Heterogeneity of glycaemic phenotypes in type 1 diabetes.

AIMS/HYPOTHESIS: Our study aims to uncover glycaemic phenotype heterogeneity in type 1 diabetes. METHODS: In the Study of the French-speaking Society of Type 1 Diabetes (SFDT1), we characterised glycaemic heterogeneity thanks to a set of complementary metrics: HbA1c, time in range (TIR), time below range (TBR), CV, Gold score and glycaemia risk index (GRI). Applying the Discriminative Dimensionality Reduction with Trees (DDRTree) algorithm, we created a phenotypic tree, i.e. a 2D visual mapping. We also carried out a clustering analysis for comparison. RESULTS: We included 618 participants with type 1 diabetes (52.9% men, mean age 40.6 years [SD 14.1]). Our phenotypic tree identified seven glycaemic phenotypes. The 2D phenotypic tree comprised a main branch in the proximal region and glycaemic phenotypes in the distal areas. Dimension 1, the horizontal dimension, was positively associated with GRI (coefficient [95% CI]) (0.54 [0.52, 0.57]), HbA1c (0.39 [0.35, 0.42]), CV (0.24 [0.19, 0.28]) and TBR (0.11 [0.06, 0.15]), and negatively with TIR (-0.52 [-0.54, -0.49]). The vertical dimension was positively associated with TBR (0.41 [0.38, 0.44]), CV (0.40 [0.37, 0.43]), TIR (0.16 [0.12, 0.20]), Gold score (0.10 [0.06, 0.15]) and GRI (0.06 [0.02, 0.11]), and negatively with HbA1c (-0.21 [-0.25, -0.17]). Notably, socioeconomic factors, cardiovascular risk indicators, retinopathy and treatment strategy were significant determinants of glycaemic phenotype diversity. The phenotypic tree enabled more granularity than traditional clustering in revealing clinically relevant subgroups of people with type 1 diabetes. CONCLUSIONS/INTERPRETATION: Our study advances the current understanding of the complex glycaemic profile in people with type 1 diabetes and suggests that strategies based on isolated glycaemic metrics might not capture the complexity of the glycaemic phenotypes in real life. Relying on these phenotypes could improve patient stratification in type 1 diabetes care and personalise disease management.

Initiation of the Fixed Combination IDegLira in Patients with Type 2 Diabetes on Prior Injectable Therapy: Insights from the EASY French Real-World Study.

INTRODUCTION: Combining basal insulin (BI) with glucagon-like peptide-1 receptor agonist (GLP-1RA) is recognized as a relevant option to optimize glucose control in type 2 diabetes (T2D). The EASY real-world study aimed to evaluate the modalities of initiation and the effectiveness of the insulin Degludec plus Liraglutide (IDegLira) fixed-ratio combination in the French health care system. METHODS: A retrospective analysis included all patients with T2D and prior injectable therapy (GLP1-RA and/or insulin) who started treatment with IDegLira from September 2016 to December 2017 in 11 French diabetes centers. Baseline characteristics, reasons for IDegLira initiation, and modes of implementation were collected from the medical records. Changes in HbA1c and body weight were determined in patients with available follow-up data (nearest 6-month visit). RESULTS: IDegLira was initiated in 629 patients previously treated with GLP-1RA alone (11.6%), insulin alone (31.5% including 16.5% with BI and 14.9% with multiple daily injections [MDI]) or a free combination of GLP-1RA and insulin (56.9% including 44.8% with BI and 12.1% with MDI), associated or not with oral agents. IDegLira starting dose (mean of 29 ± 11 dose steps) most often exceeded the recommended dose, and was significantly correlated with prior BI but not GLP-1RA dosage. At initiation, mean age, body mass index (BMI) and HbA1c were 60.1 ± 10.2 years, 33.4 ± 6.2 kg/m2 and 8.8 ± 1.7%, respectively. In 461 patients with available follow-up (median 178 days), HbA1c decreased in all subgroups submitted to treatment intensification (- 1.7 ± 1.8% [p < 0.0001], - 1.2 ± 1.8% [p < 0.001] and - 0.8 ± 1.8% [p = 0.0026] in patients with prior GLP-1RA, BI or MDI therapy, respectively) but also in those switching from BI and GLP-1RA free combination (- 0.2 ± 0.9%, p = 0.0419). Significant body weight gain occurred in patients previously treated with GLP-1RA alone (+ 1.5 ± 5.8 kg, p = 0.0572) or combined to BI (+ 1.0 ± 3.1 kg, p < 0.0001) while those on BI (- 1.4 ± 4.6 kg, p = 0.0139) or MDI (- 1.4 ± 5.0 kg, p = 0.0484) experienced weight loss. CONCLUSIONS: While providing new information on the use of IDegLira in the French healthcare system, these data confirm the effectiveness of this fixed-ratio combination in the management of T2D.

Glycaemic Variability and Hyperglycaemia as Prognostic Markers of Major Cardiovascular Events in Diabetic Patients Hospitalised in Cardiology Intensive Care Unit for Acute Heart Failure.

(1) Background: Hyperglycaemia and hypoglycaemia are both emerging risk factors for cardiovascular disease. Nevertheless, the potential effect of glycaemic variability (GV) on mid-term major cardiovascular events (MACE) in diabetic patients presenting with acute heart failure (AHF) remains unclear. This study investigates the prognostic value of GV in diabetic patients presenting with acute heart failure (AHF). (2) Methods: this was an observational study including consecutive patients with diabetes and AHF between January 2015 and November 2016. GV was calculated using standard deviation of glycaemia values during initial hospitalisation in the intensive cardiac care unit. MACE, including recurrent AHF, new-onset myocardial infarction, ischaemic stroke and cardiac death, were recorded. The predictive effects of GV on patient outcomes were analysed with respect to baseline characteristics and cardiac status. (3) Results: In total, 392 patients with diabetes and AHF were enrolled. During follow-up (median (interquartile range) 29 (6−51) months), MACE occurred in 227 patients (57.9%). In total, 92 patients died of cardiac causes (23.5%), 107 were hospitalised for heart failure (27.3%), 19 had new-onset myocardial infarction (4.8%) and 9 (2.3%) had an ischaemic stroke. Multivariable logistic regression analysis showed that GV > 50 mg/dL (2.70 mmol/L), age > 75 years, reduced left ventricular ejection fraction (LVEF < 30%) and female gender were independent predictors of MACE: hazard ratios (HR) of 3.16 (2.25−4.43; p < 0.001), 1.54 (1.14−2.08; p = 0.005), 1.47 (1.06−2.07; p = 0.02) and 1.43 (1.05−1.94; p = 0.03), respectively. (4) Conclusions: among other well-known factors of HF, a GV cut-off value of >50 mg/dL was the strongest independent predictive factor for mid-term MACE in patients with diabetes and AHF.

Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer.

BACKGROUND: In patients with low-risk differentiated thyroid cancer undergoing thyroidectomy, the postoperative administration of radioiodine (iodine-131) is controversial in the absence of demonstrated benefits. METHODS: In this prospective, randomized, phase 3 trial, we assigned patients with low-risk differentiated thyroid cancer who were undergoing thyroidectomy to receive ablation with postoperative administration of radioiodine (1.1 GBq) after injections of recombinant human thyrotropin (radioiodine group) or to receive no postoperative radioiodine (no-radioiodine group). The primary objective was to assess whether no radioiodine therapy was noninferior to radioiodine therapy with respect to the absence of a composite end point that included functional, structural, and biologic abnormalities at 3 years. Noninferiority was defined as a between-group difference of less than 5 percentage points in the percentage of patients who did not have events that included the presence of abnormal foci of radioiodine uptake on whole-body scanning that required subsequent treatment (in the radioiodine group only), abnormal findings on neck ultrasonography, or elevated levels of thyroglobulin or thyroglobulin antibodies. Secondary end points included prognostic factors for events and molecular characterization. RESULTS: Among 730 patients who could be evaluated 3 years after randomization, the percentage of patients without an event was 95.6% (95% confidence interval [CI], 93.0 to 97.5) in the no-radioiodine group and 95.9% (95% CI, 93.3 to 97.7) in the radioiodine group, a difference of -0.3 percentage points (two-sided 90% CI, -2.7 to 2.2), a result that met the noninferiority criteria. Events consisted of structural or functional abnormalities in 8 patients and biologic abnormalities in 23 patients with 25 events. Events were more frequent in patients with a postoperative serum thyroglobulin level of more than 1 ng per milliliter during thyroid hormone treatment. Molecular alterations were similar in patients with or without an event. No treatment-related adverse events were reported. CONCLUSIONS: In patients with low-risk thyroid cancer undergoing thyroidectomy, a follow-up strategy that did not involve the use of radioiodine was noninferior to an ablation strategy with radioiodine regarding the occurrence of functional, structural, and biologic events at 3 years. (Funded by the French National Cancer Institute; ESTIMABL2 ClinicalTrials.gov number, NCT01837745.).

In silico development of new PET radiopharmaceuticals from mTOR inhibitors.

Rapamycin (or sirolimus) is a macrolide that has shown to be useful as an immunosuppressant and that was studied in metabolic, neurological, or genetic disorders. Rapamycin is a specific natural inhibitor of the mechanistic target of rapamycin (mTOR) that is a kinase protein playing a pivotal role in cell growth and proliferation by activation of several metabolic processes. This work aimed to evaluate the utility of several compounds obtained from rapamycin and its semi-synthetic analogs everolimus and temsirolimus as possible radiopharmaceuticals oriented to this protein. Density Functional Theory calculations of these molecules were made and further analysis of the dual descriptor, charges populations, and of the electrostatic potential surfaces were performed. Molecular docking simulations were used to evaluate the interactions of the rapamycin with the studied candidates. They allowed us to propose two strategies for the synthesis of novel compounds based on electrophilic reactions. Molecular docking results also helped us to eliminate molecules that did not interact correctly with the target. Finally, we found for the first time, that the novel compounds synthesized through the electrophilic addition reaction that employed 18F-selectfluor, should maintain the biological activity of original compounds and could be suitable as Positron Emission Tomography radiopharmaceuticals targeting mTOR Complex1 system.

Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.

AIMS/HYPOTHESIS: This is an update of the results from the previous report of the CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study, which aims to describe the outcomes and prognostic factors in patients with diabetes hospitalised for coronavirus disease-2019 (COVID-19). METHODS: The CORONADO initiative is a French nationwide multicentre study of patients with diabetes hospitalised for COVID-19 with a 28-day follow-up. The patients were screened after hospital admission from 10 March to 10 April 2020. We mainly focused on hospital discharge and death within 28 days. RESULTS: We included 2796 participants: 63.7% men, mean age 69.7 ± 13.2 years, median BMI (25th-75th percentile) 28.4 (25.0-32.4) kg/m2. Microvascular and macrovascular diabetic complications were found in 44.2% and 38.6% of participants, respectively. Within 28 days, 1404 (50.2%; 95% CI 48.3%, 52.1%) were discharged from hospital with a median duration of hospital stay of 9 (5-14) days, while 577 participants died (20.6%; 95% CI 19.2%, 22.2%). In multivariable models, younger age, routine metformin therapy and longer symptom duration on admission were positively associated with discharge. History of microvascular complications, anticoagulant routine therapy, dyspnoea on admission, and higher aspartate aminotransferase, white cell count and C-reactive protein levels were associated with a reduced chance of discharge. Factors associated with death within 28 days mirrored those associated with discharge, and also included routine treatment by insulin and statin as deleterious factors. CONCLUSIONS/INTERPRETATION: In patients with diabetes hospitalised for COVID-19, we established prognostic factors for hospital discharge and death that could help clinicians in this pandemic period. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04324736.

Endocrine vigilance in COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus responsible for a pandemic that emerged in December 2019. Heterogeneous clinical forms are described from asymptomatic to severe hypoxaemic acute respiratory syndrome with multisystem organ failure. The impact of this coronavirus disease 2019 on the endocrine glands remains unknown. However, the results of previous studies on viruses from the same family allow us to write proposals for patients followed for chronic endocrine diseases. Currently, if these subjects are infected with SARS-CoV-2, they must not stop their treatment. In some cases, hormone replacement doses have to be increased. In case of worsening clinical signs, hormonal biological monitoring must be done. This article will be helpful for improving the management of chronic endocrine diseases that could affect thyroid, adrenals, gonads and pituitary gland functions. Proposals could be applied in COVID-19 infected subjects or in those who have been in contact with COVID-19 infected people.

Triglycerides as a Metabolic Target in Afrocaribbean Infertile Women with Polycystic Ovary Syndrome.

Background: Polycystic ovary syndrome (PCOS) is classically associated with insulin resistance, metabolic syndrome, or type 2 diabetes. Infertile Afrocaribbean (AC) women with PCOS may have metabolic features that could help to better target their management. Objective: To evaluate the characteristics of PCOS in this population and their metabolic profile to target the worst metabolic parameter. Methods: A retrospective study including infertile AC women for 4 years. PCOS was diagnosed using Rotterdam criteria and compared with non-PCOS women referred consecutively for infertility during the same period. Results: Among 981 AC women evaluated for infertility, PCOS was found in 17%. PCOS women were younger than non-PCOS women. After age and body mass index (BMI) matching, only fasting blood glucose and triglyceride levels were higher in PCOS women compared with non-PCOS women. PCOS was positively correlated with triglyceride levels and negatively with vitamin D levels. PCOS women with obesity had low high-density lipoprotein-cholesterol and increased triglyceride levels compared with those without obesity. No correlation was found between lipids or glucose levels and androgen levels. Multivariate analysis showed that only triglycerides were independently related to PCOS after adjustment for age and BMI. Conclusions: In the AC population where the prevalence of obesity and diabetes is increased, the metabolic profile of infertile women with PCOS is mainly characterized by hypertriglyceridemia, with a higher risk of visceral obesity and nonalcoholic fatty liver disease. Interventional studies would be useful to evaluate the predictive value of hypertriglyceridemia on diabetes and cardiovascular diseases in this population.

Plantains: Gluco-friendly usage.

Plantains are a staple food for a large proportion of the world's population. Rich sources of carbohydrates, they are considered taboo by most diabetes care providers. For persons living with diabetes, however, they are a preferred food item. This multi country authored article discusses the nutritional and culinary qualities of plantains. It discusses how to consume the fruit in a glucose-safe manner, by reducing the glycaemic load and total caloric load due to a low glycaemic index. Simple ways of modifying plantain preparation and serving are suggested, to help patients take this foodstuff without impacting glucose control.

A Hungry Bone Syndrome Predicted by 18F-Fluorocholine PET/CT.

Predicting hungry bone syndrome (HBS) after surgical cure of primary hyperparathyroidism (PHPT) can be challenging. A 57-year-old man diagnosed with PHPT was assessed preoperatively by F-fluorocholine PET/CT. An intense and diffuse tracer uptake of the axial and peripheral skeleton was visualized, in addition to a pathologic uptake suggestive of hyperfunctioning parathyroid gland. After the removal of a parathyroid adenoma, a severe and prolonged HBS requiring high doses of calcium and active metabolites of vitamin D was observed. This observation suggests that intense and diffuse bone uptake on F-fluorocholine PET/CT could be a predictive factor for HBS in patients with PHPT.

Hypothyroidism in patients with pseudohypoparathyroidism type Ia: clinical evidence of resistance to TSH and TRH.

OBJECTIVE: Hypothyroidism is a manifestation of multi-hormonal resistance in pseudohypoparathyroidism type Ia (PHP Ia). The objective of the study was to determine the mechanisms of hypothyroidism in PHP Ia. DESIGN: A prospective study. PATIENTS: Ten patients with PHP Ia. MEASUREMENTS: The serum concentrations of TSH, free triiodothyronine (FT(3)), free thyroxine (FT(4)), and prolactin (PRL) were measured at baseline and after stimulation with TRH (200 microg i.v). RESULTS: The median basal serum TSH concentration was 4.92 mU/l. Basal serum TSH concentration was slightly elevated in eight patients (4.22-7.0 mU/l; normal range, 0.4-3.6 mU/l), normal in one patient (2.5 mU/l), and high in one patient (13.1 mU/l). After the TRH test, TSH concentrations increased to 13.4-36.0 mU/l (normal range, 4.0-20.0 mU/l). The absolute values after the test were normal in three patients and high in seven patients. However, TSH responses relative to the baseline value (stimulated/basal TSH and expressed as a fold increase), which reflect the relative increases after TRH stimulation, were low in seven patients (2.3- to 4.3-fold TSH) and normal in three patients. Basal FT(4) concentration was normal in seven patients and low in three patients (range, 8.4-20.0 pmol/l; mean, 14.1+/-4.3 pmol/l; normal range, 10.5-23.0 pmol/l). Basal FT(3) concentration was normal in nine patients and low in one patient (range, 0.9-5.0 pmol/l; mean, 3.8+/-1.1 pmol/l; normal range, 3.3-6.1 pmol/l). FT(4) and FT(3) were not significantly increased after the TRH test. PRL concentration was normal at baseline and increased from 7 to 96 ng/ml after TRH. CONCLUSION: Our results support the hypothesis that patients with PHP Ia have impaired sensitivity to both TSH and TRH.

A PRKAR1A mutation associated with primary pigmented nodular adrenocortical disease in 12 kindreds.

CONTEXT: Primary pigmented nodular adrenocortical disease (PPNAD), a rare cause of corticotropin-independent Cushing syndrome, can be part of Carney complex (CNC), an autosomal dominant multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac myxomas, and endocrine tumors or be isolated (i). Germline PRKAR1A-inactivating mutations have been observed in both CNC and iPPNAD, but with no apparent genotype-phenotype correlation. OBJECTIVE: The objectives of the study were a detailed phenotyping for CNC manifestations in 12 kindreds bearing the same PRKAR1A mutation and a study of the consequences of the mutation and a potential founder effect. DESIGN: The study consisted of descriptive case reports. SETTING: The study was conducted at two referral centers. PATIENTS: The patients described in this study were referred for PRKAR1A gene mutation analysis because of a diagnosis of apparently iPPNAD. RESULTS: We describe a 6-bp polypyrimidine tract deletion [exon 7 IVS del (-7-->-2)] in 12 unrelated kindreds that were referred for Cushing syndrome due to PPNAD. Nine of the patients had no family history; in two, there was a family history of iPPNAD. Only one patient met the criteria for CNC. Relatives carrying the same mutation had no manifestations of CNC or PPNAD, suggesting a low penetrance of this PRKAR1A defect. A founder effect was excluded by extensive genotyping of chromosome 17 markers. CONCLUSIONS: In conclusion, a small intronic deletion of the PRKAR1A gene is a low-penetrance cause of mainly iPPNAD; it is the first PRKAR1A genetic defect to have an association with a specific phenotype.