In France, nearly 4 million people take medication for their diabetes. In recent decades, the number of diabetics has doubled worldwide with nearly 8.5% of the world’s population affected. Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin or when the body is unable to use the insulin it produces effectively. This results in an increased concentration of glucose in the blood (hyperglycemia).

Type 2 diabetes develops silently and can be diagnosed when an acute episode appears requiring medical care of the patient. Unfortunately in this case diabetes has already damaged the organs. This disease represents an increased risk of cardiovascular accidents, heart failure, and is the cause of renal failure and peripheral neuropathy.

The IHU ICAN teams are particularly mobilized to better understand the pathological mechanisms associated with diabetes in order to develop new therapies and improve patient care.

Heart failure (HF) in patients with type 2 diabetes (T2D) represents a complex and heterogeneous clinical syndrome. HF in patients with T2DM is associated with a significant risk of death, recurrent hospitalizations and deterioration in quality of life.

It is therefore essential to recognize patients with T2D and undiagnosed myocardial dysfunction who are at high risk for acute HF decompensation.

The reduction in glucose levels in type 2 diabetes leads to major metabolic changes and requires metabolic adaptation of the tissues. It is not known how cardiac metabolism can be acutely affected by changes in blood sugar.

To date, the consequences of the short-term reduction in glucose levels in the heart are not known. There is no previous publication with a similar protocol for the heart. It is therefore essential that the disciplines talk to each other in order to provide comprehensive and personalized care to patients.

The objective of our research is to demonstrate that cardiac metabolic inflexibility is present in some patients with chronic hyperglycemia and revealed during the treatment of their diabetes by insulin therapy.

Defects in metabolic flexibility will be evidenced by changes in cardiac segmental contractility on MRI and by extracellular expansion. This study uses state-of-the-art imaging, which is possible at the IHU ICAN thanks to the recent acquisition of a latest-generation 1.5T cardiovascular MRI specifically dedicated to cardiovascular and metabolic research on humans.

The IHU ICAN is very involved in setting up this project and in its execution, in particular with the participation of several of these platforms:

• ICAN BioCollection for the storage of samples and their preparations
• ICAN Imaging for MRI image acquisition and CoreLab imaging for reading and interpreting MRI images
• ICAN Omics for the assay and interpretation of relevant biomarkers

This study will therefore:

• Identify biomarkers for early detection of metabolic heart failure associated with type 2 diabetes
• Improving the prediction of the evolution of type 2 diabetes thanks to imaging

Project leader:

Pr Fabrizio Andreelli, diabetologist AP-HP, Pitié -Salpêtrière, IHU ICAN

Scientific team

• Pr Richard Isnard, cardiologist, Pitié Salpêtrière Cardiology Institute, IHU ICAN,
• Pr Alban Redheuil, medical manager of the Imaging IHU ICAN platform, head of the Cardiovascular and Thoracic Imaging (ICT) unit, Pitié Salpêtrière,
• Nadjia Kachenoura, scientific manager of the Imaging IHU ICAN platform, head of the cardiovascular imaging team of the Biomedical Imaging Laboratory, (LIB, Sorbonne University)

Today, undernutrition and obesity are problems that coexist within the same population mainly because of changes in our lifestyles: modification of our diet with increasingly processed products and reduced physical activity are among the main causes of the development of obesity. Nutrition-related diseases (obesity and malnutrition) lead to a sharp increase in physiological dysfunctions, in particular cardiometabolic and musculoskeletal complications that can be serious.

IHU ICAN teams are conducting numerous research programs to better understand the causes and mechanisms of the onset of cardiometabolic diseases and to develop new approaches to better manage patients. Obesity and nutrition are at the heart of the concerns of doctors and researchers.

Beyond weight, it is very important to assess the whole body composition of each individual, as it varies according to different body phenotypes. Obesity is an abnormal or excessive accumulation of body fat, but when combined with reduced muscle mass/function, it is referred to as sarcopenic (SO) obesity.

Current research suggests that OS may be associated with a large number of metabolic disorders and an increased risk of mortality, since these two conditions act synergistically [2], [3]. Therefore, OS has attracted increasing interest from the scientific community over the past decades. However, a universally accepted definition of OS is lacking to date, as the majority rely on criteria that consider sarcopenia and obesity separately [4], [5]. It is therefore important to better define OS in order to better manage it because this lack of definition and consistent threshold values constitute a gap in the determination of the precise rates of the prevalence of this disease[6] this has an impact on the prognosis of patients mainly, in individuals with severe obesity, because they not only have a greater quantity of adipose tissue, such as muscle tissue, while body composition is impacted as a whole.

Also, the IHU ICAN teams are carrying out a research project on sarcopenic obesity in order to better characterize it in order to improve its diagnosis and offer personalized care for patients.

This project led by Prof. Jean-Michel Oppert, nutritionist and head of the nutrition/obesity department at the Pitié-Salpêtrière Hospital, by Prof. Vlad Ratziu, gastroenterologist/hepatologist and Vittoria Zambon, researcher and nutritionist , aims to develop a gender-specific (M/F) diagnostic approach for Sarcopenic Obesity for overweight or obese people.

The data of 1427 patients, 42.7% of whom had grade III obesity, were studied: clinical examinations, biochemical analyzes and evaluation of body composition by dual-energy X-ray absorptiometry (DXA).

Once the data was listed, the ICAN I/O platform led by Maharajah PONNAIAH developed a new approach based on AI: unsupervised machine learning.

This innovative new approach will identify body phenotypes at risk for OS, and thus define more effective screening, prevention and intervention measures in the clinical management of this disease, by distinguishing between changes in muscle tissue and fat. A more precise and earlier diagnosis will also make it possible to anticipate the appearance or aggravation of comorbidities possibly associated with OS.

References

[1] W. World Health Organization and World Obesity Federation, “Obesity and overweight,” 2020. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight#:~:text=Facts.

[2] I. Abete et al., “Association of lifestyle factors and inflammation with sarcopenic obesity: data from the PREDIMED-Plus trial,” J. Cachexia. Sarcopenia Muscle, vol. 10, no. 5, pp. 974–984, 2019, doi: 10.1002/jcsm.12442.

[3] R. A. Bhanji, A. J. Montano-Loza, and K. D. Watt, “Sarcopenia in Cirrhosis: Looking Beyond the Skeletal Muscle Loss to See the Systemic Disease,” Hepatology, vol. 70, no. 6, pp. 2193–2203, Dec. 2019, doi: 10.1002/hep.30686.

[4] T. Cederholm et al., “ESPEN guidelines on definitions and terminology of clinical nutrition,” Clin. Nutr., vol. 36, no. 1, pp. 49–64, Feb. 2017, doi: 10.1016/j.clnu.2016.09.004.

[5] A. J. Cruz-Jentoft et al., “Sarcopenia: Revised European consensus on definition and diagnosis,” Age Ageing, vol. 48, no. 1, pp. 16–31, Jan. 2019, doi: 10.1093/ageing/afy169.

[6] J. A. Batsis and D. T. Villareal, “Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies,” Nat. Rev. Endocrinol., vol. 14, no. 9, pp. 513–537, Sep. 2018, doi: 10.1038/s41574-018-0062-9.

A research team from AP-HP, Inserm and Sorbonne University carried out work, within the IHU ICAN, on the effects of bariatric surgery on the severity of liver damage in patients with NASH (Non-Alcoholic Steatohepatitis or Metabolic Steatohepatitis) and severe fibrosis (bridge fibrosis or compensated cirrhosis).
This study shows that in 50% of patients who underwent bariatric surgery, despite significant weight loss (20% to 30% of initial BMI) and improvement in metabolic risk factors (mainly type 2 diabetes), severe fibrosis persists in the medium term (5 years after surgery). The results of this work were published on January 25, 2022 in the journal Hepatology.

Obesity in France concerns 17% of the adult population and it increasingly affects children and adolescents. It has many consequences on the state of health of people who are affected, including the development of “fatty liver” (liver steatosis). Hepatic steatosis is defined by the accumulation of fat in liver cells favored by the presence of metabolic risk factors (particularly diabetes and obesity).

In France, liver steatosis affects 18% of the population and 25% of the general population worldwide. Ultimately, this pathology, also called NASH, can lead to the appearance of more serious diseases such as cirrhosis or liver cancer. To date, there is no effective drug treatment for NASH, which makes research into other avenues of care for patients all the more important.
Previous work has shown dramatic improvement in NASH liver damage after bariatric surgery in parallel with weight loss. Nevertheless, efficacy data in patients with advanced forms of NASH remain limited.

The study, coordinated by Dr Raluca Pais (AP-HP, IHU ICAN), Dr Judith Aron-Wisnewsky (APHP, Inserm, Sorbonne University, IHU ICAN), Pr Vlad Ratziu (AP-HP, INSERM, Sorbonne University , IHU ICAN) and Prof. Karine Clément (AP-HP, Inserm, Sorbonne University, NutriOmics Unit), made it possible to analyze the effects of bariatric surgery on the evolution of severe histological lesions in NASH. The patients, from the “BARICAN bariatric surgery” cohort coordinated by the nutrition department led by Pr Jean-Michel Oppert at the Pitié-Salpêtrière AP-HP hospital, had an initial liver biopsy at the time of surgery. bariatric and a follow-up biopsy.

This study confirms the excellent results of bariatric surgery: overall, 29% of patients had normal histology at follow-up biopsy; 74% had NASH resolution without fibrosis progression; 70% had fibrosis regression. However, in patients with severe fibrosis before surgery, severe fibrosis persistedin 47% of cases in the medium term after surgery, despite the resolution of NASH in 69% of cases.

Patients who do not respond to bariatric surgery have a lesser improvement in metabolic risk factors (less weight loss, remission of diabetes) even if clinically significant. The factors associated with the persistence of fibrosis after bariatric surgery, in addition to the follow-up interval, were age and type of surgery (less regression of fibrosis after the sleeve regardless of weight loss). The factors associated with the absence of liver lesions after bariatric surgery were greater weight loss, improved insulin resistance and less initial severity of necroinflammatory lesions.
In conclusion, Dr. Raluca Pais specifies that “this study shows that, despite established efficacy for the regression of NASH, bariatric surgery is less effective for the regression of severe fibrosis. Fibrosis regression requires more time and probably additional mechanisms. Weight loss alone may not be enough to reverse severe fibrosis. »

Authors:

Raluca Pais: Public Assistance Paris Hospitals, Pitié-Salpêtrière Hospital, Paris, France; Sorbonne University, Paris, France; Institute of Cardiometabolism and Nutrition, Paris, France; Saint Antoine Research Center, INSERM UMRS_938 Paris, France; Judith Aron Wisnewsky: Public Assistance Paris Hospitals, Pitié-Salpêtrière Hospital, Paris, France; Sorbonne University, Paris, France; CRNH Ile de France, INSERM, UMRS U1269, Nutrition and Obesities Systemic Approaches (NutriOmics), Paris, France; Pierre Bedossa : INSERM UMRS 1138 CRC Paris, France, Paris ; Maharajah Ponnaiah : Institute of Cardiometabolism and Nutrition, Paris, France ; Jean-Michel Oppert:Public Assistance Paris Hospitals, Pitié Salpêtrière Hospital, Paris, France; Sorbonne University, Paris, France; Jean-Michel Siksik: Public Assistance Paris Hospitals, Pitié-Salpêtrière Hospital, Paris, France; Laurent Genser: Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France ; Sorbonne Université, Paris, France ; CRNH Ile de France, INSERM, UMRS U1269, Nutrition and Obesities Systemic Approaches (NutriOmics), Paris, France ; Frederic Charlotte : Assistance Publique Hôpitaux De Paris, Hôpital Pitié Salpêtrière, Paris, France ; Sorbonne Université, Paris, France ; Dominique Thabut: Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France ; Sorbonne Université, Paris, France ; Centre de Recherche Saint Antoine, INSERM UMRS_938 Paris, France ; Karine Clement: Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France ; Sorbonne Université, Paris, France ; CRNH Ile de Persistance d’une fibrose avancée (fibrose en pont, F3) avant et après la chirurgie bariatrique France, INSERM, UMRS U1269, Nutrition and Obesities Systemic Approaches (NutriOmics), Paris, France ; Vlad Ratziu : Assistance Publique Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, Paris, France ; Sorbonne Université, Paris, France ; Institute of Cardiometabolism and Nutrition, Paris, France ; INSERM UMRS 1138 CRC Paris, France, Paris.

Nadine Suffee of Professor Stéphane Hatem’s team (UMRS1166 cardiovascular and metabolic diseases) studied the consequences of a high-fat diet on the atrial myocardium and on the formation of AF substrate.

Method

Mice were fed a high-fat diet (60% fat) for 4 months and compared to a control group of mice fed a low-fat diet)

An unbiased mass spectroscopic analysis of the atrial myocardial metabolome and lipidome was performed, and then different strategies were used to characterize the atrial phenotype, including measurement of mitochondrial respiration and analysis of the electrophysiology of atrial myocytes studied by the patch clamp technique

Results

Thus, there is a shift in oxidative metabolism in the atria of mice on a high-fat diet toward the predominance of mitochondrial β-oxidation and the accumulation of long-chain lipids.

This metabolic remodeling is accompanied by changes in mitochondrial respiration measured ex vivo in atrial trabeculae and by shortening of action potential duration, an arrhythmogenic mechanism of AF, related to abnormal activation of ATP-dependent potassium channels in atrial myocytes. The activation of these repolarizing channels is the probable consequence of the lower energy efficiency of the metabolism of myocytes from obese mice. This is associated with increased expression of adipogenesis genes, accumulation of WT especially in the atrioventricular groove, and infiltration of the atrial myocardium by lymphocytes and monocytes/macrophages.

This study is the first demonstration of the role of diet on the atrial phenotype and AF substrate formation. Results show the role played by the balance between use and storage of fatty acids in the acquisition of an adipogenic and inflammatory profile of the atria. The study has lead to the identification of new mechanisms that link metabolism and myocardium: lipid elongation, activation of K-ATP channels, recruitment of immunoinflammatory cells.