Insulin Action Research Articles

Muco-Adhesive and Muco-Penetrative Formulations for the Oral Delivery of Insulin.

Insulin, a pivotal anabolic hormone, regulates glucose homeostasis by facilitating the conversion of blood glucose to energy or storage. Dysfunction in insulin activity, often associated with pancreatic β cells impairment, leads to hyperglycemia, a hallmark of diabetes. Type 1 diabetes (T1D) results from autoimmune destruction of β cells, while type 2 diabetes (T2D) stems from genetic, environmental, and lifestyle factors causing β cell dysfunction and insulin resistance. Currently, insulin therapy is used for most of the cases of T1D, while it is used only in a few persistent cases of T2D, often supplemented with dietary and lifestyle changes. The key challenge in oral insulin delivery lies in overcoming gastrointestinal (GI) barriers, including enzymatic degradation, low permeability, food interactions, low bioavailability, and long-term safety concerns. The muco-adhesive (MA) and muco-penetrative (MP) formulations aim to enhance oral insulin delivery by addressing these challenges. The mucus layer, a hydrogel matrix covering epithelial cells in the GI tract, poses significant barriers to oral insulin absorption. Its structure, composition, and turnover rate influence interactions with insulin and other drug carriers. Some of the few factors that influence mucoadhesion and mucopenetration are particle size, surface charge distribution, and surface modifications. This review discusses the challenges associated with oral insulin delivery, explores the properties of mucus, and evaluates the strategies for achieving excellent MA and MP formulations, focusing on nanotechnology-based approaches. The development of effective oral insulin formulations holds the potential to revolutionize diabetes management, providing patients with a more convenient and patient-friendly alternative to traditional insulin administration methods.

The ASSIST trial: Acute effects of manipulating strength exercise volume on insulin sensitivity in obese adults: A protocol for a randomized controlled, crossover, clinical trial.

Type 2 diabetes mellitus is a disease in which insulin action is impaired, and an acute bout of strength exercise can improve insulin sensitivity. Current guidelines for strength exercise prescription suggest that 8 to 30 sets could be performed, although it is not known how variations in exercise volume impact insulin sensitivity. Additionally, this means an almost 4-fold difference in time commitment, which might directly impact an individual's motivation and perceived capacity to exercise. This study will assess the acute effects of high- and low-volume strength exercise sessions on insulin sensitivity. After being thoroughly familiarized, 14 obese individuals of both sexes (>40 year old) will undergo 3 random experimental sessions, with a minimum 4-day washout period between them: a high-volume session (7 exercises, 3 sets per exercise, 21 total sets); a low-volume session (7 exercises, 1 set per exercise, 7 total sets); and a control session, where no exercise will be performed. Psychological assessments (feeling, enjoyment, and self-efficacy) will be performed after the sessions. All sessions will be held at night, and the next morning, an oral glucose tolerance test will be performed in a local laboratory, from which indexes of insulin sensitivity will be derived. We believe this study will aid in strength exercise prescription for individuals who claim not to have time to exercise or who perceive high-volume strength exercise intimidating to adhere to. This trial was prospectively registered (ReBEC #RBR-3vj5dc5 https://ensaiosclinicos.gov.br/rg/RBR-3vj5dc5).

Unresolved questions in the regulation of skeletal muscle insulin action by reactive oxygen species.

Reactive oxygen species (ROS) are well-established signaling molecules implicated in a wide range of cellular processes, including both oxidative stress and intracellular redox signaling. In the context of insulin action within its target tissues, ROS have been reported to exert both positive and negative regulatory effects. However, the precise molecular mechanisms underlying this duality remain unclear. This Review examines the complex role of ROS in insulin action, with a particular focus on skeletal muscle. We aim to address three critical aspects: (a) the proposed intracellular pro-oxidative redox shift elicited by insulin, (b) the evidence supporting that redox-sensitive cysteine modifications impact insulin signaling and action, and (c) cellular mechanisms underlying how ROS can paradoxically act as both enhancers and inhibitors of insulin action. This Review underscores the urgent need for more systematic research to identify specific reactive species, redox targets, and the physiological significance of redox signaling in maintaining insulin action and metabolic health, with a particular emphasis on human skeletal muscle.

Penatalaksanaan Senam Kaki Diabetes Terhadap Nilai ABI (Ankle Brachial Index) Pada Lansia : Studi Kasus

Diabetes mellitus is a metabolic disorder characterized by increased blood glucose levels due to damage to insulin secretion, less effective insulin action or both. There are many complications that arise from diabetes, one of which can cause poor blood circulation in sufferers, especially in the legs, which can later cause peripheral arterial disease (PAD). This study uses a case report approach to evaluate the implementation of nursing for elderly people with diabetes who ex perience PAD with diabetic foot exercise and success is measured by the ankle brachial index (ABI) value. The results of this study showed that there was a change in the patient's ABI value after routinely doing diabetes foot exercises for 2 weeks, the ABI value in the first week was 0.62 (right), 0.68 (left) and in the 2nd week it was 0.68 (right ), 0.82 (left). Diabetic foot exercises are an exercise that can be done by patients suffering from DM or not because the benefits of diabetic foot exercises are to help improve blood circulation in the feet and also prevent injuries.

Effect of acute intranasal insulin administration on muscle sympathetic nerve activity in healthy young adults.

Systemic insulin increases muscle sympathetic nerve activity (MSNA) via both central actions within the brainstem and peripheral activation of the arterial baroreflex. Augmented MSNA during hyperinsulinemia likely restrains peripheral vasodilation and contributes to the maintenance of blood pressure (BP). However, in the absence of insulin action within the peripheral vasculature, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans remains unknown. Herein, we hypothesized intranasal insulin administration would increase MSNA and BP in healthy young adults. Participants were assigned to time control [TC, n = 13 (5 females/8 males), 28 ± 1 yr] or 160 IU of intranasal insulin administered over 5 min [n = 15 (5 females/10 males), 26 ± 2 yr]; five (1 female/4 males) participants completed both conditions. MSNA (fibular microneurography), BP (finger photoplethysmography), and leg blood flow (LBF, femoral Doppler ultrasound) were assessed at baseline, and 15 and 30 min following insulin administration. Leg vascular conductance [LVC = (LBF ÷ mean BP) × 100] was calculated. Venous insulin and glucose concentrations remained unchanged throughout (P > 0.05). Following intranasal insulin administration, MSNA (burst frequency; baseline = 100%; minute 15, 121 ± 8%; minute 30, 118 ± 6%; P = 0.009, n = 7) and mean BP (baseline = 100%; minute 15, 103 ± 1%; minute 30, 102 ± 1%; P = 0.003) increased, whereas LVC decreased (baseline = 100%; minute 15, 93 ± 3%; minute 30, 99 ± 3%; P = 0.03). In contrast, MSNA, mean BP, and LVC were unchanged in TC participants (P > 0.05). We provide the first evidence that intranasal insulin administration in healthy young adults acutely increases MSNA and BP and decreases LVC. These results enhance mechanistic understanding of the sympathetic and peripheral hemodynamic response to insulin.NEW & NOTEWORTHY Systemic insulin increases muscle sympathetic nerve activity (MSNA) via central actions within the brainstem and peripheral activation of the arterial baroreflex. In the absence of peripheral insulin action, whether central insulin stimulation increases MSNA and influences peripheral hemodynamics in humans was unknown. We provide the first evidence that intranasal insulin administration increases MSNA and blood pressure and reduces leg vascular conductance. These results enhance mechanistic understanding of the sympathetic and hemodynamic response to insulin.

Remission of diabetes mellitus in a female dog intact

Diabetes Mellitus (DM) is one of the most common endocrinopathies among dogs. It is a set of metabolic disorders resulting from tissues' lack of sensitivity to insulin action and/or its relative or absolute deficiency. The clinical manifestations observed include polyuria, polydipsia, polyphagia, weight loss, persistent hyperglycemia, and glucosuria. Its classification and etiology in dogs are not yet well defined but may be associated with immunomediated, genetic, infectious, hormonal, metabolic, and some drug factors. According to the AHAA® 2018 guidelines (American Animal Hospital Association) for Diabetes Management in Dogs and Cats, therapeutic strategies in all cases include insulin therapy, dietary management, recognition, elimination/minimization of factors associated with insulin resistance. This report presents the case of an 8-year-old intact a dog, Yorkshire Terrier breed, presenting at the time of DM diagnosis clinical characteristics suggestive of diestrus and mammary nodule. The therapeutic approach was a new dietary management with commercial dry food as an adjunct for diabetics and calories appropriate to their body score condition, divided into equal meals before applying insulin and performing ovarian hysterectomy. After the start of treatment, a reduction in persistent hyperglycemia with improvement in clinical manifestations could be observed even before surgical approaches, as diestrus progressed to anestrus. It is concluded that, although canine DM remission is uncommon, it is possible when appropriate insulin therapy is instituted associated with dietary adjustment and reduction of factors causing insulin resistance.

Classification, Symptoms, Treatment and Preventive Strategies of Diabetes. A guide to the basic

Introduction Diabetes is a chronic metabolic disorder characterized by impaired insulin secretion and action. Risk factors for diabetes include age, obesity, low physical activity, hypertension, lipid disorders, and genetic predisposition. Symptoms of diabetes typically include frequent urination, weight loss, excessive thirst, weakness, fatigue, susceptibility to fungal infections and recurrent boils. Diabetes is a prevalent and significant societal concern, often causing anxiety, uncertainty and a sense of danger upon diagnosis. Aim of the study The aim of the study is to provide a comprehensive analysis of diabetes, including its classification, characteristic symptoms, the most frequently occurring diabetes-related complications, and preventive strategies. Through a detailed discussion of these issues, our goal is to increase public awareness of diabetes and provide readers with comprehensive knowledge about this disease. Material and method This article presents the current state of knowledge about diabetes. A literature review was conducted using the PubMed, Google Scholar and Web of Science databases, utilizing keywords such as "diabetes", "diabetes mellitus", "diabetes complications". Results The number of people with diabetes has continued to rise. Scientists predict that in a few decades, this number could reach more than half a billion globally. Many individuals may not realize that they are at risk for this civilization disease, often due to unhealthy lifestyle choices such as smoking, obesity, and lack of physical activity. Early initiation of treatment is crucial in preventing serious complications. Despite living with diabetes for years, some patients still report insufficient knowledge about their condition. Therefore, educating patients about the nature of the disease and its treatment is essential for improving their quality of life.

Anti-Inflammatory Potential of the Anti-Diabetic Drug Metformin in the Prevention of Inflammatory Complications and Infectious Diseases Including COVID-19: A Narrative Review.

Metformin, a widely used first-line anti-diabetic therapy for the treatment of type-2 diabetes, has been shown to lower hyperglycemia levels in the blood by enhancing insulin actions. For several decades this drug has been used globally to successfully control hyperglycemia. Lactic acidosis has been shown to be a major adverse effect of metformin in some type-2 diabetic patients, but several studies suggest that it is a typically well-tolerated and safe drug in most patients. Further, recent studies also indicate its potential to reduce the symptoms associated with various inflammatory complications and infectious diseases including coronavirus disease 2019 (COVID-19). These studies suggest that besides diabetes, metformin could be used as an adjuvant drug to control inflammatory and infectious diseases. In this article, we discuss the current understanding of the role of the anti-diabetic drug metformin in the prevention of various inflammatory complications and infectious diseases in both diabetics and non-diabetics.

Temporal multiscale modeling of biochemical regulatory networks: Calcium-regulated hepatocyte lipid and glucose metabolism

Hepatocyte lipid and glucose metabolism is regulated not only by major hormones like insulin and glucagon but also by many other factors, including calcium ions. Recently, mitochondria-associated membrane (MAM) dysfunction combined with incorrect IP3-receptor regulation has been shown to result in abnormal calcium signaling in hepatocytes. This dysfunction could further lead to hepatic metabolism pathology. However, the exact contribution of MAM dysfunction, incorrect IP3-receptor regulation and insulin resistance to the calcium-insulin-glucagon interplay is not understood yet. In this work, we analyze the role of abnormal calcium signaling and insulin dysfunction in hepatocytes by proposing a model of hepatocyte metabolic regulatory network with a detailed focus on the model construction details besides the biological aspect. In this work, we analyze the role of abnormal calcium signaling and insulin dysfunction in hepatocytes by proposing a model of hepatocyte metabolic regulatory network. We focus on the model construction details, model validation, and predictions. We describe the dynamic regulation of signaling processes by sigmoid Hill function. In particular, we study the effect of both the Hill function slope and the distance between Hill function extremes on metabolic processes in hepatocytes as a model of nonspecific insulin dysfunction. We also address the significant time difference between characteristic time of glucose hepatic processing and a typical calcium oscillation period in hepatocytes. Our modeling results show that calcium signaling dysfunction results in an abnormal increase in postprandial glucose levels, an abnormal glucose decrease in fasting, and a decreased amount of stored glycogen. An insulin dysfunction of glucose phosphorylation, glucose dephosphorylation, and glycogen breakdown also cause a noticeable effect. We also get some insight into the so-called hepatic insulin resistance paradox, confirming the hypothesis regarding indirect insulin action on hepatocytes via dysfunctional adipocyte lipolysis.

Assessment of Serum Insulin and VASPIN Levels Among Type 2 Diabetes Mellitus Patients with or Without Obesity: A Cross-sectional Analytical Study

ABSTRACT Introduction: A collection of diverse conditions together referred to as diabetes mellitus frequently manifest as periods of hyperglycemia and glucose intolerance, which can be caused by insufficient insulin, improper insulin action, or both. A medical condition known as obesity is the accumulation of excess body fat to the point that it may be harmful to one’s health. It has been determined that the adipokine vaspin (visceral adipose tissue-derived serpin A12) belongs to the family of serine protease inhibitors. Insulin, a polypeptide hormone, is released by the pancreatic beta cells. This hormone is both anti-catabolic and anabolic. Insulin decreases blood glucose levels by preventing its synthesis and encouraging its storage and use. Methodology: In total, 125 male and female participants of various ages participated in the current study. They included 25 healthy controls, 50 non-obese and 50 obese non–insulin-dependent diabetes mellitus patients, who visited the MDM Hospital’s outpatient clinic in Jodhpur, Rajasthan. Commercially available reagents and kits were utilized for the analysis of serum insulin and vaspin samples. Standard statistical tools were utilized to evaluate the parameters. Results and Discussion: When results were compared with healthy participants and non-obese NIDDM subjects, obese NIDDM subjects showed statistically significant higher fasting serum insulin and serum vaspin levels (P < 0.0001). Conclusion: Our study’s conclusions demonstrated a strong correlation between blood insulin and vaspin levels and diabetes and obesity. Vaspin has a positive impact on insulin resistance, obesity, type 2 diabetes, and metabolic syndrome. It also enhances glucose tolerance and insulin sensitivity, reducing diabetes complications. This novel biomarker has the potential to enhance diabetes mellitus outcomes by facilitating prompt diagnosis, improved management, and reduction of complications.

Abstract PO1-14-11: Different molecular processes are associated with recurrence in the clinical high- genomic low risk (cH/gL) and clinical low- genomic high risk (cL/gH) groups of the MINDACT clinical trial

Abstract Background: Despite the growing understanding of estrogen receptor positive/HER2-negative (ER+/HER2-) breast cancer (BC) biology, many unknowns remain regarding the mechanisms of disease recurrence. While several multigene prognostic signatures have shown clinical utility in identifying those patients at high or low genomic risk of recurrence, they can present with some limitations. In this retrospective analysis of the MINDACT trial, we interrogated the available transcriptomic data to understand which biological characteristics of the tumor are associated with recurrence in patients from the clinical high- genomic low risk (cH/gL) and clinical low- genomic high risk (cL/gH) groups (where the clinical and genomic risk were defined by a modified version of Adjuvant Online! and the 70-gene signature, respectively). Methods: These analyses focused on the subset of patients with ER+/HER2- tumors of no special type (NST) who received endocrine therapy (which comprised the majority of this NST ER+/HER2- sub-cohort) and for which central pathology and gene expression data were available (n= 1245). Scores of gene expression modules associated with key biological processes in breast cancer defined in a collection of previous publications were computed from the gene expression matrix using the formula described in Desmedt et al. (Clin. Cancer Res. 2008). Gene Set Variation Analysis method (R package ‘GSVA’ – version 1.40.1) was used to derive the enrichment scores of fifty hallmark gene sets available in the ‘H’ collection of the MSigDB database (version 7.5.1). Survival analyses were performed for disease-free survival (DFS) and distant recurrence-free survival (DRFS). Univariable and multivariable regression models, implemented by Cox regression and Fine-Gray subdistribution hazard regression methods, were performed to evaluate the association of enrichment of hallmarks and gene modules with DFS and DRFS, respectively (covariates =age, nodal status, KI67, tumor size, chemotherapy, radiotherapy). Results: DFS event occurred in 150/913 (16.4%) and 51/332 (15.4%) NST ER+/HER2- patients in the cH/gL and cL/gH groups, respectively. DRFS event occurred in 70/913 (7.7%) and 21/332 (6.3%) NST ER+/HER2- patients in the cH/gL and cL/gH groups, respectively. In the cH/gL group, we observed an association of hallmarks related to cell cycle and downregulation of gene modules related to lymphocyte-centric immune activities with worse prognosis (Table). For the cL/gH, we did not observe an association between hallmarks related to cell cycle and worse prognosis but an enrichment of hallmarks related to PI3K/AKT/mTOR signaling as well as several metabolic hallmarks related to insulin activities (Table). Of interest, in this group of patients, higher scores of the HER2-associated gene expression signature were also associated with worse prognosis. Across the two groups effects were more pronounced for DRFS than DFS. Conclusion: Different molecular processes are associated with progression in these two distinct groups of patients. The association of hallmarks related to cell cycle with survival in the cH/gL group supports the observation that adjuvant chemotherapy could benefit a subset of these patients. In the cL/gH group, the association of signatures associated with PI3K pathway and HER2 can have potential clinical relevance given their current targetability in the metastatic setting. This retrospective study is funded by the Breast Cancer Research Foundation. Table. Representative hallmarks and gene expression modules independently associated with prognosis in NST ER+/HER2- patients in the cH/gL group and in the cL/gH group #p-values reported were not corrected for multiple testing Citation Format: Christine Desmedt, Ha-Linh Nguyen, François Richard, Marion Maetens, Coralie Poncet, Laura De Meulemeester, Kim Aalders, Mauro Delorenzi, Suzette Delaloge, Jean-Yves Pierga, Etienne Brain, Suzan Vrijaldenhoven, Peter A Neijenhuis, Emiel Rutgers, Florentine Hilbers, Laura Van ’t Veer, Giuseppe Viale, Christos Sotiriou, Martine Piccart, Fatima Cardoso. Different molecular processes are associated with recurrence in the clinical high- genomic low risk (cH/gL) and clinical low- genomic high risk (cL/gH) groups of the MINDACT clinical trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-14-11.

The Effect of High Fructose Diet on Insulin Signaling in Pituitary Tissue of Liver Androgen Receptor Knockout in Female Mice

Intro: Insulin resistance affects up to a third of the US adult population and polycystic ovary syndrome affects up to 10% of reproductive-age adult women. Hyperandrogenism in females can increase predisposition to insulin resistance. Andrisse et al 2021 (PMCID: PMC9097557) showed that deleting the liver androgen receptor (LivARKO) prevented female mice from developing hyperandrogenemia (HA)-induced insulin resistance. This study placed female LivARKO mice on a high fructose diet (HFrD) to determine if LivARKO mice demonstrate blunted insulin resistance on HFrD compared to control diet. Hypothesize: It was hypothesized that (unlike HA-LivARKO) HFrD LivARKO female mice would display impaired insulin action (lowered insulin-stimulated p-AKT) in PIT tissue in comparison to the Control diet fed LivARKO female mice, suggesting that liver AR does not play a significant role in regulating HFrD-induced insulin resistance in the pituitary. Methods: Female LivARKO mice were placed on two diets: Control (Con, Research Diets Inc, RDI D12450J) and High Fructose (HFrD, RDI D02022704). After 3 months on the diet, the mice were sacrificed. Half of the mice were given a dose of 0.5 U/kg insulin before sacrificing to investigate the effects of the diets on insulin signaling. Western blots were used to determine protein expression in tissue from the pituitary tissue (PIT). BCA assays were used to standardize the protein concentration in each sample. Insulin action can be measured molecularly by examining p-AKT Serine 473 (positive regulator, Santa Cruz sc-514032). If p-AKT S473 levels increase in the presence of insulin, this indicates that insulin is likely functioning properly in the sample. Results:LivARKO female mice on a control diet (Con) for 3-months administered with insulin displayed a 3-fold significant increase in p-AKT levels in the pituitary compared to LivARKO-Con female mice not injected with insulin (basal), suggesting that LivARKO-Con mice pituitaries were insulin sensitive. However, LivARKO female mice fed a high fructose diet (HFrD) for 3-months and then administered with insulin displayed significantly lowered p-AKT levels in the pituitary compared to basal LivARKO-HFrD female mice and compared to insulin LivARKO-Con, indicating that LivARKO-HFrD female mice were experiencing insulin resistance (lowered insulin sensitivity compared to LivARKO-Con). Interestingly, p-AKT was significantly increased by 2.5 fold in LivARKO-HFrD female mice compared to LivARKO-Con, suggesting that HFrD increased insulin sensitivity in the pituitary. Conclusion: In conclusion, these data suggest that LivARKO indirectly disrupted insulin-stimulated p-AKT in PIT possibly via altering metabolites in the blood. Additionally, HFrD is known to cause insulin resistance, however, it is not known to alter p-AKT levels. Thus, the change in p-AKT levels is presumably associated with the LivARKO. Further research is required on what components of the Control Diet are prompting this difference in insulin action and if it only takes place in the LivARKO mouse model. We would like to thank the National Science Foundation for award # NSF 1931045 and the National Institutes of Health 1R01DK126892-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of intermittent hypoxia on glucose tolerance in adults with type 2 diabetes

Hypoxia stimulates glucose uptake through an insulin-independent pathway. The purpose of this single-blind randomized study was to determine the acute effect of intermittent hypoxia, consisting of alternating short bouts of breathing hypoxic and normoxic air, on glucose and insulin concentrations during an oral glucose tolerance test in adults with type 2 diabetes. It was hypothesized that intermittent hypoxia would attenuate the increase in glucose and insulin concentrations during an oral glucose tolerance test. Six adults with type 2 diabetes (5 men, age: 51±15 years, HbA1c: 7.3±1.5%) visited the laboratory on two occasions. On both visits, a 2-hour oral glucose tolerance test was performed, with venous blood samples collected 0, 30, 60, 90, and 120 min after ingestion of a high-glucose drink. Following ingestion of the drink, participants were exposed to either an intermittent hypoxia (IH) protocol, consisting of eight 4-min hypoxic cycles at a targeted arterial oxygen saturation of 80% interspersed with breathing room air to resaturation, or an intermittent normoxia (IN) protocol consisting of eight 4-min normoxic cycles interspersed with breathing room air. By design, oxygen saturation was lower during intermittent hypoxia than intermittent normoxia (81±3 vs. 97±1%, p<0.01). Relative changes in plasma glucose concentrations in response to the oral glucose tolerance tests were not different between conditions (IH vs. IN: 30: 42±15 vs. 35±15; 60: 57±26 vs. 65±30; 90: 73±32 vs. 88±30; and 120: 78±26 vs. 83±29 mg/dl, interaction effect: p=0.13). Similarly, the relative changes in insulin concentrations in response to the oral glucose tolerance tests were not different between conditions (IH vs. IN: 30: 14±17 vs. 25±17; 60: 42±36 vs. 48±35; 90: 70±58 vs. 86±60; and 120: 103±72 vs. 125±94 ulU/ml, main effect for condition: p=0.12). While these preliminary results did not reach statistical significance, the observed trends for reduced glucose concentrations in combination with lower insulin concentrations during intermittent hypoxia suggest that short bouts of hypoxia improve glucose tolerance by stimulating glucose uptake independently from the action of insulin. Data from a larger sample size of adults with type 2 diabetes are needed to confirm these preliminary findings. None. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Deletion of Mitogen-inducible gene-6 (Mig6) in the Liver Alters Glucose Homeostasis and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Progression

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a spectrum of chronic liver disease that can progress from benign steatosis to metabolic dysfunction-associated steatohepatitis (MASH) - both of which, if left untreated, can progress to cirrhosis and hepatocellular carcinoma. The strongest risk factor for progression of MASLD to MASH is insulin resistance. Previous work in our lab identified that the adaptor protein mitogen-inducible gene-6 (Mig6) is increased in obese mice and that deletion of Mig6 in the liver (LKO) improves glucose tolerance and insulin action during hyperinsulinemic-euglycemic clamps in diet-induced obese mice. Mig6 is an endogenous feedback inhibitor of epidermal growth factor receptor activation (EGFR) and regulates cellular repair and survival. Thus, we sought to elucidate the extent to which loss of Mig6 modulates the progression of MASLD to MASH. We hypothesized that liver-specific loss of Mig6 during early MASLD improves whole-body glucose homeostasis and protects against MASLD-mediated liver damage. LKO mice and matched, control littermates (CON) were fed a MASH diet (40% fat, 40% carbohydrate, 2% cholesterol; CON n=13-19, LKO n=16-22) or a low-fat-matched diet (LFD; 10% fat, 70% carbohydrate; CON n=8-16, LKO n=16-21) for up to 40 weeks. Body weights were recorded weekly, and body composition assessment, glucose and insulin tolerance tests, and hepatic histological analysis were performed after 20-, 30- and 40-weeks on each diet. Compared to the MASH-fed CON mice, MASH-fed LKO mice had lower body weights starting at 10-weeks and persisting throughout the study. Body composition analysis established these differences in body weight were due to decreases in fat, but not lean, mass. Interestingly, whereas intraperitoneal glucose tolerance tests did not identify significant differences in glucose handling between the LFD and MASH fed mice, oral glucose tolerance was significantly improved in 10- and 20-week MASH-fed LKO mice, suggesting alterations in the incretin response in this MASH model. Lastly, histological analysis revealed MASH-fed LKO mice had a preservation of hepatic lipid zonation and blunted levels of circulating alanine aminotransferase (ALT) compared to MASH-fed CON, indicating less hepatic damage in LKO mice. These results suggest that liver-specific loss of Mig6 improves whole-body glucose handling, which in turn ameliorates hepatic damage during MASLD progression. In conclusion, Mig6 prevents, or at least delays, the progression of MASLD, which may reveal a new therapeutic area for the prevention and treatment of MASH. MS was supported by a National Cancer Institute Cancer Metabolism Training Program Postdoctoral Fellowship (T32CA221709). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Novel Approaches to Control Diabetes.

Diabetes is a chronic, long-term, incurable, but controllable condition. Diabetes mellitus (DM) is a group of metabolic disorders characterized by hyperglycemia that results from defects in insulin secretion, insulin action, or both. People who have diabetes often experience a variety of symptoms, including blurry vision, excessive thirst, fatigue, frequent urination, hunger, and weight loss. This review article includes a discussion on diabetes types, symptoms, diagnostic tests, and various therapies for treating, controlling, and managing blood glucose levels, with a focus on its most recent innovation of therapies and medications. Diabetes management will also be reviewed, along with clinical pharmacodynamics, bioavailability, advantages, and complications of combined drugs/medications.

Inspiratory Muscle Strength Training to Improve Cardiometabolic Health in Patients with Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is a complex, chronic metabolic disease that is associated with a high prevalence of comorbid conditions. Traditional lifestyle interventions (e.g., diet and exercise) can counter some adverse effects of T2DM; however, participation in these activities is low. High-resistance inspiratory muscle strength training (IMST) is a time-effcient and simple breathing exercise that significantly reduces blood pressure (BP) and improves vascular endothelial function in several nondiabetic populations. Herein, we performed a blinded, randomized, sham-controlled trial to investigate the effects of a 6-week IMST regimen (30 breaths/day, 6 days/week) on glycemic control and insulin sensitivity in adults with T2DM. Currently, we have eight participants (aged 35-71 years, 5 females and 3 males) who have completed either low-resistance sham training (15% maximal inspiratory mouth pressure, n=5) or high-resistance IMST (75% maximal inspiratory mouth pressure, n=3). Our data suggests that fasting plasma glucose and fasting serum insulin did not significantly change by IMST or sham training. Utilizing a homeostatic model assessment of insulin sensitivity to evaluate insulin action, our results indicate no change by either IMST or sham training. IMST revealed a trend towards a reduction in systolic BP (pre: 133.0 ± 4.8 vs. post: 128.8 ± 4.9) and diastolic BP (pre: 84.8 ± 2.7 vs. post: 81.7 ± 3.6). These findings align with prior research indicating improved resting BP, further corroborating previous studies. We performed an exploratory analysis to examine the potential impact of IMST on lipid levels. Interestingly, IMST resulted in a trend towards a reduction in cholesterol (pre: 259.3 ± 29.4 vs. post: 230.3 ± 3.7) and LDL (pre: 153.3 ± 19.7 vs. post: 127.7 ± 8.7). Analysis of the endothelial function data is forthcoming until we have enough individuals to complete those analyses. In conclusion, our results to date are preliminary; however, we expect to see continued improvements in resting BP and cholesterol/LDL with IMST. Moreover, with a higher number of individuals in the study (our goal is to have 12 in each group), we anticipate seeing changes in glycemia or insulin action. Lastly, IMST stands out as a distinctive and time-effective exercise method, addressing adherence challenges while demonstrating enhancements in cardiometabolic health. This could be particularly advantageous for T2DM patients with an increased cardiovascular disease risk. University of Arizona College of Medicine SPARK Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

NADPH oxidase-derived reactive oxygen species regulates adipose tissue lipolysis in humans

There is mounting evidence suggesting that reactive oxygen species (ROS) generated by NADPH oxidase (NOX) regulate physiological processes, as NOX has been shown to promote increases in lipolysis in cultured adipocytes. PURPOSE: To determine the mechanisms by which NOX stimulates adipose tissue lipolysis. METHODS: Young healthy females (n = 17; mean ± SD; age: 21.7 ± 5 years; body mass index: 22.2 ± 3.8 kg/m2) participated in this study. Participants underwent microdialysis and hyperinsulinemic-euglycemic clamp (clamp) procedures. Three microdialysis probes were inserted into subcutaneous abdominal adipose tissue to monitor local adipose tissue ROS (H2O2) production and lipolysis (as indicated by dialysate glycerol). To determine whether NOX stimulates lipolysis via distinct signaling pathways, microdialysis probes were perfused with either isoproterenol (Iso; β-adrenergic agonist to stimulate canonical lipolysis signaling) or atrial natriuretic peptide (ANP to stimulate non-canonical lipolysis signaling), then perfused with a local NOX inhibitor (apocynin). A control probe was perfused with apocynin but without any agonists of lipolysis. The microdialysis procedures were then repeated under hyperinsulinemic conditions during the same study visit. RESULTS: In the fasted state, dialysate H2O2 concentrations were lower in the control and Iso probes upon apocynin perfusion (control probe without apocynin: 1.06 ± 0.5 μM, with apocynin: 0.62 ± 0.2 μM; p = 0.005; Iso probe without apocynin: 1.01 ± 0.4 μM, with apocynin: 0.66 ± 0.2 μM; p = 0.003). Apocynin perfusion did not alter dialysate H2O2 concentrations in the ANP probe under the fasted state (p = 0.11). Dialysate glycerol concentrations did not change upon apocynin perfusion under any of the microdialysis probe conditions in the fasted state (p > 0.05). During the clamp, apocynin perfusion resulted in lower dialysate H2O2 concentrations in the three conditions (control probe without apocynin: 1.22 ± 0.6 μM, with apocynin: 0.75 ± 0.3 μM; p = 0.03; Iso probe without apocynin: 1.55 ± 0.8 μM, with apocynin: 0.79 ± 0.3 μM; p = 0.01; ANP probe without apocynin: 1.55 ± 0.6 μM, with apocynin: 0.92 ± 0.3 μM; p = 0.03). Dialysate glycerol concentrations were lower in the Iso probe upon apocynin perfusion during the clamp (Iso probe without apocynin: 124.7 ± 38 μM, with apocynin: 90.9 ± 25 μM; p = 0.003). CONCLUSIONS: This study presents adipose tissue NOX as a source of in vivo ROS production in human participants. In addition, we reveal a novel mechanism of NOX in adipose tissue function whereby NOX exerts increases in β-adrenergic-mediated lipolysis during hyperinsulinemia. Our findings highlight the roles of ROS as signaling mediators and suggest that an imbalance between NOX activity and insulin action on adipose tissue could negatively affect systemic fatty acid metabolism. Porter Pre-doctoral Fellowship from the American Physiological Society and an NIH National Research Service Award (F31HL154642). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Drp1 Controls Complex II Assembly and Skeletal Muscle Metabolism by Sdhaf2 Action on Mitochondria

The Dynamin-related GTPase, Drp1 (encoded by Dnm1l) plays a central role in mitochondrial fission and is requisite for numerous cellular processes however its role in muscle metabolism remains unclear. Herein, we show that among human tissues, the highest number of significant gene correlations with DNM1L are in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced Complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized Complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial Complex II assembly, lipid oxidation, and glucose homeostasis, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic diseases. P30DK063491, DK125354. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Liver Androgen Receptor Knockout (LivARKO) Male Mice on 3-months of High Fat Diet (HFD) Did Not Experience Insulin Resistance at the Level of p-AKT in White Adipose Tissue

Introduction: Insulin resistance affects up to a third of the US adult population and polycystic ovary syndrome (PCOS) affects up to 10% of reproductive-age adult women. Andrisse et al 2021 (PMCID: PMC9097557) showed that deleting the liver androgen receptor (LivARKO) prevented female mice from developing hyperandrogenemia (HA)-induced insulin resistance. Here, we asked the question, does LivARKO prevent high fat diet (HFD) induced insulin resistance? Hypothesis: It was hypothesized that (unlike HA-LivARKO) HFD LivARKO male mice would display impaired insulin action (lowered insulin-stimulated p-AKT) in white adipose tissue in comparison to the Control diet fed LivARKO male mice, suggesting that AR does not play a significant role in regulating HFD-induced insulin resistance. Methods: Male LivARKO mice were placed on two diets: Control (Con, Research Diets Inc, RDI D12450J, Protein (20%), Carbs (70%, corn starch-50%, sucrose-maldextrin-20%, fructose-0%), Fat 10% (lard)) and High Fat (HFD, RDI D12492, Protein (20%), Carbs (20%, corn starch-0%, sucrose-maldextrin-20%, fructose-0%), Fat 60% (lard)). The mice were sacrificed after 3 months on the diet. Half of the mice were given a dose of 0.5 U/kg insulin before sacrificing to investigate the effects of the diets on insulin signaling. Western blots were used to determine protein expression in white adipose tissue (WAT). BCA assays were used to standardize the protein concentration in each sample. Insulin action can be measured molecularly by examining p-AKT Serine 473 (positive regulator, Santa Cruz sc-514032). If p-AKT S473 levels increase in the presence of insulin, this indicates that insulin is likely functioning properly in the sample. Results: Male LivARKO fed a control diet (LivARKO-Con) and administered with 0.5 U/kg insulin displayed significantly lowered p-AKT protein levels compared to male LivARKO-Con that did not get administered an i.p. injection of insulin (Basal), suggesting that male LivARKO-Con mice were experiencing insulin resistance. Additionally, male LivARKO fed a high fructose diet (LivARKO-HFrD) and administered with 0.5 U/kg insulin displayed slightly increased p-AKT protein levels compared to male LivARKO-HFrD-Basal mice. Conclusion: In conclusion, LivARKO male mice on 3-months of HFD were not experiencing insulin resistance at the level of p-AKT in WAT. We are not certain why insulin negatively regulated (or lowered) p-AKT in WAT of LivARKO-Con male mice. This could be an aspect of needing a higher n-value. Further studies in different energy storage tissues and higher n-values are warranted. We would like to thank the NSF for award # 1931045 and the NIH for award # 1R01DK126892-01A1 for supporting this work. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Disentangling fetal insulin hypersecretion and insulin resistance

Disentangling which of insulin hypersecretion and insulin resistance is upstream in obesity-related type 2 diabetes (T2D) is challenging. Here, we consider the dynamics of insulin secretion and action in the fetuses of mothers with diabetes. We argue that fetal insulin hypersecretion occurs first, with insulin resistance being an adaptive protective response.