Comparing quality of life in traditional face-to-face visits with a hybrid approach of telemedicine with in-person follow-ups in recent users of advanced closed-loop systems: a randomized controlled clinical trial in patients with type 1 diabetes.

Background: Our objective was to assess the effect of a hybrid telemedicine approach, in conjunction with face-to-face follow-up, on the quality of life in recent users of an advanced hybrid closed-loop (AHCL) system. Methods: A 1-year open randomized (1:1) clinical trial (ClinicalTrials.gov ID NCT04900636). Participants with type 1 diabetes (T1D) recent users of an AHCL system (Minimed® 780G) for at least 2-6 months, and ⩾18 years old were eligible. The primary outcome was the change in quality of life measured by the Type 1 Diabetes Life (ViDa1) Questionnaire from baseline to 12 months of hybrid telemedicine plus face-to-face follow-up compared to standard clinical practice. Additionally, impacts on A1c levels, glucose metrics, advert events, and safety outcomes were assessed. Results: Between January and December 2021, 46 participants were randomly assigned in a 1:1 ratio to either the hybrid telemedicine group (n = 23) or the control group (n = 23); 45 participants completed the study, with only 1 from the control group withdrawing before visit 3. At baseline, mean age was 37 ± 15 years and A1c was 6.9 ± 0.5%. After 12 months, no statistically significant differences in ViDa1 scores between groups were observed. Despite reducing in-person visits in the hybrid follow-up arm, there were no increases in adverse events. Overall, A1c levels significantly decreased from 6.9 ± 0.5% at baseline to 6.7 ± 0.5% after 12 months (P = 0.006) without differences between treatment arms, accompanied by reductions in glycemic variability and time below the target range. Conclusion: Our study suggests that there were no significant differences in ViDa1 scores between the two groups at the end of the follow-up. However, among adult patients with T1D who recently adopted an AHCL system, satisfactory glycemic control can be attained through a hybrid follow-up approach, reducing face-to-face visits, without increasing technical complications.

Investigating the Link between Intermediate Metabolism, Sexual Dimorphism, and Cardiac Autonomic Dysfunction in Patients with Type 1 Diabetes.

Sexual dimorphism influences cardiovascular outcomes in type 1 diabetes (T1D), with women facing a higher relative risk of macrovascular events compared to men, especially after menopause. This study hypothesizes that abnormalities in intermediate metabolism may be associated with cardiac autonomic neuropathy (CAN) in T1D. We aim to assess low molecular weight metabolites (LMWM) as markers of CAN in T1D, considering the effects of sexual dimorphism and age. In this cross-sectional study, we included 323 subjects with T1D (147 women and 176 men), with a mean age of 41 ± 13 years. A total of 44 women and 41 men were over 50 years old. CAN was assessed using Ewing's tests, and serum metabolites were analyzed by proton nuclear magnetic resonance spectroscopy (1H-NMR). Patients with CAN had lower levels of valine, isoleucine, and threonine, and higher levels of lactate, compared to those without CAN. These differences persisted after adjusting for BMI and estimated glucose disposal rate (eGDR). In a logistic regression model (R² = 0.178, p < 0.001), the main determinants of CAN included isoleucine [Exp(ß) = 0.972 (95% CI 0.952; 0.003)], age [Exp(ß) = 1.031 (95% CI 1.010; 1.053)], A1c [Exp(ß) = 1.361 (95% CI 1.058; 1.752)], and microangiopathy [Exp(ß) = 2.560 (95% CI 1.372; 4.778)]. Sex influenced LMWM profiles, with over half of the metabolites differing between men and women. However, no interactions were found between CAN and sex, or between sex, age, and CAN, on metabolomics profiles. Our findings suggest an association between CAN and LMWM levels in T1D. The sexual dimorphism observed in amino acid metabolites was unaffected by the presence of CAN.

Obesity and polycystic ovary syndrome influence on intestinal permeability at fasting, and modify the effect of diverse macronutrients on the gut barrier.

Women with the extremely prevalent polycystic ovary syndromegather multiple cardiovascular risk factors and chronic subclinical inflammation. Interactions between diet, adiposity, and gut microbiota modulate intestinal permeabilityand bacterial product translocation, and may contribute to the chronic inflammation process associated with the polycystic ovary syndrome. In the present study, we aimed to address the effects of obesity, functional hyperandrogenism, and diverse oral macronutrients on intestinal permeabilityby measuring circulating markers of gut barrier dysfunction and endotoxemia. Participants included 17 non-hyperandrogenic control women, 17 women with polycystic ovary syndrome, and 19 men that were submitted to glucose, lipid, and protein oral loads. Lipopolysaccharide-binding protein, plasma soluble CD14, succinate, zonulin family peptide, and glucagon-like peptide-2 were determined at fasting and after oral challenges. Macronutrient challenges induced diverse changes on circulating intestinal permeabilitybiomarkers in the acute postprancial period, with lipids and proteins showing the most unfavorable and favorable effects, respectively. Particularly, lipopolysaccharide-binding protein, zonulin family peptide, and glucagon-like peptide-2 responses were deregulated by the presence of obesity after glucose and lipid challenges. Obese subjects showed higher fasting intestinal permeabilitybiomarkers levels than non-obese individuals, except for plasma soluble CD14. The polycystic ovary syndromeexacerbated the effect of obesity further increasing fasting glucagon-like peptide-2, lipopolysaccharide-binding protein, and succinate concentrations. We observed specific interactions of the polycystic ovary syndromewith obesity in the postprandial response of succinate, zonulin family peptide, and glucagon-like peptide-2. In summary, obesity and polycystic ovary syndromemodify the effect of diverse macronutrients on the gut barrier, and alsoinfluence intestinal permeabilityat fasting,contributing to the morbidity of functional hyperandrogenism by inducing endotoxemia and subclinical chronic inflammation.

"Arterial stiffness is not associated with changes in the circadian pattern of blood pressure in patients with type 1 diabetes mellitus and cardiovascular autonomic dysfunction".

INTRODUCTION: Cardiovascular autonomic neuropathy (CAN) associates an abnormal circadian pattern in blood pressure (BP) regulation that might be aggravated by the coexistence of arterial stiffness. We aimed to evaluate the effect of arterial stiffness in the circadian rhythm of BP in patients with type 1 diabetes and CAN. METHODS: Cross-sectional study including 56 consecutive patients with type 1 diabetes and CAN, with (n = 28) or without (n = 24) arterial stiffness as defined by an ankle-brachial index above 1.2. CAN was diagnosed by BP and heart rate responses to active standing and cardiovascular autonomic reflex tests. Absence of nocturnal decrease in BP-"non-dipping" pattern- was defined by a daytime to nighttime decrease in mean BP smaller than 10%. RESULTS: The study's subjects mean age was 40 ± 11 years-old, their mean duration of diabetes was 22 ± 10 years, and their mean A1c was 7.9 ± 1.5%. A "non-dipping" pattern was observed in 28 patients (54%) regardless of the presence or absence of arterial stiffness. Age, waist circumference, body mass index, and A1c, were introduced as independent variables into a multiple regression analysis. The stepwise model (R2: 0.113, p = 0.016) retained only A1c levels (ß: ‒ 0.333, 95% confidence interval [CI]: -3.10 to -0.33) as significant predictor of the percentage of nighttime decrease in mean BP. CONCLUSIONS: A non-dipping pattern in BP is very common in patients with type 1 diabetes presenting with subclinical CAN and is associated with a poorer metabolic control. On the contrary, coexistence of arterial stiffness is not associated with abnormalities in circadian BP regulation.

Prevalence and incidence of type 2 diabetes mellitus in patients with adrenal incidentalomas: a study of 709 cases.

AIM: To evaluate the prevalence and incidence of type 2 diabetes in patients with nonfunctioning adrenal incidentalomas (NFAI) or adrenal incidentalomas (AI) with autonomous cortisol secretion (ACS). METHODS: In this single-center retrospective study, all patients with adrenal incidentalomas ≥1 cm and ACS or NFAI studied between 2013 and 2020 were included. ACS was defined by a post-dexamethasone suppression test (DST) serum cortisol concentration ≥1.8 µg/dl, in the absence of signs of hypercortisolism, and NFAI was defined as a DST < 1.8 µg/dl without biochemical evidence of hypersecretion of other hormones. RESULTS: Inclusion criteria were met by 231 patients with ACS and 478 with NFAI. At diagnosis, type 2 diabetes was present in 24.3% of patients. No differences were found in the prevalence of type 2 diabetes (27.7 vs. 22.6%, P = 0.137) between patients with ACS and NFAI. However, fasting plasma glucose values and glycated hemoglobin levels were significantly higher in patients with ACS than with NFAI (112 ± 35.6 vs. 105 ± 29 mg/dl, P = 0.004; and 6.5 ± 1.4 vs. 6.1 ± 0.9%, P = 0.005, respectively). Furthermore, patients with type 2 diabetes had higher urinary free cortisol (P = 0.039) and late-night salivary cortisol levels (P = 0.010) than those without type 2 diabetes. After a median follow-up of 28 months, no differences were found in the incidence of type 2 diabetes between the groups (HR 1.17, 95% 0.52-2.64). CONCLUSION: Type 2 diabetes was present in one fourth of our cohort. We found no differences in its prevalence or incidence between the groups. However, glycemic control might be worse among diabetic patients with ACS. Higher concentrations of urinary and salivary cortisol were found in patients with than without type 2 diabetes.

Switching to an advanced hybrid closed-loop system in real-world practice improves hypoglycemia awareness and metabolic control in adults with type 1 diabetes, particularly in those with impaired perception of hypoglycemia symptoms.

AIMS: To evaluate the efficacy of an advance closed-loop (AHCL) system in restoring awareness of hypoglycemia in patients with type 1 diabetes (T1D). METHODS: We conducted a prospective study including 46 subjects with T1D flash glucose monitoring (FGM) or continuous glucose monitoring (CGM) switching to a Minimed 780G® system. Patients were classified in three groups according to the therapy used before switching to Minimed® 780G: multiple dose insulin (MDI) therapy + FGM (n = 6), continuous subcutaneous insulin infusion + FGM (n = 21), and sensor-augmented pump with predictive low-glucose suspend (n = 19). FGM/CGM data were analyzed at baseline, after 2 and 6 months on AHCL. Clarke's score of hypoglycemia awareness was compared at baseline and 6 months recordings. We also compared the efficacy of the AHCL system in improving A1c among patients with appropriate perception of symptoms of hypoglycemia compared to those presenting with impaired awareness of hypoglycemia (IAH). RESULTS: Participants had a mean age of 37 ± 15 and a diabetes duration of 20 ± 10 years. At baseline, 12 patients (27%) showed IAH as defined by a Clarke's score ≥ 3. Patients with IAH were older and had lower estimated glomerular filtration rate (eGFR) compared with those who did not have IAH; with no differences in baseline CGM metrics or A1c. An overall decrease in A1c was observed after 6 months on AHCL system (from 6.9 ± 0.5% to 6.7 ± 0.6%, P < 0.001), regardless of prior insulin therapy. The improvement in metabolic control was greater in patients with IAH, showing a reduction in A1c from 6.9 ± 0.5 to 6.4 ± 0.4% vs 6.9 ± 0.5 to 6.8 ± 0.6% (P = 0.003), showing a parallel increase in total daily boluses of insulin and automatic bolus correction administered by the AHCL system. In patients with IAH Clarke's score decreased from 3.6 ± 0.8 at baseline to 1.9 ± 1.6 after 6 months (P < 0.001). After 6 months on AHCL system, only 3 patients (7%) presented with a Clarke's score ≥ 3, resulting in an absolute risk reduction of 20% (95% confidence interval: 7-32) of having IAH. CONCLUSIONS: Switching from any type of insulin administration to AHCL system improves restoration of hypoglycemia awareness and metabolic control in patients with T1D, particularly in adults with impaired perception of hypoglycemia symptoms. TRIAL REGISTRATION: ClinicalTrial.gov ID NCT04900636.

Sex differences and sex steroids influence on the presentation and severity of cardiovascular autonomic neuropathy of patients with type 1 diabetes.

BACKGROUND: Sex differences characterize cardiovascular outcomes in patients with type 1 diabetes. Cardioautonomic neuropathy is a common complication of type 1 diabetes that associates increased morbi-mortality. Data regarding the interplay between sex and cardiovascular autonomic neuropathy are scarce and controversial in these patients. We aimed to address sex-related differences in the prevalence of seemingly asymptomatic cardioautonomic neuropathy in type 1 diabetes, and their associations with sex steroids. METHODS: We conducted a cross-sectional study including 322 consecutively recruited patients with type 1 diabetes. Cardioautonomic neuropathy was diagnosed using Ewing's score and power spectral heart rate data. We assessed sex hormones by liquid chromatography/tandem mass spectrometry. RESULTS: When considering all subjects as a whole, asymptomatic cardioautonomic neuropathy prevalence was not significantly different between women and men. When age was taken into account, the prevalence of cardioautonomic neuropathy was similar among young men and those > 50 years. However, in women > 50 years, the prevalence of cardioautonomic neuropathy doubled that of young women [45.8% (32.6; 59.7) vs. 20.4% (13.7; 29.2), respectively]. The OR of having cardioautonomic neuropathy was 3.3 higher in women > 50 years than in their younger counterparts. Furthermore, women presented more severe cardioautonomic neuropathy than men. These differences were even more marked when women were classified according their menopausal status instead of age. Peri- and menopausal women had an OR 3.5 (1.7; 7.2) of having CAN compared with their reproductive-aged counterparts [CAN prevalence: 51% (37; 65) vs. 23% (16; 32), respectively]. A binary logistic regression model (R2: 0.161; P = 0.001) displayed age > 50 years as a significant determinant of cardioautonomic neuropathy only in women. Androgens were positively associated with heart rate variability in men, and negatively in women. Accordingly, cardioautonomic neuropathy was associated with increased testosterone/estradiol ratio in women but to decreased testosterone concentrations in men. CONCLUSIONS: Menopause in women with type 1 diabetes is accompanied by an increase in the prevalence of asymptomatic cardioautonomic neuropathy. This age-related excess risk of cardioautonomic neuropathy is not observed in men. Men and women with type 1 diabetes have opposite associations between circulating androgens and indexes of cardioautonomic function. Trial registration ClinicalTrials.gov Identifier: NCT04950634.

Effect of Iron Depletion by Bloodletting vs. Observation on Oxidative Stress Biomarkers of Women with Functional Hyperandrogenism Taking a Combined Oral Contraceptive: A Randomized Clinical Trial.

Women with functional hyperandrogenism show both increased markers of oxidative stress and a mild iron overload. Combined oral contraceptives (COC) may worsen redox status in the general population. Since iron depletion ameliorates oxidative stress in other iron overload states, we aimed to address the changes in the redox status of these women as a consequence of COC therapy and of bloodletting, conducting a randomized, controlled, parallel, open-label clinical trial in 33 adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. After three months of treatment with a COC, participants were randomized (1:1) to three scheduled bloodlettings or observation for another nine months. After taking a COC, participants showed a mild decrease in their plasma electrochemical antioxidant capacity, considering fast-acting antioxidants [MD: −1.51 (−2.43 to −0.60) µC, p = 0.002], and slow-acting antioxidants [MD: −1.90 (−2.66 to −1.14) µC, p < 0.001]. Women submitted to bloodletting showed a decrease in their non-enzymatic antioxidant capacity levels (NEAC) throughout the trial, whereas those individuals in the control arm showed a mild increase in these levels at the end of the study (Wilks' λ: 0.802, F: 3.572, p = 0.041). Decreasing ferritin and plasma hemoglobin during the trial were associated with worse NEAC levels. COC may impair redox status in women with functional hyperandrogenism. Decreasing iron stores by scheduled bloodletting does not override this impairment.

Bloodletting has no effect on the blood pressure abnormalities of hyperandrogenic women taking oral contraceptives in a randomized clinical trial.

Normoferritinemic women with functional hyperandrogenism show a mild iron overload. Iron excess, hyperandrogenism, and cardioautonomic dysfunction contribute to blood pressure (BP) abnormalities in these patients. Furthermore, combined oral contraceptives (COC) prescribed for hyperandrogenic symptoms may worse BP recordings. Iron depletion by phlebotomy appears to lower BP in other acquired iron overload conditions. We aimed to determine the effect of iron depletion on the office BP, ambulatory BP monitoring, and frequency of hypertension in patients with functional hyperandrogenism submitted to standard therapy with COC. We conducted a phase 2 randomized, controlled, parallel, open-label clinical trial (NCT02460445) in adult women with functional hyperandrogenism including hyperandrogenic polycystic ovary syndrome and idiopathic hyperandrogenism. After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to three scheduled bloodlettings or observation for another 9 months. Main outcome measures were the changes in office BP, 24-h-ambulatory BP, and frequency of hypertension in both study arms. From June 2015 to June 2019, 33 women were included in the intention-to-treat analyses. We observed an increase in mean office systolic BP [mean of the differences (MD): 2.5 (0.3-4.8) mmHg] and night-time ambulatory systolic BP [MD 4.1 (1.4-6.8) mmHg] after 3 months on COC. The percentage of nocturnal BP non-dippers also increased, from 28.1 to 92.3% (P < 0.001). Office and ambulatory BP did not change throughout the experimental period of the trial, both when considering all women as a whole or as a function of the study arm. The frequency of the non-dipping pattern in BP decreased during the experimental period [OR 0.694 (0.577-0.835), P < 0.001], regardless of the study arm. Decreasing iron stores by scheduled bloodletting does not override the BP abnormalities caused by COC in women with functional hyperandrogenism.

Iron Overload in Functional Hyperandrogenism: In a Randomized Trial, Bloodletting Does Not Improve Metabolic Outcomes.

CONTEXT: Functional hyperandrogenism may be associated with a mild increase in body iron stores. Iron depletion exerts a beneficial effect on metabolic endpoints in other iron overload states. OBJECTIVES: (i) To determine the effect of iron depletion on the insulin sensitivity and frequency of abnormal glucose tolerance in patients with functional hyperandrogenism submitted to standard therapy with combined oral contraceptives (COC). ii) To assess the overall safety of this intervention. DESIGN: Randomized, parallel, open-label, clinical trial. SETTING: Academic hospital. PATIENTS: Adult women with polycystic ovary syndrome or idiopathic hyperandrogenism. INTERVENTION: After a 3-month run-in period of treatment with 35 µg ethinylestradiol plus 2 mg cyproterone acetate, participants were randomized (1:1) to 3 scheduled bloodlettings or observation for another 9 months. MAIN OUTCOME MEASURES: Changes in insulin sensitivity index and frequency of prediabetes/diabetes, and percentage of women in whom bloodletting resulted in plasma hemoglobin <120 g/L and/or hematocrit <0.36. RESULTS: From 2015 to 2019, 33 women were included by intention-to-treat. During the follow-up, insulin sensitivity did not change in the whole group of women or between study arms [mean of the differences (MD): 0.0 (95%CI: -1.6 to 1.6)]. Women in the experimental arm showed a similar odds of having prediabetes/diabetes than women submitted to observation [odds ratio: 0.981 (95%CI: 0.712 to 1.351)]. After bloodletting, 4 (21.1%) and 2 women (10.5%) in the experimental arm had hemoglobin (Hb) levels <120 g/L and hematocrit (Hct) values <0.36, respectively, but none showed Hb <110 g/L or Hct <0.34. CONCLUSIONS: Scheduled bloodletting does not improve insulin sensitivity in women with functional hyperandrogenism on COC.