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Context: Patients with type 1 diabetes (T1D) have higher cardiovascular disease (CVD) risk than the general population., Objective: This observational study aims to evaluate sex-related differences in CVD prevalence and CVD risk estimates in a large cohort of T1D adults., Methods: We conducted a multicenter, cross-sectional study involving 2041 patients with T1D (mean age 46 years; 44.9% women). In patients without pre-existing CVD (primary prevention), we used the Steno type 1 risk engine to estimate the 10-year risk of developing CVD events., Results: CVD prevalence (n = 116) was higher in men than in women aged ≥55 years (19.2 vs 12.8%, P = .036), but comparable between the 2 sexes in those aged <55 years (P = .91). In patients without pre-existing CVD (n = 1925), mean 10-year estimated CVD risk was 15.4 ± 0.4% without any significant sex difference. However, stratifying this patient group by age, the 10-year estimated CVD risk was significantly higher in men than in women until age 55 years (P < .001), but this risk equalized after this age. Carotid artery plaque burden was significantly associated with age ≥55 years and with a medium and high 10-year estimated CVD risk, without any significant sex difference. Diabetic retinopathy and sensory-motor neuropathy were also associated with higher 10-year CVD risk and female sex., Conclusion: Both men and women with T1D are at high CVD risk. The 10-year estimated CVD risk was higher in men aged <55 years than in women of similar age, but these sex differences disappeared at age ≥55 years, suggesting that female sex was no longer protective., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

All vitamin D tests carried out for outpatients aged 18 years or older during the last 3 years at an Italian University Hospital was reviewed. The serum vitamin D concentrations measured since the Italian coronavirus diseases 2019 (COVID-19) lockdown to present did not significantly differ from the previous 2 years (78 vs. 77 nmol/l; P = 0.277), whilst the prevalence of vitamin D deficiency was found to be even marginally lower in 2020 (16.0% vs. 17.9%; P = 0.003). These results suggest that vitamin D deficiency in our province has not increased during the Italian COVID-19 outbreak or in correspondence with the nationwide lockdown., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Context: Nonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance (IR) and predicts type 2 diabetes. Currently, it is uncertain whether NAFLD may directly cause IR or vice versa., Objective: To test the hypothesis that NAFLD is causally related to IR., Design and Methods: We performed a Mendelian randomization (MR) in 904 obese children/adolescents using an NAFLD-related genetic risk score (GRS) as an instrumental variable. We assessed NAFLD by ultrasonography and IR by homeostasis model assessment (HOMA-IR). We also interrogated the MAGIC Consortium dataset of 46 186 adults to assess the association between PNPLA3 rs738409 (ie, the most robust NAFLD-related polymorphism) and HOMA-IR, and we performed a 2-sample MR with 2 large datasets to test reverse causation (HOMA-IR increasing the risk of NAFLD)., Results: Nonalcoholic fatty liver disease prevalence increased by 20% for every increase in the GRS (β-coefficient = 0.20, P < 0.001), and NAFLD was associated with ln-HOMA-IR (β-coefficient = 0.28, P < 0.001). Thus, the expected increase in ln-HOMA-IR for every increase in the GRS (expected β-coefficient) was 0.056 (0.28*0.20) in the case of complete NAFLD-HOMA-IR causal association, and 0.042 in the case of 75% causality. In our cohort, the GRS did not predict ln-HOMA-IR (β-coefficient = 0.007, P = 0.75). In the MAGIC cohort, the PNPLA3 rs738409 did not associate with ln-HOMA-IR. The 2-sample MR failed to show a causal association between ln-HOMA-IR and NAFLD., Conclusions: Our study shows that genetically-influenced NAFLD does not increase HOMA-IR, and genetically-influenced HOMA-IR does not increase the risk of NAFLD. Shared pathogenic pathways or NAFLD subtypes not "captured" by our MR design might underpin the association between NAFLD and HOMA-IR., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Nonalcoholic fatty liver disease (NAFLD) is increasingly diagnosed worldwide and is the most common chronic liver disease in Western countries. In this review, we discuss the role of NAFLD as a novel cardiometabolic risk factor for the development of type 2 diabetes (T2DM) and for the development of major chronic complications and poor glycemic control in people with established T2DM., Evidence Acquisition: This is a clinical, narrative review and not a systematic review and meta-analysis. PubMed was extensively searched for articles using the keywords "nonalcoholic fatty liver disease" or "fatty liver" combined with "diabetes risk," "cardiovascular risk," "cardiovascular mortality," "chronic kidney disease," or "diabetic nephropathy" between 1990 and 2012. Articles published in languages other than English were excluded from the analysis., Evidence Synthesis: NAFLD exacerbates hepatic insulin resistance and increases the risk of developing T2DM. Growing evidence also indicates that NAFLD may worsen glycemic control in people with T2DM and may contribute to the development and progression of the most important chronic complications of diabetes, such as cardiovascular disease and chronic kidney disease., Conclusions: The adverse impact of NAFLD on risk for T2DM and its major chronic vascular complications deserves particular attention among endocrinologists/cardiologists/hepatologists, in view of the implications for screening and surveillance strategies in the growing number of patients with NAFLD. Clinicians who manage patients with NAFLD should not only focus on liver disease, but should also recognize the increased risk of developing T2DM and its chronic vascular complications and undertake early, aggressive risk factor modification.

The hemostatic balance is a complex system where the delicate equilibrium is regulated by several factors, including hormones. This review summarizes current knowledge of the effects of most frequent endocrine and metabolic diseases (such as hypothyroidism, hyperthyroidism, Cushing's syndrome, GH-related pituitary dysfunctions, pituitary prolactin-producing adenomas, polycystic ovary syndrome, primary hyperparathyroidism, and metabolic syndrome) on coagulation and fibrinolysis. Overt hypothyroidism appears to be associated with a bleeding tendency, whereas all other endocrine diseases appear to be associated with a thrombotic tendency. Globally, the disorders of coagulation and fibrinolysis usually range from mild to moderate, and, rarely, to severe laboratory abnormalities (for example, bleeding diathesis in overt hypothyroidism mainly due to an acquired von Willebrand's disease type 1). Further larger and high-quality studies are needed to provide more definitive information on the effects of endocrine disorders on coagulation and fibrinolysis.

Background: Anaemia associated with chronic kidney disease (CKD) has substantial public health importance. However, the association of haemoglobin concentrations with inflammation in the setting of decreased kidney function is not well established., Methods: We analysed cross-sectional data from 7389 outpatient adults, who were referred by general practitioners for routine blood testing between June 2006 and June 2007. Glomerular filtration rate (eGFR) was estimated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation. Multivariable linear regression analysis was used to identify factors independently associated with haemoglobin concentrations across eGFR categories as the main outcome., Results: Of the 7389 participants included in the analytic cohort 2221 (30.1%) participants had eGFR >/=90 mL/min/m(2), 4310 (58.3%) 60-89 mL/min/m(2) and 858 (11.6%) <60 mL/min/m(2). There were significant, graded, increases in high sensitivity C-reactive protein (hs-CRP) and haemoglobin concentrations across eGFR categories independent of age, gender, plasma glucose and lipids (P < 0.0001 for trends). In the multivariable regression analysis, increased hs-CRP concentrations were independently associated with lower haemoglobin concentrations at different stages of eGFR (P < 0.0001 for all). Other independent predictors of lower haemoglobin were older age, female gender and lower eGFR., Conclusions: Our findings suggest that increased plasma hs-CRP concentrations are independently associated with anaemia in the setting of decreased kidney function in a large cohort of unselected adult outpatients.

Background: A potentially modifiable and underestimated risk factor for cardiovascular disease (CVD) in subjects with kidney dysfunction is 25-hydroxyvitamin D deficiency, although the relationship between inadequate vitamin D status and manifest CVD in type 2 diabetic subjects with mild kidney impairment has not been extensively examined., Methods: We evaluated the relationship between serum 25-hydroxyvitamin D concentrations, baseline kidney function (estimated using the modification of diet in renal disease equation) and manifest CVD (myocardial infarction, angina, ischaemic stroke, coronary revascularization or carotid endarterectomy) among 462 consecutive patients with type 2 diabetes., Results: In the whole population, the mean age was 62+/-7 years, 64% were men, 76.3% had hypertension and the mean estimated glomerular filtration rate (GFR) was 94+/-33 ml/min/1.73 m(2). Kidney function was strongly and inversely associated with CVD. In multivariate logistic regression analysis, there was an inverse association between serum 25-hydroxyvitamin D concentrations and prevalent CVD [odds ratio 0.95 (95% CI 0.92-0.98; P=0.001)] in the whole population independent of baseline kidney function and other known risk factors. Additionally, the association between serum 25-hydroxyvitamin concentrations and CVD [odds ratio 0.97 (95% CI 0.94-0.99; P=0.045)] remained statistically significant in participants in the lowest estimated GFR tertile after adjustment for potential confounders., Conclusions: Decreased 25-hydroxyvitamin D concentrations are independently associated with prevalent CVD in type 2 diabetic patients with mild kidney dysfunction.

The purposes of this study were 1) to compare soluble tumor necrosis factor-alpha receptors, which are thought to reflect the degree of TNF-alpha activation, in nondiabetic subjects and type 1 diabetic patients, and 2) to evaluate the effects of smoking and microvascular complications on soluble tumor necrosis factor-alpha receptor levels in type 1 diabetic individuals. Plasma soluble tumor necrosis factor-alpha receptor levels (R1 and R2) were measured in 50 young type 1 diabetic patients without clinical macroangiopathy and in a matched group of 20 healthy volunteers. When diabetic patients were grouped according to smoking and microvascular complication status, the groups of patients had similar values of age, sex, body mass index, blood pressure, lipids, creatinine, and glycometabolic control. Nevertheless, soluble tumor necrosis factor-alpha receptor-R1 levels but not R2 levels, were markedly elevated (P < 0.05 or less) in complicated vs. uncomplicated (2.40 +/- 0.3 vs. 1.80 +/- 0.1 ng/ml) patients and in smokers vs. nonsmokers (2.66 +/- 0.4 vs. 1.76 +/- 0.1 ng/ml). In a two-factor ANOVA, both smoking (P < 0.01) and microvascular complications (P < 0.05) were independent predictors of soluble tumor necrosis factor-alpha receptor-R1. Soluble tumor necrosis factor-alpha receptor levels of diabetic patients who did not smoke or without complications were similar to those of healthy controls. In conclusion, smoking and microvascular complications seem to exert an additive and deleterious impact on TNF-alpha activation, as reflected by levels of soluble tumor necrosis factor-alpha receptors, in young adults with type 1 diabetes.

The aim of this study was to ascertain whether the presence of hypertension conveys a more severe degree of insulin resistance in type 2 diabetes mellitus and, if so, which biochemical pathways are involved. We quantitated the rates of total glucose disposal, glycogen synthesis (GS), glycolysis, glucose oxidation, endogenous glucose production, and LOX in the basal state and during a 4-h euglycemic ( approximately 5 mM) hyperinsulinemic ( approximately 300 pM) clamp carried out in combination with a dual-tracer infusion ([(3)H]-3- and [(14)C]-U-D-glucose) and indirect calorimetry in 42 nonobese noninsulin-treated type 2 diabetic subjects (22 hypertensive and 20 normotensive) and 23 nonobese nondiabetic subjects (9 without and 14 with essential hypertension). Compared with normotensive controls, both groups of diabetic subjects were markedly insulin resistant. In the basal state, all glucose fluxes were similar in diabetic subjects with or without hypertension. During insulin infusion, total glucose disposal was significantly reduced in hypertensive diabetic subjects, compared with their normotensive counterparts (18.7 +/- 1.0 vs. 28.6 +/- 3.0 micromol/min.kg lean body mass; P < 0.01). This difference was almost entirely explained by a marked reduction in GS (4.5 +/- 2.0 vs. 12.5 +/- 3.3 micromol/min.kg lean body mass; P < 0.01). Endogenous glucose production was not different in the two diabetic groups during insulin infusion and was significantly higher than in normotensive controls. Lipid oxidation was less suppressed by hyperinsulinemia in hypertensive than in normotensive diabetic subjects (1.46 +/- 0.1 vs. 0.91 +/- 0.1 micromol/min.kg lean body mass; P < 0.01). Glucose fluxes were not significantly different in nondiabetic subjects with essential hypertension and in normotensive diabetic individuals. These results indicate that hypertension markedly aggravates insulin resistance featuring type 2 diabetes mellitus. The molecular defects underlying this phenomenon involve primarily GS.

Antihypertensive treatment is frequently needed in type 2 diabetes. In this study we measured the rates of total, oxidative, and nonoxidative glucose disposal, glycogen synthesis, glycolysis, endogenous glucose production, and lipid oxidation using a 4-h euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 300 pmol/L) clamp in combination with a dual glucose tracer infusion ([3-(3)H]- and [U-14C] D-glucose) and indirect calorimetry in 40 nonobese subjects with type 2 diabetes. Subjects were studied twice: after a 4-week run-in period and after a 16-week period of double blind, randomized treatment with 4-6 mg/day lacidipine, a calcium channel blocker (n = 19), or 10-20 mg/day lisinopril, an angiotensin-converting enzyme inhibitor (n = 21). Antihypertensive treatment resulted in a significant increase in total glucose disposal during insulin clamp as well as in basal and insulin-stimulated nonoxidative glucose disposal rates. On the contrary, oxidative glucose disposal was significantly decreased by antihypertensive treatment, mainly in the basal state. The changes in glucose disposal rates were not significantly different in subjects treated with lacidipine and in those treated with lisinopril. The suppression of endogenous glucose production during insulin clamp was significantly greater after lacidipine than after lisinopril. These results suggest that treatment of subjects with type 2 diabetes with either lacidipine or lisinopril has no adverse effect on glucose metabolism. Conversely, both drugs seem to improve insulin sensitivity.

To evaluate the effects of chronic cigarette smoking on insulin sensitivity in patients with noninsulin-dependent diabetes mellitus (NIDDM), we examined 28 smokers and 12 nonsmokers with NIDDM, of similar sex, age, body mass index, waist/hip ratio, alcohol consumption, physical activity level, glycometabolic control, diabetes duration, and treatment. Insulin and C-peptide responses to oral glucose load were significantly higher in smokers than nonsmokers, whereas glucose levels were not substantially different. During insulin clamp (20 mU/min.m2), carried out in combination with tritiated glucose infusion and indirect calorimetry, total glucose disposal was markedly reduced in smokers vs. nonsmokers [19 +/- 1.2 vs. 33 +/- 5 mumol/min.kg fat-free mass (FFM); P < 0.001], in a dose-dependent fashion (F = 6.8, P < 0.001 by ANOVA when subjects were categorized for number of cigarettes smoked per day). Oxidative (9 +/- 1 vs. 14 +/- 2 mumol/min.kg FFM; P < 0.01) and nonoxidative (10 +/- 1 vs. 19 +/- 4 mumol/min.kg FFM; P < 0.01) pathways of insulin-mediated intracellular glucose metabolism were similarly reduced in smokers vs. nonsmokers. Plasma free fatty acid levels (240 +/- 33 vs. 130 +/- 23 microEq/L; P < 0.05) and lipid oxidation rate (1.39 +/- 0.1 vs. 0.95 +/- 0.2 mumol/ min.kg FFM; P < 0.05) were less suppressed by hyperinsulinemia in smokers than nonsmokers. In conclusion, chronic cigarette smoking seems to markedly aggravate insulin resistance in patients with NIDDM.