John P Kirwan

Pennington Biomedical Research Center · Integrated Physiology and Molecular Medicine

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhan...

Introduction: Data are lacking on the long-term effects of metabolic surgery vs medical intervention on NAFLD in patients with obesity and T2D. Methods: A multi-center, prospective, observational study was performed with adults enrolled in the Alliance of Randomized trials of Medicine vs Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium....

Exercise is a known intervention to alleviate insulin resistance. This study investigated how a 12-week endurance exercise intervention changes skeletal muscle mitochondrial and lipid droplet architecture in patients with type 2 diabetes. Participants completed 12 weeks of endurance exercise at 70% of their VO2 max five days a week at one hour a da...

Introduction: There is immense dispute as to whether perturbations in skeletal muscle mitochondrial function contribute to the onset and progression of type 2 diabetes (T2D). The purpose of this study was to examine differences in mitochondrial dynamics, structure, and energetic function in humans across the spectrum of insulin sensitivity. Methods...

Sarcopenic obesity, or the loss of muscle mass and function associated with excess adiposity, is a largely untreatable medical condition associated with diminished quality of life and increased risk of mortality. To date, it remains somewhat paradoxical and mechanistically undefined as to why a subset of adults with obesity develop muscular decline...

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhanc...

Importance SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID . Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infect...

Exercise is a first-line treatment for type 2 diabetes and preserves β-cell function by hitherto unknown mechanisms. We postulated that proteins from contracting skeletal muscle may act as cellular signals to regulate pancreatic β-cell function. We used electric pulse stimulation (EPS) to induce contraction in C2C12 myotubes and found that treatmen...

Sleep loss typically imposes negative effects on animal health. However, humans with a rare genetic mutation in the dec2 gene ( dec2 P384R ) present an exception; these individuals sleep less without the usual effects associated with sleep deprivation. Thus, it has been suggested that the dec2 P384R mutation activates compensatory mechanisms that a...

Sleep loss typically imposes negative effects on animal health. However, humans with a rare genetic mutation in the dec2 gene (dec2P384R) present an exception; these individuals sleep less without the usual effects associated with sleep deprivation. Thus, it has been suggested that the dec2P384R mutation activates compensatory mechanisms that allow...

Soybean products have nutrients, dietary fiber, and phytoalexins beneficial for cardiovascular and overall health. Despite their high consumption in Asian populations, their safety in Western diets is debated. We conducted a dose-escalating clinical trial of the safety and tolerability of soybean products in eight older adults (70-85 years) with ob...

Background and objective: The effect of exercise training on whole-body insulin sensitivity has not been systematically summarized. We aimed to summarize the data from randomized controlled trials evaluating the effect of exercise training on insulin action, in adults. Subjects: MEDLINE, EMBASE, and CENTRAL databases were searched until January...

Type 2 diabetes is a systemic, multifactorial disease that is a leading cause of morbidity and mortality globally. Despite a rise in the number of available medications and treatments available for management, exercise remains a first-line prevention and intervention strategy due to established safety, efficacy, and tolerability in the general popu...

The expansive and rapid spread of the SARS-CoV-2 virus has resulted in a global pandemic of COVID-19 infection and disease. Though initially perceived to be acute in nature, many patients report persistent and recurrent symptoms beyond the infectious period. Emerging as a new epidemic, “long-COVID”, or post-acute sequelae of coronavirus disease (PA...

Objective: To collect qualitative data on approaches that can potentially reduce barriers to, and create strategies for, increasing SARS-CoV-2 testing uptake in underserved Black communities in Louisiana. Methods: A series of eight focus groups, including 41 participants, were conducted in primarily Black communities. The Nominal Group Technique...

BACKGROUND Relative Energy Deficiency in Sport (RED-S) as a consequence of athlete malnutrition remains a prominent issue, though it remains under-recognized in part due to the perceived outward health of athletes. The Eat2Win app was designed to combat RED-S and athlete malnutrition by providing education, behavior modification and connection with...

Background: Relative energy deficiency in sport (RED-S) as a consequence of athlete malnutrition remains a prominent issue. However, it remains underrecognized, in part due to the perceived outward health of athletes. The Eat2Win app was designed to combat RED-S and athlete malnutrition by providing education, behavior modification, and direct com...

Background Obesity is a disease that may involve disrupted connectivity of brain networks. Bariatric surgery is an effective treatment for obesity, and the positive effects on obesity-related conditions may be enhanced by exercise. Herein, we aimed to investigate the possible synergistic effects of Roux-en-Y Gastric Bypass (RYGB) and exercise train...

Breast cancer is a common and deadly disease that causes tremendous physical, emotional, and financial burden on patients and society. Early-stage breast cancer and less aggressive subtypes have promising prognosis for patients, but in aggressive subtypes, and as cancers progress, treatment options and responses diminish, dramatically decreasing su...

We evaluated the effect of diets low in energy density (1 kcal/g) and high in either potatoes (Potato) or pulses (Bean) on blood glucose control in participants with insulin resistance. We hypothesized that the Potato and Bean diets would have equivalent effects. This was an 8-week randomized, parallel design, controlled feeding study comparing Pot...

Bariatric surgery improves glucose homeostasis and glycemic control in patients with type 2 diabetes. Over the past 20 years, a breadth of studies has been conducted in humans and rodents aimed to identify the regulatory nodes responsible for surgical remission of type 2 diabetes. The review herein discusses central mechanisms of type 2 diabetes re...

Hepatocellular carcinoma (HCC) is the most frequent primary hepatic malignancy and a leading cause of cancer-related death globally. HCC is associated with an indolent clinical presentation, resulting in frequent advanced stage diagnoses where surgical resection or transplant therapies are not an option and medical therapies are largely ineffective...

Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cac...

NAFLD is common in T2DM, linked to insulin resistance and beta-cell dysfunction, and can be assessed with validated liver scores for steatosis and fibrosis. The longitudinal impact of weight loss with or without bariatric/metabolic surgery (BMS) on NAFLD in T2DM is not clear. Patients with T2DM (N=52, age 48±9 yrs, 30 (58%) female, BMI 36.3±2.9 kg/...

Introduction: Obstructive sleep apnea (OSA) is a prevalent sleep disorder with high type 2 diabetes (T2D) risk. OSA therapy includes positive airway pressure (PAP) treatment, which resolves breathing events but modestly improves metabolic health. Metformin is recommended for T2D prevention but is not advocated in patients with OSA. Our pilot study...

Introduction: Obesity is the primary determinant of nonalcoholic fatty liver disease (NAFLD) . Interventions that decrease body weight, such as bariatric surgery and/or calorie restriction (CR) , may serve as effective therapies for NAFLD. The purpose of this study was to compare the effects of Roux-en-Y gastric bypass surgery (RYGB) to CR on hepat...

Background: Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified an orally available mitochondrial-targeted fu...

OBJECTIVE The overall aim of the Alliance of Randomized Trials of Medicine versus Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) consortium is to assess the durability and longer-term effectiveness of metabolic surgery compared with medical/lifestyle management in patients with type 2 diabetes (NCT02328599). RESEARCH DESIGN AND METHODS A total o...

The SARS-CoV-2 pandemic continues to rage around the world. At the same time, despite strong public health measures and high vaccination rates in some countries, a post-COVID-19 syndrome has emerged which lacks a clear definition, prevalence, or etiology. However, fatigue, dyspnea, brain fog, and lack of smell and/or taste are often characteristic...

Aims: Long-term data from randomized clinical trials comparing metabolic (bariatric) surgery vs. a medical/lifestyle intervention for treatment of patients with obesity/overweight and type 2 diabetes (T2D) are lacking. The Alliance of Randomized Trials of Medicine vs. Metabolic Surgery in Type 2 Diabetes (ARMMS-T2D) is a consortium of four randomiz...

Background Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial‐targeted furazano[3,4‐b]py...

This consensus statement is an update of the 2010 American College of Sports Medicine position stand on exercise and type 2 diabetes. Since then, a substantial amount of research on select topics in exercise in individuals of various ages with type 2 diabetes has been published while diabetes prevalence has continued to expand worldwide. This conse...

Precipitated by chronic psychological stress, immune system dysregulation, and a hyperinflammatory state, the sequelae of post-acute Covid-19 (long Covid) include depression and new-onset diabetes. We hypothesize that exercise counters the neuropsychiatric and endocrine sequelae of long Covid by inducing the release of circulating factors that medi...

The inflammatory response is an obstacle to success in both allogeneic and autologous islet transplantation. In autologous islet transplantation (AIT), however, the recipient is also the donor, permitting pretreatment of donor/recipient for a controlled duration prior to transplantation. We sought to exploit this feature of (AIT) by pretreating don...

Objective Metabolically healthy obesity (MHO) is often defined as the absence of metabolic syndrome in the presence of obesity. However, phenotypic features of MHO are unclear. Insulin sensitivity in MHO was cross-sectionally compared with metabolically unhealthy obesity (MUO) and a reference group of young healthy participants without obesity. Me...

Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat pa...

Background Muscle atrophy and strength loss are common adverse outcomes following bariatric surgery. This randomized, controlled trial investigated the effects of exercise training on bariatric surgery‐induced loss of muscle mass and function. Additionally, we investigated the effects of the intervention on molecular and histological mediators of m...

Background Enhanced metabolic plasticity and diversification of energy production is a hallmark of highly proliferative breast cancers. This contributes to poor pharmacotherapy efficacy, recurrence, and metastases. We have previously identified a mitochondrial-targeted furazano[3,4-b]pyrazine named BAM15 that selectively reduces bioenergetic coupli...

Background: The breath print is a quantitative measurement of molecules in exhaled breath and represents a new frontier for biomarker identification. It is unknown whether this state-of-the-art, noninvasive method can detect malnutrition. We hypothesize that individuals with malnutrition will present with a distinguishable breath print. Methods:...

Background There are limited data from randomized control trials to support or refute the contention that whole-grains may enhance protein metabolism in humans. The objectives were threefold: 1) to examine the clinical effects of a whole-grain diet on whole-body protein turnover; 2) the cellular effects of whole-grains on protein synthesis in skele...

Mitochondria undergo continuous cycles of fission and fusion to promote inheritance, regulate quality control, and mitigate organelle stress. More recently, this process of mitochondrial dynamics has been demonstrated to be highly sensitive to nutrient supply, ultimately conferring bioenergetic plasticity to the organelle. However, whether regulato...

Triple negative breast cancer (TNBC) is an aggressive and highly metastatic breast cancer subtype with limited treatment options. Obesity and insulin resistance are associated with a worse prognosis in those with TNBC. Moringa oleifera (moringa) is a tropical edible plant used for both food and medicinal purposes and found to have anti-obesity and...

Mitochondria are essential to the onset and progression of cancer through energy production, reactive oxygen species regulation, and macromolecule synthesis. Genetic and functional adaptations of mitochondria to the tumor environment drive proliferative and metastatic potential. The advent of DNA and RNA sequencing removed critical barriers to the...

Importance The National COVID Cohort Collaborative (N3C) is a centralized, harmonized, high-granularity electronic health record repository that is the largest, most representative COVID-19 cohort to date. This multicenter data set can support robust evidence-based development of predictive and diagnostic tools and inform clinical care and policy....

The extent to which the benefits of bariatric surgery may be maintained by lifestyle changes after surgery is unclear. Our hypothesis is that exercise may sustain some metabolic benefits and counteract some of the adverse effects of surgery. In this review, we present findings supporting the proposition that exercise is key to improving overall hea...

Background: Targeting mitochondrial function has regained traction as a viable anti-cancer strategy. Here, we characterized the phenotypic and transcriptomic landscape of human triple negative breast cancer (TNBC) cells following exposure to the mitochondrial uncoupler BAM15. Methods: Cell viability and IC50 were determined by MTS assay after treat...

Valosin containing protein (VCP) is a hexameric type II AAA ATPase required for several cellular processes including ER-associated degradation, organelle biogenesis, autophagy and membrane fusion. VCP contains three domains: a regulatory N-terminal domain and two ATPase domains (D1 and D2). Mutations in the N-terminal and D1 domains are associated...

Objective: To investigate the long-term effects of medical and surgical treatments of type 2 diabetes mellitus (T2DM) on patient reported outcomes (PROs). Background: Robust data on PROs from randomized trials comparing medical and surgical treatments for T2DM are lacking. Methods: The Surgical Treatment And Medications Potentially Eradicate D...

PurposeThe aim of this exploratory study was to investigate whether the degree of weight loss properly reflects improvements in cardiometabolic health among patients who underwent Roux-en-Y gastric bypass.Methods In this ancillary analysis from a clinical trial, patients were clustered into tertiles according to the magnitude of the percentage weig...

Background Metabolic surgery has beneficial metabolic effects, including remission of type 2 diabetes. We hypothesized that duodenojejunal bypass (DJB) surgery can protect against development of type 1 diabetes (T1D) by enhancing regulation of cellular and molecular pathways that control glucose homeostasis.MethodsBBDP/Wor rats, which are prone to...

Background and aims A diminution in skeletal muscle mitochondrial function due to ectopic lipid accumulation and excess nutrient intake is thought to contribute to insulin resistance and the development of type 2 diabetes. However, the functional integrity of mitochondria in insulin-resistant skeletal muscle remains highly controversial. Methods 1...

Many adults receive inadequate sleep, which elevates obesity and type 2 diabetes risk and may hinder benefits of calorie restriction (CR). We hypothesized that short sleepers would experience less weight loss and diminished glycemic benefits compared to adequate sleepers during CR. We performed secondary analyses in participants randomized to 25% C...

There is limited Level-1 evidence from well-powered randomized controlled trials (RCTs) examining improved glycemic control after metabolic surgery in patients with type 2 diabetes (T2D) and obesity. ARMMS-T2D is a multi-center consortium conducting a follow-up study of 4 merged RCTs in 256 patients with baseline Class 1-3 obesity and T2D, randomly...

The cancer anorexia-cachexia syndrome (CACS) is a common, debilitating condition with limited therapeutic options. The defining feature of CACS is weight loss, which suggests a state of negative energy balance. It is unclear whether this net reduction in energy is due solely to anorexia or if a combination of anorexia and increased energy expenditu...

Introduction Patients with type 2 diabetes experience resolution of hyperglycemia within days after Roux-en-Y gastric bypass (RYGB) surgery. This is attributed, in part, to enhanced secretion of hindgut factors following exclusion of the gastric remnant and proximal intestine during surgery. However, evidence of the mechanisms of remission remain l...

Background: Asthma physiology affects respiratory function and inflammation, factors that may contribute to elevated resting energy expenditure (REE) and altered body composition. Objective: We hypothesized that asthma would present with elevated REE compared to weight-matched healthy controls. Methods: Adults with asthma (n = 41) and healthy contr...

Introduction: Reductions in β-cell number and function contribute to the onset type 2 diabetes (T2D). Roux-en-Y gastric bypass (RYGB) surgery can resolve T2D within days of operation, indicating a weight-independent mechanism of glycemic control. We hypothesized that RYGB normalizes glucose homeostasis by restoring β-cell structure and function....

Purpose of Review Sleep and obesity share a bidirectional relationship, and weight loss has been shown to enhance sleep. Aiming to extend sleep on its own or as part of a lifestyle intervention may attenuate health consequences of short sleep. This review highlights several sleep extension approaches, discusses feasibility of each, and summarizes f...

Background: Bariatric surgery improves cardiovascular health, which might be partly ascribed to beneficial alterations in the autonomic nervous system. However, it is currently unknown whether benefits from surgery on cardiac autonomic regulation in post-bariatric patients can be further improved by adjuvant therapies, namely exercise. We investig...

The shortage of essential medical care has become a major health concern as the Covid‐19 pandemic continues to unfold. The population of Sao Paulo, Brazil, has been severely impacted due to the very‐high prevalence of Covid‐19 cases, and as the health system promptly adjusted to accommodate infected patients, the problem of access to essential care...

Purpose: Obesity is an independent risk factor for the development, morbidity, and mortality of breast cancer. Calorie restriction (CR) is the first line therapy for obesity management, with growing evidence and application in the treatment of breast cancer. In non-tumor bearing patients, ~20% of weight loss is attributed to reductions in skeletal...

Background/Objectives This was an out-of-hospital screening of health status and lifestyle during the Covid-19 pandemic in post-operative bariatric patients from Sao Paulo, Brazil, prevented from face-to-face health care. Subjects/Methods In this cross-sectional study, 66 patients were remotely (via phone call) and in-person (by home visit) assess...

Rationale and Objectives Adiposity and physical fitness levels are major drivers of cardiometabolic risk, but these relationships have not been well-characterized in chronic kidney disease (CKD). We examined the associations of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intrahepatic fat and physical function with inflammation...

Overweight and obesity are major risk factors for diabetes, cardiovascular disease, and lung disease. These diseases are the most commonly reported health conditions that predispose individuals with SARS-CoV-2 infection to require hospitalization including intensive care unit admissions. The innate immune response is the host’s first line of defens...

Obesity is a leading cause of preventable death worldwide. Despite this, current strategies for the treatment of obesity remain ineffective at achieving long-term weight control. This is due, in part, to difficulties in identifying tolerab