Prediabetes Is Independently Associated with Subclinical Carotid Atherosclerosis: An Observational Study in a Non-Urban Mediterranean Population.

This was a prospective, observational study to compare the burden of subclinical atherosclerosis as measured by carotid ultrasonography in a cohort of subjects with prediabetes vs. subjects with normal glucose tolerance (NGT) from a non-urban Mediterranean population. Atherosclerosis was assessed through carotid intima-media thickness (c-IMT), the presence/absence of carotid plaques, and plaque number. Among 550 subjects included, 224 (40.7%) had prediabetes. The mean c-IMT and the prevalence of carotid plaque were significantly higher in the prediabetes group compared to the NGT group (0.72 vs. 0.67 mm, p < 0.001; and 37.9% vs. 19.6%; p < 0.001, respectively). Older age, male gender, and increased systolic blood pressure were positively correlated with c-IMT and were independent predictors of the presence of plaques. In contrast, prediabetes and low-density lipoprotein (LDL)-c were predictors of the presence of plaque (odds ratio [OR] = 1.64; 95% confidence interval [CI] = 1.05-2.57; p = 0.03 and OR = 1.01; 95% CI = 1.00-1.02; p = 0.006, respectively) together with tobacco exposure and the leukocyte count (OR = 1.77; 95% CI = 1.08-2.89; p = 0.023 and OR = 1.20; 95% CI = 1.05-1.38; p = 0.008, respectively). In a non-urban Mediterranean population, prediabetes was associated with established subclinical carotid atherosclerosis. These findings could have implications for the prevention and treatment of CV risk in these subjects before the first symptoms of cardiovascular disease appear.

How Many Patients with Type 2 Diabetes Meet the Inclusion Criteria of the Cardiovascular Outcome Trials with SGLT2 Inhibitors? Estimations from a Population Database in a Mediterranean Area.

OBJECTIVE: Regulatory agencies require the assessment of cardiovascular (CV) safety for new type 2 diabetes (T2D) therapies through CV outcome trials (CVOTs). However, patients included in CVOTs assessing sodium-glucose cotransporter-2 inhibitors (SGLT2i) might not be representative of those seen in clinical practice. This study examined the proportion of patients that would have been enrolled into three main SGLT2i CVOTs to determine whether these trials' eligibility criteria can be applied to a real-world Mediterranean T2D population. METHODS: Cross-sectional, retrospective, cohort study of T2D patients registered in primary care centres of the Catalan Institute of Health using medical records from a population database (SIDIAP) that includes approximately 74% of the population in Catalonia (Spain). Eligibility criteria were according to those of three SGLT2i CVOTs: EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), and DECLARE-TIMI 58 (dapagliflozin). RESULTS: By the end of 2016, the database included 373,185 patients with T2D with a mean age of 70 ± 12 years, 54.9% male, with a mean duration of T2D of 9 ± 6 years, and a mean glycated haemoglobin (HbA1c) of 7.12% ± 1.32 (59% with HbA1c < 7%). Of these, 86,534 (23%) had established CV disease and 28% chronic renal failure (estimated glomerular filtration < 60 ml/min/1.73m2). Among all included patients, only 8.2% would have qualified for enrolment into the EMPA-REG OUTCOME trial, 29.6% into the CANVAS program, and 38% into the DECLARE-TIMI 58 trial. The main limiting factors for inclusion would have been a previous history of CV disease and the baseline HbA1c value. CONCLUSION: The external validity of the analysed CVOTs is clearly limited when applying the same eligibility criteria to a T2D Mediterranean population.

Glycaemic control after treatment intensification in patients with type 2 diabetes uncontrolled on two or more non-insulin antidiabetic drugs in a real-world setting.

AIM: To assess glycaemic control after treatment intensification in patients with type 2 diabetes uncontrolled on ≥2 non-insulin antidiabetic drugs (NIADS). METHODS: A retrospective cohort study, using electronic health records from the SIDIAP database (2010-2014), was conducted. Intensification was defined as the prescription of any new antidiabetic drug in patients treated with ≥2 NIADS and HbA1c >7%. The primary outcome was the absolute change in HbA1c 6-12 months after any intensification. Secondary analyses included the percentage of patients reaching HbA1c <7%, HbA1c <8%, and a reduction of HbA1c >1% after the first intensification. RESULTS: There were 21 241 intensifications in 15 205 patients with a mean (SD) HbA1c of 9.02% (±1.35). Insulin and dipeptidyl peptidase-4 inhibitors (DPP4i) were the most frequently added therapies. The mean baseline-adjusted HbA1c reduction was 0.78% (95% CI, -0.80 to -0.76), varying from -0.69% with DPP4i to -0.85% with glucagon-like peptide-1 receptor agonists while the addition of insulin was associated with a reduction >1%. After the first intensification, 48.9% of patients achieved HbA1c <8%, 16.2% HbA1c <7%, and 43.1% a reduction >1%. High previous HbA1c was positively associated with the reduction of HbA1c >1% [odds ratio (OR) 2.13 (95% CI: 2.05-2.21)], but inversely associated with the attainment of HbA1c <7% [OR 0.64 (0.61-0.67)] or < 8% [OR 0.63 (0.60-0.65)]. Older age, male gender, higher Charlson index, and short diabetes duration were associated with achievement of HbA1c <7%. CONCLUSIONS: Despite intensification, most patients failed the glycaemic goal of HbA1c <7%. The reduction depended mainly on preintensification HbA1c values, with small differences between drugs.

Prognosis of cardiovascular and non-cardiovascular multimorbidity after acute coronary syndrome.

OBJECTIVE: To examine the prognosis of patients with cardiovascular and non-cardiovascular multimorbidity after acute coronary syndrome compared to patients without prior multimorbidity. METHODS: This multicenter prospective cohort study in Switzerland included 5,635 patients hospitalized with acute coronary syndrome between 2009 and 2014, with a one-year follow-up period. We defined cardiovascular and non-cardiovascular multimorbidity as having at least two prior comorbidities before the index hospitalization. Multivariable adjusted Cox proportional models were built to assess the one-year risk of recurrent cardiovascular events, defined as cardiovascular mortality and non-fatal myocardial infarction or stroke. The final model was adjusted for age, gender, body mass index, tobacco consumption, education, and family history of cardiovascular disease, prescription of high-dose statinsat discharge and use of cardiac rehabilitation after discharge. RESULTS: Overall, 3,664 patients (65%) had no multimorbidity, 1,839 (33%) had cardiovascular multimorbidity, 62 (1%) had non-cardiovascular multimorbidity, and 70 (1%) had both cardiovascular and non-cardiovascular multimorbidity. The multivariate risk of recurrent cardiovascular events was increased among patients with cardiovascular multimorbidity (hazard ratio (HR) 2.05, 95% CI: 1.54-2.73, p<0.001) and patients with non-cardiovascular multimorbidity (HR 2.57, 95% CI: 1.04-6.35, p = 0.04) compared to patients without multimorbidity. Patients with cardiovascular and non-cardiovascular multimorbidity had the highest risk of recurrence with a HR of 5.19, 95% CI: 2.79-9.64, p<0.001, compared to patients without multimorbidity. CONCLUSIONS: Multimorbidity increased by two-fold the risk of cardiovascular events over the year after an acute coronary syndrome. The magnitude of this increased risk was similar for patients with cardiovascular or non-cardiovascular multimorbidity.

Effects of sardine-enriched diet on metabolic control, inflammation and gut microbiota in drug-naïve patients with type 2 diabetes: a pilot randomized trial.

BACKGROUND: Nutrition therapy is the cornerstone of treating diabetes mellitus. The inclusion of fish (particularly oily fish) at least two times per week is recommended by current international dietary guidelines for type 2 diabetes. In contrast to a large number of human studies examining the effects of oily fish on different cardiovascular risk factors, little research on this topic is available in patients with type 2 diabetes. The aims of this pilot study were to investigate the effects of a sardine-enriched diet on metabolic control, adiponectin, inflammatory markers, erythrocyte membrane fatty acid (EMFA) composition, and gut microbiota in drug-naïve patients with type 2 diabetes. METHODS: 35 drug-naïve patients with type 2 diabetes were randomized to follow either a type 2 diabetes standard diet (control group: CG), or a standard diet enriched with 100 g of sardines 5 days a week (sardine group: SG) for 6 months. Anthropometric, dietary information, fasting glycated hemoglobin, glucose, insulin, adiponectin, inflammatory markers, EMFA and specific bacterial strains were determined before and after intervention. RESULTS: There were no significant differences in glycemic control between groups at the end of the study. Both groups decreased plasma insulin (SG: -35.3%, P = 0.01, CG: -22.6%, P = 0.02) and homeostasis model of assessment--insulin resistance (HOMA-IR) (SG: -39.2%, P = 0.007, CG: -21.8%, P = 0.04) at 6-months from baseline. However only SG increased adiponectin in plasma compared to baseline level (+40.7%, P = 0.04). The omega-3 index increased 2.6% in the SG compared to 0.6% in the CG (P = 0.001). Both dietary interventions decreased phylum Firmicutes (SG and CG: P = 0.04) and increased E. coli concentrations (SG: P = 0.01, CG: P = 0.03) at the end of the study from baseline, whereas SG decreased Firmicutes/Bacteroidetes ratio (P = 0.04) and increased Bacteroides-Prevotella (P = 0.004) compared to baseline. CONCLUSIONS: Although enriching diet with 100 g of sardines 5 days a week during 6 months to a type 2 diabetes standard diet seems to have neutral effects on glycemic control in drug-naïve patients with type 2 diabetes, this nutritional intervention could have beneficial effects on cardiovascular risk. Furthermore, both dietary interventions decreased HOMA-IR and altered gut microbiota composition of drug-naïve patients with type 2 diabetes. TRIAL REGISTRATION: Trial number and name of the registry: NCT02294526, ClinicalTrials.gov.

Circulating SFRP5 levels are elevated in drug-naïve recently diagnosed type 2 diabetic patients as compared with prediabetic subjects and controls.

BACKGROUND: Secreted frizzled-related protein 5 (SFRP5) has been linked to obesity. Results are conflicting regarding its association with type 2 diabetes (T2D) in humans. We aimed to investigate circulating SFRP5 in prediabetes and T2D and its potential association with parameters of insulin resistance and beta-cell function. METHODS: We studied 70 drug-naïve T2D patients, 70 prediabetic subjects and 70 controls. All subjects were body mass index matched to the T2D patients and overweight or obese. SFRP5, hormones and cytokines levels were measured by ELISA. RESULTS: Serum SFRP5 levels were elevated in T2D patients as compared with prediabetic subjects (median 15.6, interquartile range [9-24.5] ng/mL vs 9.8 [5-14.2] ng/mL, p < 0.001, respectively) and controls (15.6 [9-24.5] ng/mL vs 10.4 [6.7-16.6] ng/mL, P < 0.001, respectively). No differences were found in serum SFRP5 levels between prediabetic subjects and controls (9.8 [5-14.2] ng/mL vs 10.4 [6.7-16.6] ng/mL, p = 0.472, respectively). After adjusting for potential confounders (age, gender, body mass index, triglycerides, high-density lipoprotein cholesterol and blood pressure), T2D was still associated with higher values of SFRP5 as compared with prediabetes in multinomial logistic regression analysis (fully adjusted odds ratio 3.50, 95% confidence interval 1.40-8.79, p = 0.008). The association was more subtle when comparing T2D with normal glucose tolerance state (fully adjusted odds ratio 2.18, 95% confidence interval 0.91-5.21, p = 0.078). CONCLUSIONS: Circulating SFRP5 levels were independently associated with T2D as compared with prediabetes and normal glucose tolerance state.

Oscillating glucose and constant high glucose induce endoglin expression in endothelial cells: the role of oxidative stress.

AIM: High glucose-induced oxidative stress has been suggested as one of the mediators of endothelial damage in diabetes. The major endothelial protein, endoglin, has been found overexpressed in the vessels during pathological situations, but little is known about its relation to diabetic vascular complications. To clarify the role of endoglin in endothelial injury, we sought to determine the effects of high and oscillating glucose on its expression. MATERIALS: Furthermore, the activation of the Krüppel-like factor 6 (KLF-6) and the hypoxia-inducible factor-1α (HIF-1α) as possible regulators of endoglin expression has been evaluated. The possible role of the oxidative stress has been studied evaluating the effects of the antioxidant alpha-lipoic acid (ALA) and the cellular antioxidant response mediated by NAD(P)H: quinine-oxido-reductase-1 (NQO-1) and heme oxygenase-1 (HO-1). RESULTS: Primary HUVECs were cultured for 21 days in normal, high and oscillating glucose (5, 25 and 5/25 mmol/l every 24 h, respectively) with/without ALA. In oscillating and high glucose total endoglin, its soluble form (sEng), KLF-6 and HIF-1α were significantly increased. Simultaneously, the oxidative DNA stress markers 8-OHdG and H2A.X were elevated. Moreover, ENG gene transcriptional rate increased during glucose exposures concomitantly with increased KLF-6 nuclear translocations. ALA significantly reduced all these phenomena. Interestingly, during oscillating and chronic high glucose, NQO-1 and HO-1 did not increase, but ALA induced their overexpression. CONCLUSIONS: Together, these findings provide novel clue about endoglin in the regulation of high glucose-mediated vascular damage in HUVECs and the role of oxidative stress in this regulation.

Circulating miR-192 and miR-193b are markers of prediabetes and are modulated by an exercise intervention.

CONTEXT: Diabetes is frequently diagnosed late, when the development of complications is almost inevitable, decreasing the quality of life of patients. However, early detection of affected individuals would allow the implementation of timely and effective therapies. OBJECTIVE: Here we set to describe the profile of circulating microRNAs (miRNAs) in prediabetic patients with the intention of identifying novel diagnostic and therapeutic tools. DESIGN: We used real-time RT-PCR to measure the abundance of 176 miRNAs in serum of a cohort of 92 control and prediabetic individuals with either impaired fasting glucose or impaired glucose tolerance, as well as newly diagnosed diabetic patients. We validated the results in a second cohort of control and prediabetic subjects undergoing a therapeutic exercise intervention, as well as in a mouse model of glucose intolerance. RESULTS: We identified two miRNAs, miR-192 and miR-193b, whose abundance is significantly increased in the prediabetic state but not in diabetic patients. Strikingly, these miRNAs are also increased in plasma of glucose-intolerant mice. Moreover, circulating levels of miR-192 and miR-193b return to baseline in both prediabetic humans and glucose-intolerant mice undergoing a therapeutic intervention consisting in chronic exercise, which succeeded in normalizing metabolic parameters. CONCLUSIONS: Our data show that the pattern of circulating miRNAs is modified by defects in glucose metabolism in a similar manner in mice and humans. This circulating miRNA signature for prediabetes could be used as a new diagnostic tool, as well as to monitor response to intervention.

REV-ERB ALPHA polymorphism is associated with obesity in the Spanish obese male population.

REV-ERB ALPHA has been shown to link metabolism with circadian rhythms. We aimed to identify new polymorphisms in the promoter of REV-ERB ALPHA and tested whether these polymorphisms could be associated with obesity in the Spanish population. Of the 1197 subjects included in our study, 779 were obese (BMI 34.38±3.1 kg/m2) and 418 lean (BMI 23.27±1.5 kg/m2). In the obese group, 469 of the 779 had type 2 diabetes. Genomic DNA from all the subjects was obtained from peripheral blood cells and the genotyping in the REV-ERB ALPHA promoter was analyzed by High Resolution Melting. We found six polymorphisms in the REV-ERB ALPHA promoter and identified rs939347 as a SNP with the highest frequency in the total population. We did not find any association between rs939347 and type 2 diabetes (p = 0.101), but rs939347 was associated with obesity (p = 0.036) with the genotype AA exhibiting higher frequency in the obese (5.2% in total obese vs 2.4% in lean). This association was found only in men (p = 0.031; 6.5% AA-carriers in obese men vs 1.9% AA-carriers in lean men), with no association found in the female population (p = 0.505; 4.4% AA-carriers in obese women vs 2.7% AA-carriers in lean women). Our results suggest that the REV-ERB ALPHA rs939347 polymorphism could modulate body fat mass in men. The present work supports the role of REV-ERB ALPHA in the development of obesity as well as a potential target for the treatment of obesity.

Differential methylation of TCF7L2 promoter in peripheral blood DNA in newly diagnosed, drug-naïve patients with type 2 diabetes.

TCF7L2 is the susceptibility gene for Type 2 diabetes (T2D) with the largest effect on disease risk that has been discovered to date. However, the mechanisms by which TCF7L2 contributes to the disease remain largely elusive. In addition, epigenetic mechanisms, such as changes in DNA methylation patterns, might have a role in the pathophysiology of T2D. This study aimed to investigate the differences in terms of DNA methylation profile of TCF7L2 promoter gene between type 2 diabetic patients and age- and Body Mass Index (BMI)- matched controls. We included 93 type 2 diabetic patients that were recently diagnosed for T2D and exclusively on diet (without any pharmacological treatment). DNA was extracted from whole blood and DNA methylation was assessed using the Sequenom EpiTYPER system. Type 2 diabetic patients were more insulin resistant than their matched controls (mean HOMA IR 2.6 vs 1.8 in controls, P<0.001) and had a poorer beta-cell function (mean HOMA B 75.7 vs. 113.6 in controls, P<0.001). Results showed that 59% of the CpGs analyzed in TCF7L2 promoter had significant differences between type 2 diabetic patients and matched controls. In addition, fasting glucose, HOMA-B, HOMA-IR, total cholesterol and LDL-cholesterol correlated with methylation in specific CpG sites of TCF7L2 promoter. After adjustment by age, BMI, gender, physical inactivity, waist circumference, smoking status and diabetes status uniquely fasting glucose, total cholesterol and LDL-cholesterol remained significant. Taken together, newly diagnosed, drug-naïve type 2 diabetic patients display specific epigenetic changes at the TCF7L2 promoter as compared to age- and BMI-matched controls. Methylation in TCF7L2 promoter is further correlated with fasting glucose in peripheral blood DNA, which sheds new light on the role of epigenetic regulation of TCF7L2 in T2D.

Haptoglobin genotype and risk of diabetic nephropathy in patients with type 1 diabetes mellitus: a study on a Spanish population.

BACKGROUND: Few reports have studied the possible association between the haptoglobin (Hp) genotype and the risk of diabetic nephropathy (DN) in type 1 diabetes (T1D), with conflicting results to date. AIMS: To study whether the 2-2 Hp genotype is associated with an increased risk of overt DN in a Spanish population with T1D. METHODS: We performed a case-control study in a Spanish population. CASES: T1D patients with end-stage renal disease (stage 5 of NKF-KDOQI), awaiting reno-pancreatic transplantation or having already been transplanted (reno-pancreatic or renal alone). CONTROLS: T1D patients, matched for sex and time of diabetes evolution, with preserved renal function and normal urinary albumin excretion. Hp genotyping was done using polymerase chain reaction and electrophoresis. RESULTS: We included 57 cases and 57 controls in the study. There were no statistically significant differences in gender (70% vs. 61% males, p=1.0) or the duration of diabetes (23.0 ± 6.7 vs. 20.8 ± 9.3 years; p=0.1), although the age of onset of diabetes was lower in the cases (14.1 ± 6.8 vs. 17.7 ± 10.1 years, p=0.03). The frequency of genotypes 1-1, 1-2 and 2-2 was 19.3%, 42.1% and 38.6% in cases and 17.5%, 49.1% and 33.4% in controls, respectively, with no statistically significant differences between groups (p=0.8). Conditional logistic regression analysis showed no significant association between genotype 2-2 of Hp and the development of DN (OR 1.14, CI 0.52-2.52). CONCLUSIONS: In our sample of a Spanish population with T1D, no association was found between the Hp genotype and risk of overt DN.

Hypertension remission 1 year after bariatric surgery: predictive factors.

BACKGROUND: There is scarce information about predictive factors of hypertension (HT) remission after bariatric surgery (BS). The aims of this study were to determine the clinical characteristics differentiating obese patients with and without HT and to evaluate the predictive factors associated with the risk of persistence of HT after BS. PATIENTS AND METHODS: From January 2007 to December 2009, a review of patients who had undergone BS was performed. Patients were classified as hypertensive if having permanent use of antiHT drugs or clinical BP ≥ 140/90 mm Hg. Weight, waist circumference (WC), and blood pressure were determined with standardized procedures. RESULTS: Five hundred twenty-6 patients met the inclusion criteria; 264 (50%) were hypertensive, 74 (34%) of whom had type 2 diabetes. Before BS, older age, male gender, and greater WC differentiated hypertensive from normotensive patients. The prevalence of HT significantly fell to 35% (P<.0001) at 12 months after BS. The use of multivariate logistic regression showed that age ≥ 40, male gender and WC ≥ 130 cm were significant predictors of having HT before surgery. Regarding persistence of HT at the 12-month follow-up, the only independent predictors observed were time since diagnosis of HT ≥ 10 years and the number of antiHT drugs used. Presurgical BMI, WC, excess weight (EW), EW loss, surgical procedure, type 2 diabetes, and vitamin D status were not significant predictors. CONCLUSIONS: Bariatric surgery is associated with a high rate of HT remission. Older age, male gender, and higher WC differentiated hypertensive-obese from normotensive patients. After BS, longer duration and severity of HT were independently associated with no remission of HT.

Simultaneous GLP-1 and insulin administration acutely enhances their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes.

OBJECTIVE: To test the hypothesis that the simultaneous administration of GLP-1 and insulin may increase their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes. RESEARCH DESIGN AND METHODS: In two groups of persons with type 2 diabetes, two sets of experiments were performed. The first group had two normoglycemic-normoinsulinemic clamps with or without GLP-1 and two normoglycemic-hyperinsulinemic clamps with or without GLP-1. The second group had two hyperglycemic-normoinsulinemic clamps and two hyperglycemic-hyperinsulinemic clamps with or without GLP-1. RESULTS: During the normoglycemic-hyperinsulinemic clamp, flow-mediated dilatation (FMD) increased, while soluble intercellular adhesion molecule (sICAM-1), plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), nitrotyrosine, and interleukin (IL)-6 decreased compared with normoglycemic-normoinsulinemic clamp. Similar results were obtained with the infusion of GLP-1 during the normoglycemic-normoinsulinemic clamp. The combination of hyperinsulinemia and GLP-1 in normoglycemia was accompanied by a further FMD increase and sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 decrease. During the hyperglycemic-normoinsulinemic clamp, FMD significantly decreased, while sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 significantly increased. When hyperglycemia was accompanied by hyperinsulinemia or by the simultaneous infusion of GLP-1, these phenomena were attenuated. The simultaneous presence of hyperinsulinemia and GLP-1 had an increased beneficial effect. CONCLUSIONS: Our results show that the combination of insulin and GLP-1 is more effective than insulin or GLP-1 alone in improving endothelial dysfunction, inflammation, and oxidative stress in type 2 diabetes.

Diagnosis and classification of autoimmune diabetes mellitus.

Diabetes mellitus is increasing in prevalence worldwide. The economic costs and burden of the disease are considerable given the cardiovascular complications and co-morbidities that it may entail. Two major groups of diabetes mellitus have been defined, type 1, or immune-based, and type 2. In recent years, other subgroups have been described in-between these major groups. Correct classification of the disease is crucial in order to ascribe the most efficient preventive, diagnostic and treatment strategies for each patient. In the present review, we discuss the epidemiology, etiopathogenesis, diagnostic criteria and clinical classification of what is currently known as autoimmune diabetes. In addition, the other groups of diabetes mellitus will be regarded in relation to their pathogenesis and potential autoimmunity features.

Gastric inhibitory polypeptide receptor methylation in newly diagnosed, drug-naïve patients with type 2 diabetes: a case-control study.

GIP action in type 2 diabetic (T2D) patients is altered. We hypothesized that methylation changes could be present in GIP receptor of T2D patients. This study aimed to assess the differences in DNA methylation profile of GIPR promoter between T2D patients and age- and Body Mass Index (BMI)-matched controls. We included 93 T2D patients (cases) that were uniquely on diet (without any anti-diabetic pharmacological treatment). We matched one control (with oral glucose tolerance test negative, non diabetic), by age and BMI, for every case. Cytokines and hormones were determined by ELISA. DNA was extracted from whole blood and DNA methylation was assessed using the Sequenom EpiTYPER system. Our results showed that T2D patients were more insulin resistant and had a poorer ß cell function than their controls. Fasting adiponectin was lower in T2D patients as compared to controls (7.0±3.8 µgr/mL vs. 10.0±4.2 µgr/mL). Levels of IL 12 in serum were almost double in T2D patients (52.8±58.3 pg/mL vs. 29.7±37.4 pg/mL). We found that GIPR promoter was hypomethylated in T2D patients as compared to controls. In addition, HOMA-IR and fasting glucose correlated negatively with mean methylation of GIPR promoter, especially in T2D patients. This case-control study confirms that newly diagnosed, drug-naïve T2D patients are more insulin resistant and have worse ß cell function than age- and BMI-matched controls, which is partly related to changes in the insulin-sensitizing metabolites (adiponectin), in the proinflammatory profile (IL12) and we suggest in the methylation pattern of GIPR. Our study provides novel findings on GIPR promoter methylation profile which may improve our ability to understand type 2 diabetes pathogenesis.

Vitamin C further improves the protective effect of glucagon-like peptide-1 on acute hypoglycemia-induced oxidative stress, inflammation, and endothelial dysfunction in type 1 diabetes.

OBJECTIVE: To test the hypothesis that acute hypoglycemia induces endothelial dysfunction and inflammation through the generation of an oxidative stress. Moreover, to test if the antioxidant vitamin C can further improve the protective effects of glucagon-like peptide 1 (GLP-1) on endothelial dysfunction and inflammation during hypoglycemia in type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 20 type 1 diabetic patients underwent four experiments: a period of 2 h of acute hypoglycemia with or without infusion of GLP-1 or vitamin C or both. At baseline, after 1 and 2 h, glycemia, plasma nitrotyrosine, plasma 8-iso prostaglandin F2a (PGF2a), soluble intracellular adhesion molecule-1a (sICAM-1a), interleukin-6 (IL-6), and flow-mediated vasodilation were measured. At 2 h of hypoglycemia, flow-mediated vasodilation significantly decreased, while sICAM-1, 8-iso-PGF2a, nitrotyrosine, and IL-6 significantly increased. The simultaneous infusion of GLP-1 or vitamin C significantly attenuated all of these phenomena. Vitamin C was more effective. When GLP-1 and vitamin C were infused simultaneously, the deleterious effect of hypoglycemia was almost completely counterbalanced. RESULTS: At 2 h of hypoglycemia, flow-mediated vasodilation significantly decreased, while sICAM-1, 8-iso-PGF2a, nitrotyrosine, and IL-6 significantly increased. The simultaneous infusion of GLP-1 or vitamin C significantly attenuated all of these phenomena. Vitamin C was more effective. When GLP-1 and vitamin C were infused simultaneously, the deleterious effect of hypoglycemia was almost completely counterbalanced. CONCLUSIONS: This study shows that vitamin C infusion, during induced acute hypoglycemia, reduces the generation of oxidative stress and inflammation, improving endothelial dysfunction, in type 1 diabetes. Furthermore, the data support a protective effect of GLP-1 during acute hypoglycemia, but also suggest the presence of an endothelial resistance to the action of GLP-1, reasonably mediated by oxidative stress.

Glucose abnormalities associated with impaired nocturnal fall in blood pressure in normotensive severely obese patients.

BACKGROUND: The purpose of this study was to identify factors affecting the nocturnal decline in blood pressure (BP) in severe obesity. METHODS: Clinical, biochemical, polysomnographic data, glucose tolerance status, and body fat composition were obtained in 82 candidates for bariatric surgery (mean age: 40 (11) years; BMI: 46 (4)kg/m(2)). To determine the nocturnal BP fall we used 24-h ambulatory BP monitoring to measure the magnitude (Δ) of nocturnal decline, the % day-night systolic BP (SBP) and diastolic BP (DBP), dipper status and nocturnal hypertension (HT). RESULTS: Twenty-three percent of patients had nocturnal HT. Sixty percent had non dipper status, of which 95% had nocturnal HT. No specific factors were associated with the average 24-h SBP and DBP. Having glucose abnormalities was of primary importance for all variables evaluating nocturnal BP decline independent of daytime BP levels and severity of obesity. In comparing patients with or without glucose tolerance abnormalities, the night-time SBP and DBP were significantly higher and the Δ nocturnal decline and % day-night in both SBP and DBP were significantly lower in those with glucose tolerance abnormalities. In an adjusted multivariate model, having both glucose abnormalities and nocturnal HT remained associated with non dipper status with an OR of 3.13 (95% CI 1.11-8.87, p=0.03) and 14.93 (95% CI 1.77-125.62, p=0.001), respectively. CONCLUSION: In normotensive severely obese patients, non dipper status and nocturnal HT are common, and the presence of glucose abnormalities was the primary variable associated with impaired nocturnal fall in BP.

Vitamin C further improves the protective effect of GLP-1 on the ischemia-reperfusion-like effect induced by hyperglycemia post-hypoglycemia in type 1 diabetes.

BACKGROUND: It has been reported that hyperglycemia following hypoglycemia produces an ischemia-reperfusion-like effect in type 1 diabetes. In this study the possibility that GLP-1 has a protective effect on this phenomenon has been tested. METHODS: 15 type 1 diabetic patients underwent to five experiments: a period of two hours of hypoglycemia followed by two hours of normo-glycemia or hyperglycemia with the concomitant infusion of GLP-1 or vitamin C or both. At baseline, after 2 and 4 hours, glycemia, plasma nitrotyrosine, plasma 8-iso prostaglandin F2alpha, sCAM-1a, IL-6 and flow mediated vasodilation were measured. RESULTS: After 2 h of hypoglycemia, flow mediated vasodilation significantly decreased, while sICAM-1, 8-iso-PGF2a, nitrotyrosine and IL-6 significantly increased. While recovering with normoglycemia was accompanied by a significant improvement of endothelial dysfunction, oxidative stress and inflammation, a period of hyperglycemia after hypoglycemia worsens all these parameters. These effects were counterbalanced by GLP-1 and better by vitamin C, while the simultaneous infusion of both almost completely abolished the effect of hyperglycemia post hypoglycemia. CONCLUSIONS: This study shows that GLP-1 infusion, during induced hyperglycemia post hypoglycemia, reduces the generation of oxidative stress and inflammation, improving the endothelial dysfunction, in type 1 diabetes. Furthermore, the data support that vitamin C and GLP-1 may have an additive protective effect in such condition.

Glucagon-like peptide 1 reduces endothelial dysfunction, inflammation, and oxidative stress induced by both hyperglycemia and hypoglycemia in type 1 diabetes.

OBJECTIVE: Hyperglycemia and hypoglycemia currently are considered risk factors for cardiovascular disease in type 1 diabetes. Both acute hyperglycemia and hypoglycemia induce endothelial dysfunction and inflammation, raising the oxidative stress. Glucagon-like peptide 1 (GLP-1) has antioxidant properties, and evidence suggests that it protects endothelial function. RESEARCH DESIGN AND METHODS: The effect of both acute hyperglycemia and acute hypoglycemia in type 1 diabetes, with or without the simultaneous infusion of GLP-1, on oxidative stress (plasma nitrotyrosine and plasma 8-iso prostaglandin F2alpha), inflammation (soluble intercellular adhesion molecule-1 and interleukin-6), and endothelial dysfunction has been evaluated. RESULTS: Both hyperglycemia and hypoglycemia acutely induced oxidative stress, inflammation, and endothelial dysfunction. GLP-1 significantly counterbalanced these effects. CONCLUSIONS: These results suggest a protective effect of GLP-1 during both hypoglycemia and hyperglycemia in type 1 diabetes.