Insulin Resistance Postburn: Underlying Mechanisms and Current Therapeutic Strategies

AbstractAmong several animal groups (eutherian mammals, birds, reptiles), lifespan positively correlates with body mass over several orders of magnitude. Contradicting this pattern are domesticated dogs, with small dog breeds exhibiting significantly longer lifespans than large dog breeds. The underlying mechanisms of differing aging rates across body masses are unclear, but it is generally agreed that metabolism is a significant regulator of the aging process. Herein, we performed a targeted metabolomics analysis on primary fibroblasts isolated from small and large breed young and old dogs. Regardless of size, older dogs exhibited lower glutathione and ATP, consistent with a role for oxidative stress and bioenergetic decline in aging. Furthermore, several size-specific metabolic patterns were observed with aging, including the following: (i) An apparent defect in the lower half of glycolysis in large old dogs at the level of pyruvate kinase. (ii) Increased glutamine anaplerosis into the TCA cycle in large old dogs. (iii) A potential defect in coenzyme A biosynthesis in large old dogs. (iv) Low nucleotide levels in small young dogs that corrected with age. (v) An age-dependent increase in carnitine in small dogs that was absent in large dogs. Overall, these data support the hypothesis that alterations in metabolism may underlie the different lifespans of small vs. large breed dogs, and further work in this area may afford potential therapeutic strategies to improve the lifespan of large dogs.

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Infectious disease-associated encephalopathies

Critical Care ◽

10.1186/s13054-021-03659-6 ◽

2021 ◽

Vol 25 (1) ◽

Author(s):

Maria C. Barbosa-Silva ◽

Maiara N. Lima ◽

Denise Battaglini ◽

Chiara Robba ◽

Paolo Pelosi ◽

...

Keyword(s):

Infectious Disease ◽

Cognitive Deficits ◽

Brain Function ◽

Cell Activation ◽

Therapeutic Strategies ◽

Barrier Dysfunction ◽

Glial Cell Activation ◽

The Central Nervous System ◽

Underlying Mechanisms

AbstractInfectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious disease-associated encephalopathy. The systemic inflammatory process may result in neuroinflammation, with glial cell activation and increased levels of cytokines, reduced neurotrophic factors, blood–brain barrier dysfunction, neurotransmitter metabolism imbalances, and neurotoxicity, and behavioral and cognitive impairments often occur in the late course. Even though infectious disease-associated encephalopathies may cause devastating neurologic and cognitive deficits, the concept of infectious disease-associated encephalopathies is still under-investigated; knowledge of the underlying mechanisms, which may be distinct from those of encephalopathies of non-infectious cause, is still limited. In this review, we focus on the pathophysiology of encephalopathies associated with peripheral (sepsis, malaria, influenza, and COVID-19), emerging therapeutic strategies, and the role of neuroinflammation. Graphic abstract

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Potential Therapeutic Strategies for Fat Induced Insulin Resistance

Journal of Korean Endocrine Society ◽

10.3803/jkes.2009.24.2.65 ◽

2009 ◽

Vol 24 (2) ◽

pp. 65

Author(s):

Cheol Soo Choi

Keyword(s):

Insulin Resistance ◽

Therapeutic Strategies

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Adipose tissue hypoxia and insulin resistance

Journal of Investigative Medicine ◽

10.1136/jim-2016-000106 ◽

2016 ◽

Vol 64 (4) ◽

pp. 830-832 ◽

Cited By ~ 14

Author(s):

Neda Rasouli

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Tissue Hypoxia ◽

Sequence Of Events ◽

Adipose Tissue Dysfunction ◽

Underlying Mechanisms ◽

Key Events

Despite the well-established association of obesity with insulin resistance and inflammation, the underlying mechanisms and sequence of events leading to inflammation and insulin resistance remain unknown. Adipose tissue hypoxia has been proposed as one of the possible key events during the process of fat expansion that leads to adipose tissue dysfunction. The focus of this paper is reviewing the evidence on adipose tissue hypoxia in obesity and its relation to insulin resistance.

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Commensal microbe-derived acetate suppresses NAFLD/NASH development via hepatic FFAR2 signalling in mice

Microbiome ◽

10.1186/s40168-021-01125-7 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Ryo Aoki ◽

Masayoshi Onuki ◽

Koya Hattori ◽

Masato Ito ◽

Takahiro Yamada ◽

...

Keyword(s):

Insulin Resistance ◽

Gut Microbiome ◽

Resistant Starch ◽

Short Chain Fatty Acids ◽

Global Changes ◽

Severe Liver ◽

Acetate Production ◽

Germ Free ◽

Free Fatty Acid Receptor ◽

Underlying Mechanisms

Abstract Background Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH). Alterations in the gut microbiome have been implicated in the development of NAFLD/NASH, although the underlying mechanisms remain unclear. Results We found that the consumption of the prebiotic inulin markedly ameliorated the phenotype of NAFLD/NASH, including hepatic steatosis and fibrosis, in mice. Inulin consumption resulted in global changes in the gut microbiome, including concomitant enrichment of the genera Bacteroides and Blautia, and increased concentrations of short-chain fatty acids, particularly acetate, in the gut lumen and portal blood. The consumption of acetate-releasing resistant starch protected against NAFLD development. Colonisation by Bacteroides acidifaciens and Blautia producta in germ-free mice resulted in synergetic effects on acetate production from inulin. Furthermore, the absence of free fatty acid receptor 2 (FFAR2), an acetate receptor, abolished the protective effect of inulin, as indicated by the more severe liver hypertrophy, hypercholesterolaemia and inflammation. These effects can be attributed to an exacerbation of insulin resistance in the liver, but not in muscle or adipose tissue. Conclusion These findings demonstrated that the commensal microbiome–acetate–FFAR2 molecular circuit improves insulin sensitivity in the liver and prevents the development of NAFLD/NASH.

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Pathophysiological Molecular Mechanisms of Obesity: A Link between MAFLD and NASH with Cardiovascular Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms222111629 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11629

Author(s):

Jorge Gutiérrez-Cuevas ◽

Arturo Santos ◽

Juan Armendariz-Borunda

Keyword(s):

Insulin Resistance ◽

Metabolic Disorders ◽

Molecular Mechanisms ◽

Causes Of Death ◽

Cardiovascular Prevention ◽

Atherogenic Dyslipidemia ◽

Metabolic Dysfunction ◽

Systemic Insulin Resistance ◽

Underlying Mechanisms

Obesity is now a worldwide epidemic ensuing an increase in comorbidities’ prevalence, such as insulin resistance, type 2 diabetes (T2D), metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease (CVD), autoimmune diseases, and some cancers, CVD being one of the main causes of death in the world. Several studies provide evidence for an association between MAFLD and atherosclerosis and cardio-metabolic disorders, including CVDs such as coronary heart disease and stroke. Therefore, the combination of MAFLD/NASH is associated with vascular risk and CVD progression, but the underlying mechanisms linking MAFLD/NASH and CVD are still under investigation. Several underlying mechanisms may probably be involved, including hepatic/systemic insulin resistance, atherogenic dyslipidemia, hypertension, as well as pro-atherogenic, pro-coagulant, and pro-inflammatory mediators released from the steatotic/inflamed liver. MAFLD is strongly associated with insulin resistance, which is involved in its pathogenesis and progression to NASH. Insulin resistance is a major cardiovascular risk factor in subjects without diabetes. However, T2D has been considered the most common link between MAFLD/NASH and CVD. This review summarizes the evidence linking obesity with MAFLD, NASH, and CVD, considering the pathophysiological molecular mechanisms involved in these diseases. We also discuss the association of MAFLD and NASH with the development and progression of CVD, including structural and functional cardiac alterations, and pharmacological strategies to treat MAFLD/NASH and cardiovascular prevention.

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Pathology, Risk Factors, and Oxidative Damage Related to Type 2 Diabetes-Mediated Alzheimer’s Disease and the Rescuing Effects of the Potent Antioxidant Anthocyanin

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/4051207 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Muhammad Sohail Khan ◽

Muhammad Ikram ◽

Tae Ju Park ◽

Myeong Ok Kim

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Alzheimer's Disease ◽

Inflammatory Cytokines ◽

Amyloid Beta ◽

Acid Oxidation ◽

Chronic Hyperglycemia ◽

Underlying Mechanisms

The pathology and neurodegeneration in type 2 diabetes- (T2D-) mediated Alzheimer’s disease (AD) have been reported in several studies. Despite the lack of information regarding the basic underlying mechanisms involved in the development of T2D-mediated AD, some common features of the two conditions have been reported, such as brain atrophy, reduced cerebral glucose metabolism, and insulin resistance. T2D phenotypes such as glucose dyshomeostasis, insulin resistance, impaired insulin signaling, and systemic inflammatory cytokines have been shown to be involved in the progression of AD pathology by increasing amyloid-beta accumulation, tau hyperphosphorylation, and overall neuroinflammation. Similarly, oxidative stress, mitochondrial dysfunction, and the generation of advanced glycation end products (AGEs) and their receptor (RAGE) as a result of chronic hyperglycemia may serve as critical links between diabetes and AD. The natural dietary polyflavonoid anthocyanin enhances insulin sensitivity, attenuates insulin resistance at the level of the target tissues, inhibits free fatty acid oxidation, and abrogates the release of peripheral inflammatory cytokines in obese (prediabetic) individuals, which are responsible for insulin resistance, systemic hyperglycemia, systemic inflammation, brain metabolism dyshomeostasis, amyloid-beta accumulation, and neuroinflammatory responses. In this review, we have shown that obesity may induce T2D-mediated AD and assessed the recent therapeutic advances, especially the use of anthocyanin, against T2D-mediated AD pathology. Taken together, the findings of current studies may help elucidate a new approach for the prevention and treatment of T2D-mediated AD by using the polyflavonoid anthocyanin.

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EET Analog Treatment Improves Insulin Signaling in a Genetic Mouse Model of Insulin Resistance

10.2337/figshare.16811251.v1 ◽

2021 ◽

Author(s):

Kakali Ghoshal ◽

Xiyue Li ◽

Dungeng Peng ◽

John R. Falck ◽

Raghunath Reddy Anugu ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Signaling ◽

Genetic Model ◽

Water Soluble ◽

Hepatic Insulin Resistance ◽

Epoxyeicosatrienoic Acid ◽

Genetic Mouse Model ◽

Hepatic Insulin Signaling ◽

Underlying Mechanisms

We previously showed that global deletion of the cytochrome P450 epoxygenase Cyp2c44, a major epoxyeicosatrienoic acid (EET) producing enzyme in mice, leads to impaired hepatic insulin signaling resulting in insulin resistance. This finding led us to investigate whether administration of a water soluble EET analog restores insulin signaling in vivo in Cyp2c44(-/-) mice and investigated the underlying mechanisms by which this effect is exerted. Cyp2c44(-/-) mice treated with the analog EET-A for 4 weeks improved fasting glucose and glucose tolerance compared to Cyp2c44(-/-) mice treated with vehicle alone. This beneficial effect was accompanied by enhanced hepatic insulin signaling, decreased expression of gluconeogenic genes and increased expression of glycogenic genes. Mechanistically, we show that insulin-stimulated phosphorylation of insulin receptor β (IRβ) is impaired in primary Cyp2c44(-/-) hepatocytes and this can be restored by cotreatment with EET-A and insulin. Plasma membrane fractionations of livers indicated that EET-A enhances the retention of IRβ in membrane rich fractions, thus potentiating its activation. Altogether, EET analogs ameliorate insulin signaling in a genetic model of hepatic insulin resistance by stabilizing membrane-associated IRβ and potentiating insulin signaling.

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Adipocytokines in Non-functional Adrenal Incidentalomas and Relation with Insulin Resistance Parameters

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530318666181009112042 ◽

2019 ◽

Vol 19 (3) ◽

pp. 326-332

Author(s):

Gamze Akkus ◽

Mehtap Evran ◽

Murat Sert ◽

Tamer Tetiker

Keyword(s):

Insulin Resistance ◽

Waist Circumference ◽

Resistance Index ◽

Adrenal Incidentaloma ◽

Control Group ◽

Adrenal Incidentalomas ◽

Sodium Potassium ◽

Insulin Resistance Index ◽

High Insulin ◽

Underlying Mechanisms

Objective: Adrenal incidentalomas are diagnosed incidentally during radiological screenings and require endocrinological investigations for hormonal activity and malignancy. In certain studies, it has been reported that non-functional incidentalomas can be associated with high adipocytokines levels affecting the insulin resistance just like the adipose tissue with metabolic syndrome. Here, we studied serum adipocytokine levels including leptin, resistin, visfatin, omentin 1 and adiponectin in subjects with non-functional adrenal incidentaloma. Methods: Seventy-seven (77) patients (Female 57; Male 20) with non-functional adrenal incidentaloma (NFAI) were enrolled in the study. All patients’ past medical history, physical examination including Body Mass Index (BMI) and waist circumference were performed. The patients’ demographic, radiologic, hormonal and biochemical parameters were recorded. To compare the parameters, a control group (CG) (n=30) was formed from healthy volunteers. Both groups were matched for age, gender, waist circumference and BMI. Serum adipocytokines including leptin, resistin, visfatin, omentin 1 and adiponectin were measured quantitatively by ELISA. Fasting plasma glucose, insulin, sodium, potassium, cortisol, adrenocorticotropic hormone (ACTH), lipid profiles, and dehidroepiandrostenedion sulphate (DHEAS) were measured. Results: Mean age of the patients was 52.2±10.4 years. BMI and waist circumference of NFAI patients were 26.2±3.28 kg/m2 and 90.2 ±7.5cm, respectively. The mean age of the control group was 48.0±8.16. BMI and waist circumference values for the control group were 25.3±3.5 kg/m2 and 88.3±9.6 cm, respectively. When both groups were compared for age, gender, BMI and waist circumference were non-significant (p>0.05). Serum fasting insulin, total cholesterol, LDL, triglyceride levels of the NFAI group were significantly higher than CG (p<0.05). The insulin resistance index (HOMAIR) values of the NFAI subjects were found to be higher than CG (2.5±1.37, 1.1±0.3 p=0.00). Resistin level of NFAI group was also found to be higher than CG [286.6 ng/L vs. 197 ng/L; (P=0,00)], respectively. Leptin levels of NFAI were significantly higher than CG [441.1 ng/mL vs. 186.5 ng/mL; (P=0.00)] respectively. Adiponectin levels were significantly reduced in the NFAI group than in the CG [10.7 mg/L vs. 30.8 mg/L; (P=0.00)]. Comparision of visfatin and omentin levels was nonsignificant. Conclusion: In this study on subjects with non-functional adrenal incidentaloma, we found not only significantly decreased serum adiponectin levels but also increased leptin, resistin levels as well as dyslipidemia, hypertension and high insulin resistance index. All of which could affect insulin resistance and cardiovascular risk factors. The underlying mechanisms of these findings are unknown, hence further studies are needed.

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The Adipokines in Cancer Cachexia

International Journal of Molecular Sciences ◽

10.3390/ijms21144860 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4860 ◽

Cited By ~ 1

Author(s):

Michele Mannelli ◽

Tania Gamberi ◽

Francesca Magherini ◽

Tania Fiaschi

Keyword(s):

Insulin Resistance ◽

Cardiovascular Disease ◽

Skeletal Muscle ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Cancer Cachexia ◽

Muscle Wasting ◽

Therapeutic Strategies ◽

Skeletal Muscle Wasting ◽

Circulating Levels

Cachexia is a devastating pathology induced by several kinds of diseases, including cancer. The hallmark of cancer cachexia is an extended weight loss mainly due to skeletal muscle wasting and fat storage depletion from adipose tissue. The latter exerts key functions for the health of the whole organism, also through the secretion of several adipokines. These hormones induce a plethora of effects in target tissues, ranging from metabolic to differentiating ones. Conversely, the decrease of the circulating level of several adipokines positively correlates with insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease. A lot of findings suggest that cancer cachexia is associated with changed secretion of adipokines by adipose tissue. In agreement, cachectic patients show often altered circulating levels of adipokines. This review reported the findings of adipokines (leptin, adiponectin, resistin, apelin, and visfatin) in cancer cachexia, highlighting that to study in-depth the involvement of these hormones in this pathology could lead to the development of new therapeutic strategies.

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