (Prospective Randomized Trial on Intensive SMBG Management Added Value in Noninsulin-Treated T2DM Patients) Study psychosocial data, we evaluated the impact of 12 months of structured SMBG on the individual domains of DSQoL and LOC questionnaires, including the role of selected confounders. Results: The score for Satisfaction, Impact, and Worry domains (DSQoL) improved when compared with baseline, without significant differences between structured SMBG regimen (intervention group, n = 501) and active control group (n = 523). Scores for Internal, Chance, and Powerful Others domains (LOC) improved compared with baseline, with a significant between-group change in Chance (P = 0.0309). For DSQoL domain score, improvements were associated with higher number of SMBG measurements (P = 0.007), older age (P = 0.013), and male sex (P = 0.0133) for Satisfaction and with male sex (P

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.

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 ≥65years, 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±5.5years. 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 4years, and having a body mass index ≥30kg/m2. 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. © 2015, Springer-Verlag Italia.

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 24 h 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 (55.5 mosm/L) and hyperosmolality (385 mosm/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.

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.

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.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized pathology with a high prevalence and a possible evolution to its inflammatory counterpart (non-alcoholic steatohepatitis, or NASH). The pathophysiology of NAFLD and NASH has many links with the metabolic syndrome, sharing a causative factor in insulin resistance. According to a two-hit hypothesis, increased intrahepatic triglyceride accumulation (due to increased synthesis, decreased export, or both) is followed by a second step (or "hit"), which may lead to NASH. The latter likely involves oxidative stress, cytochrome P450 activation, lipid peroxidation, increased inflammatory cytokine production, activation of hepatic stellate cells and apoptosis. However, both "hits" may be caused by the same factors. The aim of this article is to overview the biochemical steps of fat regulation in the liver and the alterations occurring in the pathogenesis of NAFLD and NASH.

Diabetic nephropathy (DN) develops in about 40% of insulin-dependent type 1 diabetes mellitus (T1DM) patients, and is associated not only with diabetes duration and metabolic control, but also with a genetic predisposition. Constitutive alterations of cytoskeletal proteins may play a role in the development of DN. We investigated the expression of these proteins in cultured skin fibroblasts, obtained from long-term T1DM patients with and without DN but comparable metabolic control, and from matched healthy subjects, by means of 2-DE electrophoresis and MS-MALDI analyses. In T1DM with DN, compared to the other two groups, quantitative analyses revealed an altered expression of 17 spots (p

OBJECTIVE—We aimed at assessing the degree of association and the predictive power of the metabolic syndrome with regard to clinically detectable complications in patients with diabetes. RESEARCH DESIGN AND METHODS—Metascreen is a cross-sectional survey of metabolic syndrome and clinically detected diabetes complications performed in 8,497 patients (7,859 with type 2 diabetes and 638 with type 1 diabetes) randomly chosen in 176 diabetes outpatient clinics throughout Italy. The metabolic syndrome was defined according to either the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) or the International Diabetes Federation (IDF) diagnostic criteria. Multivariate analyses of the association(s) between either AHA/NHLBI or IDF metabolic syndrome and clinical complications were performed. Receiver-operator characteristic (ROC) curves were constructed to compare the predictive power of the two sets of diagnostic criteria of the metabolic syndrome. RESULTS—Either definition of the metabolic syndrome was an independent statistical indicator of the presence of nephropathy and neuropathy (P < 0.02–0.01) in type 1 diabetes and of all complications (P < 0.0001), including cardiovascular disease and retinopathy, in type 2 diabetes. For each complication, the ROC curves based on either AHA/NHLBI or IDF metabolic syndrome were similar to each other and to the ROC curves constructed with all continuous traits compounding the metabolic syndrome. CONCLUSIONS—The metabolic syndrome, defined according to AHA/NHLBI or IDF diagnostic criteria, is an independent clinical indicator and may be involved in the pathogenesis of both macro- and microvascular complications of diabetes.

Background and Purpose— Disruption of the endothelial layer is the first step in the atherogenic process. Experimental studies have shown that endothelial progenitor cells (EPCs) are involved in endothelial homeostasis and repair. Conversely, EPC depletion has been demonstrated in the setting of established atherosclerotic diseases. With this background, we evaluated whether variations in the number of EPCs are associated with subclinical atherosclerosis in healthy subjects. Methods— Carotid intima-media thickness (IMT), high-sensitive C-reactive protein (hsCRP), levels of circulating EPCs, and cardiovascular risk were compared in 137 healthy subjects. Six subpopulations of progenitor cells were determined by flow cytometry on the basis of the surface expression of CD34, CD133, and KDR antigens: CD34 + , CD133 + , CD34 + CD133 + , CD34 + KDR + , CD133 + KDR + , and CD34 + CD133 + KDR + . Results— Among different antigenic profiles of EPCs, only CD34 + KDR + cells were significantly reduced in subjects with increased IMT. Specifically, CD34 + KDR + cells were inversely correlated with IMT, even after adjustment for hsCRP and 10-year Framingham risk and independently of other cardiovascular parameters. Conclusions— Depletion of CD34 + KDR + EPCs is an independent predictor of early subclinical atherosclerosis in healthy subjects and may provide additional information beyond classic risk factors and inflammatory markers.

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 p47(phox) subunit of NAD(P)H oxidase from the cytosol to the membrane and generation of radical oxygen species through a PKC delta-dependent mechanism. The insulin-induced translocation of p47(phox) was PKC delta 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 delta, and p47(phox) translocation and promotes ERK1/2 phosphorylation. Pravastatin inhibited radical oxygen species production by inhibiting PKC delta. These observations offer a robust explanation for the positive effects of pravastatin treatment in patients with insulin resistance syndrome.

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 ∼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 ∼40% increased prevalence (odds ratio 1.37 [95% CI 1.14–1.70]). Microalbuminuria was threefold more frequent in patients with GDR ≤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.

OBJECTIVES We sought to establish whether a reduction in endothelial progenitor cells (EPCs) has a putative role in peripheral vascular disease (PVD) of type 2 diabetic patients. BACKGROUND Peripheral vascular disease is a common and severe complication of diabetes mellitus. Impaired collateralization of diabetic vasculopathy has been extensively shown, but causes leading to its pathogenesis are not fully understood. Recently, EPCs have been found to contribute to vascular repair and angiogenesis. Diabetes has been associated with low levels of circulating EPCs, but no data are available in the literature on the relationship between EPCs and PVD in diabetes. METHODS Flow cytometric analysis was used to quantify circulating progenitor cells (CPCs, CD34+) and EPCs (CD34+KDR+) in 51 patients and 17 control subjects. RESULTS The CPCs and EPCs from diabetic patients were reduced by 33% and 40%, respectively, compared with healthy subjects (p < 0.001). An inverse correlation was found between the number of EPCs and the values of fasting glucose (r = -0.49, p = 0.006). Peripheral vascular disease was associated with a 47% reduction in EPCs (p < 0.0001) and EPC levels directly correlated with the ankle-brachial index (r = 0.70, p = 0.01). The subgroup of diabetic patients with PVD also had reduced CPCs by 32% (p = 0.037), whereas patients with ischemic foot lesions had the lowest levels of both EPCs and CPCs (p = 0.02). CONCLUSIONS Our data demonstrate decreased EPC levels in diabetic patients and, for the first time, show that PVD is associated with an extensively low number of EPCs. Depletion of circulating EPCs in diabetic patients may be involved in the pathogenesis of peripheral vascular complications.

BACKGROUND No data are available on the relationship between myocardial perfusion and left ventricular (LV) function in type 1 diabetes mellitus (T1DM), which may constitute a factor explaining the progressive contractile dysfunction to the overt phase of diabetic cardiomyopathy. HYPOTHESIS This study was undertaken to test whether myocardial perfusion abnormalities are present at rest and during exercise and whether they are related to contractile dysfunction in T1DM. METHODS Twenty-two patients with T1DM, aged 32 +/- 8.3 years, without macro- or microvascular complications, and 10 controls, aged 31 +/- 3 years, were studied. Left ventricular function and myocardial perfusion were assessed by two-dimensional and myocardial contrast echocardiography at rest and during handgrip (HG). RESULTS Fourteen patients with T1DM showed a decline in LV ejection fraction (LVEF) during HG (Group 1) while 8 had a normal response (Group 2). Both basal myocardial blood volume (MBV) and velocity (beta) were normal in T1DM. During exercise, MBV and beta increased and were associated with an increase in myocardial blood flow (MBF) in controls. In T1DM, beta did not change and MBV increased only in Group 2, while this increase was not observed in Group 1 (controls: 14.9 +/- 2.3 vs. Group 1: 7.6 +/- 1.6, p < 0.001; and vs. Group 2: 10.2 +/- 2.8, p < 0.001), beta (0.86 +/- 0.12 vs. 0.68 +/- 0.14, p < 0.001; and vs. 0.67 +/- 0.15, p < 0.001). A correlation between the ratio exercise MBF/resting MBF and LVEF at peak exercise in T1DM was observed (r = 0.805, p < 0.001). CONCLUSIONS A large proportion of patients with T1DM exhibit abnormalities in myocardial adaptable capacity to match an acute overload, which are related to a defective increase in myocardial perfusion.

Background: With advancing age the risk of developing serious nutritional deficiencies increases, and disturbances to the actions of insulin and insulin-like growth factor, coupled with reduced protein/amino acid (AA) intake, impair protein synthesis in muscles. Objective: To assess the effects of administering oral AAs on walking capacity and perceived walking impairment, isometric muscular strength, and myocardial function at rest and during isometric exercise. Methods: One hundred elderly subjects (aged >65 years) with reduced physical activity were randomized to receive an oral AA mixture (12 g/day) or placebo for 3 months. At baseline and after 3 months of therapy we assessed physical capacity with the 6-min walk test, and perceived physical impairment with the walking impairment questionnaire (WIQ); we assessed maximal isometric muscular strength of the right hand with a handgrip dynamometer, and left ventricular ejection fraction (LVEF) using quantitative two-dimensional echocardiography at rest and during acute overload. Results: Three months of AA treatment resulted in significant increases in 6-min walk distance (268.8 ± 34.9 vs. 212 ± 40 m, p < 0.001), WIQ scores (distance: 68.3 ± 12 vs. 53 ± 14.8%, p < 0.001; speed: 72.2 ± 14.4 vs. 52.8 ± 12%, p < 0.001; stairs: 98.2 ± 24 vs. 72.4 ± 22%, p < 0.001), and in maximal muscular isometric strength (20.2 ± 2 vs. 14 ± 2.8 kg, p < 0.001). Moreover, peak stress LVEF was higher during AA administration when compared to placebo administration (67 ± 7 vs. 56 ± 9%, p < 0.01). Left ventricular response to exercise normalized during AA administration in 24 out of 32 (75%) patients with abnormal LV response at baseline, whereas it remained unchanged in the placebo group. Conclusion: An oral AA supply such as that used in this study improves ambulatory capacity, maximal isometric muscle strength and myocardial ability to match an acute overload in elderly subjects without affecting the main metabolic parameters. These functional gains may translate into increased perceived walking capacity.

In this cross-sectional, case-control study we explored the association of proliferative diabetic retinopathy (PDR) with insulin resistance (IR) in type 2 diabetics with serum creatinine less than 2.0 mg/dl. For each PDR case, one reference case with background diabetic retinopathy (BDR) and two controls without retinopathy were identified. IR was evaluated by hyperinsulinemic euglycemic clamp; retinopathy was evaluated by indirect ophthalmoscopy and photography. Patients were matched by age, gender, and body mass index. PDR patients (n = 28) had higher IR and low-density lipoprotein cholesterol and triglyceride levels than BDR patients (n = 29), but comparable levels of glycosylated hemoglobin. Compared with patients without retinopathy (n = 58), those with PDR had higher IR, low-density lipoprotein cholesterol, and albuminuria (P < 0.05); those with BDR had higher glycosylated hemoglobin (P < 0.05), but comparable IR. At multivariate regression analysis, IR was the only independent marker of PDR among patients with retinopathy (P = 0.016). IR also retained its independent predictive value at multiple comparison among all groups (by Kruskal-Wallis test, P = 0.019). In type 2 diabetes, IR is an independent specific marker of proliferative retinopathy that may characterize patients at increased risk for blindness who may benefit most from early screening and therapeutic intervention. Longitudinal studies are needed to evaluate the role of IR in the pathogenesis of proliferative retinopathy.

Injection of insulin lispro (LP) before meals provides a more physiologic insulin activity profile than regular human insulin, but the relatively short duration of action of LP may allow the blood glucose (BG) level to increase during the late postprandial period (4-7 hours after meals) unless basal insulin is optimally replaced. One approach to basal insulin optimization has been to combine small doses of NPH with LP before meals. When used in a similar fashion, premixed, fixed-ratio insulin preparations containing LP and NPL (an LP-based intermediate-acting insulin) may provide the basis for an optimized basal-bolus insulin regimen.This study assessed mean late postprandial glycemic control during treatment with a premixed formulation consisting of a high proportion of LP (75% LP/25% NPL; H) and a premixed formulation consisting of a medium proportion of LP (50% LP/50% NPL; M). The H/M formulation was given before meals and was compared with treatment with preprandial LP + NPH (LP + N) in patients with type 1 diabetes mellitus (DM).This multicenter, randomized, open-label, 2-period crossover study was conducted at 4 centers in Italy and 1 center in France. Patients eligible for the study had type 1 DM, wereor = 18 years of age, and had a glycosylated hemoglobin (HbA(1c))150% of the upper limit of normal. Patients were randomly assigned to 1 of 2 treatment sequences: LP self-mixed with NPH before meals plus NPH alone at bedtime for 8 weeks (LP + N) followed by preprandial H or M, plus NPH alone at bedtime for 8 weeks (H/M), or the opposite sequence. Assessments included 8-point self-monitored BG profiles, HbA(1c), and hypoglycemia (any sign or symptom of hypoglycemia or BG3.0 mmol/L [54.0 mg/dL]). The primary outcome measure was the late postprandial BG value, calculated as the mean of the combined prelunch (late postbreakfast), predinner (late postlunch), and bedtime (late postdinner) values.A total of 89 patients with type 1 DM were enrolled (44 men, 45 women; mean [SD] age, 38.3 [12.8] years; mean [SD] body weight, 70.8 [11.6] kg; mean [SD] body mass index, 24.6 [3.0] kg/m(2); mean [SD] duration of diabetes, 17.8 [10.5] years; mean HbA(1c), 7.9% [0.88%]). The mean (SD) late postprandial BG values were similar between treatments (8.9 [2.1] mmol/L [160.3 (37.8) mg/dL] for H/M vs 9.0 [1.8] mmol/L [162.1 (32.4) mg/dL] for LP + N), as were the end point HbA(1c) values (7.8% [0.9%] for H/M vs 7.9% [0.8%] for LP + N). The rate of hypoglycemia was significantly higher during treatment with H/M, primarily because of episodes occurring between 12 PM and 6 PM, but was relatively low in both groups (mean/median rate per patient per 30 days: 2.87/2.14 for H/M and 2.11/1.07 for LP + N; P0.05).In this population of patients with type 1 DM, preprandial H/M provided an effective alternative regimen for prandial and basal insulin replacement. Late postprandial BG control, an indicator of basal insulin sufficiency, was similar to that achieved with an intensified regimen of LP + N injected separately before meals, and the end point HbA(1c) was similar between the 2 treatments.

In patients with chronic diseases education should improve knowledge about the disease and increase certainty in knowledge. We present here a technique to measure changes in certainty after an educational intervention. For this purpose, before and after a course, patients answer a questionnaire in which answers are accompanied by an estimate of the degree of certainty. Answers are then assigned to areas of knowledge defined a priori: mastered (certaintyor = 90%, correctnessor = 90%), hazardous (certaintyor = 90%, correctnessor = 50%), uncertain (certaintyor = 50%, correctnessor = 90%) and residual. Finally differences in the distribution of answers among different areas are analysed statistically. Using this technique in a group of patients with type I diabetes who followed a course on insulin use, we found significant changes in the distribution of answers among different areas of knowledge. Thus changes in certainty can be analysed quantitatively and used to evaluate better the effect of therapeutic education.

Nonesterified fatty acids (NEFA) induce vascular effects, such as the inhibition of insulin-induced nitric oxide (NO) production. In small arteries, relaxation is largely NO-independent. We aimed to assess the effect of elevated NEFA on NO-independent vasodilation. Protocols were performed before and after 120 min of a lipid emulsion infusion. We performed: (1) the flow-induced dilatation of the brachial artery (NO-dependent), (2) intrabrachial bradykinin (BK) infusion before and after inhibition of prostaglandins (PG) and NO and (3) intraarterial infusion of ouabain, a Na+/K+ ATPase blocker, alone or in combination with BaCl2, a potassium channel blocker. No changes in flow-mediated vasodilation were induced by elevated NEFA. After the inhibition of PG and NO, BK increased forearm blood flow (FBF) similarly, indicating that the increase in FBF is not dependent on NO and PG production. However, elevated NEFA blunt FBF on both occasions. Coinfusion of ouabain with BaCl2 caused a significant decline in FBF in baseline condition (−48±5%, p

Background Endothelial dysfunction has been described in obesity. This study examines the impact of visceral obesity on nitric oxide-independent relaxation in the human forearm. Methods and results In ten viscerally obese and ten matched controls forearm blood flow (FBF) was measured by venous occlusion plethysmography during intrabrachial infusion of: (1) sodium nitroprusside; (2) bradykinin, before and after inhibition of vasoactive prostaglandins and nitric oxide; (3) potassium; (4) ouabain (Na+/K+ATPase inhibitor) alone or (5) in combination with BaCl2(KIRinhibitor). Baseline FBF and endothelium-independent vasodilatation were similar in the two groups. In obese patients, bradykinin-induced increase of FBF was significantly less than in controls ( P

Moderate alcohol (ETOH) intake has been associated with a significant reduction in risk for infarction among general populations. In this study, we assessed the effects of low-dose ETOH (40 g over 3-h period as vodka) on the interaction between glucose (G), insulin, and lactate (L) during the insulin-modified frequently sampled i.v. glucose tolerance test (FSIGT) (0.3 U/kg body weight between 20-25 min) in eight normal volunteers. In the control (C) study, water was administered. An insulin-independent two-compartment model was used to describe G and L kinetics. Insulin sensitivity (S(I)) was significantly higher in the ETOH study than in the C study (2.49 +/- 0.52 vs. 0.92 +/- 0.20 10(-4) min(-1)microU(-1)ml, C vs. ETOH; P = 0.0391). No significant differences were observed in G effectiveness (0.029 +/- 0.004 vs. 0.033 +/- 0.004 min(-1)). Blood L levels were higher during FSIGT when ETOH was administered [area under the curve (AUC), 201 plus minus 16 vs. 123 +/- 23 mmol/liter in 240 min; P = 0.0001]. The dynamic analysis of blood L concentrations showed that ETOH also significantly decreased L clearance (0.0016 +/- 0.0011 vs. 0.0029 +/- 0.0002 min(-1); P = 0.0156), whereas no difference was observed for the fractional conversion of the rate of G disappearance to L (0.0033 +/- 0.0012 vs. 0.0031 +/- 0.0005 min(-1)). ETOH decreased baseline plasma FFA concentration; AUC of FFA was markedly reduced with ETOH (65 +/- 14 vs. 109 plus minus 17 mmol/liter in 240 min; P = 0.0063) and inversely correlated with S(I) (r = 0.693; P = 0.0029). The amount of C-peptide in 240 min as well as the amounts before and after insulin administration were not different between the two tests. We concluded that G and L kinetics derived from FSIGT shows that moderate ETOH intake: 1) improves insulin action; 2) decreases L clearance; and 3) does not affect beta cell function. Because ETOH at moderate doses has a marked antilipolytic action, it might improve insulin action by improving substrate competition. The present findings suggest that moderate alcohol consumption in the diet should not be discouraged.

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 (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.

Aim. To identify the characteristics associated with multidimensional impairment, evaluated through the Multidimensional Prognostic Index (MPI), a validated predictive tool for mortality derived from a standardized Comprehensive Geriatric Assessment (CGA), in a cohort of elderly diabetic patients treated with oral hypoglycemic drugs.Methods and Results. The study population consisted of 1342 diabetic patients consecutively enrolled in 57 diabetes centers distributed throughout Italy, within the Metabolic Study. Inclusion criteria were diagnosis of type 2 diabetes mellitus (DM), 65 years old or over, and treatment with oral antidiabetic medications. Data concerning DM duration, medications for DM taken during the 3-month period before inclusion in the study, number of hypoglycemic events, and complications of DM were collected. Multidimensional impairment was assessed using the MPI evaluating functional, cognitive, and nutritional status; risk of pressure sores; comorbidity; number of drugs taken; and cohabitation status. The mean age of participants was 73.3 ± 5.5 years, and the mean MPI score was 0.22 ± 0.13. Multivariate analysis showed that advanced age, female gender, hypoglycemic events, and hospitalization for glycemic decompensation were independently associated with a worse MPI score.Conclusion. Stratification of elderly diabetic patients using the MPI might help to identify those patients at highest risk who need better-tailored treatment.

Aims The effect of metabolic control on hepatic synthesis of plasma proteins in Type 1 diabetes mellitus (T1DM), in the post-absorptive and post-prandial state, is not known. Methods We measured fractional synthetic rates (FSR) of albumin and fibrinogen in six insulin-infused T1DM patients and in five to nine control subjects, before and for approx. 4 h after a mixed liquid meal. Phenylalanine tracer precursor/product relationships and steady-state conditions were used. In the post-absorptive state, patients were studied in near euglycaemic conditions after an overnight intravenous insulin infusion. During the meal (approx. 11 kcal/kg), the insulin infusion rate was increased to maintain plasma glucose concentrations below approx. 10 mmol/l. Results Post-absorptive FSR of albumin (5.7 ± 0.6%/day) and fibrinogen (11.3 ± 0.6%/day) in T1DM were similar to control values (6.4 ± 0.9 and 13.1 ± 1.1, respectively). After the meal, albumin FSR increased (P = 0.0032 by anova) in both groups (T1DM, to 14.4 ± 2.7%/day; controls, to 18.2 ± 3.7%/day). Fibrinogen FSR also increased (P = 0.0048 by anova) in both the T1DM (to 18.2 ± 2.6) and the control subjects (to 27.3 ± 6.2). There was no difference between T1DM and control subjects in the post-prandial FSR of both proteins. Conclusions Albumin and fibrinogen FSR in T1DM can be maintained within near-normal ranges by insulin infusion under post-absorptive and post-prandial conditions. Diabet. Med. 18, 915–920 (2001)

Background Endothelial dysfunction is an early feature of atherosclerosis. The relationship between insulin action and hypertriglyceridaemia on endothelial function is still debated. Materials and Methods This study was designed to determine the effect of a 3 month treatment with Gemfibrozil (GF) on flow-mediated vasodilatation and insulin sensitivity. Ten type 2 diabetic patients were randomised in crossover, double blind fashion, either to GF, 600 mg b.i.d. or placebo, for 12 weeks. Lipid profile, low-density lipoprotein (LDL) distribution and flotation properties, insulin action and flow-mediated vasodilatation (FMD) by brachial artery ultrasound, were assessed. Results GF decreased serum triglyceride (TG) concentration with an absolute difference of 1·79 ± 1·28 mmol L−1 (P

The effect of 7 day continuous subcutaneous infusion of octreotide (200 microg day(-1)) was evaluated in seven insulin-pump treated Type 1 diabetic patients (age 43+/-1.5 year; BMI 25.1+/-0.7 kg m(-2); HbA(1c) 7.4+/-0.3%). A 24-h metabolic and hormonal profile, and a euglycaemic hyperinsulinaemic clamp (0.25, 0.5, 1.0 mg kg(-1) min(-1)), with [3H]glucose infusion and indirect calorimetry, were performed before and after a 7-day octreotide infusion. Mean 24-h plasma glucose was similar before and after octreotide (9.7+/-0.8 vs. 9.1+/-1.0 mmol l(-1)) but insulin requirement dropped by 45% (49+/-4 vs. 27+/-2 U day(-1); P0.01). Both 24-h plasma hGH and glucagon were suppressed by octreotide (1.85+/-0.35 vs. 0.52+/-0.04 microg l(-1), and 117+/-23 vs. 102+/-14 ng l(-1), respectively). Glucose utilisation increased after octreotide (insulin 0.5 mU kg(-1) min(-1) clamp 3.09+/-0.23 vs. 4.19+/-0.19 mg kg(-1) min(-1); 1 mU kg(-1) min(-1) clamp 5.64+/-0.61 vs. 7.93+/-0.57 mg kg(-1) min(-1); both P0.05) and endogenous glucose production was similarly suppressed. Glucose oxidation was not affected by octreotide, while the improvement in glucose storage (insulin 1.0 mU kg(-1) min(-1) clamp 3.89+/-0.60 vs. 5.64+/-0.67 mg kg(-1) min(-1), P0.05) entirely accounted for the increase in glucose disposal. Endogenous glucose production was more effectively suppressed at the two lower insulin infusion rates (P0.05). Energy expenditure declined after octreotide. Continuous subcutaneous octreotide infusion suppresses counterregulatory hormones, increases insulin-mediated glucose metabolism by enhancing glucose storage, and reduces energy expenditure. These results support a role for counterregulatory hormones in the genesis of insulin resistance and the catabolic state of Type 1 diabetes.

Type 2 diabetes is a heterogeneous disorder characterized by defects in insulin secretion and action. Insulin resistance is a key feature of type 2 diabetes. However, insulin resistance alone does not appear to be sufficient to cause diabetes. Longitudinal studies have shown that the development of overt hyperglycemia is associated with a decline in beta-cell secretion. In patients with impaired glucose tolerance or in the early stages of type 2 diabetes, first-phase insulin release is almost invariably lost despite the enhancement of second-phase secretion. Both animal and human studies support the critical physiologic role of the first-phase of insulin secretion in the maintenance of postmeal glucose homeostasis. This effect is primarily mediated at the level of the liver, allowing prompt inhibition of endogenous glucose production (EGP) and thereby restraining the mealtime rise in plasma glucose. In type 2 diabetes, the loss of the early surge of insulin release is a precocious and quite common defect that plays a pathogenic role in postmeal hyperglycemia and one that may require specific therapeutic intervention. This becomes even more apparent if the negative impact of prandial glucose spikes is taken into consideration. Epidemiological evidence exists to indicate that 2-h postload plasma glucose levels are strongly associated with all-cause and cardiovascular mortality relative risk. Indeed the acute elevation of plasma glucose concentration triggers an array of tissue responses that may contribute to the development of diabetic complications. Considering that type 2 diabetes begins with meal-related hyperglycemia in many patients, it becomes apparent that normalization of postmeal plasma glucose levels should be the target for rational therapy and the goal in the early stages of the disease. If a primary goal of diabetes therapy is control of postmeal glucose excursion, then the regulation of glucose absorption from the gut and entry into the circulation is an important mechanism to consider. The restoration of the rapid increase in plasma insulin concentration may be quite an efficient therapeutic approach.

OBJECTIVE Vasculoprotective endothelial progenitor cells (EPCs) are regulated by stromal-derived factor-1α (SDF-1α) and are reduced in type 2 diabetes. Because SDF-1α 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-1α, 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-1α and a decrease in MCP-1. CONCLUSIONS Sitagliptin increases circulating EPCs in type 2 diabetic patients with concomitant upregulation of SDF-1α. This ancillary effect of DPP-4 inhibition might have potential favorable cardiovascular implications.

An extrapancreatic effect of sulfonylureas has been postulated. However, in vivo results have been disputed because the amelioration of insulin action that follows sulfonylurea may represent the relief from glucose toxicity rather than a direct effect of the drug. Therefore, we studied the hypoglycemic action of gliclazide acutely and after 2 months of therapy in seven type 2 diabetic patients. All patients received a 240-minute IV glucose infusion with [3-3H]glucose. In a random order, 160 mg gliclazide (study 1) or placebo (study2) was given orally before glucose infusion. Finally, the effect of 160 mg gliclazide was reassessed after a two-month treatment with the same sulfonylurea (80 mg t. i. d.). Basal plasma glucose, insulin, C-peptide and endogenous glucose production (EGP) were similar before the two initial studies. During glucose infusion, EGP was more suppressed after gliclazide in spite of comparable increase in plasma insulin and C-peptide. After the two-month therapy, basal plasma glucose levels and HbA1c were lower while plasma insulin and C-peptide were higher with respect to baseline (p < 0.05). Gliclazide further reduced plasma glucose, the incremental area above baseline, and EGP during glucose infusion, while plasma insulin and C-peptide achieved higher plateaus (p < 0.05). When data were pooled, plasma glucose concentration and EGP correlated both in the basal state (r = 0.71) and during the last hour of glucose infusion (r = 0.84; both p < 0.05). These data suggest that gliclazide enhances the suppression of EGP induced by insulin and that this effect is greater with chronic treatment because of concomitant improvement of insulin secretion.

We assessed the efficacy of gemfibrozil therapy on lipid profile and glucose metabolism in a large cohort of (type 2) non-insulin-dependent diabetic patients. We enrolled 217 type 2 diabetic patients with plasma triglyceride concentrations equal to or above 2 mmol/l: 110 were randomized to gemfibrozil (600 mg twice daily) and 107 to placebo treatment in a double blind fashion. Each treatment was followed for 20 weeks. To assess postprandial glucose metabolism and insulin secretion, at time 0 and 20 weeks, a standard meal containing 12.5 g of proteins, 40.1 g of carbohydrate, 10 g of lipids was given. No differences in demographic characteristics were observed between patients randomized either to gemfibrozil or to placebo therapy. No differences were observed in total cholesterol and LDL-cholesterol concentration changes between the baseline observations and week 20 of both treatments. At variance, both treatments significantly increased HDL cholesterol. Gemfibrozil treatment significantly decreased plasma triglyceride concentration from 316±84 to 214±82 mg/dl (P < 0.001), whereas with placebo triglyceride levels increased from 318 + 93 to 380 + 217 mg/dl. No changes were observed in non-esterified fatty acid concentrations or in fasting plasma glucose concentrations, in HbA1C values, insulin and C-peptide concentrations. Gemfibrozil treatment: 1) significantly reduces circulating triglyceride concentration; 2) does not significantly affect cholesterol concentration; 3) does not worsen glucose metabolism.

An unexplained paradox puzzles diabetologists: diabetic patients must face both poor vessel growth in ischemic heart and limbs and increased angiogenesis in retinal complications (1,2). Endothelial progenitor cells (EPCs) are marrow-derived cells involved in adult neovascularization and endothelial homeostasis (3,4). It has been postulated that low EPCs in peripheral blood may have a role in cardiovascular disease, and we have demonstrated that EPCs are reduced in macrovascular diabetes complications (5,6). On the other hand, an excess of EPCs may be involved in pathologic neoangiogenesis of cancer and proliferative retinopathy (7,8). Therefore, diabetes complications may be associated with both decreased and increased EPCs. Recently, novel therapeutic approaches have been directed to enrich the EPC pool in ischemic diseases and to block EPC function in proliferative diseases (9,10). These approaches in diabetic subjects require cautious evaluation of the implications carried by the paradox and new studies to unravel its causes (11,12). This study was carried out to investigate the contemporaneous effects of retinal and peripheral vascular complications on circulating progenitor cells. Ethics committee approval was obtained, and after giving informed consent, 60 type 2 diabetic patients were prospectively included. Patients were characterized in terms of peripheral arterial disease (PAD) and diabetic retinopathy (DR) as the most representative complications at the two extremities of the diabetic paradox. PAD was diagnosed by minimal criteria (including history of claudication or rest pain, pulse examination, ankle-brachial indexes, and ultrasonography) and eventually confirmed by angiography. Diabetic retinopathy (severe nonproliferative or proliferative) was defined by a dilated and comprehensive eye examination and acquisition of high-quality stereoscopic photographs by …

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

Glucagon stimulates in vitro liver phenylalanine (Phe) degradation, thus inducing net protein catabolism. Whether these effects occur also in vivo in humans is not known. Therefore, we studied the effects of physiological hyperglucagonemia on Phe rate of appearance (Ra), hydroxylation, and oxidation in seven normal volunteers during infusions of somatostatin with replacement doses of insulin and growth hormone. Steady-state Phe kinetics were evaluated using the L-[1-14C]Phe tracer both at the end of a 3-h basal glucagon replacement period (glucagon concentration: 212 +/- 115 ng/l) and after a 3-h hormone infusion at the rate of approximately 3 ng x kg-1 x min-1 (--> 654 +/- 280 ng/l). Hyperglucagonemia did not change plasma Phe concentration and Ra but increased Phe oxidation by approximately 30% (P < 0.01). Oxidation was also increased by approximately 24% (P < 0.01) using plasma [14C]tyrosine (Tyr) specific activity as a precursor pool. Phe hydroxylation to Tyr estimated by assuming a fixed ratio of Tyr to Phe Ra (0.73) did not change. Nonhydroxylated Phe disposal decreased by approximately 6% (P = 0.08). These data show that in humans in the postabsorptive state, hyperglucagonemia, with near maintenance of basal insulin and growth hormone concentrations, stimulates Phe oxidation but not Phe hydroxylation, suggesting a different regulation of these two Phe catabolic steps. Glucagon may also reduce Phe availability for protein synthesis.

Microalbuminuria predicts early mortality and renal disease in non-insulin-dependent diabetic patients. In insulin-dependent diabetic patients, angiotensin converting enzyme inhibition decreases microalbuminuria and retards the progression of renal disease. The aim of this study was to evaluate the effect of low dose ramipril on albumin excretion rate (AER) and blood pressure in non-insulin-dependent diabetic patients with persistent microalbuminuria (AER > 20 P

We assessed the effect of hyperglycemia on glucose uptake in the presence of normal basal insulin levels or somatostatin-induced hypoinsulinemia in seven normal volunteers during a 200-min hyperglycemic clamp (+ 9 mmol/l) carried out with [3-3H]glucose and indirect calorimetry. Hyperglycemia increased glucose uptake to 22.4 +/- 2.6 and 21.3 +/- 1.6 mumol.kg-1.min-1 with and without insulin replacement, respectively. Normoinsulinemia increased glucose oxidation (delta = + 4.5 +/- 0.6 mumol.kg-1.min-1) and nonoxidative glucose metabolism (delta = + 5.2 +/- 1.7 mumol.kg-1.min-1), whereas with insulinopenia, glucose oxidation did not change (delta = -0.3 +/- 0.6 mumol.kg-1.min-1), and nonoxidative glucose metabolism increased (delta = + 48.7 +/- 0.8 mumol.kg-1.min-1). Nonoxidative glucose metabolism was higher during insulinopenic (13.5 +/- 1.8 mumol.kg-1.min-1) than normoinsulinemic hyperglycemia (9.8 +/- 2.7 mumol.kg-1.min-1; P < 0.01). Plasma FFA concentration and lipid oxidation were higher with insulinopenia. Blood lactate and alanine concentrations were greater with normoinsulinemia. In conclusion: 1) hyperglycemia promotes glucose uptake by stimulating both nonoxidative and oxidative glucose disposal; 2) the ability of hyperglycemia to enhance total body glucose uptake is similar with and without normoinsulinemia; 3) although acute insulinopenia does not impair the ability of hyperglycemia to stimulate glucose uptake, it plays a critical role in determining the intracellular metabolic fate of glucose taken up in response to hyperglycemia.

To investigate body protein turnover and the pathogenesis of increased concentration of plasma phenylalanine in liver cirrhosis, we have studied phenylalanine and leucine kinetics in cirrhotic (diabetic and nondiabetic) patients, and in normal subjects, both in the postabsorptive state and during a mixed meal, using combined intravenous and oral isotope infusions. Postabsorptive phenylalanine concentration and whole body rate of appearance (Ra) were approximately 40% greater (P < 0.05) in patients than in controls. Leucine concentrations were comparable, but intracellular leucine Ra was also increased (P < 0.05), suggesting increased whole body protein breakdown. Postprandial phenylalanine Ra was also greater (P < 0.05) in the patients. This difference was due to a diminished fractional splanchnic uptake of the dietary phenylalanine (approximately 40% lower in the cirrhotics vs. controls, P < or = 0.05). Postprandial leucine Ra was also increased in the patients, but splanchnic uptake of dietary leucine was normal. Thus both increased body protein breakdown and decreased splanchnic extraction of dietary phenylalanine can account for the increased phenylalanine concentrations in liver cirrhosis.

Aims: In diabetes, endothelial damage promotes macroangiopathy and endothelial regeneration is impaired, owing to reduced endothelial progenitor cells (EPCs). Given that insulin influences endothelial biology, we compared the effects of add-on basal insulin analogues on endothelial damage and regeneration in type 2 diabetes (T2D). Methods: This was a 6-month randomized crossover trial comparing add-on insulin detemir versus glargine in poorly controlled T2D with macroangiopathy. At baseline, crossover (3 months) and study end (6 months), we measured HbA1c, EPCs, circulating endothelial cells (CECs), VCAM-1, ICAM-1 and E-selectin. Body weight and hypoglycaemic episodes were also recorded. Results: Forty-two patients completed the study, randomly assigned to the glargine–detemir (n = 21) or the detemir–glargine (n = 21) schedule. At crossover, EPC levels did not change compared with baseline, but significantly increased at study end. CECs decreased over time and were significantly reduced at study end. ICAM-1, VCAM-1 and E-selectin were significantly reduced at crossover and further decreased at study end. No differences were seen in these effects between detemir and glargine. HbA1c showed a carryover effect and its reduction was similar with detemir and glargine in the first arm. Incidence of hypoglycaemia and weight gain was lower with detemir than with glargine in both arms. Conclusion: Optimized glycaemic control by add-on basal insulin improved indexes of endothelial damage and regeneration. Compared to glargine, detemir achieved similar endothelial protection with lower weight gain and less hypoglycaemia. These results might have implications for therapy of aging T2D patients with cardiovascular disease.

Although insulin resistance in T2DM (type 2 diabetes mellitus) is usually referred to glucose and lipid metabolism, the question whether such a resistance affects also amino acid and protein metabolism is both relevant and not easy to be answered. Available data indicate a reduced response to insulin in the inhibition of proteolysis at low, near basal hormone levels, whereas such a response appears to be normal at high physiological doses. In most studies in T2DM subjects the stimulation of whole-body protein synthesis in the presence of hyperinsulinemia and euaminoacidemia appears to be normal, although one single study reported lower rates in male T2DM subjects with obesity. The response to insulin of plasma protein synthesis (albumin and fibrinogen) is also normal. However, some metabolic steps of amino acids related to vascular complications (methionine and arginine) exhibit a defective response to insulin in T2DM subjects with nephropathy. In summary, although gross alterations in the response of whole-body protein turnover are not evident in T2DM, specific investigations reveal subtle abnormalities in metabolic steps of selected amino acids. Furthermore, the effects of interaction between diabetes (with the associated insulin resistance) and older age in the pathogenesis of sarcopenia in the elderly deserve more specific studies.

Introduction: The prevalence of patients with 'borderline' levels of cardiovascular risk factors has been rarely investigated, being often reported in studies evaluating abnormal values of these parameters. The BORDERLINE study represents a pilot experience to primarily identify the prevalence of 'high-normal' conditions, such as pre-hypertension, lipid and glucose levels in the upper range of normality in the setting of general practice in Italy. Aim: The aim of this study was to evaluate the prevalence of patients with 'borderline' values of cardiovascular risk factors in Italy. Methods: Involved physicians were asked to evaluate the first 20 outpatients, consecutively seen in June 2009. Data were collected in a study-designed case-report form, in which physicians identified thresholds rather than reported absolute values of several clinical parameters. High-normal values were defined as follows: blood pressure (BP) 130-140/85-90 mmHg; total cholesterol 180-200 mg/dL; low-density lipoprotein cholesterol (LDL-C) 130-150 mg/dL; high-density lipoprotein cholesterol (HDL-C) 30-40 mg/dL in males and 40-50 mg/dL in females; triglycerides 130-150 mg/dL and fasting glucose 100-110 mg/dL. Results: Fifty-three Italian physicians provided valuable clinical data on 826 individual outpatients, among which 692 (83.7%, 377 women, mean age 60.9 ± 13.2 years, body mass index 26.6 ± 5.0 kg/m 2) were included in the present analysis. Prevalence of borderline values of systolic BP and total cholesterol levels were at least comparable with those in the normal limits of the corresponding parameters, whereas prevalence of borderline diastolic BP, LDL-C, HDL-C, triglycerides and fasting glucose levels was significantly lower than that of normal values, but higher than that of abnormal values of the corresponding parameters. Conclusions: Using this sample of healthy subjects in the setting of general practice in Italy, our results demonstrated a relatively high prevalence of borderline values of cardiovascular risk factors, which was at least comparable with that of normal, but significantly higher than that of abnormal thresholds. These preliminary findings may prompt more extensive investigations in the area of 'borderline' cardiovascular risk. This information may, in fact, potentially enable the design of more effective prevention strategies in the future to limit the burden of cardiovascular disease in the general population in Italy. © 2011 Adis Data Information BV. All rights reserved.

Rationale: Acquisition of a procalcific phenotype by resident or circulating cells is important for calcification of atherosclerotic plaques, which is common in diabetes. Objective: We aim to identify and characterize circulating calcifying cells, and to delineate a pathophysiological role for these cells in type 2 diabetes. Methods and Results: We demonstrate for the first time that a distinct subpopulation of circulating cells expressing osteocalcin and bone alkaline phosphatase (OC + BAP + ) has procalcific activity in vitro and in vivo. The study of naïve patients with chronic myeloid leukemia indicated that OC + BAP + cells have a myeloid origin. Myeloid calcifying OC + BAP + cells (MCCs) could be differentiated from peripheral blood mononuclear cells, and generation of MCCs was closely associated with expression of the osteogenic transcription factor Runx2. In gender-mismatched bone marrow–transplanted humans, circulating MCCs had a much longer half-life compared with OC − BAP − cells, suggesting they belong to a stable cell repertoire. The percentage of MCCs was higher in peripheral blood and bone marrow of type 2 diabetic patients compared with controls but was lowered toward normal levels by optimization of glycemic control. Furthermore, diabetic carotid endoarterectomy specimens showed higher degree of calcification and amounts of cells expressing OC and BAP in the α-smooth muscle actin–negative areas surrounding calcified nodules, where CD68 + macrophages colocalize. High glucose increased calcification by MCCs in vitro, and hypoxia may regulate MCC generation in vitro and in vivo. Conclusions: These data identify a novel type of blood-derived procalcific cells potentially involved in atherosclerotic calcification of diabetic patients.

In this study, we assessed the effects of alcohol intake on glucose counterregulation in response to acute insulin-induced hypoglycemia in IDDM patients and in normal control subjects. Nine euglycemic IDDM patients and 9 normal control subjects were studied. After a baseline period, insulin (0.15 U/kg) was administered subcutaneously to induce hypoglycemia. Each IDDM patient was studied 3 times. In the first study, alcohol was orally administered as wine. In the second (control) study, water was administered instead of wine. In the third study, wine was given; however, a continuous infusion of heparin plus intralipid was administered to prevent the fall in plasma free fatty acid. Normal control subjects underwent only the alcohol and the control studies. In IDDM patients alcohol intake impairs, whereas in normal subjects it supports glucose counterregulation. Alcohol intake is associated with normal catecholamine responses in both IDDM diabetic patients and normal subjects. In both IDDM patients and normal subjects, hepatic glucose production in the recovery phase of the alcohol study was normal. Plasma glucose rate of disappearance was significantly increased by alcohol intake in IDDM (13.72 ± 0.82 vs. 11.84 ± 0.53 μmol · kg−1 · min−1; P < 0.05). Alcohol intake in both normal subjects and IDDM patients decreased plasma free fatty acid (267 ± 22 vs. 156 ± 20 μM; P < 0.01 and 356 ± 29 vs. 96 ± 12 μM; P < 0.01). We hypothesized that in IDDM patients, deficient glucose recovery during alcohol intake is the result of the ability of alcohol to depress lipolysis.

The effects of two different plasma glucose concentrations (5 and 10 mmol/L) on lipolysis and ketogenesis during baseline and in response to epinephrine infusion were evaluated in insulin-dependent diabetic patients. Each insulin-dependent diabetic subject was studied during euglycemia, hyperglycemia with hypoinsulinemia, and hyperglycemia with hyperinsulinemia. Total ketone body (TKB) concentrations were significantly higher in hyperglycemic-hypoinsulinemic diabetics than in hyperglycemic-hyperinsulinemic and normoglycemic diabetics. Hyperglycemic-hyperinsulinemics had higher TKB concentrations than euglycemic diabetics. During epinephrine infusion, the ketone body rate of appearance and concentration significantly increased in all groups. Plasma FFA concentrations were significantly higher in hyperglycemic-hypoinsulinemic diabetics than in the other groups. During epinephrine infusion, the plasma FFA rate of appearance and concentration significantly increased in all groups. The apparent fraction of FFA converted to ketones was increased by epinephrine in all groups, except in hyperglycemic-hyperinsulinemic diabetics. In conclusion, this study demonstrates that although insulin alone decreases FFA and TKB concentrations, it does not affect the fraction of FFA converted to ketones. If hyperinsulinemia is superimposed on hyperglycemia, there is both a reduction of ketogenesis capacity, compared to hyperglycemia alone, and a decrease in the apparent fraction of FFA converted to ketone bodies.

New effort has been made to develop closed-loop glucose control, using subcutaneous (SC) glucose sensing and continuous subcutaneous insulin infusion (CSII) from a pump, and a control algorithm. An approach based on a model predictive control (MPC) algorithm has been utilized during closed-loop control in type 1 diabetes patients. Here we describe the preliminary clinical experience with this approach. In Padova, two out of three subjects showed better performance with the closed-loop system compared to open loop. Altogether, mean overnight plasma glucose (PG) levels were 134 versus 111 mg/dl during open loop versus closed loop, respectively. The percentage of time spent at PG > 140 mg/dl was 45% versus 12%, while postbreakfast mean PG was 165 versus 156 mg/dl during open loop versus closed loop, respectively. Also, in Montpellier, two patients out of three showed a better glucose control during closed-loop trials. Avoidance of nocturnal hypoglycemic excursions was a clear benefit during algorithm-guided insulin delivery in all cases. This preliminary set of studies demonstrates that closed-loop control based entirely on SC glucose sensing and insulin delivery is feasible and can be applied to improve glucose control in patients with type 1 diabetes, although the algorithm needs to be further improved to achieve better glycemic control. Six type 1 diabetes patients (three in each of two clinical investigation centers in Padova and Montpellier), using CSII, aged 36 ± 8 and 48 ± 6 years, duration of diabetes 12 ± 8 and 29 ± 4 years, hemoglobin A1c 7.4% ± 0.1% and 7.3% ± 0.3%, body mass index 23.2 ± 0.3 and 28.4 ± 2.2 kg/m2, respectively, were studied on two occasions during 22 h overnight hospital admissions 2–4 weeks apart. A Freestyle Navigator® continuous glucose monitor and an OmniPod® insulin pump were applied in each trial. Admission 1 used open-loop control, while admission 2 employed closed-loop control using our MPC algorithm.

Cardiovascular diseases still represent the leading cause of mortality and hospitalization, worldwide. As a consequence of the marked demographic changes observed in the general population, the improved survival rate after an acute cardiovascular event and the progressive rise of costs (mostly due to technological and pharmacological innovations), the estimated burden of cardiovascular diseases will be soon become insurmountable for national healthcare systems. In this view, an integrated approach aimed at improving strategies for cardiovascular disease prevention and, thus, limiting the negative outcomes, would probably be successful. Such an approach may not only achieve long-term benefits, but even significant advantages in the short to medium term, mostly in asymptomatic high-risk individuals. Indeed, this latter population of asymptomatic high-risk individuals would mostly benefit from extensive application and improvement of strategies for cardiovascular disease prevention with a favourable cost-benefit ratio. The Italian Society for Cardiovascular Disease Prevention — Societa Italiana per la Prevenzione Cardiovascolare (SIPREC) — has recognized this strategic aim, focusing a significant part of its institutional actions on the effort for providing educational supports and consensus documents, which represent an overview of the scientific knowledge and personal clinical expertise by national and international key opinion leaders. Expert committees periodically generate ‘state-of-the-art’ documents on specific scientific topics with relevant socioeconomic implications and large clinical impact. The present article is dedicated to healthcare professionals, is based on the available evidence, and provides information on diagnostic algorithms and therapeutic options on abnormal glucose regulation (or dysglycaemia). The relationship between abnormalities in glucose metabolism and cardiovascular complications represents an important and relatively early target for cardiovascular disease prevention. SIPREC identified, even in this clinical setting, a group of scientific experts in order to form a multidisciplinary ‘task force’. This group has been asked to explain in a short, simple and effective fashion the epidemiological impact and the pathophysiological nature of the problem, its clinical features, potential diagnostic algorithms and therapeutic options, and its influence on the clinical practice of both specialist physicians and general practitioners. This work provides the background for discussing novel future strategies for cardiovascular prevention. It is also aimed at highlighting the importance of an emerging marker of cardiovascular risk, which is often not recognized and underestimated.

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.