Diabetes mellitus is a chronic disease characterized by high social, economic and health burden, mostly due to the high incidence and morbidity of diabetes complications. Numerous studies have shown ...that optimizing metabolic control may reduce the risk of micro and macrovascular complications related to the disease, and the algorithms suggest that an appropriate and timely step of care intensification should be proposed after 3 months from the failure to achieve metabolic goals. Nonetheless, many population studies show that glycemic control in diabetic patients is often inadequate. The phenomenon of clinical inertia in diabetology, defined as the failure to start a therapy or its intensification/de-intensification when appropriate, has been studied for almost 20 years, and it is not limited to diabetes care, but also affects other specialties. In the present manuscript, we have documented the issue of inertia in its complexity, assessing its dimensions, its epidemiological weight, and its burden over the effectiveness of care. Our main goal is the identification of the causes of clinical inertia in diabetology, and the quantification of its social and health-related consequences through the adoption of appropriate indicators, in an effort to advance possible solutions and proposals to fight and possibly overcome clinical inertia, thus improving health outcomes and quality of care. Keywords: Clinical inertia, Diabetes care, Italian association of medical diabetologists, Therapeutic inertia, Type 2 diabetes mellitus
Background
The pharmacological stimulation of GLP-1 receptors is associated with an increase in heart rate. A pooled analysis of patient-level data from phase III trials with albiglutide revealed a ...significant increase in the risk of atrial fibrillation. Aim of the present meta-analysis is to summarize all available evidence on the effects of individual GLP-1 receptor agonists (RA), and of the whole class, on the incidence of atrial fibrillation.
Methods
A Medline search for GLP-1 RA (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration ≥12 weeks, enrolling patients with type 2 diabetes and comparing a GLP-1 RA with placebo or any other non-GLP-1 RA drug.
Results
Of the 113 trials fulfilling the inclusion criteria, 19 did not report information on atrial fibrillation, whereas 63 reported zero events in all treatment groups. In the remaining trials (enrolling 17,966 and 15,305 patients in GLP-1 RA and comparator arms, respectively, 55.3% women, with a mean age of 57.0 ± 3.8 years), treatment with GLP-1 RA was not associated with a significant increase in the incidence of atrial fibrillation Mantel–Haenszel OR (95% CI) 0.87 (0.71–1.05),
p
= 0.15.
Conclusions
In conclusion, available data suggest that GLP-1 RA is not associated with atrial fibrillation, with the only possible exception of albiglutide. Newly onset atrial fibrillation deserves to be investigated as an event of special interest in future trials with GLP-1 RA.
A state of subclinical systemic inflammation is characteristically present in obesity/insulin resistance and type 2 diabetes mellitus (T2DM). The aim of the study was to develop an integrated measure ...of the circulating cytokines involved in the subclinical systemic inflammation and evaluate its relation with whole-body insulin sensitivity and glucose metabolism in T2DM. T2DM patients (
n
= 17, M/F 13/4, age = 55.0 ± 1.7 years, BMI = 33.5 ± 1.5 kg/m
2
, HbA
1c
= 7.7 ± 0.3 %) and normal glucose-tolerant (NGT) subjects (
n
= 15, M/F 7/8, age = 49.1 ± 2.5 years, BMI = 31.8 ± 1.2 kg/m
2
, HbA
1c
= 5.6 ± 0.1 %) were studied in a cross-sectional design. Whole-body insulin sensitivity was quantified by the euglycemic clamp. Beta-cell function disposition index (DI) was calculated using insulin and glucose values derived from an oral glucose tolerance test and the euglycemic clamp. Body fat mass was evaluated by dual-energy X-ray absorptiometry. Plasma cytokine TNF-α, IL-6, MCP-1, osteopontin, fractalkine and adiponectin values were divided into quintiles. A score ranging from 0 (lowest quintile) to 4 (highest quintile) was assigned. The inflammatory score (IS) was the sum of each cytokine score from which adiponectin score was subtracted in each study subject. Inflammatory cytokine levels were all higher in T2DM. IS was higher in T2DM as compared to NGT (10.0 ± 1.1 vs. 4.8 ± 0.8;
p
< 0.001). IS positively correlated with fasting plasma glucose (
r
= 0.638,
p
< 0.001), 1-h plasma glucose (
r
= 0.483,
p
= 0.005), 2-h plasma glucose (
r
= 0.611,
p
< 0.001) and HbA1c (
r
= 0.469,
p
= 0.007). IS was inversely correlated with insulin sensitivity (
r
= −0.478,
p
= 0.006) and DI (
r
= −0.523,
p
= 0.002). IS did not correlate with BMI and body fat mass. IS was an independent predictor of fasting plasma glucose and had a high sensibility and sensitivity to predict insulin resistance (
M/I
< 4). A state of subclinical inflammation defined and quantifiable by inflammatory score including TNF-α, IL-6, MCP-1, osteopontin, fractalkine and adiponectin is associated with both hyperglycemia and whole-body insulin resistance in T2DM.
Background
Nonalcoholic fatty liver disease (NAFLD) is linked to a raised risk of cardiovascular diseases (CVD), although the underlying mechanisms are not completely known. A reduced myocardial ...mechano‐energetic efficiency (MEE) has been found to be an independent predictor of CVD.
Objective
To evaluate the association between NAFLD and a compromised MEE.
Methods
Myocardial MEE was assessed by a validated echocardiography‐derived measure in 699 nondiabetic individuals subdivided into two groups according to ultrasonography defined presence of NAFLD.
Results
Subjects with NAFLD displayed higher levels of systolic (SBP) and diastolic blood pressure (DBP), triglycerides, fasting and postload glucose, high‐sensitivity C‐reactive protein (hsCRP), insulin resistance (IR) estimated by HOMA‐IR and liver IR index, and lower values of high‐density lipoprotein (HDL) in comparison with those without NAFLD. Presence of NAFLD was associated with increased levels of myocardial oxygen demand and reduced values of MEE. MEE was negatively correlated with male sex, age, BMI, waist circumference, SBP, DBP, total cholesterol, triglycerides, fasting and postload glucose, HOMA‐IR and liver IR index, hsCRP and positively with HDL levels. In a multivariable regression analysis, presence of NAFLD was associated with MEE regardless of several cardio‐metabolic risk factors such as age, gender, waist circumference, SBP, DBP, total and HDL cholesterol, triglycerides, glucose tolerance and hsCRP (β = −0.09, P = 0.04), but not independently of IR estimates.
Conclusion
Ultrasound‐defined presence of NAFLD is associated with a decreased MEE, a predictor of adverse cardiovascular events. The relationship between NAFLD and a compromised MEE is dependent of IR.
Irisin, a novel myokine, was proposed to be able to regulate glucose homeostasis and obesity in mice. Whether irisin levels are associated with cardio-metabolic variables, insulin sensitivity, and ...vascular atherosclerosis in humans remain unsettled. To determine the associations between circulating irisin levels, cardio-metabolic variables, insulin sensitivity, and common carotid intima-media thickness (IMT), an indicator of vascular atherosclerosis, a cross-sectional evaluation of circulating irisin levels and cardio-metabolic variables in 192 White adults was conducted. Insulin sensitivity and insulin clearance were assessed by euglycemic–hyperinsulinemic clamp. Common carotid IMT was measured by ultrasound. After adjusting for age and gender, irisin levels were positively correlated with body fat mass (
r
= 0.12,
P
< 0.05), fasting (
r
= 0.17,
P
< 0.01), 2 h post-load insulin (
r
= 0.15,
P
< 0.02) levels, and IMT (
r
= 0.29,
P
< 0.0001) and were negatively correlated with insulin-stimulated glucose disposal (
r
= −0.18,
P
= 0.007), Matsuda index (
r
= −0.13,
P
< 0.04), disposition index (
r
= −0.278,
P
< 0.0001), and insulin clearance (
r
= −0.26,
P
< 0.0001). After adjusting for age, gender, and BMI, individuals in the highest tertile of irisin levels exhibited higher body fat mass (
P
< 0.01), fasting (
P
< 0.05), 2 h post-load (
P
< 0.01) insulin levels, carotid IMT (
P
< 0.001), lower insulin-stimulated glucose disposal (
P
< 0.001), Matsuda index (
P
< 0.01), disposition index (
P
< 0.01), and insulin clearance (
P
< 0.001) as compared with subjects in the lowest tertile of circulating irisin levels. Irisin is inversely associated with insulin sensitivity and positively associated with carotid IMT in humans, suggesting either increased release by adipose/muscle tissue in response to deterioration of insulin sensitivity or a compensatory increase in irisin to overcome an underlying irisin resistance.
The multipole response of neutron-rich O and Sn isotopes is computed in Tamm-Dancoff and random-phase approximations using the canonical Hartree-Fock-Bogoliubov quasi-particle basis. The calculations ...are performed using an intrinsic Hamiltonian composed of a Vlowk potential, deduced from the CD-Bonn nucleon-nucleon interaction, corrected with phenomenological density dependent and spin-orbit terms. The effect of these two pieces on energies and multipole responses is discussed. The problem of removing the spurious admixtures induced by the center-of-mass motion and by the violation of the number of particles is investigated. The differences between the two theoretical approaches are discussed quantitatively. Attention is then focused on the dipole strength distribution, including the low-lying transitions associated with the pygmy resonance. Monopole and quadrupole responses are also briefly investigated. A detailed comparison with the available experimental spectra contributes to clarify the extent of validity of the two self-consistent approaches.
Abstract Objective To examine whether individuals with normal glucose tolerance (NGT), whose 1-h post-load plasma glucose is ≥155 mg/dl, or with impaired glucose tolerance (IGT) have an increased ...carotid intima–media thickness (IMT), as compared with NGT individuals with 1-h post-load plasma <155 mg/dl. Methods Atherosclerosis risk factors, oral glucose tolerance test (OGTT), and ultrasound manual measurement of IMT were analyzed in 400 non-diabetic Caucasians. Results As compared with individuals with a 1-h post-load plasma glucose <155 mg/dl, NGT individuals with a 1-h post-load plasma glucose ≥155 mg/dl exhibited higher hsCRP (2.0 ± 1.5 vs. 1.5 ± 1.0, P = 0.008), and IMT (0.82 ± 0.20 vs. 0.71 ± 0.16; P = 0.006), and lower insulin sensitivity (71 ± 39 vs. 105 ± 57; P < 0.0001), and IGF-1 levels (214 ± 88 vs. 176 ± 49; P < 0.03). No significant differences were observed in metabolic and cardiovascular risk factors between IGT and NGT subjects with a 1-h post-load glucose ≥155 mg/dl. Of the three glycemic parameters, 1-h and 2-h post-load glucose, but not fasting glucose, were significantly correlated with IMT. In a stepwise multivariate regression analysis in a model including age, gender, and a variety of atherosclerosis risk factors, the three variables that remained significantly associated with IMT were age ( P < 0.0001), BMI ( P < 0.0001), and 1-h post-load glucose ( P = 0.02) accounting for 20.2% of its variation. Conclusions NGT subjects with a 1-h post-load glucose ≥155 mg/dl have an atherogenic profile similar to IGT individuals. These data suggest that a cutoff point of 155 mg/dl for the 1-h post-load glucose during OGTT may be helpful in the identification of NGT subjects at increased risk for cardiovascular disease.
Aims/hypothesis
We determined the contribution to insulin resistance of the PH domain leucine-rich repeat protein phosphatase (PHLPP), which dephosphorylates Akt at Ser473, inhibiting its activity. ...We measured the abundance of PHLPP in fat and skeletal muscle from obese participants. To study the effect of PHLPP on insulin signalling,
PHLPP
(also known as
PHLPP1
) was overexpressed in HepG2 and L6 cells.
Methods
Subcutaneous fat samples were obtained from 82 morbidly obese and ten non-obese participants. Skeletal muscle samples were obtained from 12 obese and eight non-obese participants. Quantification of PHLPP-1 in human tissues was performed by immunoblotting. The functional consequences of recombinant
PHLPP1
overexpression in hepatoma HepG2 cells and L6 myoblasts were investigated.
Results
Of the 82 obese participants, 31 had normal fasting glucose, 33 impaired fasting glucose and 18 type 2 diabetes. PHLPP-1 abundance was twofold higher in the three obese groups than in non-obese participants (
p
= 0.004). No differences were observed between obese participants with normal fasting glucose, impaired fasting glucose or type 2 diabetes. PHLPP-1 abundance was correlated with basal Akt Ser473 phosphorylation (
r
= −0.48;
p
= 0.001), BMI (
r
= 0.44;
p
< 0.0001), insulin (
r
= 0.35;
p
< 0.0001) and HOMA (
r
= 0.38;
p
< 0.0001). PHLPP-1 abundance was twofold higher in the skeletal muscle of 12 obese participants than in that of eight non-obese participants (
p
< 0.0001). Insulin treatment of HepG2 cells resulted in a dose- and time-dependent upregulation of PHLPP-1. Overexpression of
PHLPP1
in HepG2 cells and L6 myoblasts resulted in impaired insulin signalling involving Akt/glycogen synthase kinase 3, glycogen synthesis and glucose transport.
Conclusions/interpretation
Increased abundance of PHLPP-1, production of which is regulated by insulin, may represent a new molecular defect in insulin-resistant states such as obesity.
Abstract Background Carotid Intima-Media Thickness (C-IMT) is a reliable predictor of cardiovascular events. We examined if increased C-IMT was associated with defects in glucose metabolism in ...non-diabetic subjects independently of age. Methods In 366 Caucasian non-diabetic subjects of the CARAMERIS study, we measured glucose response during a 75 g-Oral Glucose Tolerance Test (OGTT), insulin sensitivity index (ISI, by Matsuda Index), Liver Insulin Resistance Index (Liver-IR), insulin secretion by ΔAUC Ins0-120 /Glu0-120 (ΔI/ΔG) and beta cell function (Disposition Index, DI). Results Subjects were divided in two groups according to the median age (AGE1 ≤ 45 y; AGE2 > 45 y). Only 5 subjects in AGE1 and 32 in AGE2 had C-IMT > 0.9 mm. Compared to AGE1, AGE2 had a worse cardio-metabolic profile, increased cholesterol, glucose and insulin concentrations, blood pressure and C-IMT. Both ΔI/ΔG ratio and DI were significantly reduced in AGE2. By considering tertiles of C-IMT in each AGE group (G1-G3, where G3 comprised the highest C-IMT), we found that G3 showed increased OGTT glucose profiles and Liver IR, decreased ISI and DI, compared to G1 in each AGE group. Conclusions Increased C-IMT, but within normal ranges, is associated independently of age with altered postprandial glucose profile, increased peripheral and hepatic insulin resistance, decreased b-cell function. C-IMT measurement should become a routine analysis even in younger subjects to predict the risk of cardio-metabolic disease.
A link between increased blood viscosity and type 2 diabetes has been previously reported. Herein, we investigated the association of blood viscosity with prediabetes, identified by glycated ...hemoglobin A1c (HbA1c) according to the new American Diabetes Association criteria, and subclinical atherosclerosis.
The study cohort includes 1136 non-diabetic adults submitted to anthropometrical evaluation, an oral glucose tolerance test and ultrasound measurement of carotid intima-media thickness (IMT). Whole blood viscosity was estimated using a validated formula based on hematocrit and total plasma proteins.
After adjusting for age, and gender, individuals with HbA1c-defined prediabetes (HbA1c 5.7–6.4% 39–47 mmol/mol) exhibited significantly higher values of hematocrit, and predicted blood viscosity as compared with controls. Increased levels of IMT were observed in subjects with HbA1c-defined prediabetes in comparison to controls. Predicted blood viscosity was positively correlated with age, waist circumference, blood pressure, cholesterol, triglycerides, fibrinogen, white blood cell, HbA1c, fasting and 2-h post-load glucose levels, fasting insulin, IMT and inversely correlated with HDL and Matsuda index of insulin sensitivity. Of the three glycemic parameters, i.e. HbA1c, fasting and 2-h post-load glucose, only HbA1c showed a significant correlation with predicted blood viscosity (β = 0.054, P = 0.04) in a multivariate regression analysis model including multiple atherosclerosis risk factors.
The study shows that individuals with HbA1c-defined prediabetes have increased predicted blood viscosity and IMT. The HbA1c criterion may be helpful to capture individuals with an increased risk of diabetes and cardiovascular disease who may benefit from an intensive lifestyle intervention.
•Subjects with HbA1c-defined prediabetes have increased blood viscosity and hematocrit.•HbA1c is an independent contributor of blood viscosity and hematocrit.•Blood viscosity and hematocrit are associated with carotid intima-media thickness.•Carotid intima-media thickness is increased in subjects with HbA1c-defined prediabetes.•A HbA1c value of 5.7–6.4% may identify subjects with increased cardio-metabolic risk.
PDF
