Polypharmacy in elderly patients with type 2 diabetes receiving oral antidiabetic treatment.

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(2). 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.

Widespread increase in myeloid calcifying cells contributes to ectopic vascular calcification in type 2 diabetes.

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.

The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha.

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.

Time course and mechanisms of circulating progenitor cell reduction in the natural history of type 2 diabetes.

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 >or=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 >or=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.

Low CD34+ cell count and metabolic syndrome synergistically increase the risk of adverse outcomes.

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.

Why to screen heart disease in diabetes.

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.

A stepwise approach to assess the impact of clustering cardiometabolic risk factors on carotid intima-media thickness: the metabolic syndrome no-more-than-additive.

BACKGROUND: Cardiovascular risk factors cluster in the metabolic syndrome (MS), but it is not known whether the risk associated with the syndrome is higher than the sum of its parts. In this study, we explored the relationship between clustering cardiometabolic risk factors and carotid intima-media thickness (c-IMT). METHODS AND RESULTS: Cardiovascular parameters and c-IMT were determined in 240 middle-aged healthy participants, divided into groups according to their number of MS components. Higher number of MS components were associated with higher mean c-IMT. Analysis of synergy revealed that c-IMT increase at component clustering fitted an additive model. Redefinition of cutpoints for MS traits, optimized to detect high c-IMT, did not improve the interaction between components. When metabolic factors were rendered independent, a synergistic interaction between factors in increasing the likelihood of having a high c-IMT was detected. Synergic as well was the interaction between metabolic factors with other risk factors that are not consequence of insulin resistance, such as low-density lipoprotein-cholesterol level and smoking habit. CONCLUSION: A stepwise approach reveals that the lack of synergy in the interactions between MS components is attributable to their mutual interdependence, possibly owing to the common pathophysiological background. Indeed, if MS is a unique clinical entity, it should be no more than the sum of its parts.

Insulin generates free radicals in human fibroblasts ex vivo by a protein kinase C-dependent mechanism, which is inhibited by pravastatin.

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.

Early myocardial dysfunction in the diabetic heart: current research and clinical applications.

Patients with diabetes mellitus have a high incidence of heart failure, which contributes significantly to their increased cardiovascular morbidity and mortality. One of the major complications of diabetes is the development of cardiomyopathy, a condition characterized by defects of contractile function in the absence of significant coronary artery disease or systemic hypertension. Experimental data in animal models show that contractile depression begins as early as 1 week after induction of diabetes, and the dysfunction is related to an isomyosin distribution shift from V(1) with high adenosine triphosphatase (ATPase) to V(3) with low ATPase activity. Moreover, diabetes is associated with an increased or poorly regulated rate of amino acid catabolism at the cardiac level. Abnormal responses to acute left ventricular (LV) overload induced by exercise (isometric or isotonic) have been demonstrated in patients with diabetes. Impaired augmentation of LV ejection fraction occurs in up to 40% of patients with diabetes. Analysis of the LV afterload-pump function (LV circumferential wall stress-ejection fraction) relationship shows that defective contractile recruitment is the main cause of this anomaly. Exercise-induced LV dysfunction may be the first manifestation of cardiac involvement in patients with diabetes. Increasing the supply of amino acids in addition to conventional therapy significantly attenuates this phenomenon. Although the precise underlying pathophysiologic mechanism is not completely known, these observations may eventually be important in designing an optimal dietary or supplemental approach for patients with diabetes in order to prevent progressive myocardial dysfunction.

PC-1 amino acid variant Q121 is associated with a lower glomerular filtration rate in type 2 diabetic patients with abnormal albumin excretion rates.

OBJECTIVE: To study the relationships between the PC-1 K121Q variant and diabetic nephropathy (DN) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 125 patients with type 2 diabetes and abnormal albumin excretion rate (AER) (range 20-5416 microg/min) were followed up for 4 years with repeated measurements of glomerular filtration rate (GFR). Genomic DNA was extracted from all patients, and the PC-1 K121Q polymorphism was determined by the PCR AvaII restriction enzyme. A subset of 64 patients underwent a percutaneous kidney biopsy at baseline, and glomerular structure was analyzed by electron microscopic morphometric analysis. At baseline, age (56 +/- 8 vs. 59 +/- 7 years), BMI (28.3 +/- 4.3 vs. 28.6 +/- 3.7 kg/m(2)), known duration of type 2 diabetes (11.1 +/- 7 vs. 11.9 +/- 8 years), and HbA(1c) (8.6 +/- 1.8 vs. 8.4 +/- 1.7%) were similar in K121K (KK, n = 87, 73 men/14 women) and XQ (35 K121Q + 3 Q121Q, n = 38, 27 men/11 women) patients. Baseline GFR was 96 +/- 28 ml. min(-1). 1.73 m(-2) and was related (P = 0.01-0.001) to age, known diabetes duration, and systolic blood pressure. RESULTS: XQ patients had lower GFR (P < 0.05) than KK patients (88 +/- 30 vs. 100 +/- 26 ml. min(-1). 1.73 m(-2)); this difference persisted also after factoring in age and known diabetes duration. The rate of progression of DN was similar in KK and XQ patients: %deltaGFR was 4.1/year (median, range: 22.9-30.6) vs. 4.2/year (9.8-26.7). Morphometric parameters of diabetic glomerulopathy were similar in the two genotype groups. CONCLUSIONS: Among patients with type 2 diabetes with abnormal AER, those carrying the Q PC-1 genotype have more severe DN but not a faster GFR decline than KK patients, thus suggesting faster DN development since diabetes diagnosis in XQ patients.

Concomitance of diabetic retinopathy and proteinuria accelerates the rate of decline of kidney function in type 2 diabetic patients.

OBJECTIVE: To evaluate the rate of progression of renal disease in proteinuric type 2 diabetic patients with and without retinopathy. RESEARCH DESIGN AND METHODS: Thirty-eight proteinuric type 2 diabetic patients with diabetic retinopathy and 27 without were enrolled in an observational study for the evaluation of rate of glomerular filtration rate (GFR) decline and followed up for a median period of 6 years. GFR was determined at least once per year, and blood pressure, glycated hemoglobin, and proteinuria were determined every 4 months. RESULTS: Although the two groups had comparable GFR, albuminuria, blood pressure, and HbA(1c) at entry of the study, the rate of decline of GFR was higher in type 2 diabetic patients with retinopathy (-6.5 +/- 4.4 ml/year) than in those without (-1.8 +/- 4.8 ml/year; P < 0.0001). Protein and albumin excretion rate increased significantly in patients with retinopathy, while they did not change in those without. Mean blood pressure between the two groups of patients were similar both at entry and during the follow-up, although the proportion of patients treated with at least two antihypertensive drugs was higher in patients with retinopathy. On a multiple regression analysis, only mean blood pressure and proteinuria were significant determinants of progression of renal disease in type 2 diabetic patients with retinopathy. CONCLUSIONS: The rate of progression of renal disease in proteinuric type 2 diabetic patients with retinopathy is faster than that observed in those without retinopathy. The screening for retinopathy identifies patients at high risk for rapid deterioration of kidney function.

Putative pancreatic cancer-associated diabetogenic factor: 2030 MW peptide.

INTRODUCTION: Pancreatic adenocarcinoma causes diabetes mellitus by releasing factors interfering with glucose metabolism. AIMS: We verified in isolated rat hepatocytes the molecular weight (MW) of the fraction from pancreatic cancer cell conditioned media (CM) that altered glucose metabolism and ascertained, using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) analysis, whether there is any common peptide in CM and in the sera of patients with pancreatic cancer. METHODOLOGY: Sera was obtained from patients with pancreatic cancer ( n = 14) and chronic pancreatitis ( n = 9) and healthy control subjects ( n = 10). Conditioned medium (CM) was obtained from the following cell lines: MIA PaCa 2, PSK-1, PANC-1, and CAPAN-1. Two fractions (MW of less than 30,000 Da and less than 10,000 Da) were obtained from patients' sera, from CM, and from non-CM (NCM) after two-step ultrafiltration. Rat hepatocytes were incubated with CM and NCM. The peptide profile of patients' sera, CM, and NCM were analyzed using MALDI-MS. RESULTS: In rat hepatocytes, glucose metabolism was impaired by CM from all the pancreatic cancer cell lines and by CM with an MW of less than 10,000 Da. Two peptides (m/z 2030 and 2726) were found in CM and patients' sera. Only the peptide at m/z 2030 was found to be associated with the presence of diabetes. CONCLUSION: A peptide at m/z 2030 may be a putative pancreatic cancer-associated diabetogenic factor.