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  • Author: Jean-François Deleuze x
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João Pedro Ferreira, Zohra Lamiral, Constance Xhaard, Kévin Duarte, Emmanuel Bresso, Marie-Dominique Devignes, Edith Le Floch, Claire Dandine Roulland, Jean-François Deleuze, Sandra Wagner, Bruno Guerci, Nicolas Girerd, Faiez Zannad, Jean-Marc Boivin, and Patrick Rossignol

Objective:

Determining the factors associated with new-onset pre-diabetes and type 2 diabetes mellitus (T2D) is important for improving the current prevention strategies and for a better understanding of the disease.

Design:

To study the factors (clinical, circulating protein and genetic) associated with new onset pre-diabetes and T2D in an initially healthy (without diabetes) populational familial cohort with a long follow-up (STANISLAS cohort).

Methods:

A total of 1506 participants attended both the visit 1 and visit 4, separated by ≈20 years. Over 400 proteins, GWAS and genetic associations were studied using models adjusted for potential confounders. Both prospective (V1 to V4) and cross-sectional (V4) analyses were performed.

Results:

People who developed pre-diabetes (n = 555) and/or T2D (n = 73) were older, had higher BMI, blood pressure, glucose, LDL cholesterol, and lower eGFR. After multivariable selection, PAPP-A (pappalysin-1) was the only circulating protein associated with the onset of both pre-diabetes and T2D with associations persisting at visit 4 (i.e. ≈20 years later). FGF-21 (fibroblast growth factor 21) was a strong prognosticator for incident T2D in the longitudinal analysis, but not in the cross-sectional analysis. The heritability of the circulating PAPP-A was estimated at 44%. In GWAS analysis, the SNP rs634737 was associated with PAPP-A both at V1 and V4. External replication also showed lower levels of PAPP-A in patients with T2D.

Conclusions:

The risk of developing pre-diabetes and T2D increases with age and with features of the metabolic syndrome. Circulating PAPP-A, which has an important genetic component, was associated with both the development and presence of pre-diabetes and T2D.

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Maria Lytrivi, Valérie Senée, Paraskevi Salpea, Federica Fantuzzi, Anne Philippi, Baroj Abdulkarim, Toshiaki Sawatani, Sandra Marín-Cañas, Nathalie Pachera, Anne Degavre, Pratibha Singh, Céline Derbois, Doris Lechner, Laurence Ladrière, Mariana Igoillo-Esteve, Cristina Cosentino, Lorella Marselli, Jean-François Deleuze, Piero Marchetti, Décio L Eizirik, Marc Nicolino, Annabelle Chaussenot, Cécile Julier, and Miriam Cnop

Objective

DNAJC3, also known as P58IPK, is an Hsp40 family member that interacts with and inhibits PKR-like ER-localized eIF2α kinase (PERK). Dnajc3 deficiency in mice causes pancreatic β-cell loss and diabetes. Loss-of-function mutations in DNAJC3 cause early-onset diabetes and multisystemic neurodegeneration. The aim of our study was to investigate the genetic cause of early-onset syndromic diabetes in two unrelated patients, and elucidate the mechanisms of β-cell failure in this syndrome.

Methods

Whole exome sequencing was performed and identified variants were confirmed by Sanger sequencing. DNAJC3 was silenced by RNAi in INS-1E cells, primary rat β-cells, human islets, and induced pluripotent stem cell-derived β-cells. β-cell function and apoptosis were assessed, and potential mediators of apoptosis examined.

Results

The two patients presented with juvenile-onset diabetes, short stature, hypothyroidism, neurodegeneration, facial dysmorphism, hypoacusis, microcephaly and skeletal bone deformities. They were heterozygous compound and homozygous for novel loss-of-function mutations in DNAJC3. DNAJC3 silencing did not impair insulin content or secretion. Instead, the knockdown induced rat and human β-cell apoptosis and further sensitized cells to endoplasmic reticulum stress, triggering mitochondrial apoptosis via the pro-apoptototic Bcl-2 proteins BIM and PUMA.

Conclusions

This report confirms previously described features and expands the clinical spectrum of syndromic DNAJC3 diabetes, one of the five monogenic forms of diabetes pertaining to the PERK pathway of the endoplasmic reticulum stress response. DNAJC3 deficiency may lead to β-cell loss through BIM- and PUMA-dependent activation of the mitochondrial pathway of apoptosis.