Patient-centered Management of Type 2 Diabetes Mellitus Based on Specific Clinical Scenarios: Systematic Review, Meta-analysis and Trial Sequential Analysis.

INTRODUCTION: New antihyperglycemic medications have been proven to have cardiovascular (CV) and renal benefits in type 2 diabetes mellitus (T2DM); however, an evidence-based decision tree in specific clinical scenarios is lacking. MATERIALS AND METHODS: Systematic review and meta-analysis of randomized controlled trials (RCTs), with trial sequential analysis (TSA). Randomized controlled trial inclusion criteria were patients with T2DM from 1 of these subgroups: elderly, obese, previous atherosclerotic CV disease (ASCVD), previous coronary heart disease (CHD), previous heart failure (HF), or previous chronic kidney disease (CKD). Randomized controlled trials describing those subgroups with at least 48 weeks of follow-up were included. Outcomes: 3-point major adverse cardiovascular events (MACE), CV death, hospitalization due to HF, and renal outcomes. We performed direct meta-analysis with the number of events in the intervention and control groups in each subset, and the relative risk of the events was calculated. RESULTS: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RA) were the only antihyperglycemic agents related to a reduction in CV events in different populations. For obese and elderly populations, GLP-1 RA were associated with benefits in 3-point MACE; for patients with ASCVD, both SGLT2i and GLP-1 RA had benefits in 3-point MACE, while for patients with CHD, only SGLT2i were beneficial. CONCLUSIONS: SGLT2i and GLP-1 RA reduced CV events in selected populations: SGLT2i led to a reduction in events in patients with previous CHD, ASCVD, and HF. GLP-1 RA led to a reduction in CV events in patients with ASCVD, elderly patients, and patients with obesity. Trial sequential analysis shows that these findings are conclusive. This review opens a pathway towards evidence-based, personalized treatment of T2DM. REGISTRATION: PROSPERO CRD42019132807.

Superior Effects of High-Intensity Interval vs. Moderate-Intensity Continuous Training on Endothelial Function and Cardiorespiratory Fitness in Patients With Type 1 Diabetes: A Randomized Controlled Trial.

This study aimed to compare the effect of high-intensity interval training (HIIT) with moderate-intensity continuous training (MCT) on endothelial function, oxidative stress and clinical fitness in patients with type 1 diabetes. Thirty-six type 1 diabetic patients (mean age 23.5 ± 6 years) were randomized into 3 groups: HIIT, MCT, and a non-exercising group (CON). Exercise was performed in a stationary cycle ergometers during 40 min, 3 times/week, for 8 weeks at 50-85% maximal heart rate (HRmax) in HIIT and 50% HRmax in MCT. Endothelial function was measured by flow-mediated dilation (FMD) [endothelium-dependent vasodilation (EDVD)], and smooth-muscle function by nitroglycerin-mediated dilation [endothelium-independent vasodilation (EIVD)]. Peak oxygen consumption (VO2peak) and oxidative stress markers were determined before and after training. Endothelial dysfunction was defined as an increase < 8% in vascular diameter after cuff release. The trial is registered at ClinicalTrials.gov, identifier: NCT03451201. Twenty-seven patients completed the 8-week protocol, 9 in each group (3 random dropouts per group). Mean baseline EDVD was similar in all groups. After training, mean absolute EDVD response improved from baseline in HIIT: + 5.5 ± 5.4%, (P = 0.0059), but remained unchanged in MCT: 0.2 ± 4.1% (P = 0.8593) and in CON: -2.6 ± 6.4% (P = 0.2635). EDVD increase was greater in HIIT vs. MCT (P = 0.0074) and CON (P = 0.0042) (ANOVA with Bonferroni). Baseline VO2peak was similar in all groups (P = 0.96). VO2peak increased 17.6% from baseline after HIIT (P = 0.0001), but only 3% after MCT (P = 0.055); no change was detected in CON (P = 0.63). EIVD was unchanged in all groups (P = 0.18). Glycemic control was similar in all groups. In patients with type 1 diabetes without microvascular complications, 8-week HIIT produced greater improvement in endothelial function and physical fitness than MCT at a similar glycemic control.

Elevated serum interleukin-6 is predictive of coronary artery disease in intermediate risk overweight patients referred for coronary angiography.

BACKGROUND: Interleukin-6 (IL-6) plays a central role in atherosclerosis and inflammation. It may improve risk prediction in patients at intermediate cardiovascular risk. OBJECTIVE: To analyze the impact of serum IL-6 in predicting early angiographic coronary artery disease in patients at intermediate cardiovascular risk with chest pain. METHODS: In a cross-sectional study, patients referred for coronary angiography due to suspected coronary artery disease (CAD) were included. Coronary artery disease was defined as the presence of at least 30% stenosis in one or more coronary artery. Severity of CAD was classified by the anatomic burden score. Performance of serum IL-6 assay was compared with ACC/AHA atherosclerotic cardiovascular disease (ASCVD) risk score and hs-CRP through receiver operating characteristic (ROC) curves. RESULTS: We have included 48 patients with a mean 10-year ASCVD risk of 10.0 ± 6.8%. The prevalence of CAD was 72.9%. The presence of CAD was associated with higher mean levels of IL-6 (p = 0.025). Patients with CAD had significantly more overweight than subjects without CAD. In 27% of patients, IL-6 was >1.0 pg/mL and 100% of these patients had CAD, while only 64% in those with IL-6 <1.0 pg/mL, corresponding to a positive predictive value of 100% (p = 0.015). The area under the receiver operating characteristic (ROC) curve of IL-6, hs-CRP and ASCVD were respectively 0.72, 0.60 and 0.54. Intermediate risk patients with IL-6 >1.0 pg/mL were further reclassified into ASCVD high risk due to the presence of coronary lesions. CONCLUSION: In intermediate risk patients referred for coronary angiography, a serum IL-6 level above 1 pg/mL is predictive of significant CAD. IL-6 determination may be useful to reclassify ASCVD intermediate risk patients into higher risk categories.

Validation of HOMA-IR in a model of insulin-resistance induced by a high-fat diet in Wistar rats.

Objective The present study aimed to validate homeostasis model assessment of insulin resistance (HOMA-IR) in relation to the insulin tolerance test (ITT) in a model of insulin-resistance in Wistar rats induced by a 19-week high-fat diet. Materials and methods A total of 30 male Wistar rats weighing 200-300 g were allocated into a high-fat diet group (HFD) (55% fat-enriched chow, ad lib, n = 15) and a standard-diet group (CD) standard chow, ad lib, n = 15), for 19 weeks. ITT was determined at baseline and in the 19th week. HOMA-IR was determined between the 18-19th week in three different days and the mean was considered for analysis. Area under the curve (AUC-ITT) of the blood glucose excursion along 120 minutes after intra-peritoneal insulin injection was determined and correlated with the corresponding fasting values for HOMA-IR. Results AUC-ITT and HOMA-IR were significantly greater after 19th week in HFD compared to CD (p < 0.001 for both). AUC-OGTT was also higher in HFD rats (p = 0.003). HOMA-IR was strongly correlated (Pearson's) with AUC-ITT r = 0.637; p < 0.0001. ROC curves of HOMA-IR and AUC-ITT showed similar sensitivity and specificity. Conclusion HOMA-IR is a valid measure to determine insulin-resistance in Wistar rats. Arch Endocrinol Metab. 2016;60(2):138-42.

Validation of HOMA-IR in a model of insulin-resistance induced by a high-fat diet in Wistar rats

ABSTRACT Objective The present study aimed to validate homeostasis model assessment of insulin resistance (HOMA-IR) in relation to the insulin tolerance test (ITT) in a model of insulin-resistance in Wistar rats induced by a 19-week high-fat diet. Materials and methods A total of 30 male Wistar rats weighing 200-300 g were allocated into a high-fat diet group (HFD) (55% fat-enriched chow, ad lib, n = 15) and a standard-diet group (CD) standard chow, ad lib, n = 15), for 19 weeks. ITT was determined at baseline and in the 19th week. HOMA-IR was determined between the 18-19th week in three different days and the mean was considered for analysis. Area under the curve (AUC-ITT) of the blood glucose excursion along 120 minutes after intra-peritoneal insulin injection was determined and correlated with the corresponding fasting values for HOMA-IR. Results AUC-ITT and HOMA-IR were significantly greater after 19th week in HFD compared to CD (p < 0.001 for both). AUC-OGTT was also higher in HFD rats (p = 0.003). HOMA-IR was strongly correlated (Pearson’s) with AUC-ITT r = 0.637; p < 0.0001. ROC curves of HOMA-IR and AUC-ITT showed similar sensitivity and specificity. Conclusion HOMA-IR is a valid measure to determine insulin-resistance in Wistar rats. Arch Endocrinol Metab. 2016;60(2):138-42.

Endothelial dysfunction as a predictor of cardiovascular disease in type 1 diabetes.

Macro and microvascular disease are the main cause of morbi-mortality in type 1 diabetes (T1DM). Although there is a clear association between endothelial dysfunction and atherosclerosis in type 2 diabetes, a cause-effect relationship is less clear in T1DM. Although endothelial dysfunction (ED) precedes atherosclerosis, it is not clear weather, in recent onset T1DM, it may progress to clinical macrovascular disease. Moreover, endothelial dysfunction may either be reversed spontaneously or in response to intensive glycemic control, long-term exercise training and use of statins. Acute, long-term and post-prandial hyperglycemia as well as duration of diabetes and microalbuminuria are all conditions associated with ED in T1DM. The pathogenesis of endothelial dysfunction is closely related to oxidative-stress. NAD(P)H oxidase over activity induces excessive superoxide production inside the mitochondrial oxidative chain of endothelial cells, thus reducing nitric oxide bioavailability and resulting in peroxynitrite formation, a potent oxidant agent. Moreover, oxidative stress also uncouples endothelial nitric oxide synthase, which becomes dysfunctional, inducing formation of superoxide. Other important mechanisms are the activation of both the polyol and protein kinase C pathways as well as the presence of advanced glycation end-products. Future studies are needed to evaluate the potential clinical applicability of endothelial dysfunction as a marker for early vascular complications in T1DM.

HOMA-IR is associated with significant angiographic coronary artery disease in non-diabetic, non-obese individuals: a cross-sectional study.

UNLABELLED: Insulin resistance is a major component of metabolic syndrome, type 2 Diabetes Mellitus (T2DM) and coronary artery disease (CAD). Although important in T2DM, its role as a predictor of CAD in non-diabetic patients is less studied. In the present study, we aimed to evaluate the association of HOMA-IR with significant CAD, determined by coronary angiography in non-obese, non-T2DM patients. We also evaluate the association between 3 oral glucose tolerance test (OGTT) based insulin sensitivity indexes (Matsuda, STUMVOLL-ISI and OGIS) and CAD. We conducted a cross-sectional study with 54 non-obese, non-diabetic individuals referred for coronary angiography due to suspected CAD. CAD was classified as the "anatomic burden score" corresponding to any stenosis equal or larger than 50 % in diameter on the coronary distribution. Patients without lesions were included in No-CAD group. Patients with at least 1 lesion were included in the CAD group. A 75 g oral glucose tolerance test (OGTT) with measurements of plasma glucose and serum insulin at 0, 30, 60, 90 and 120 min was obtained to calculate insulin sensitivity parameters. HOMA-IR results were ranked and patients were also categorized into insulin resistant (IR) or non-insulin resistant (NIR) if they were respectively above or below the 75th percentile (HOMA-IR > 4.21). The insulin sensitivity tests results were also divided into IR and NIR, respectively below and above each 25th percentile. Chi square was used to study association. Poisson Regression Model was used to compare prevalence ratios between categorized CAD and IR groups. RESULTS: Fifty-four patients were included in the study. There were 26 patients (48 %) with significant CAD. The presence of clinically significant CAD was significant associated with HOMA-IR above p75 (Chi square 4.103, p = 0.0428) and 71 % of patients with HOMA-IR above p75 had significant CAD. Subjects with CAD had increased prevalence ratio of HOMA-IR above p75 compared to subjects without CAD (PR 1.78; 95 % CI 1.079-2.95; p = 0.024). Matsuda index, Stumvoll-ISI and OGIS index were not associated with significant CAD. We concluded that, in patients without diabetes or obesity, in whom a coronary angiography study is indicated, a single determination of HOMA-IR above 4.21 indicates increased risk for clinical significant coronary disease. The same association was not seen with insulin sensitivity indexes such as Matsuda, Stunvoll-ISI or OGIS. These findings support the need for further longitudinal research using HOMA-IR as a predictor of cardiovascular disease.

Insulin resistance and triglyceride/HDLc index are associated with coronary artery disease.

BACKGROUND: Insulin-resistance is associated with cardiovascular disease but it is not used as a marker for disease in clinical practice. AIMS: To study the association between the homeostatic model assessment (HOMA-IR) and triglyceride/HDLc ratio (TG/HDLc) with the presence of coronary artery disease in patients submitted to cardiac catheterization. METHODS: In a cross-sectional study, 131 patients (57.0 +/- 10 years-old, 51.5% men) underwent clinical, laboratory and angiographic evaluation and were classified as No CAD (absence of coronary artery disease) or CAD (stenosis of more than 30% in at least one major coronary artery). RESULTS: Prevalence of coronary artery disease was 56.7%. HOMA-IR and TG/HDLc index were higher in the CAD vs No CAD group, respectively: HOMA-IR: 3.19 (1.70-5.62) vs. 2.33 (1.44-4.06), p = 0.015 and TG/HDLc: 3.20 (2.38-5.59) vs. 2.80 (1.98-4.59) p = 0.045) - median (p25-75). After a ROC curve analysis, cut-off values were selected based on the best positive predictive value for each variable: HOMA-IR = 6.0, TG/HDLc = 8.5 and [HOMA-IRxTG/HDLc] = 28. Positive predictive value for coronary artery disease for HOMA-IR>6.0 was 82.6%, for TG/HDLc>8.5 was 85.7% and for [HOMA-IRxTG/HDLc]>28 was 88.0%. Adjusted relative risk (age, gender, diabetes, body mass index, systolic blood pressure) for the presence of coronary artery disease was: for HOMA-IR>6.0, 1.47 (95.CI: 1.06-2.04, p = 0.027), for TG/HDLc>8.5, 1.46 (95% CI:1.07-1.98), p = 0.015) and for [HOMA-IR x TG/HDLc] >28, 1.64 (95%CI: 1.28-2.09), p < 0.001). CONCLUSIONS: Increased HOMA-IR, TG/HDLc and their product are positively associated with angiographic coronary artery disease, and may be useful for risk stratification as a high-specificity test for coronary artery disease.

Increased urinary TGF-beta1 and cortical renal GLUT1 and GLUT2 levels: additive effects of hypertension and diabetes.

BACKGROUND/AIM: Diabetes and mesangial stretch caused by hypertension increase mesangial matrix deposition which is induced by local production of transforming growth factor beta 1 (TGF-beta1). Both conditions are associated with cortical GLUT1 overexpression. We evaluated the effect of genetically determined hypertension and its association with diabetes on urinary TGF-beta1 and cortical GLUT1 and GLUT2 expression. METHODS: We studied Wistar-Kyoto rats (controls, C) and spontaneously hypertensive rats (SHR), weighing approximately 210 g, 30 days after the injection of streptozotocin (diabetic, D) or citrate buffer (10 C, 9 SHR, 12 C-D and 15 SHR-D). Twenty-four-hour urine was collected for glucose, albumin, and TGF-beta1 determinations. Catheters were implanted into the femoral artery to measure the arterial blood pressure in conscious animals 1 day later. Then GLUT1 and GLUT2 protein levels (Western blotting) in renal cortex and medulla were evaluated. RESULTS: The cortical GLUT1 levels were 5, 2, and 7 times higher in SHR, C-D, and SHR-D groups versus C group (p < 0.05); the GLUT2 contents were 1.5, 1.8, and 2.3 times higher in SHR, C-D and SHR-D groups versus C group (p < 0.05). The urinary TGF-beta1 level was elevated by diabetes and diabetes and hypertension, but not by hypertension alone: 1.39 +/- 0.2, 2.34 +/- 0.6, 18.2 +/- 3.2, and 28.8 +/- 7.6 ng/24 h, respectively, in C, SHR, C-D, and SHR-D groups (p < 0.05). CONCLUSIONS: Diabetes, hypertension, and especially their association increase the renal cortical GLUT1 and GLUT2 levels. The magnitude of GLUT1 overexpression caused by hypertension is higher than that induced by diabetes alone. The impact on urinary TGF-beta1 occurs when diabetes and hypertension are associated, suggesting an effect that is triggered in the presence of GLUT1 overexpression and hyperglycemia.

Patogênese da nefropatia diabética: o papel das citocinas / Pathogenesis of diabetic nephropathy: citokines role

Os autores abordam a patogênese da nefropatia diabética (ND) em seus aspectos hemodinâmicos-renais e metabólicos, com ênfase na formaçäo da matriz extra celular (MEC). O aumento da pressäo capilar intra-glomerular é um fator patogenético bem estabelecido, mas seu mecanismo de lesäo, embora desconhecido, pode envolver distensäo glomerular, levando a um aumento da produçäo de MEC. Existe entretanto um efeito direto da glicose, observado em glomérulos in vitro, onde altas concentraçöes de glicose estimulam o aumento de síntese da MEC. Este efeito pode ser tanto direto, via ativaçäo da proteina quinase C, como indireto pela formaçäo de produtos de glicosilaçäo nao-enzimática ou pela ativaçao da via dos polióis. O TGF-beta (Transforming Growth Factor Beta) é uma citocina que promove aumento de síntese e a reduçäo da degradaçao da MEC, levando ao acúmulo desta. Aumentos dos níveis de RNAm para TGF-beta no glomérulo de ratos diabéticos já foram documentados nas fases iniciais da ND experimental e a presença de reaçäo imunohistoquímica para TGF-beta já foi detectada em ratos e em pacientes com ND estabelecida. O TGF-beta também regula, in vitro, o aumento de síntese de MEC induzido pela angiotensina II e pelo tromboxane A2. A IGF-1 (Insulin Growth Factor-1) pode ter papel significativo na hipertrofia renal diabética, enquanto que o TNF-alpha (Tumor Necrosis Factor) participa na regulaçäo do aumento da permeabilidade do endotélio glomerular. As demais citocinas (EGF, FGF, IL-1, PDGF e TGF-a) ainda precisam ser melhor estudadas.