French National Authority for Health assessment of metabolic surgery for type 2 diabetes remission-A meta-analysis in patients with class I to III obesity.

OBJECTIVE: Randomized controlled trials (RCTs) have demonstrated the superiority of metabolic surgery (MS) over medical therapy (MT) in patients with obesity and type 2 diabetes, leading, to a joint statement in 2016 proposing MS to patients with class I obesity and uncontrolled glycemia. Yet, these RCTs included few patients with class I obesity (body mass index 30-35 kg/m2) and even fewer patients with overweight. Our aim was to provide an updated systematic review (SR) with meta-analysis (MA) of RCTs reporting diabetes remission (DR) after MS in these patients. RESEARCH DESIGN AND METHODS: We included in the SR with MA only RCTs with at least 24-month follow-up found in Medline, Cochrane Library, Embase, and LiSSA between January 2008 and September 2022 comparing DR post-MT versus post-MS. We calculated relative risk (RR) and 95 % confidence intervals (CIs) using the Mantel-Haenszel random-effects approach to examine differences in DR between patients allocated to MS versus MT. RESULTS: DR was significantly higher in MS versus MT after 36 months' follow-up in patients with obesity (RR = 6.65 [95 %CI 2.24;19.79]; I² = 27 %; 5 trials, 404 patients), but also specifically in patients with class I obesity (RR = 5.27 [1.31;21.23]; I² = 0 %; 4 trials, 80 patients). Furthermore, and in line with previous results, all additional MAs performed in patients with obesity in this work favor MS (specifically Roux-en-Y gastric bypass) over MT at 24, 36 (only) and 60 months of follow-up. CONCLUSIONS: Although the data available in patients with class I obesity and type 2 diabetes remains limited, MA shows higher rates of DR after MS compared with MT after 36 months' follow-up in these patients. Consequently, the French National Authority for Health French (HAS) recommends MS for these patients.

Partial Versus Total Thyroidectomy: What Influences Most Surgeons' Decision? Analysis of a Nationwide Cohort of 375,810 Patients Over 10 Years.

National and international guidelines about thyroid surgery seem to be moving more and more towards less radical surgical procedures but everyday practice does not seem to always align with them. We describe for the first time the role of non-surgical parameters in the surgeon's choice for thyroid surgery. OBJECTIVE: The ain of this study was to describe thyroid surgery and to identify the factors leading to either a total or a partial thyroidectomy regardless of the severity of the thyroid disease. SUMMARY BACKGROUND DATA: National and international guidelines about thyroid surgery seem to be moving more and more toward less radical surgical procedures but everyday practice does not seem to always align with them. METHODS: We based this nationwide retrospective cohort study on a national database that compiles discharge abstracts for every admission for thyroidectomy to French acute healthcare facilities (PMSI database 2010 to 2019). RESULTS: In this study, 375,810 patients (male: 23%; age = 53 ±â€Š15 years) had a thyroidectomy (partial: 28%) for cancer (17%), hyperthyroidism (16%), nonfunctioning goiter (64%), or other (3%). We noticed a global trend toward more partial thyroidectomy (P < 0.001) with a significant increase in the proportion of lobectomy in the post-ATA recommendations' period (P < 0.001) as well as in the "French Levothyrox crisis" period, in which we saw an unexpected rise of adverse events notifications associated with the marketing of a new formula of Levothyrox (P < 0.001) amid widespread media coverage. In a multivariate analysis, we also identified that complete resection was more frequently performed in centers with a caseload >40/year [P < 0.001, odds ratio (OR) = 1.48], for obese patients (body mass index >30 kg/m2; P < 0.001, OR = 1.42), and according to the indication of surgery (OR benign = 1, OR cancer = 2.25, OR hyperthyroidism = 4.13). CONCLUSION: We describe for the first time the role of non-surgical parameters in the surgeon's choice for thyroid surgery.

Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet-Induced Obese Minipigs.

OBJECTIVE: A minipig model was employed to explore the changes in endogenous leptin transport into the central nervous system and in hypothalamic sensitivity to exogenous leptin when individuals are placed on high-fat diet (HFD) compared with standard diet. METHODS: Serum and cerebrospinal fluid (CSF) leptin concentrations during 10 weeks of HFD versus standard diet and exogenous leptin-induced STAT3 phosphorylation in the hypothalamus of minipigs were assessed, and the hypothalamic leptin-sensitive cells were characterized by immunofluorescence. RESULTS: The efficiency of the passage of endogenous blood-borne leptin into the CSF (measured as the log [CSF:serum leptin ratio]) decreased over time in minipigs fed a HFD (ß = -0.04 ± 0.005 per kilogram of weight gain in HFD; P < 0.0001), while it remained stable in minipigs fed a standard diet. However, the ability of peripherally administered leptin to activate its receptor in hypothalamic neurons was preserved in obese minipigs at 10 weeks of HFD. CONCLUSIONS: Together, these data are consistent with the existence of an early-onset tranport deficiency for endogenous circulating leptin into the brain in individuals developing obesity, preceding the acquisition of hypothalamic leptin resistance. Although additional studies are required to identify the underlying mechanisms, our study paves the way for the development of new preclinical pharmacological models targeting the restoration of the shuttling of peripheral leptin into the central nervous system to manage obesity.

Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion.

OBJECTIVES: Genome-wide association studies (GWAS) have identified >100 loci independently contributing to type 2 diabetes (T2D) risk. However, translational implications for precision medicine and for the development of novel treatments have been disappointing, due to poor knowledge of how these loci impact T2D pathophysiology. Here, we aimed to measure the expression of genes located nearby T2D associated signals and to assess their effect on insulin secretion from pancreatic beta cells. METHODS: The expression of 104 candidate T2D susceptibility genes was measured in a human multi-tissue panel, through PCR-free expression assay. The effects of the knockdown of beta-cell enriched genes were next investigated on insulin secretion from the human EndoC-ßH1 beta-cell line. Finally, we performed RNA-sequencing (RNA-seq) so as to assess the pathways affected by the knockdown of the new genes impacting insulin secretion from EndoC-ßH1, and we analyzed the expression of the new genes in mouse models with altered pancreatic beta-cell function. RESULTS: We found that the candidate T2D susceptibility genes' expression is significantly enriched in pancreatic beta cells obtained by laser capture microdissection or sorted by flow cytometry and in EndoC-ßH1 cells, but not in insulin sensitive tissues. Furthermore, the knockdown of seven T2D-susceptibility genes (CDKN2A, GCK, HNF4A, KCNK16, SLC30A8, TBC1D4, and TCF19) with already known expression and/or function in beta cells changed insulin secretion, supporting our functional approach. We showed first evidence for a role in insulin secretion of four candidate T2D-susceptibility genes (PRC1, SRR, ZFAND3, and ZFAND6) with no previous knowledge of presence and function in beta cells. RNA-seq in EndoC-ßH1 cells with decreased expression of PRC1, SRR, ZFAND6, or ZFAND3 identified specific gene networks related to T2D pathophysiology. Finally, a positive correlation between the expression of Ins2 and the expression of Prc1, Srr, Zfand6, and Zfand3 was found in mouse pancreatic islets with altered beta-cell function. CONCLUSIONS: This study showed the ability of post-GWAS functional studies to identify new genes and pathways involved in human pancreatic beta-cell function and in T2D pathophysiology.

Randomised, prospective, medico-economic nationwide French study of islet transplantation in patients with severely unstable type 1 diabetes: the STABILOT study protocol.

INTRODUCTION: Islet transplantation may be an appropriate treatment option for patients with severely unstable type 1 diabetes experiencing major glucose variability with severe hypoglycaemia despite intensive insulin therapy. Few data are available on the costs associated with islet transplantation in relation to its benefits. The STABILOT study proposes to assess the economic impact of islet transplantation in comparison with the current best medical treatment defined as sensor-augmented pump (SAP) therapy. METHODS: The trial will adopt an open-label, randomised, multicentred design. The study will include 30 patients with severely unstable type 1 diabetes. Eligible participants will be 18-65 years old, with type 1 diabetes duration >5 years, a negative basal or stimulated C-peptide, and severe instability defined by persistent, recurrent and disabling severe hypoglycaemia, despite optimised medical treatment. Participants will be randomised into two groups: one group with immediate registration for islet transplantation, and one group with delayed registration for 1 year while patients receive SAP therapy. The primary endpoint will be the incremental cost-utility ratio at 1 year between islet transplantation and SAP therapy. Perspectives of both the French Health Insurance System and the hospitals will be retained. ETHICS AND DISSEMINATION: Ethical approval has been obtained at all sites. The trial has been approved by ClinicalTrials.gov (Trial registration ID NCT02854696). All participants will sign a free and informed consent form before randomisation. Results of the study will be communicated during national and international meetings in the field of diabetes and transplantation. A publication will be sought in journals usually read by physicians involved in diabetes care, transplantation and internal medicine. TRIAL REGISTRATION NUMBER: NCT02854696; Pre-results.

Creating conditions for the success of the French industrial advanced therapy sector.

Although the European Union merely followed the initiatives of the United States and Japan by introducing special regimes for orphan medicinal products, it has introduced a special status for a new category of biological medicinal products, advanced therapy medicinal products (ATMPs), adopting specific associated regulations. European Regulation (which constitutes the highest legal instrument in the hierarchy of European law texts) [EC] No. 1394/2007, published in 2007, uses this term to define somatic cell therapy medicinal products, tissue-engineered products, and gene therapy medicinal products, possibly combined with medical devices. The stated objective was two-fold: both to promote their industrialization and market access, while guaranteeing a high level of health protection for patients. Since publication of the regulation, few marketing authorizations have been granted in Europe, and these have not been accompanied by commercial success. However, certain recent studies show that this is a growing sector and that France remains the leading European nation in terms of clinical trials. This round table brought together a panel of representatives of French public and private protagonists from the advanced therapy sector. The discussions focused on the conditions to ensure the success of translational research and, more generally, the French advanced therapy sector. These enabled a number of obstacles to be identified, which once lifted, by means of recommendations, would facilitate the development and success of this sector.

Poorly differentiated thyroid carcinomas: application of the Turin proposal provides prognostic results similar to those from the assessment of high-grade features.

AIMS: To investigate the performance of two proposed methods for assessing the prognosis of poorly differentiated thyroid carcinomas (PDTC): the Turin proposal and Hiltzik's histological grade (HHG). This was done using a series of 82 thyroid carcinomas of follicular origin. RESULTS: The two methods were able to classify patients accurately into two different prognosis groups. Although the Turin proposal and HHG displayed discrepant cases, they provided similar prognostic information. The Turin proposal gave accurate numbers and thresholds of PTDC criteria (loss of follicular architecture and mitoses, necrosis or convoluted nuclei). One Turin criterion, convoluted nuclei, failed to provide any prognostic value. Hiltzik's histological grade was also a simple and reliable method, allowing detection of tumours with high-grade features (mitosis and/or tumour necrosis), notably some papillary carcinomas that displayed an intermediate prognosis. We show that Ki67 labelling (≥ 4%) was an independent factor and predictor of cause-specific survival. CONCLUSION: With similar performances in predicting prognosis, the Turin proposal and HHG provided complementary results in identifying a larger group of 'intermediate prognosis' thyroid carcinomas, which require adequate treatment and follow-up.

Genetic and functional assessment of the role of the rs13431652-A and rs573225-A alleles in the G6PC2 promoter that are strongly associated with elevated fasting glucose levels.

OBJECTIVE: Genome-wide association studies have identified a single nucleotide polymorphism (SNP), rs560887, located in a G6PC2 intron that is highly correlated with variations in fasting plasma glucose (FPG). G6PC2 encodes an islet-specific glucose-6-phosphatase catalytic subunit. This study examines the contribution of two G6PC2 promoter SNPs, rs13431652 and rs573225, to the association signal. RESEARCH DESIGN AND METHODS: We genotyped 9,532 normal FPG participants (FPG <6.1 mmol/l) for three G6PC2 SNPs, rs13431652 (distal promoter), rs573225 (proximal promoter), rs560887 (3rd intron). We used regression analyses adjusted for age, sex, and BMI to assess the association with FPG and haplotype analyses to assess comparative SNP contributions. Fusion gene and gel retardation analyses characterized the effect of rs13431652 and rs573225 on G6PC2 promoter activity and transcription factor binding. RESULTS: Genetic analyses provide evidence for a strong contribution of the promoter SNPs to FPG variability at the G6PC2 locus (rs13431652: ß = 0.075, P = 3.6 × 10(-35); rs573225 ß = 0.073 P = 3.6 × 10(-34)), in addition to rs560887 (ß = 0.071, P = 1.2 × 10(-31)). The rs13431652-A and rs573225-A alleles promote increased NF-Y and Foxa2 binding, respectively. The rs13431652-A allele is associated with increased FPG and elevated promoter activity, consistent with the function of G6PC2 in pancreatic islets. In contrast, the rs573225-A allele is associated with elevated FPG but reduced promoter activity. CONCLUSIONS: Genetic and in situ functional data support a potential role for rs13431652, but not rs573225, as a causative SNP linking G6PC2 to variations in FPG, though a causative role for rs573225 in vivo cannot be ruled out.

Should genetic testing be performed in each patient with sporadic pheochromocytoma at presentation?

BACKGROUND: According to previous studies, around 15% of patients with an apparently sporadic pheochromocytoma and a negative family history had a hereditary disease. This high frequency together with the financial support provided to reference laboratories of molecular genetics by the French government led to a nearly systematic screening in each patient with a pheochromocytoma. OBJECTIVE: To check the efficiency of systematic genetic screening in patients with apparently sporadic pheochromocytoma, by analysing the 6 years experience of a multidisciplinary team in this field. METHODS: One hundred patients with a pheochromocytoma-only phenotype and no family history were included. Patients with extra-adrenal tumours were excluded. Prevalence of hereditary forms was determined and analyzed according to age at onset, sex. Cost of the genetic analysis was calculated. RESULTS: A germline mutation in one of the five susceptibility genes (VHL, RET, SDHD, SDHC, SDHB) was identified in eight patients (8%) with an age of onset between 13 and 57 years. Among them, six had a bilateral pheochromocytoma and only two had a unilateral tumour. If the guidelines for genetic screening were age of onset less than 50 or bilateral pheochromocytoma, no patients with a hereditary tumour would be missed and a 24% cost reduction would be achieved. CONCLUSIONS: According to these data, a genetic predisposition test for hereditary pheochromocytoma seems not recommended in patients with a unilateral adrenal tumour diagnosed after 50 in the absence of familial, clinical, biological or imaging features for a familial disease.