Loss of hepatic Sirt7 accelerates diethylnitrosamine (DEN)-induced formation of hepatocellular carcinoma by impairing DNA damage repair.

The mammalian sirtuin family (SIRT1-SIRT7) has shown diverse biological roles in the regulation and maintenance of genome stability under genotoxic stress. SIRT7, one of the least studied sirtuin, has been demonstrated to be a key factor for DNA damage response (DDR). However, conflicting results have proposed that Sirt7 is an oncogenic factor to promote transformation in cancer cells. To address this inconsistency, we investigated properties of SIRT7 in hepatocellular carcinoma (HCC) regulation under DNA damage and found that loss of hepatic Sirt7 accelerated HCC progression. Specifically, the number, size, and volume of hepatic tumor colonies in diethylnitrosamine (DEN) injected Sirt7-deficient liver were markedly enhanced. Further, levels of HCC progression markers and pro-inflammatory cytokines were significantly elevated in the absence of hepatic Sirt7, unlike those in the control. In chromatin, SIRT7 was stabilized and colocalized to damage site by inhibiting the induction of γH2AX under DNA damage. Together, our findings suggest that SIRT7 is a crucial factor for DNA damage repair and that hepatic loss-of-Sirt7 can promote genomic instability and accelerate HCC development, unlike early studies describing that Sirt7 is an oncogenic factor [BMB Reports 2024; 57(2): 98-103].

[Diabetes and pancreas or islet transplantation: psychological issues]. / Diabète et transplantation du pancréas ou d'îlots de Langerhans : enjeux psychologiques.

Diabetes is a chronic and progressive disease that affects an increasing number of patients. The prevalence of associated psychological comorbidities is high and often requires the implementation of targeted psychological interventions. Pancreas or islet transplantation remains a therapeutic option to consider, for a part of patients with type 1 diabetes unstable disease or established complications. From the clinical indication to the waiting period for a transplantation, then to the postoperative and long-term care, the diabetic patient is found to experience perpetual changes that may test his adaptability. In this article, the psychological aspects of the pancreas or islet transplantation, as well as the role of a liaison psychiatrist in a transplantation unit will be discussed.

Le diabète est une maladie chronique et évolutive atteignant un nombre croissant de patients. La prévalence des comorbidités psychiques associées est élevée et nécessite souvent l'implémentation d'interventions psychologiques ciblées. La transplantation du pancréas ou d'îlots de Langerhans est une option thérapeutique à considérer pour certains patients avec un diabète de type 1 instable ou des complications installées. De l'indication clinique à la période d'attente pour une greffe, puis des suites postopératoires jusqu'à la vie d'après la greffe, le patient diabétique vit des transitions multiples le mettant à l'épreuve. Dans cet article, nous discutons les aspects psychologiques de ces transplantations ainsi que les interventions du psychiatre de liaison au sein d'un service de transplantation.

[Diabetology: what's new in 2023]. / Diabétologie: ce qui a changé en 2023.

Diabetology is a continuously evolving discipline, many molecules are developed and treatment recommendations change often according to the latest published studies. It is therefore often difficult for the primary care physician to be up to date. After lifestyle measures that must always be preferred before any drug, metformin remains the pharmacological basis of treatment. Current recommendations favor the introduction of an SGLT2 inhibitor or a GLP-1 receptor agonist after metformin because these molecules have shown beneficial cardiovascular and renal effects. The purpose of this article is to guide the primary care physician to choose the most suitable pharmacological treatment for each patient, in the light of the 2023 novelties in the field of diabetes.

La diabétologie est une discipline en évolution continue, de nombreuses molécules sont développées et les recommandations de traitement changent fréquemment en fonction des dernières études publiées. Il est donc souvent difficile pour le médecin de premier recours d'être à jour. Après les mesures du style de vie qu'il faut toujours privilégier avant toute approche médicamenteuse, la metformine reste la base pharmacologique du traitement. Les recommandations actuelles préconisent d'instaurer un inhibiteur du SGLT2 ou un agoniste du récepteur du GLP-1 après la metformine car ces molécules ont montré des effets bénéfiques cardiovasculaires et rénaux. Le but de cet article est de fournir une aide au médecin de premier recours dans le choix du traitement pharmacologique le plus adapté à chaque patient, à la lumière des nouveautés 2023 dans le domaine du diabète.

Inhibition of SIRT7 overcomes sorafenib acquired resistance by suppressing ERK1/2 phosphorylation via the DDX3X-mediated NLRP3 inflammasome in hepatocellular carcinoma.

AIMS: Sirtuin 7 (SIRT7) plays an important role in tumor development, and has been characterized as a potent regulator of cellular stress. However, the effect of SIRT7 on sorafenib acquired resistance remains unclear and a possible anti-tumor mechanism beyond this process in HCC has not been clarified. We examined the therapeutic potential of SIRT7 and determined whether it functions synergistically with sorafenib to overcome chemoresistance. METHODS: Cancer Genome Atlas-liver HCC data and unbiased gene set enrichment analyses were used to identify SIRT7 as a potential effector molecule in sorafenib acquired resistance. Two types of SIRT7 chemical inhibitors were developed to evaluate its therapeutic properties when synergized with sorafenib. Mass spectrometry was performed to discover a direct target of SIRT7, DDX3X, and DDX3X deacetylation levels and protein stability were explored. Moreover, an in vivo xenograft model was used to confirm anti-tumor effect of SIRT7 and DDX3X chemical inhibitors combined with sorafenib. RESULTS: SIRT7 inhibition mediated DDX3X depletion can re-sensitize acquired sorafenib resistance by disrupting NLRP3 inflammasome assembly, finally suppressing hyperactive ERK1/2 signaling in response to NLRP3 inflammasome-mediated IL-1ß inhibition. CONCLUSIONS: SIRT7 is responsible for sorafenib acquired resistance, and its inhibition would be beneficial when combined with sorafenib by suppressing hyperactive pro-cell survival ERK1/2 signaling.

The Imageable Genome.

Understanding human disease on a molecular level, and translating this understanding into targeted diagnostics and therapies are central tenets of molecular medicine1. Realizing this doctrine requires an efficient adaptation of molecular discoveries into the clinic. We present an approach to facilitate this process by describing the Imageable Genome, the part of the human genome whose expression can be assessed via molecular imaging. Using a deep learning-based hybrid human-AI pipeline, we bridge individual genes and their relevance in human diseases with specific molecular imaging methods. Cross-referencing the Imageable Genome with RNA-seq data from over 60,000 individuals reveals diagnostic, prognostic and predictive imageable genes for a wide variety of major human diseases. Having both the critical size and focus to be altered in its expression during the development and progression of any human disease, the Imageable Genome will generate new imaging tools that improve the understanding, diagnosis and management of human diseases.

Redefining Foot Symptoms in a Kidney-Pancreas-Transplanted Type 1 Diabetic Patient: Challenging the Conventional Charcot Foot Diagnosis.

BACKGROUND Acute Charcot foot can be difficult to diagnose, especially because of other alternate diagnoses that can mimic this condition, particularly stress fracture and acute bone and joint infections, which are 2 conditions that require immediate management. Here, we present the case of a patient who received kidney-pancreas-transplantation for type 1 diabetes mellitus, who consulted for right foot pain after walking. CASE REPORT Our patient was a 47-year-old man who had benefited from a kidney-pancreas transplantation in 2014 for type 1 diabetes and terminal kidney failure and was recently followed for a right foot plantar ulcer that was fully healed. He later presented for right foot pain after walking. Clinical examination showed a red, swollen, and warm foot. Blood test results were unremarkable. Imaging (X-ray/MRI) revealed features compatible with acute Charcot foot. The management consisted of prompt right-foot offloading followed by physiotherapy and adapted orthopedic insoles. CONCLUSIONS This case shows the successful treatment of an active phase of Charcot foot, which avoided the classic transition to chronic Charcot foot with severe osteoarticular destruction. Arguments were developed to rule out other possible diagnoses. The underlying mechanisms of Charcot foot in diabetic patients are related to the neurological and micro-vascular complications induced by poor glycemic control, but the mechanisms are unclear. This case report may help clinicians to better understand and consider another less known and less frequent diagnosis when faced with these clinical features.

SGLT-2 inhibitors improve cardiovascular and renal outcomes in patients with CKD: a systematic review and meta-analysis.

The effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors on cardiovascular and renal outcomes has not been systematically reviewed across baseline kidney function groups. We conducted a systematic review and meta-analysis of randomized control trials (RCTs) with SGLT-2 inhibitors in patients with and without CKD. We performed a PubMed/Medline search of randomized, placebo-controlled, event-driven outcome trials of SGLT-2 inhibitors versus active or placebo control in patients with and without diabetes from inception to November 2022. CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2 (PROSPERO registration CRD4202016054). The primary outcome was cardiovascular death. Secondary outcomes included hospitalization for heart failure, major adverse cardiovascular events, CKD progression, all-cause mortality, treatment discontinuation, and acute kidney injury (AKI). The relative risk (RR) was estimated using a random-effects model. Twelve RCTs were included in this meta-analysis (89,191 patients, including 38,949 with eGFR < 60 ml/min/1.73m2). Use of an SGLT-2 inhibitor in patients with CKD was associated with a lower incidence of cardiovascular death (RR 0.87; 95% CI 0.79-0.95) and of heart failure (RR 0.67; 95% CI 0.61-0.75), compared with placebo. Heart failure risk reduction with SGLT-2 inhibitors was larger among patients with CKD compared with patients without CKD (RR for the interaction 0.87, 95% CI 0.75-1.02, and p-value for interaction 0.08). SGLT-2 inhibitors were associated with a lower incidence of CKD progression among patients with pre-existing CKD: RR 0.77 (95% CI 0.68-0.88), compared with placebo. Among patients with CKD, a lower risk of AKI (RR 0.82; 95% CI 0.72-0.93) and treatment discontinuation was seen with SGLT-2 inhibitors compared with placebo. SGLT-2 inhibitors offer substantial protection against cardiovascular and renal outcomes in patients with CKD. These results strongly advocate in favor of using them in patients with CKD and keeping them as kidney function declines.

GLP-1 receptor agonists effect on cognitive function in patients with and without type 2 diabetes.

Glucagon-like peptide 1 (GLP-1) is a hormone of the incretin family, secreted in response to nutrient ingestion, and plays a role in metabolic homeostasis. GLP-1 receptor agonist has a peripheral and a central action, including stimulation of glucose-dependent insulin secretion and insulin biosynthesis, inhibition of glucagon secretion and gastric emptying, and inhibition of food intake. Through their mechanism, their use in the treatment of type 2 diabetes has been extended to the management of obesity, and numerous trials are being conducted to assess their cardiovascular effect. Type 2 diabetes appears to share common pathophysiological mechanisms with the development of cognitive disorders, such as Alzheimer's and Parkinson's disease, related to insulin resistance. In this review, we aim to examine the pathological features between type 2 diabetes and dementia, GLP-1 central effects, and analyze the relevant literature about the effect of GLP-1 analogs on cognitive function of patients with type 2 diabetes but also without. Results tends to show an improvement in some brain markers (e.g. hippocampal connections, cerebral glucose metabolism, hippocampal activation on functional magnetic resonance imaging), but without being able to demonstrate a strong correlation to cognitive scores. Some epidemiological studies suggest that GLP-1 receptor agonists may offer a protective effect, by delaying progression to dementia when diabetic patients are treated with GLP-1 receptor agonists. Ongoing trials are in progress and may provide disease-modifying care for Alzheimer's disease and Parkinson's disease patients in the future.

Mitochondria-associated programmed cell death as a therapeutic target for age-related disease.

Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research.

Combined lactic acidosis and ketoacidosis in a female diabetic patient with severe heart failure.

SGLT2i are now recommended in a wide spectrum of indications including type 2 diabetes (T2DM), heart failure, and chronic kidney disease. This medication class is now available in combination with metformin, which is still a fundamental treatment in patients with T2DM. Despite excellent proven safety profile for both drugs, the expanding use of these agents in clinical practice may lead to an increased incidence of rare side effects, like metformin-associated lactic acidosis (MALA) and euglycemic diabetic ketoacidosis (EDKA), which can be life-threatening. A 58-year-old woman with T2DM and severe heart failure treated by metformin and empagliflozin developed progressive EDKA triggered by fasting that was also complicated by severe acute renal failure and MALA. She was successfully treated with intermittent hemodialysis. This case report highlights the importance of the recognition of rare, but very serious adverse effects due to combined metformin and SGLT2i therapy.

Sarcopenic obesity: epidemiology, pathophysiology, cardiovascular disease, mortality, and management.

Sarcopenic obesity is defined as the coexistence of sarcopenia and obesity in the same individual, characterized by of the co-presence of body fat accumulation and muscle loss. This condition is currently a major concern as it is associated with frailty and disabilities such as cardiovascular disease, fractures, dementia, cancer, and increased all-cause mortality. Particularly, older individuals remain at risk of sarcopenic obesity. Progress at several levels is needed to improve the global prognostic outlook for this condition, including the elaboration and implementation of a more uniform definition that may favor the identification and specification of prevalence by age group. Furthermore, improvements in the understanding of the pathogenesis of sarcopenic obesity may lead to the development of more specific therapeutic interventions to improve prognosis. We reviewed the knowledge on sarcopenic obesity and its associations with cardiovascular diseases and mortality.

[Management of type 2 diabetes on oral nutritional supplement]. / Prise en charge du diabète de type 2 chez le patient dénutri sous supplément nutritif oral.

The management of a patient with type 2 diabetes is well known and is the subject of numerous studies. Protein-calorie malnutrition, on the other hand, is an entity that is still under-diagnosed and under-treated. When artificial nutrition is introduced, glucose homeostasis can be disturbed in case of (pre-)diabetes. To date, few recommendations based on expert opinion exist on the management of diabetes after the introduction of enteral or parenteral nutrition. This article proposes an algorithm for the management of type 2 diabetes when oral nutritional supplements are introduced.

La prise en charge d'un patient diabétique de type 2 est bien connue et fait l'objet de nombreuses études. La dénutrition protéino-calorique quant à elle est une entité encore sous-diagnostiquée et sous-traitée. Lors de la mise en place d'une nutrition artificielle, l'équilibre glycémique peut être perturbé en cas de prédiabète ou de diabète. À ce jour, quelques recommandations basées sur des avis d'experts existent sur la prise en charge du diabète après la mise en place d'une nutrition entérale ou parentérale. Cet article propose un algorithme de prise en charge du diabète de type 2, lors de l'introduction de suppléments nutritifs oraux.

[The diabetic foot : a complex and multidisciplinary management]. / Pied diabétique : une prise en charge complexe et multidisciplinaire.

Diabetic foot syndrome is a common complication in people with diabetes and peripheral sensory impairment. This complex situation requires early clinical detection by various health care professionals, but also by patients and their relatives. The clinical course, the severity of the prognosis and the management will be determined by the speed of the diagnosis. In the case of confirmed disease, multidisciplinary management is necessary. The most important intervention, both for prevention and treatment, is the discharge of the affected foot.

Le syndrome du pied diabétique est une complication fréquente chez les personnes ayant un diabète et une atteinte de la sensibilité périphérique. Cette situation complexe nécessite une détection clinique précoce, par les divers professionnels de la santé mais aussi par les patients et leurs proches. L'évolution clinique, la gravité du pronostic et la prise en charge seront déterminées par la rapidité du diagnostic. En cas d'atteinte confirmée, une prise en charge multidisciplinaire est nécessaire. L'intervention la plus importante, tant pour la prévention que le traitement, est la décharge du pied atteint.

Association Between Prehospital Blood Glucose Levels and Outcomes in Patients With COVID-19 Infection: A Retrospective Cohort Study.

BACKGROUND: Hyperglycaemia is associated with worse outcomes in many settings. However, the association between dysglycaemia and adverse outcomes remains debated in COVID-19 patients. This study determined the association of prehospital blood glucose levels with acute medical unit (intensive care unit or high dependency unit) admission and mortality among COVID-19-infected patients. METHODS: This was a single-centre, retrospective cohort study based on patients cared for by the prehospital medical mobile unit from a Swiss university hospital between March 2020 and April 2021. All adult patients with confirmed or suspected COVID-19 infection during the study period were included. Data were obtained from the prehospital medical files. The main exposure was prehospital blood glucose level. A 7.8 mmol/L cut-off was used to define high blood glucose level. Restricted cubic splines were also used to analyse the exposure as a continuous variable. The primary endpoint was acute medical unit admission; secondary endpoints were 7-day and 30-day mortality. Multivariable logistic regressions were performed to compute odds ratios. RESULTS: A total of 276 patients were included. The mean prehospital blood glucose level was 8.8 mmol/l, and 123 patients presented high blood glucose levels. The overall acute medical unit admission rate was 31.2%, with no statistically significant difference according to prehospital blood glucose levels. The mortality rate was 13.8% at 7 days and 25% at 30 days. The 30-day mortality rate was higher in patients with high prehospital blood glucose levels, with an adjusted odds ratio of 2.5 (1.3-4.8). CONCLUSIONS: In patients with acute COVID-19 infection, prehospital blood glucose levels do not seem to be associated with acute medical unit admission. However, there was an increased risk of 30-day mortality in COVID-19 patients who presented high prehospital blood glucose levels.

Overview of growth differentiation factor 15 in metabolic syndrome.

Growth and differentiation factor 15 (GDF15) is a member of the transforming growth factor-ß (TGF-ß) superfamily. GDF15 has been linked with several metabolic syndrome pathologies such as obesity and cardiovascular diseases. GDF15 is considered to be a metabolic regulator, although its precise mechanisms of action remain to be determined. Glial cell-derived neurotrophic factor family receptor alpha-like (GRAL), located in the hindbrain, has been identified as the receptor for GDF15 and signals through the coreceptor receptor tyrosine kinase (RET). Administration of GDF15 analogues in preclinical studies using various animal models has consistently been shown to induce weight loss through a reduction in food intake. GDF15, therefore, represents an attractive target to combat the current global obesity epidemic. In this article, we review current knowledge on GDF15 and its involvement in metabolic syndrome.

Overweight and obesity in adult patients with phenylketonuria: a systematic review.

BACKGROUND: Excess weight is a rising concern in patients with phenylketonuria (PKU). It is commonly observed in children and adolescents with PKU; but data on adults are inconsistent. This review aims to summarize available data on excess weight in adult PKU individuals. METHODS: We conducted a systematic search of literature in English, from inception to October 2021, on PubMed and Embase to identify articles on overweight and obesity in adult PKU patients. Prevalence of overweight and obesity, body mass index (BMI) and gender differences were the outcomes of interest. RESULTS: Of 260 articles identified, only 8 fulfilled quality criteria for inclusion after screening of titles, abstracts and full texts. The mean BMI of adult PKU patients in these studies ranged from 26 ± 5.4 to 30.3 ± 1.8 kg/m2. When compared to matched controls, adult PKU patients had higher BMI and higher prevalence of obesity. However, results were inconsistent when PKU adults were compared to the general population. The prevalence of obesity in the included studies varied widely between 4.5% up to 72% in individual studies. Obesity was 2-3 times more frequent in female PKU patients. CONCLUSIONS: Excess weight is frequent in adult PKU patients, especially in females, even if the difference with the general population is debatable. The heterogeneity of the studies makes it difficult to interpret the results and the factors that contribute to obesity. Content of the diet, psychological status, diet-associated disordered eating, patient's social environment and lifestyle are listed as potentials contributors to excess weight in PKU adult population. Further studies are needed to better elucidate this question. In the meantime, weight control and healthy eating habits should be considered in the management and follow-up of these patients.

Influence of Skin Commensals on Therapeutic Outcomes of Surgically Debrided Diabetic Foot Infections-A Large Retrospective Comparative Study.

In diabetic foot infections (DFI), the clinical virulence of skin commensals are generally presumed to be low. In this single-center study, we divided the wound isolates into two groups: skin commensals (coagulase-negative staphylococci, micrococci, corynebacteria, cutibacteria) and pathogenic pathogens, and followed the patients for ≥ 6 months. In this retrospective study among 1018 DFI episodes (392 [39%] with osteomyelitis), we identified skin commensals as the sole culture isolates (without accompanying pathogenic pathogens) in 54 cases (5%). After treatment (antibiotic therapy [median of 20 days], hyperbaric oxygen in 98 cases [10%]), 251 episodes (25%) were clinical failures. Group comparisons between those growing only skin commensals and controls found no difference in clinical failure (17% vs. 24 %, p = 0.23) or microbiological recurrence (11% vs. 17 %, p = 0.23). The skin commensals were mostly treated with non-beta-lactam oral antibiotics. In multivariate logistic regression analysis, the isolation of only skin commensals was not associated with failure (odds ratio 0.4, 95% confidence interval 0.1-3.8). Clinicians might wish to consider these isolates as potential pathogens when selecting a targeted antibiotic regimen, which may also be based on oral non-beta-lactam antibiotic agents effective against the corresponding skin pathogens.

[News in diabetology: what's new in 2022]. / Diabétologie : ce qui a changé en 2022.

Diabetology is a constantly evolving discipline, many molecules appear on the market and treatment recommendations change quite frequently according to the latest published studies. It is therefore often difficult for the primary care physician to be up to date. After lifestyle measures that must of course be preferred before any drug approach, metformin remains the pharmacological basis of treatment. Current recommendations favor the introduction of an SGLT2 inhibitor or a GLP-1 receptor agonist after metformin because these molecules have shown beneficial cardiovascular and renal effects. The purpose of this article is to help the primary care physician to choose the most suitable pharmacological treatment for each patient, in the light of the 2022 novelties in the field of diabetes.

La diabétologie est une discipline en constante évolution. De nombreuses molécules apparaissent sur le marché et les recommandations de traitement changent assez fréquemment en fonction des dernières études publiées. Il est donc souvent difficile pour le médecin de premier recours d'être à jour. Après les mesures sur le style de vie, qu'il faut bien sûr privilégier avant toute approche médicamenteuse, la metformine reste la base pharmacologique du traitement. Les recommandations actuelles préconisent d'instaurer un inhibiteur du SGLT2 (sodium-glucose transporteur de type 2) ou un agoniste du récepteur du GLP-1 (Glucagon-like Peptide-1) après la metformine car ces molécules ont montré des effets bénéfiques cardiovasculaires et rénaux. Le but de cet article est d'aider le médecin de premier recours à choisir le traitement pharmacologique le plus adapté à chaque patient, à la lumière des nouveautés 2022 dans le domaine du diabète.

Current knowledge of morbidities and direct costs related to diabetic foot disorders: a literature review.

Diabetes is a chronic disease associated with numerous complications including diabetic foot disorders, which are associated with significant morbidity and mortality as well as high costs. The costs associated with diabetic foot disorders comprise those linked to care (direct) and loss of productivity and poor quality of life (indirect). Due to the constant increase in diabetes prevalence, it is expected that diabetic foot disorder will require more resources, both in terms of caregivers and economically. We reviewed findings on management, morbidity, mortality, and costs related to diabetic foot disorder.