[Prevention of type 2 diabetes and its complications]. / Prévention du diabète de type 2 et de ses complications.

Type 2 diabetes (T2D) represents a major medical and public health problem. The ability to prevent or delay T2D by modifying some of its risk factors has been hypothesized for several decades. Indeed, the slow and gradual deterioration of glycaemia prior to the diabetes diagnosis constitutes a period during which interventions could be effective in preventing T2D. Lifestyle modifications demonstrated that modest weight loss (at least 7% of initial weight) and moderate to intense physical activity of at least 150 minutes per week, markedly and significantly delayed the onset of T2D in subjects at high risk of developing the disease. Pharmacological interventions indicated that metformin should be considered, particularly in young patients (< 60 years) with a body mass index ≥ 35 kg/m², and in women with a history of gestational diabetes. Bariatric surgery, which allows significant weight loss in subjects with severe or morbid obesity, has also demonstrated important preventive effectiveness and metabolic surgery in now considered in at-risk patients with less severe obesity. In conclusion, in overweight or obese adults at high risk of developing T2D, treatment aimed at losing weight (including bariatric surgery) and increasing physical activity should be implemented, and a pharmacotherapy might be considered case by case.

Le diabète de type 2 (DT2) constitue un problème majeur, tant au niveau médical individuel qu'en termes de santé publique. La capacité de prévenir ou retarder le DT2 en modifiant certains facteurs de risque est une hypothèse envisagée depuis plusieurs décennies. En effet, la lente et graduelle détérioration de la glycémie avant le diagnostic de diabète constitue une période au cours de laquelle des interventions pourraient se révéler efficaces. Les modifications de comportement concernant le mode de vie ont démontré qu'une perte de poids modeste (au moins 7 % du poids initial) et une activité physique modérée à intense d'au moins 150 minutes par semaine retardaient, de manière importante et significative, l'apparition du DT2 chez des sujets à haut risque de développer la maladie. Au niveau médicamenteux, la metformine s'est également révélée efficace, en particulier chez les patients jeunes (< 60 ans) avec un indice de masse corporelle ≥ 35 kg/m², et chez les femmes avec des antécédents de diabète gestationnel. La chirurgie bariatrique, qui permet d'obtenir une perte de poids importante chez les sujets avec obésité sévère ou morbide, a également démontré une grande efficacité pour prévenir la survenue d'un DT2. Une chirurgie métabolique est même maintenant envisagée chez des sujets à risque avec une obésité moins sévère. En conclusion, chez les adultes en surpoids ou obèses à haut risque de développer un DT2, une prise en charge visant à perdre du poids (y compris via la chirurgie bariatrique) et augmenter l'activité physique devrait être mise en place, couplée le cas échéant à une approche pharmacologique.

[Patient with type 2 diabetes and coronary heart disease developing heart failure]. / Vignette thérapeutique de l'étudiant. Patient avec un diabète de type 2, une coronaropathie et une insuffisance cardiaque.

Patients with type 2 diabetes (T2D) are frequently exposed to comorbidities, mainly cardiovascular complications. Thus, a polypharmacy is often mandatory, targeting not only T2D but also comorbidities such as coronary artery disease and heart failure. Interestingly, some drugs improve glucose control, cardiovascular prognosis and heart failure outcome. This versatility may cause trouble regarding prescriptions by practitioners, especially because of the restricted conditions for the reimbursement in Belgium. This clinical vignette aims at discussing the path of pharmacotherapy for a patient with T2D who suffers from a myocardial infarction and subsequently develops a heart failure. It will mainly focus on the place of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporters 2 (gliflozins) as well as the potential of their combination in this context, considering the current restrictions for the reimbursement.

Le patient avec un diabète de type 2 (DT2) est souvent exposé à diverses comorbidités, notamment cardiovasculaires. Dès lors, une polymédication est souvent nécessaire, ciblant le DT2 lui-même, mais aussi les comorbidités comme une coronaropathie et une insuffisance cardiaque. De façon intéressante, certaines médications améliorent à la fois le contrôle glycémique, le pronostic cardiovasculaire et le devenir de l'insuffisance cardiaque. Cette polyvalence peut jeter le trouble en ce qui concerne les prescriptions chez les praticiens, notamment en lien avec les conditions restrictives de remboursement en Belgique. Cette vignette clinique a pour but d'illustrer le cheminement de la pharmacothérapie d'un patient avec un DT2 qui présente un infarctus du myocarde puis, secondairement, une insuffisance cardiaque. Elle ciblera surtout la place des agonistes des récepteurs du glucagon-like peptide-1 et des inhibiteurs des cotransporteurs sodium-glucose de type 2 (gliflozines), et expliquera l'intérêt de leur combinaison dans ce contexte en tenant compte des conditions actuelles de remboursement.

[Don't neglect metabolic syndrome]. / Vignette diagnostique de l'étudiant. Ne pas négliger le syndrome métabolique.

The concept of «metabolic syndrome¼ was brought to the forefront in the early 2000s in international literature, but this interest seems to have faded somewhat in recent years. However, this constellation of cardiovascular risk factors should not be neglected. Taken individually, they hardly seem problematic, but when they are present within the same individual, they significantly increase the risk of cardiovascular morbidity and mortality. This clinical vignette aims to draw attention to the usefulness of the search for metabolic syndrome in clinical practic.

Le concept de «syndrome métabolique¼ a été mis en avant de la scène au début des années 2000 dans la littérature internationale, mais cet intérêt semble s'être quelque peu estompé au cours des dernières années. Il convient cependant de ne pas négliger cette constellation de facteurs de risque cardiovasculaire qui, pris individuellement, ne paraissent guère problématiques, mais qui, lorsqu'ils co-existent chez une même personne, augmentent sensiblement le risque de morbi-mortalité. Cette vignette clinique a pour but d'attirer l'attention sur l'importance de la recherche d'un syndrome métabolique dans la pratique clinique.

Gestational weight gain: Toward best practices in managing gestational weight gain in patients with obesity: Comparison of recommendations.

BACKGROUND AND AIMS: In 2009, the Institute of Medicine (IOM) issued recommendations for gestational weight gain (GWG) based on body mass index (BMI). Several studies have challenged those recommendations for women with obesity, considering them too liberal and advising more limited weight gain - or even weight loss - during pregnancy to improve maternal and neonatal outcomes. Our aim was to study how gestational weight gain in women with obesity impacted maternal and fetal complications in the Belgian population. We did this by comparing the results from two groups of patients with obesity: those who met the 2009 IOM standards and those who satisfied the stricter recommendations suggested by other authors. MATERIALS AND METHODS: This is a retrospective cohort study using data collected at the Centre d'Epidémiologie Périnatale (CEpiP) from obese (BMI ≥ 30 kg/m2) pregnant women with live singleton deliveries between 2010 and 2019 in Wallonia-Brussels Federation (n = 65,314). RESULTS: Compared to obese patients whose GWG satisfied the IOM standards, those with GWG meeting the stricter recommendations had lower rates of gestational hypertension (7.1 % vs. 10.1 %; p = 0.0059), cesarean section (22.1 % vs. 26.3 %; p = 0.0074), and macrosomia (12.0 % vs. 17.7 %; p < 0.0001). There was no significant difference in the rate of preterm delivery (6.9 % vs 5.8 %; p = 0.12) or small-for-gestational-age births (7.2 % vs. 6.2 %; p = 0.16). CONCLUSION: Gestational weight gain below that currently recommended by the IOM appears beneficial to the health of mothers with obesity and their children. These data, from our population, further challenge the standards proposed since 2009.

Adipose tissue macrophage infiltration and hepatocyte stress increase GDF-15 throughout development of obesity to MASH.

Plasma growth differentiation factor-15 (GDF-15) levels increase with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) but the underlying mechanism remains poorly defined. Using male mouse models of obesity and MASLD, and biopsies from carefully-characterized patients regarding obesity, type 2 diabetes (T2D) and MASLD status, we identify adipose tissue (AT) as the key source of GDF-15 at onset of obesity and T2D, followed by liver during the progression towards metabolic dysfunction-associated steatohepatitis (MASH). Obesity and T2D increase GDF15 expression in AT through the accumulation of macrophages, which are the main immune cells expressing GDF15. Inactivation of Gdf15 in macrophages reduces plasma GDF-15 concentrations and exacerbates obesity in mice. During MASH development, Gdf15 expression additionally increases in hepatocytes through stress-induced TFEB and DDIT3 signaling. Together, these results demonstrate a dual contribution of AT and liver to GDF-15 production in metabolic diseases and identify potential therapeutic targets to raise endogenous GDF-15 levels.

Exploring the role of purinergic receptor P2RY1 in type 2 diabetes risk and pathophysiology: Insights from human functional genomics.

OBJECTIVE: Human functional genomics has proven powerful in discovering drug targets for common metabolic disorders. Through this approach, we investigated the involvement of the purinergic receptor P2RY1 in type 2 diabetes (T2D). METHODS: P2RY1 was sequenced in 9,266 participants including 4,177 patients with T2D. In vitro analyses were then performed to assess the functional effect of each variant. Expression quantitative trait loci (eQTL) analysis was performed in pancreatic islets from 103 pancreatectomized individuals. The effect of P2RY1 on glucose-stimulated insulin secretion was finally assessed in human pancreatic beta cells (EndoCßH5), and RNA sequencing was performed on these cells. RESULTS: Sequencing P2YR1 in 9,266 participants revealed 22 rare variants, seven of which were loss-of-function according to our in vitro analyses. Carriers, except one, exhibited impaired glucose control. Our eQTL analysis of human islets identified P2RY1 variants, in a beta-cell enhancer, linked to increased P2RY1 expression and reduced T2D risk, contrasting with variants located in a silent region associated with decreased P2RY1 expression and increased T2D risk. Additionally, a P2RY1-specific agonist increased insulin secretion upon glucose stimulation, while the antagonist led to decreased insulin secretion. RNA-seq highlighted TXNIP as one of the main transcriptomic markers of insulin secretion triggered by P2RY1 agonist. CONCLUSION: Our findings suggest that P2RY1 inherited or acquired dysfunction increases T2D risk and that P2RY1 activation stimulates insulin secretion. Selective P2RY1 agonists, impermeable to the blood-brain barrier, could serve as potential insulin secretagogues.