Role of High-Throughput Whole Genome Sequencing for the Diagnosis and Care of Atypical Diabetes (GLUCOGEN)

The main objective of the study is to assess the contribution of whole genome sequencing (WGS) coupled with a multidisciplinary conciliation meeting (MCM) on diagnosis of atypical forms of diabetes compared to an in-silico analysis of a panel of validated genes (ISApanel), corresponding to current practice, in a randomized trial.

Notably, the questions it aims to answer are:

• The feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes,
• The contribution of WGS coupled with MCM on number of genetic alterations likely causal of diabetes identified and with a modification in care and support of patients.

After inclusion and sampling for genotyping, patients will be followed for 5 years.

The target population is 1020 adults with atypical diabetes for whom it is possible to obtain a blood sample.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus
• Intervention / Treatment: Diagnostic test: WGS coupled with MCM

Detailed Description

The prevalence of diabetes is 7.4% in France among people aged 20 to 79 years in 2015. We must also consider "pre-diabetes" (subjects with glucose intolerance), whose prevalence is equivalent to that of diabetes (2012 estimate). The incidence of diabetes is exploding both for type 2 diabetes, which represents 85% of diabetes, and for type 1 diabetes, which represents 10% of cases and starts one out of two times before the age of 20. Diabetes typing is essential to guide therapeutic choices, particularly the use of insulin. This typing is based on the pathophysiology of the disease, distinguishing insulinopenia from autoimmune causes in type 1 diabetes, monogenic diabetes, secondary or atypical diabetes and type 2 diabetes, where insulinopenia and insulin resistance coexist. Thus, while a formal biological diagnosis is possible for some forms of atypical diabetes and for type 1 diabetes, no biological parameter is currently available for type 2 diabetes, which remains a diagnosis of exclusion. As a result, diabetes represents a source of diagnostic and therapeutic erraticism, amplified by the clinical heterogeneity of type 2 diabetes, which is obvious and underestimated, and by a clinical phenotyping of patients that is often defective. The economic consequences are important because the health costs are very different depending on whether or not patients are treated with insulin. Type 1 and type 2 diabetes are examples of chronic, non-transmissible, multigenic, multifactorial diseases. However, less than 10% of the heritability of type 2 diabetes is currently explained by the associated genetic variants. And although genetic tests exist to diagnose certain monogenic diabetes, this diagnosis is made in less than 20% of cases, mainly in the presence of an atypical clinical presentation of diabetes. Moreover, there is no reason to rule out the hypothesis of paucigenic forms, at the interface of monogenic diabetes and multigenic forms as usually envisaged, as has been observed in chronic pancreatitis, which is also accompanied by diabetes.

The study will be conducted according to a randomized trial design comparing two diagnostic strategies defined as follows:

• Control strategy: in silico analysis of a panel of validated genes (ISApanel - Diabetome 1). Patients recruited along the control procedure will stay in their group using current genetic diagnosis practices and standard of care that may differ from one center to another.
• Intervention strategy: whole genome sequencing coupled with multidisciplinary conciliation meeting.

We plan to randomize one patient in the control group for two in the intervention group.

The main objective of the study is to assess the contribution of whole genome sequencing (WGS) coupled with a multidisciplinary conciliation meeting (MCM) on diagnosis of atypical forms of diabetes compared to an in-silico analysis of a panel of validated genes (ISApanel), corresponding to current practice.

The target population is 1020 adults with atypical diabetes for whom it is possible to obtain a blood sample.

• Study Type: Interventional
• Enrollment (Estimated): 1020
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jean-François Gautier; Phone Number: +33 01 49 95 90 20; Email: jean-francois.gautier@aphp.fr

Study Locations

• France
  • Amiens, France
    • Recruiting
    • University Hospital
    • Contact: Abdallah AL SALAMEH; Phone Number: 333 22 45 58 89; Email: Al-Salameh.Abdallah@chu-amiens.fr
    • Principal Investigator: Abdallah AL SALAMEH
  • Angers, France
    • Recruiting
    • University Hospital
    • Principal Investigator: Ingrid ALLIX
    • Contact: Ingrid ALLIX; Phone Number: 332 41 35 42 40; Email: ingrid.allix@chu-angers.fr
  • Besançon, France
    • Recruiting
    • University Hospital Jean Minjoz
    • Principal Investigator: Sophie BOROT
    • Contact: Sophie BOROT; Phone Number: 333 81 66 87 88; Email: sophie.borot@univ-fcomte.fr
  • Bordeaux, France
    • Recruiting
    • University Hospital Haut Lévêque
    • Contact: Vincent RIGALLEAU; Phone Number: 335 57 65 69 14; Email: vincent.rigalleau@chu-bordeaux.fr
    • Principal Investigator: Vincent RIGALLEAU
  • Brest, France
    • Recruiting
    • University Hospital Cavale Blanche
    • Principal Investigator: Philippe THUILLIER
    • Contact: Philippe THUILLIER; Phone Number: 332 98 22 33 33; Email: philippe.thuillier@chu-brest.fr
  • Corbeil-Essonnes, France
    • Recruiting
    • Centre hospitalier Sud Francilien
    • Contact: Coralie AMADOU; Phone Number: 331 61 69 34 27; Email: coralie.amadou@gmail.com
    • Principal Investigator: Coralie AMADOU
  • Dijon, France
    • Recruiting
    • University Hospital Bocage
    • Principal Investigator: Bruno VERGES
    • Contact: Bruno VERGES; Phone Number: 333 80 29 34 53; Email: bruno.verges@chu-dijon.fr
  • Grenoble, France
    • Recruiting
    • University Hospital Michallon
    • Principal Investigator: Sandrine LABLANCHE
    • Contact: Sandrine LABLANCHE; Phone Number: 334 76 76 55 09; Email: slablanche@chu-grenoble.fr
  • Le Kremlin-Bicêtre, France
    • Not yet recruiting
    • Assistance Publique Hôpitaux de Paris, Bicêtre Hospital
    • Principal Investigator: Jacques YOUNG
    • Contact: Jacques YOUNG; Email: jacques.young@aphp.fr
  • Lyon, France
    • Recruiting
    • University Hospital Louis Pradel
    • Principal Investigator: Sybil CHARRIERE
    • Contact: Sybil CHARRIERE; Phone Number: 330 27 85 77 86; Email: sybil.charriere@chu-lyon.fr
  • Lyon, France
    • Recruiting
    • University Hospital Sud
    • Principal Investigator: Emmanuel DISSE
    • Contact: Emmanuel DISSE; Phone Number: 334 78 86 19 40; Email: emmanuel.disse@chu-lyon.fr
  • Marseille, France
    • Recruiting
    • University Hospital Conception
    • Principal Investigator: Patrice DARMON
    • Contact: Patrice DARMON; Phone Number: 334 91 38 41 22; Email: patrice.darmon@ap-hm.fr
  • Montpellier, France
    • Recruiting
    • University Hospital Lapeyronie
    • Principal Investigator: Ariane SULTAN
    • Contact: Ariane SULTAN; Phone Number: 334 67 33 84 02; Email: a-sultan@chu-montpellier.fr
  • Nancy, France
    • Not yet recruiting
    • University Hospital
    • Principal Investigator: Bruno GUERCI
    • Contact: Bruno GUERCI; Phone Number: 333 83 15 55 63; Email: b.guerci@chru-nancy.fr
  • Nantes, France
    • Recruiting
    • University Hospital Laennec
    • Principal Investigator: Samy HADJADJ
    • Contact: Samy HADJADJ; Phone Number: 332 53 48 27 29; Email: samy.hadjadj@univ-nantes.fr
  • Nice, France
    • Not yet recruiting
    • University Hospital L'Archet
    • Principal Investigator: Nicolas CHEVALIER
    • Contact: Nicolas CHEVALIER; Phone Number: 334 92 03 55 19; Email: chevalier.n@chu-nice.fr
  • Paris, France
    • Recruiting
    • Assistance Publique Hôpitaux de Paris, Lariboisière Hospital
    • Principal Investigator: Jean-François GAUTIER
    • Contact: Jean-François GAUTIER; Phone Number: 331 49 95 90 20; Email: jean-francois.gautier@aphp.fr
  • Paris, France
    • Recruiting
    • Assistance Publique Hôpitaux de Paris, Bichat - Claude Bernard Hospital
    • Contact: Louis POTIER; Phone Number: 331 40 25 88 80; Email: louis.potier@aphp.fr
    • Principal Investigator: Louis POTIER
  • Paris, France
    • Recruiting
    • Assistance Publique Hôpitaux de Paris, Cochin Hospital
    • Contact: Danièle DUBOIS-LAFORGUE; Phone Number: 331 58 41 33 71; Email: daniele.dubois@aphp.fr
    • Principal Investigator: Danièle DUBOIS-LAFORGUE
  • Paris, France
    • Recruiting
    • Assistance Publique Hôpitaux de Paris, Saint Antoine Hospital
    • Contact: Camille VATIER; Phone Number: 331 49 28 24 07; Email: camille.vatier@aphp.fr
    • Principal Investigator: Camille VATIER
  • Paris, France
    • Recruiting
    • Assistance Publique Hôpitaux de Paris- La Pitié Salpêtrière Hospital
    • Contact: Cécile CIANGURA; Phone Number: 331 42 17 80 51; Email: cecile.ciangura@aphp.fr
    • Principal Investigator: Cécile CIANGURA
  • Poitiers, France
    • Not yet recruiting
    • University Hospital
    • Contact: Héléna MOSBAH; Email: helena.mosbah@chu-poitiers.fr
    • Principal Investigator: Héléna MOSBAH
  • Rennes, France
    • Recruiting
    • Rennes University Hospital
    • Principal Investigator: Agathe GUENEGO
    • Contact: Agathe GUENEGO; Phone Number: 332 99 26 71 42; Email: agathe.guenego@chu-rennes.fr
  • Rouen, France
    • Recruiting
    • University Hospital Bois Guillaume
    • Principal Investigator: Gaetan PREVOST
    • Contact: Gaetan PREVOST; Phone Number: 332 32 88 92 55; Email: gaetan.prevost@chu-rouen.fr
  • Strasbourg, France
    • Recruiting
    • Strasbourg University Hospital
    • Principal Investigator: Laurent MEYER
    • Contact: Laurent MEYER; Phone Number: +33 03 88 12 77 21; Email: laurent.meyer@chru-strasbourg.fr
  • Toulouse, France
    • Recruiting
    • University Hospital Rangueil
    • Principal Investigator: Pierre Gourdy
    • Contact: Pierre GOURDY; Phone Number: 335 61 32 33 61; Email: pierre.gourdy@inserm.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subjects ≥18 years with confirmed diabetes mellitus according to WHO criteria (World Health Organization: Definition and diagnosis of diabetes mellitus and intermediate hyperglycemia: Report of a WHO/IDF Consultation. Geneva, World Health Org., 2006.)
• Age ≤ 45 years at diabetes diagnosis
• Body mass index ≤ 35 kg/m² at diabetes diagnosis
• Negative results of specific antibodies determination (GAD65, IA2, ZnT8) until the inclusion visit
• Presenting atypical diabetes defined by at least one of the following:
• Exocrine pancreatic disease
• Familial history: diabetes diagnosed in a parent, child or sibling
• Notion of familial consanguinity
• Syndromic clinical features (dysmorphy, developmental delay, mental retardation…) or unusual abnormalities/features that are not part of diabetic complications or co-morbidities;
• Early occurrence of microvascular complications (≤ 5 years after diabetes diagnosis)
• Major insulinopenia at diagnosis (C peptide < 0.2 nmol/L and/or documented ketosis)
• Patient who conserved endogenous insulin secretion (positive C peptide value) but a need for insulin therapy initiation during the first year following diagnosis due to therapeutic failure of well conducted therapeutic intensification
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Patient with a social security number in compliance with the French law (dispositions relatives aux recherches impliquant la personne humaine prévues aux articles L 1121-1 et suivants du Code de la Santé Publique)
• Signed and dated informed consent form

Exclusion Criteria:

• Pregnant or breastfeeding woman,
• Any contraindication to the study exams including known allergies or contraindication to contrasts for the scan
• Patient with known monogenic diabetes (defined as identification of class 4 and 5 variants according to ACMG)
• First or second-degree relatives with monogenic diabetes established by molecular genetics (class 4 and 5 variants according to ACMG)
• Patient with known secondary diabetes (i.e. endocrine disorders such as Cushing syndrome, pancreatectomy, drug-induced diabetes)
• Patient who had a bone marrow transplant
• Any condition which in the Investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol,
• Individuals under legal protection (sauvegarde de justice).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: control procedure; In-silico analysis of a panel of validated genes (ISApanel). Patients recruited along control procedure will stay in their arm using current genetic diagnosis practices and standard of care that may differ from one center to another
Experimental: intervention procedure; WGS coupled with MCM	Diagnostic test: WGS coupled with MCM; Whole genome will be screened and analysis will focus on pathogenic and likely pathogenic variants. The list of variants of interest will be recorded until examination and discussion during the MCM. MCM will edit a final synthesis concerning the pathogenicity of identified variants.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with one or several genetic alterations likely causal of diabetes	Number of patients in each group with one or several genetic alterations likely causal of diabetes	At 6 months in control group and 12 months in interventional group

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with an impact on treatment modification	Number of patients in each group with an impact on treatment modification including discontinuation and reason of this modification	5 years
Number of genetic alterations likely causal of diabetes	Number of genetic alterations likely causal of diabetes (classified as class 4 or 5 variants)	At 6 months in control group and 12 months in interventional group
Feasibility of the whole genome sequencing (WGS) coupled with multidisciplinary conciliation meeting (MCM) on diagnosis of atypical forms of diabetes: time to access to the genetic data	time between blood sampling and availability of genetic data by GLUCOGEN laboratories	At 6 months in control group and 12 months in interventional group
Feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes: time between blood sampling and MCM	time between blood sampling and MCM	At 6 months in control group and 12 months in interventional group
Feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes: time between blood sampling and access to WGS report	time between blood sampling and access to WGS report produced by GLUCOGEN laboratory	At 6 months in control group and 12 months in interventional group
Feasibility of the WGS coupled with MCM on diagnosis of atypical forms of diabetes: time between blood sampling and date of the WGS result visit	time between blood sampling and date of the WGS result visit	5 years
Genotype-Insulin secretion phenotype association	Genotype-phenotype associations corresponding to insulin secretion	At 6 months in control group and 12 months in interventional group
Genotype-Insulin sensitivity phenotype association	Genotype-phenotype associations corresponding to insulin sensitivity • Body composition	At 6 months in control group and 12 months in interventional group
Genotype-body composition phenotype association	Genotype-phenotype associations corresponding to body composition	At 6 months in control group and 12 months in interventional group
Glycemic control without insulin treatment	Percentage of patients with glycated hemoglobin (HbA1c) target below 7% without insulin treatment at 2, 3, 4 and 5 years	5 years
Glycemic control without severe hypoglycemia	Percentage of patients with glycated hemoglobin (HbA1c) target below 7% without severe hypoglycemia in the last 6 months and with a change in body mass index < 1 kg/m² in the last 6 months at 2, 3, 4 and 5 years	5 years
Number of long-term micro and macro vascular complications associated with diabetes and time to occurrence of the first complication	Number of long-term micro and macro vascular complications associated with diabetes and time to occurrence of the first complication: Retinopathy; Nephropathy; Neuropathy; Cardiovascular disease; Liver disease	5 years
Patient-Reported Outcomes (PROs), evaluated with SF36 questionnaire	SF36 questionnaire at baseline, every 6 months during the first 2 years, then every year until 5 years.	5 years
Patient-Reported Outcomes (PROs), evaluated with Euroquol Dimension (EQ-5D-5L) questionnaire	EQ-5D-5L questionnaire at baseline, every 6 months during the first 2 years, then every year until 5 years. • ADDQOL questionnaire	5 years
Patient-Reported Outcomes (PROs), evaluated with Audit of Diabetes Dependent Quality of Life (ADDQOL) questionnaire	ADDQOL questionnaire at baseline, every 6 months during the first 2 years, then every year until 5 years.	5 years
Number of participants agreeing to have access to secondary findings (SF)	Number of participants agreeing to have access to secondary findings (SF)	At 6 months in control group and 12 months in interventional group
Number and type of SFs (class 4 or 5 variant(s)) identified in participants that specifically consent to have access to SF	Number and type of SFs (class 4 or 5 variant(s)) identified in participants that specifically consent to have access to SF	At 6 months in control group and 12 months in interventional group
Percentage of SFs in the studied population	Percentage of SFs in the studied population	At 6 months in control group and 12 months in interventional group
Number and type of medical consequences following identification of SFs	Number and type of medical consequences following identification of SFs	5 years
Direct costs associated with current diagnosis practices (ISApanel)	Direct costs associated with current diagnosis practices (ISApanel)	5 years
Direct costs associated with WGS coupled with MCM	Direct costs associated with WGS coupled with MCM	5 years
Incremental cost-effectiveness ratio of WGS coupled with MCM compared to current diagnosis practices (ISApanel)	Incremental cost-effectiveness ratio of WGS coupled with MCM compared to current diagnosis practices (ISApanel)	5 years
Incremental cost-utility ratio of WGS coupled with MCM compared to current diagnosis practices (ISApanel)	Incremental cost-utility ratio of WGS coupled with MCM compared to current diagnosis practices (ISApanel)	5 years
Cost-benefit of WGS coupled with MCM compared to current diagnosis practices	Cost-benefit of WGS coupled with MCM compared to current diagnosis practices (ISApanel) in terms of cost of wandering diagnosis and care procedure avoided	5 years
Psychosocial issues related to genetic testing for atypical diabetes	Qualitative data related to patients' expectations regarding genetic testing related to atypical diabetes and needs to receive SF information.	At 6 months in control group and 12 months in interventional group
Psychosocial issues related to genetic testing for atypical diabetes	Qualitative data (discourse - semi-structured individual interviews) related to patients experience following genetic testing results for atypical diabetes; Qualitative data (discourse - semi-structured individual interviews) related to patients' experience of the GLUCOGEN trial	5 years
Psychosocial issues related to patients' experience of the GLUCOGEN trial	Quantitative data (questionnaire)	18 months
Psychosocial issues related to professional's experience of the GLUCOGEN research protocol	Qualitative data (observation), including information regarding doctor-patient relationship and decision-making processes.	12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number and characteristics of new genomic variations responsible for diabetes development	Number and characteristics of new genomic variations responsible for diabetes development	At 6 months in control group and 12 months in interventional group
Number and characteristics of genomic variations and their association with defined phenotypes including integrated diagnostic biomarkers	Number and characteristics of genomic variations and their association with defined phenotypes including integrated diagnostic biomarkers	At 6 months in control group and 12 months in interventional group
Number and characteristics of genomic variations known as drug targets	Number and characteristics of genomic variations known as drug targets	At 6 months in control group and 12 months in interventional group
Number and characteristics of genomic variations of metabolism, transport or drug targets of diabetes and their consequences on treatment response	Number and characteristics of genomic variations of metabolism, transport or drug targets of diabetes and their consequences on treatment response	At 6 months in control group and 12 months in interventional group
Number and characteristics of molecular targets in atypical diabetes	Number and characteristics of molecular targets in atypical diabetes	At 6 months in control group and 12 months in interventional group

Collaborators and Investigators

• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Collaborators: Hospices Civils de Lyon; Central Hospital, Nancy, France; Rennes University Hospital; University Hospital, Toulouse; Nantes University Hospital; APHP; Commissariat A L'energie Atomique; Imagine Institute; Université Lumière Lyon 2
• Investigators: Principal Investigator: Jean-François GAUTIER, Institut National de la Santé Et de la Recherche Médicale, France

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2024
• Primary Completion (Estimated): November 1, 2031
• Study Completion (Estimated): November 1, 2034

Study Registration Dates

• First Submitted: February 2, 2024
• First Submitted That Met QC Criteria: August 21, 2024
• First Posted (Actual): August 26, 2024

Study Record Updates

• Last Update Posted (Actual): April 9, 2026
• Last Update Submitted That Met QC Criteria: April 8, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Next generation sequencing genome; Diagnostic study; Medico-economic study
• Additional Relevant MeSH Terms: Endocrine System Diseases; Pathologic Processes; Metabolic Diseases; Glucose Metabolism Disorders; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Disease; Diabetes Mellitus
• Other Study ID Numbers: C17-27; 2021-A02597-34 (Other Identifier: ANSM)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No