Stress-induced Insulin Resistance Research Articles

Antioxidant Phytochemicals as Potential Therapy for Diabetic Complications.

The global prevalence of diabetes continues to increase partly due to rapid urbanization and an increase in the aging population. Consequently, this is associated with a parallel increase in the prevalence of diabetic vascular complications which significantly worsen the burden of diabetes. For these diabetic vascular complications, there is still an unmet need for safe and effective alternative/adjuvant therapeutic interventions. There is also an increasing urge for therapeutic options to come from natural products such as plants. Hyperglycemia-induced oxidative stress is central to the development of diabetes and diabetic complications. Furthermore, oxidative stress-induced inflammation and insulin resistance are central to endothelial damage and the progression of diabetic complications. Human and animal studies have shown that polyphenols could reduce oxidative stress, hyperglycemia, and prevent diabetic complications including diabetic retinopathy, diabetic nephropathy, and diabetic peripheral neuropathy. Part of the therapeutic effects of polyphenols is attributed to their modulatory effect on endogenous antioxidant systems. This review attempts to summarize the established effects of polyphenols on endogenous antioxidant systems from the literature. Moreover, potential therapeutic strategies for harnessing the potential benefits of polyphenols for diabetic vascular complications are also discussed.

PDIA4, a new endoplasmic reticulum stress protein, modulates insulin resistance and inflammation in skeletal muscle.

Endoplasmic reticulum (ER) stress has emerged as a key player in insulin resistance (IR) progression in skeletal muscle. Recent reports revealed that ER stress-induced the expression of protein disulfide isomerase family a member 4 (PDIA4), which may be involved in IR-related diseases. A previous study showed that metformin modulated ER stress-induced IR. However, it remained unclear whether metformin alleviated IR by regulating PDIA4 expression in skeletal muscle. Herein, we used palmitate-induced IR in C2C12 cells and a high-fat diet-induced IR mouse model to document the relations between metformin, IR, and PDIA4. In C2C12 cells, palmitate-induced IR increased inflammatory cytokines and PDIA4 expression. Besides, knocking down PDIA4 decreased palmitate-induced IR and inflammation in C2C12 cells. Furthermore, metformin modulated PDIA4 expression and alleviated IR both in vitro and in vivo. In addition, serum PDIA4 concentrations are associated with IR and inflammatory cytokines levels in human subjects. Thus, this study is the first to demonstrate that PDIA4 participates in the metformin-induced effects on skeletal muscle IR and indicates that PDIA4 is a potential novel therapeutic target for directly alleviating IR.

Secreted MUP1 that reduced under ER stress attenuates ER stress induced insulin resistance through suppressing protein synthesis in hepatocytes

Disturbed endoplasmic reticulum (ER) stress response driven by the excessive lipid accumulation in the liver is a characteristic feature in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Restoring metabolic homeostasis by targeting ER stress is a potentially therapeutic strategy for NAFLD. Here we aim to identify novel proteins or pathways involved in regulating ER stress response and therapeutic targets for alleviating NAFLD. Proteomic and transcriptomic analysis demonstrated that major urinary proteins (MUPs) were significantly reduced in the livers from NAFLD mouse models. Then we confirmed that MUP1, the major secreted form of MUPs, was reduced at mRNA and protein expression levels in hepatocytes both in vivo and in vitro under ER stress. We further illustrated that MUP1 protein levels in the urine were reduced in mice with NAFLD, which was reversed by GLP-1 receptor agonist treatment. To study the relationship between ER stress and MUP1 biology, our analysis demonstrated that MUP1 was misfolded and trapped in the ER under ER stress in vivo. Interestingly, we discovered that recombinant MUP1 treatment in hepatocytes increased calcium efflux from the ER, which resulted in transient ER stress response, including reduced protein synthesis. These responses facilitated the alleviation of chemical induced ER stress in hepatocytes, which was suggested as “pre-adaptive ER stress”. Besides, recombinant MUP1 pretreatment also improved ER stress-induced insulin resistance in hepatocytes. Our findings revealed a novel and critical role of MUP1, and recombinant MUP1 or its potential derivates may serve as a promising therapeutic target for alleviating NAFLD.

Reduction in Insulin Mediated ERK Phosphorylation by Palmitate in Liver Cells Is Independent of Fatty Acid Induced ER Stress.

Saturated free fatty acids (FFAs) such as palmitate in the circulation are known to cause endoplasmic reticulum (ER) stress and insulin resistance in peripheral tissues. In addition to protein kinase B (AKT) signaling, extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance. However, there are conflicting data regarding role of ERK signaling in ER stress-induced insulin resistance. In this study, we investigated the effects of ER stress on insulin resistance and ERK phosphorylation in Huh-7 cells and evaluated how oleate prevents palmitate-mediated ER stress. Treatment with insulin resulted in an increase of 38–45% in the uptake of glucose in control cells compared to non-insulin-treated control cells, along with an increase in the phosphorylation of AKT and ERK. We found that treatment with palmitate increased the expression of ER stress genes, including the splicing of X box binding protein 1 (XBP1) mRNA. At the same time, we observed a decrease in insulin-mediated uptake of glucose and ERK phosphorylation in Huh-7 cells, without any change in AKT phosphorylation. Supplementation of oleate along with palmitate mitigated the palmitate-induced ER stress but did not affect insulin-mediated glucose uptake or ERK phosphorylation. The findings of this study suggest that palmitate reduces insulin-mediated ERK phosphorylation in liver cells and this effect is independent of fatty-acid-induced ER stress.

Rutas glucometabólicas alteradas en pacientes infectados con SARS-CoV-2

In SARS-CoV-2 virus infection, HIF-1 overexpression drives a glycolysis-dependent metabolic change for increased cell proliferation and cytokine synthesis in various cells and tissues; Furthermore, due to the insufficient amount of ATP, various metabolic pathways that induce hyperglycemia are accelerated; an indicator of poor prognosis and high mortality in patients without a previous diagnosis of diabetes. Hyperglycemia is the result of oxidative stress-induced insulin resistance and increased glycolysis, as well as dysregulation of hormones such as glucagon, growth hormone, glucocorticoids, and insulin; whose synthesis decreases due to the transdifferentiation of beta cells. These hyperglycemic and hypoglycemic conditions have been associated, in COVID-19 patients, with new-onset diabetes, cardiomyocyte damage, and other cardiac problems with lung deterioration; as well as the presence of acute kidney injury and hypometabolism of glucose in the brain.

Effect of melatonin on stress-induced hyperglycemia and insulin resistance in critically-ill patients: A randomized double-blind, placebo-controlled clinical trial.

Background:Hyperglycemia is a common finding which is associated with increased mortality and morbidity among critically ill patients. There is currently no evidence that melatonin could improve stress induced hyperglycemia (SIH). In this study, we evaluated the effect of melatonin on blood sugar and insulin resistance (IR) in critically-ill patients.Methods:104 critically-ill patients with SIH divided into two groups, receiving melatonin (6 mg BD for 3 days) or placebo. Changes of blood sugar, IR indices including homeostasis model assessment for insulin resistance and homeostasis model assessment adiponectin (HOMA-AD) ratios, Glasgow coma scale (GCS) were evaluated on the 4th day of melatonin prescription. On the 7Th day of study, changes of ventilator dependency and delirium were considered. Mortality and intensive care unit (ICU) stay were also compared between groups.Results:On day 4, patients in the melatonin group had significantly lower blood glucose and HMOA-IR level compared with the placebo group (P=0.04 and P=0.03, respectively) whereas HOMA-AD level did not differ significantly from placebo group (p>0.2). Also, we did not observe any significant difference in GCS level at this time between groups (p>0.2). On day 7, melatonin could not improve ventilator dependency and delirium significantly (p>0.2) and also could not reduce mortality and ICU stay in comparison with placebo (p>0.2, P=0.2, respectively).Conclusion:Melatonin supplementation showed positive effect on blood sugar and somehow insulin resistance whereas it could not improve ICU complications.

Adipocyte lipolysis drives acute stress-induced insulin resistance

Stress hyperglycemia and insulin resistance are evolutionarily conserved metabolic adaptations to severe injury including major trauma, burns, or hemorrhagic shock (HS). In response to injury, the neuroendocrine system increases secretion of counterregulatory hormones that promote rapid mobilization of nutrient stores, impair insulin action, and ultimately cause hyperglycemia, a condition known to impair recovery from injury in the clinical setting. We investigated the contributions of adipocyte lipolysis to the metabolic response to acute stress. Both surgical injury with HS and counterregulatory hormone (epinephrine) infusion profoundly stimulated adipocyte lipolysis and simultaneously triggered insulin resistance and hyperglycemia. When lipolysis was inhibited, the stress-induced insulin resistance and hyperglycemia were largely abolished demonstrating an essential requirement for adipocyte lipolysis in promoting stress-induced insulin resistance. Interestingly, circulating non-esterified fatty acid levels did not increase with lipolysis or correlate with insulin resistance during acute stress. Instead, we show that impaired insulin sensitivity correlated with circulating levels of the adipokine resistin in a lipolysis-dependent manner. Our findings demonstrate the central importance of adipocyte lipolysis in the metabolic response to injury. This insight suggests new approaches to prevent insulin resistance and stress hyperglycemia in trauma and surgery patients and thereby improve outcomes.

Ginsenoside Mc1 improves liver steatosis and insulin resistance by attenuating ER stress

Ethnopharmacological relevanceGinsenoside, a major pharmacologically active ingredient in ginseng, has been known to exhibit beneficial properties such as antioxidant and anti-inflammatory effects. Ginsenoside compound Mc1 is one of the newly identified de-glycosylated ginsenosides. Endoplasmic reticulum (ER) stress has implicated in the development of non-alcoholic fatty liver disease (NAFLD) through apoptosis and lipid accumulation. Aim of the studyWe aimed to examine the protective effects of Mc1 treatment on ER stress-induced cell death and impaired insulin signaling in HepG2 human hepatoblastoma cells and ER stress-induced liver steatosis and insulin resistance in a diet-induced obesity (DIO) mouse model. Materials and methodsHepG2 cells were treated with palmitate and Mc1 to evaluate the effects of Mc1 on ER stress-induced damage. C57BL/6 mice were fed with a high-fat diet (HFD) for 4 weeks and received an intraperitoneal injection of either vehicle or Mc1 (10 mg/kg/day). The control mice were fed with a chow diet and injected with vehicle for the same period. ER stress, cell death, and degree of steatosis were evaluated in the liver tissues of mice. The effect of Mc1 treatment on glucose metabolism was also determined. ResultsMc1 co-treatment reduced the palmitate-induced ER stress and death of HepG2 cells. The palmitate-induced insulin resistance improved after Mc1 co-treatment. Consistent with the in vitro data, chronic Mc1 supplementation reduced ER stress and apoptotic damage in the liver of obese mice. Mc1 treatment ameliorated glucose intolerance and insulin resistance through the suppression of c-Jun N-terminal kinase (JNK) phosphorylation. In addition, Mc1 treatment reduced obesity-induced lipogenesis and prevented fat accumulation in the liver of DIO mice. ConclusionsMc1 exerted protective effects against ER stress-induced apoptotic damage, insulin resistance and lipogenesis in palmitate-treated hepatocytes and in the liver of DIO mice. Therefore, Mc1 supplementation could be a potential therapeutic strategy to prevent NAFLD in patients with obesity and insulin resistance.

Discussion on: Effective reduction in stress induced postoperative hyperglycemia in hyperglycemia in bariatric surgery by better carb loading

DR. BENJAMIN VEENSTRA (Chicago, Illinois): As a fellow bariatric surgeon, I can appreciate the usefulness of these enhanced recovery programs, especially this foray into the preoperative carbohydrate loading. Your paper examines this preop carb loading, specifically the two-drink compositions, the simple versus the more complex or GED, and finds that there is decreased post-op glycemic variability in patients with more complex drink. I have a few questions. Effective reduction in stress induced postoperative hyperglycemia in bariatric surgery by better carb loadingThe American Journal of SurgeryVol. 219Issue 3PreviewPreoperative carbohydrate loading is a recommended component of enhanced recovery protocols (ERP’s), however the impact on postoperative stress-induced insulin resistance remains poorly studied in both diabetics and non-diabetics. Full-Text PDF

Performance of a closed-loop glucose control system, comprising a continuous glucose monitoring system and an AI-based controller in swine during severe hypo- and hyperglycemic provocations

Intensive care unit (ICU) patients develop stress induced insulin resistance causing hyperglycemia, large glucose variability and hypoglycemia. These glucose metrics have all been associated with increased rates of morbidity and mortality. The only way to achieve safe glucose control at a lower glucose range (e.g., 4.4–6.6 mmol/L) will be through use of an autonomous closed loop glucose control system (artificial pancreas). Our goal with the present study was to assess the safety and performance of an artificial pancreas system, composed of the EIRUS (Maquet Critical Care AB) continuous glucose monitor (CGM) and novel artificial intelligence-based glucose control software, in a swine model using unannounced hypo- and hyperglycemia challenges. Fourteen piglets (6 control, 8 treated) underwent sequential unannounced hypoglycemic and hyperglycemic challenges with 3 IU of NovoRapid and a glucose infusion at 17 mg/kg/min over the course of 5 h. In the Control animals an experienced ICU physician used every 30-min blood glucose values to maintain control to a range of 4.4–9 mmol/L. In the Treated group the artificial pancreas system attempted to maintain blood glucose control to a range of 4.4–6.6 mmol/L. Five of six Control animals and none of eight Treated animals experienced severe hypoglycemia (< 2.22 mmol/L). The area under the curve 3.5 mmol/L was 28.9 (21.1–54.2) for Control and 4.8 (3.1–5.2) for the Treated animals. The total percent time within tight glucose control range, 4.4–6.6 mmol/L, was 32.8% (32.4–47.1) for Controls and 55.4% (52.9–59.4) for Treated (p < 0.034). Data are median and quartiles. The artificial pancreas system abolished severe hypoglycemia and outperformed the experienced ICU physician in avoiding clinically significant hypoglycemic excursions.

Mitochondrial stress protein HSP60 regulates ER stress-induced hepatic lipogenesis.

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are associated with hepatic steatosis and insulin resistance. Molecular mechanisms underlying ER stress and/or mitochondrial dysfunction that cause metabolic disorders and hepatic steatosis remain to be fully understood. Here, we found that a high fat diet (HFD) or chemically induced ER stress can stimulate mitochondrial stress protein HSP60 expression, impair mitochondrial respiration, and decrease mitochondrial membrane potential in mouse hepatocytes. HSP60 overexpression promotes ER stress and hepatic lipogenic protein expression and impairs insulin signaling in mouse hepatocytes. Mechanistically, HSP60 regulates ER stress-induced hepatic lipogenesis via the mTORC1-SREBP1 signaling pathway. These results suggest that HSP60 is an important ER and mitochondrial stress cross-talking protein and may control ER stress-induced hepatic lipogenesis and insulin resistance.

Effective reduction in stress induced postoperative hyperglycemia in bariatric surgery by better carb loading

BackgroundPreoperative carbohydrate loading is a recommended component of enhanced recovery protocols (ERP’s), however the impact on postoperative stress-induced insulin resistance remains poorly studied in both diabetics and non-diabetics. MethodsUsing our ERP, a preoperative grape juice group (Grape) was compared to the use of 25 g maltodextrin/3 g citrulline (G.E.D.™, SOF Health, LLC) for carbohydrate loading. ResultsThe population included 171 patients (Grape n = 96; GED n = 75). Glycemic variability was significantly worse for the Grape group on POD 0 in both non-diabetic (70% vs 41%; p < 0.05) and diabetic patients (66% vs 34%; p < 0.05). Significantly more Grape patients required postoperative insulin regardless of diabetic status. ConclusionFollowing bariatric surgery, the impact of stress induced hyperglycemia is primarily on POD 0 in non-diabetics whereas the effect extends into POD 1 for diabetics. Preoperative loading with G.E.D.™ versus grape juice is associated with a significantly lower rate of glycemic variation and postoperative insulin requirement, demonstrating that drink composition and treatment process reduces the severity of postoperative stress induced hyperglycemia in bariatric surgery patients.

Myc Is Required for Adaptive β-Cell Replication in Young Mice but Is Not Sufficient in One-Year-Old Mice Fed With a High-Fat Diet

Failure to expand pancreatic β-cells in response to metabolic stress leads to excessive workload resulting in β-cell dysfunction, dedifferentiation, death, and development of type 2 diabetes. In this study, we demonstrate that induction of Myc is required for increased pancreatic β-cell replication and expansion during metabolic stress-induced insulin resistance with short-term high-fat diet (HFD) in young mice. β-Cell-specific Myc knockout mice fail to expand adaptively and show impaired glucose tolerance and β-cell dysfunction. Mechanistically, PKCζ, ERK1/2, mTOR, and PP2A are key regulators of the Myc response in this setting. DNA methylation analysis shows hypomethylation of cell cycle genes that are Myc targets in islets from young mice fed with a short-term HFD. Importantly, DNA hypomethylation of Myc response elements does not occur in islets from 1-year-old mice fed with a short-term HFD, impairing both Myc recruitment to cell cycle regulatory genes and β-cell replication. We conclude that Myc is required for metabolic stress-mediated β-cell expansion in young mice, but with aging, Myc upregulation is not sufficient to induce β-cell replication by, at least partially, an epigenetically mediated resistance to Myc action.

1074-P: Performance of an Artificial Pancreas System in Swine during Severe Hypo- and Hyperglycemic Provocations

Introduction: Intensive care unit (ICU) patients develop stress induced insulin resistance causing hyperglycemia, large glucose variability and hypoglycemia, all of which increase mortality rates. Tight glucose control (TGC) in the ICU is challenging, and usually significantly increases the risk for treatment induced hypoglycemia. The only way to achieve safe TGC will be through use of an artificial pancreas (AP) system. Our goal with the present study was to assess the safety and performance of an AP system, composed of the EIRUS (Getinge AB) continuous glucose monitor (CGM) and novel artificial intelligence-based (AI-based) glucose control software, in a swine model using unannounced hypo- and hyperglycemia challenges. Methods: Fourteen piglets (6 control, 8 treated) underwent sequential unannounced (to the AP system) hypoglycemic and hyperglycemic challenges with 3 U of insulin aspart and a large glucose infusion over the course of 5 hours. In the control animals an ICU physician used every 30-minute arterial blood glucose values to maintain control to a range of 4.4 - 9 mmol/L through use of 20% dextrose for hypoglycemia and insulin aspart for hyperglycemia. In the treated group the AP system attempted to maintain blood glucose control to a range of 4.4 - 6.6 mmol/L in a fully autonomous mode. Results: Five of six control animals and none of eight treated animals experienced severe hypoglycemia (&amp;lt; 2.22 mmol/L). The area under the curve 3.5 mmol/L was 28.9 (21.1 - 54.2) for control and 4.8 (3.1 - 5.2) for the treated animals. The percent time in range 4.4 - 6.6 mmol/L was 32.8 (32.4 - 47.1) for the control and 55.4 (52.9 - 59.4) for the treated animals. After the start of the experiment the control animals underwent 4 (3-5) human interventions to maintain control whereas the treated animals underwent none. Data are median (25-75). Conclusions The AP system abolished severe hypoglycemia and outperformed the ICU physician both in avoiding hypoglycemic excursions and maximizing time in range. Disclosure J. DeJournett: Employee; Self; Ideal Medical Technologies. L. DeJournett: Stock/Shareholder; Self; Ideal Medical Technologies.

169 - Oxidized neutral lipid lipolysis regulates insulin signaling during acute stress

Acute hyperglycemia and systemic insulin resistance (IR) often develop after injury or surgery. This stress response, appropriately known as critical illness diabetes, leads to increased post-operative complications and mortality. Insulin administration reduces this hyperglycemia in some patients but has a risk of dangerous hypoglycemia. The underlying mechanisms driving IR are unknown, which limits the development of alternative therapies and emphasizes the need to elucidate the pathophysiology. It is, however, known that surgical animal models rapidly develop adipose IR, and impaired insulin action in adipose alone can result in whole-body IR. Therefore, we focused on how adipose contributes to stress-induced IR. We have previously demonstrated using a mouse model of surgery that the development of IR and hyperglycemia are dependent on adipose lipolysis. Furthermore, β-adrenergic stimulation of adipocytes causes inhibition and dissociation of mTORC1 and mTORC2, key steps in the insulin cascade, in a lipolysis-dependent manner. Therefore, we hypothesized that a product of adipose lipolysis was responsible for the development of IR. We found that lipid extracts isolated from forskolin-stimulated 3T3-L1 adipocytes inhibited the activity of mTORC in vitro, however “traditional” lipolytic products (DAG, MAG, fatty acids) had no effect. Interestingly, stimulating peroxidation of fatty acids further exacerbated mTORC inhibition, while antioxidants reversed this effect. This suggests that the active species is an oxidized fatty acid. In fact, incubation of mTORC with in vitro auto-oxidized fatty acids is sufficient to inhibit kinase activity. Therefore, we propose that lipolysis breaks down oxidized TAGs into oxidized fatty acids, which cause mTORC dissociation and attenuation of insulin signaling during the stress response. Our work will elucidate a novel role for oxidized TAGs and their lipolytic products in the regulation of insulin signaling. Defining the mechanism by which catecholamine-stimulated lipolysis attenuates insulin signaling will provide novel therapeutic targets for improved post-operative glucose homeostasis.

Iron Overload Plays an Important Role in ER Stress-Induced Insulin Resistance in Human Skeletal Muscle Cells

Aim: In this study, we investigated the relationship and molecular mechanisms between iron-overload and ER-stress-induced insulin resistance in human skeletal muscle cells. Methods: Intracellular iron was measured using calcein AM. Iron metabolism-related genes were analyzed by immunoblotting and PCR. The study was conducted using iron supplementation, which was achieved by palmitate, FeSO4 and FeCl3 administration, and iron reduction, which occurred by DFO, DS and Bapta AM administration, and knockdown of tfR1 or IRP2 genes, to investigate the effects of iron metabolism on insulin sensitivity in HSMMs. Intracellular calcium was detected using Fluo-3/AM staining. TfR1 internalization regulated by calcium was detected by GFP-labelled transferrin. Results: Endoplasmic reticulum stress by tunicamycin, thapsigargin, or palmitate evoked insulin resistance and simultaneously increased intracellular iron. Iron chelator, DFO, dramatically prevented ER-stress inducer-induced insulin resistance and iron donor impaired insulin sensitivity in vitro and in vivo through activation of JNK. Among several iron metabolism-related genes, tfR1 plays a predominant role for maintaining iron homeostasis in HSMMs. Treatment of ER-stress inducer positively regulated translocation of tfR1 by intracellular calcium, but protein levels of tfR1 did not change. Iron reduction, by adding iron chelator, calcium chelator, or knockdown of tfR1 or IRP2, dramatically prevented ER-stress-induced insulin resistance through the reduction of iron-overload. Conclusions/Interpretation: The current study shows ER-stress inducer evoked insulin resistance through iron overload. Reduction of intracellular iron, by iron chelator, significantly prevents insulin resistance. Therefore, attempts to block iron overload might be a strategy for preventing insulin resistance and diabetes. Disclosure K. Lee: None. R. Cui: None. D. Kim: None. S. Choi: None. W. Lee: None. Y. Kang: None. T. Kim: None. H. Moon: None. J. Jeon: None. S. Han: None. H. Kim: None.

Creating smooth SI. B-spline basis function representations of insulin sensitivity

Abstract In the intensive care unit (ICU), stress-induced insulin resistance leading to hyperglycemia is commonplace. If safe and effective glycemic control (GC) can be provided, a significant reduction in the negative effects of dysglycemia can be achieved. The Intensive Control Insulin-Nutrition-Glucose (ICING) model has worked particularly well in guiding patient-specific GC. The current method to identify patient- and time- specific insulin sensitivity (SI) with this model employs a discrete stepwise hourly function, which is effective, but not physiologically representative at hourly transitions. 2nd Order B-spline basis functions (BF) are investigated as a more continuous and physiologically relevant alternative for two different cohorts of patient data (Benchmark, 20 patients; Stochastic TARgeted (STAR) sub-cohort, 72 patients). Various knot-widths (KW) of 2nd Order B-spline BFs were investigated and compared to the currently used step function BF in terms of physiological relevance, identifiability, robustness to false measurements, and susceptibility to noise to ensure the most physiologically realistic representation of SI. The 180 min KW 2nd Order B-spline BFs provided the most physiologically realistic fit to the blood glucose (BG) measurements in both cohorts (Standard Deviation of relative fitting error: Benchmark 8.7% vs. 9.35% BG meter, STAR sub-cohort 6.0% vs. 6.0% BG meter), while also having significantly less susceptibility to false BG measurements compared to the current BF. The 180 min 2nd Order B-spline BF provides a smooth second order continuous, more physiologically representative, and identifiable model of the dynamics of SI, and a more realistic resulting BG solution. The outcome provides a promising new addition to the ICING model and STAR GC protocol, while also opening up several new potential continuous time analyses of SI dynamics, not previously possible.

Zmynd17 controls muscle mitochondrial quality and whole-body metabolism.

Muscle mitochondria are crucial for systemic metabolic function, yet their regulation remains unclear. The zinc finger MYND domain-containing protein 17 (Zmynd17) was recently identified as a muscle-specific gene in mammals. Here, we investigated the role of Zmynd17 in mice. We found Zmynd17 predominantly expressed in skeletal muscle, especially in fast glycolytic muscle. Genetic Zmynd17 inactivation led to morphologic and functional abnormalities in muscle mitochondria, resulting in decreased respiratory function. Metabolic stress induced by a high-fat diet upregulated Zmynd17 expression and further exacerbated muscle mitochondrial morphology in Zmynd17-deficient mice. Strikingly, Zmynd17 deficiency significantly aggravated metabolic stress-induced hepatic steatosis, glucose intolerance, and insulin resistance. Furthermore, middle-aged mice lacking Zmynd17 exhibited impaired aerobic exercise performance, glucose intolerance, and insulin resistance. Thus, our results indicate that Zmynd17 is a metabolic stress-inducible factor that maintains muscle mitochondrial integrity, with its deficiency profoundly affecting whole-body glucose metabolism.-Fujita, R., Yoshioka, K., Seko, D., Suematsu, T., Mitsuhashi, S., Senoo, N., Miura, S., Nishino, I., Ono, Y. Zmynd17 controls muscle mitochondrial quality and whole-body metabolism.

Skeletal muscle insulin resistance is induced by 4-hydroxy-2-hexenal, a by-product of n-3 fatty acid peroxidation

Aims/hypothesisOxidative stress is involved in the pathophysiology of insulin resistance and its progression towards type 2 diabetes. The peroxidation of n-3 polyunsaturated fatty acids produces 4-hydroxy-2-hexenal (4-HHE), a lipid aldehyde with potent electrophilic properties able to interfere with many pathophysiological processes. The aim of the present study was to investigate the role of 4-HHE in the development of insulin resistance.Methods4-HHE concentration was measured in plasma from humans and rats by GC–MS. Insulin resistance was estimated in healthy rats after administration of 4-HHE using hyperinsulinaemic–euglycaemic clamps. In muscle cells, glucose uptake was measured using 2-deoxy-d-glucose and signalling pathways were investigated by western blotting. Intracellular glutathione was measured using a fluorimetric assay kit and boosted using 1,2-dithiole-3-thione (D3T).ResultsCirculating levels of 4-HHE in type 2 diabetic humans and a rat model of diabetes (obese Zucker diabetic fatty rats), were twice those in their non-diabetic counterparts (33 vs 14 nmol/l, p < 0.001), and positively correlated with blood glucose levels. During hyperinsulinaemic–euglycaemic clamps in rats, acute intravenous injection of 4-HHE significantly altered whole-body insulin sensitivity and decreased glucose infusion rate (24.2 vs 9.9 mg kg−1 min−1, p < 0.001). In vitro, 4-HHE impaired insulin-stimulated glucose uptake and signalling (protein kinase B/Akt and IRS1) in L6 muscle cells. Insulin-induced glucose uptake was reduced from 186 to 141.9 pmol mg−1 min−1 (p < 0.05). 4-HHE induced carbonylation of cell proteins and reduced glutathione concentration from 6.3 to 4.5 nmol/mg protein. Increasing intracellular glutathione pools using D3T prevented 4-HHE-induced carbonyl stress and insulin resistance.Conclusions/interpretation4-HHE is produced in type 2 diabetic humans and Zucker diabetic fatty rats and blunts insulin action in skeletal muscle. 4-HHE therefore plays a causal role in the pathophysiology of type 2 diabetes and might constitute a potential therapeutic target to taper oxidative stress-induced insulin resistance.

Glycemic Monitoring in Critical Care using Nonlinear State Estimators

As it is already known, patients under physiological stress, i.e., during a stay at an intensive care unit (ICU), often experience stress-induced hyperglycemia and insulin resistance even if they are not diagnosed with diabetes. In order to perform tight glycemic control (TGC) either by human intervention or by means of an automatic insulin infusion system, a proper monitoring system of the critical variables needs to be available. In this paper, the problem of estimating the state of the glucose-insulin system for a critically ill patient is investigated. Unlike most contributions, the interstitial glucose is assumed to be continuously measured by a continuous glucose monitor (CGM) instead of plasma glucose which is not usually available in most clinical facilities. Moreover, the measurement noise is characterized by a non-Gaussian noise as is suggested in recent studies. Three nonlinear filters are investigated, the Extended Kalman Filter (EKF), the Unscented Kalman Filter (UKF), and the Particle Filter (PF), under three different scenarios.