Insulin Resistance In Type 2 Diabetes Research Articles

TGS1/PIMT regulates pro-inflammatory macrophage mediated paracrine insulin resistance: Crosstalk between macrophages and skeletal muscle cells

Macrophage-driven chronic low-grade inflammatory response is intimately associated with pathogenesis of insulin resistance and type 2 diabetes (T2D). However, the molecular basis for skewing of pro-inflammatory macrophage is still elusive. Here, we describe the mechanism and significance of TGS1/PIMT (PRIP-Interacting protein with Methyl Transferase domain) in regulating macrophage activation and polarization and its impact on the development of insulin resistance in skeletal muscle cells. We show altered expression of TGS1 in M1 polarized cultured macrophages, bone marrow-derived (BMDM) and adipose tissue macrophages. Moreover, in High Fat Diet (HFD)-fed mice enhanced TGS1 expression is predominantly localized to the nucleus of adipose tissue macrophages suggesting its potential functional role. Gain and loss of TGS1 expression in macrophage further established its role in the secretion of pro-inflammatory mediators. Mechanistically, TGS1 controls the transcription of numerous genes linked to inflammation by forming a complex with Histone Acetyl Transferase (HAT)-containing transcriptional co-activators CBP and p300. Functionally, TGS1 mediated macrophage inflammatory response induces the development of insulin resistance in skeletal muscle cells and adipocytes. Our findings thus demonstrate an unexpected contribution of TGS1 in the regulation of macrophage mediated inflammation and insulin resistance highlighting that TGS1 antagonism could be a promising therapeutic target for the management of inflammation and insulin resistance in T2D.

Interleukin-33 inhibits glucose uptake in human adipocytes and its expression in adipose tissue is elevated in insulin resistance and type 2 diabetes.

Interleukin-33 (IL-33) is associated with obesity-related inflammation. We aim to investigate IL-33 expression in subcutaneous adipose tissue (SAT) in type 2 diabetes (T2D) subjects and its effects on human adipocyte glucose uptake. Expression of IL-33 was analysed in SAT from cohort studies including subjects with and without obesity and T2D and correlated with insulin resistance and obesity markers. Magnetic resonance imaging (MRI) of tissue fat volumes was performed. We investigated the effects of IL-33 treatment on ex vivo adipocyte glucose uptake. T2D subjects had higher IL-33 gene and protein expression in SAT than the control subjects. IL-33 mRNA expression was positively correlated with markers of dysglycemia (e.g. HbA1c), insulin resistance (e.g. HOMA-IR) and adiposity (BMI, visceral adipose tissue volume, liver and pancreas fat %). In multiple linear regression analyses, insulin resistance and T2D status were the strongest predictors of IL-33, independent of BMI. IL-33 mRNA expression was negatively correlated with expression of genes regulating adipocyte glucose uptake, lipid storage, and adipogenesis (e.g.glucose transporter 1 and 4 (GLUT1/4), fatty acid binding protein 4 (FABP4), and PPARG). Additionally, incubation of SAT with IL-33 reduced adipocyte glucose uptake and GLUT4 gene and protein expression. Our findings suggest that T2D subjects have higher IL-33 gene and protein expressionin SATthan control subjects, which is associated with insulin resistance and reduced gene expression of lipid storage and adipogenesis markers. IL-33 may reduce adipocyte glucose uptake. This opens up a potential pharmacological route for reversing insulin resistance in T2D and prediabetes.

New insights into mechanisms of endothelial insulin resistance in type 2 diabetes.

Insulin resistance in the vasculature is a hallmark of type 2 diabetes (T2D), and blunting of insulin-induced vasodilation is its primary consequence. Individuals with T2D exhibit a marked impairment in insulin-induced dilation in resistance arteries across vascular beds. Importantly, reduced insulin-stimulated vasodilation and blood flow to skeletal muscle limits glucose uptake and contributes to impaired glucose control in T2D. The study of mechanisms responsible for the suppressed vasodilatory effects of insulin has been a growing topic of interest for not only its association with glucose control and extension to T2D but also its relationship with cardiovascular disease development and progression. In this mini-review, we integrate findings from recent studies by our group with the existing literature focused on the mechanisms underlying endothelial insulin resistance in T2D.

ADAM17 cleaves the insulin receptor ectodomain on endothelial cells and causes vascular insulin resistance.

Inflammation and vascular insulin resistance are hallmarks of type 2 diabetes (T2D). However, several potential mechanisms causing abnormal endothelial insulin signaling in T2D need further investigation. Evidence indicates that the activity of ADAM17 (a disintegrin and metalloproteinase-17) and the presence of insulin receptor (IR) in plasma are increased in subjects with T2D. Accordingly, we hypothesized that in T2D, increased ADAM17 activity sheds the IR ectodomain from endothelial cells and impairs insulin-induced vasodilation. We used small visceral arteries isolated from a cross-sectional study of subjects with and without T2D undergoing bariatric surgery, human cultured endothelial cells, and recombinant proteins to test our hypothesis. Here, we demonstrate that arteries from subjects with T2D had increased ADAM17 expression, reduced presence of tissue inhibitor of metalloproteinase-3 (TIMP3), decreased extracellular IRα, and impaired insulin-induced vasodilation versus those from subjects without T2D. In vitro, active ADAM17 cleaved the ectodomain of the IRβ subunit. Endothelial cells with ADAM17 overexpression or exposed to the protein kinase-C activator, PMA, had increased ADAM17 activity, decreased IRα presence on the cell surface, and increased IR shedding. Moreover, pharmacological inhibition of ADAM17 with TAPI-0 rescued PMA-induced IR shedding and insulin-signaling impairments in endothelial cells and insulin-stimulated vasodilation in human arteries. In aggregate, our findings suggest that ADAM17-mediated shedding of IR from the endothelial surface impairs insulin-mediated vasodilation. Thus, we propose that inhibition of ADAM17 sheddase activity should be considered a strategy to restore vascular insulin sensitivity in T2D.NEW & NOTEWORTHY To our knowledge, this is the first study to investigate the involvement of ADAM17 in causing impaired insulin-induced vasodilation in T2D. We provide evidence that ADAM17 activity is increased in the vasculature of patients with T2D and support the notion that ADAM17-mediated shedding of endothelial IRα ectodomains is a novel mechanism causing vascular insulin resistance. Our results highlight that targeting ADAM17 activity may be a potential therapeutic strategy to correct vascular insulin resistance in T2D.

217-LB: Hepatic Mig6 Ablation Restores Glucose Homeostasis during Diet-Induced Obesity and Aging

Hepatic epidermal growth factor receptor (EGFR) expression and activation are decreased during steatosis in humans and animal models of obesity. Restoring EGFR activation in obesity-induced endoplasmic reticulum (ER) stress and diabetes is a potential therapy to improve liver function and metabolism in type 2 diabetes (T2D) . Mitogen-inducible gene 6 (Mig6) is an inducible feedback inhibitor of EGFR activity; we previously observed that liver Mig6 expression was increased during obesity-induced insulin resistance in mice and by both pharmacological- and fatty acid-driven ER stress in hepatocytes, leading to decreased EGF-mediated EGFR activation. To test Mig6 as a potential target to treat insulin resistance in T2D, we examined liver-specific Mig6 knockout mice (LKO) and their littermate controls (CON) . LKO mice exhibited reduced liver fat content and normalized glycogen storage with diet-induced obesity. In addition, we observed enhanced hepatic insulin action and whole-body glucose tolerance, due to increased hepatic glucose uptake, as determined by hyperinsulinemic-euglycemic clamps. Using whole transcriptome sequencing, peroxisomal and mitochondrial beta-oxidation genes were decreased by Mig6 ablation, correlating with a compromised gene expression of liver gluconeogenic enzymes. Moreover, analysis of mice aged for one year, a different physiological insult causing insulin resistance and liver oxidative stress, we were able to recapitulate the main findings as with diet-induced obesity: decreased gluconeogenesis, enhanced liver glucose uptake leading to increased glucose tolerance. Moreover, in aged LKO mice, liver oxidative stress markers were reduced. In conclusion, we postulate that hepatic Mig6 deficiency partially reverts the effects of diabetes by decreasing hepatic glucose output and reducing cellular oxidative stress, thereby establishing Mig6 as a therapeutic candidate for treating insulin resistance in obesity and T2D. Disclosure J. M. Irimia-dominguez: None. E. A. Bloom-saldana: None. P. T. Fueger: Consultant; Protomer Technologies.

Endothelial HSP72 is not reduced in type 2 diabetes nor is it a key determinant of endothelial insulin sensitivity.

Impaired endothelial insulin signaling and consequent blunting of insulin-induced vasodilation is a feature of type 2 diabetes (T2D) that contributes to vascular disease and glycemic dysregulation. However, the molecular mechanisms underlying endothelial insulin resistance remain poorly known. Herein, we tested the hypothesis that endothelial insulin resistance in T2D is attributed to reduced expression of heat shock protein 72 (HSP72). HSP72 is a cytoprotective chaperone protein that can be upregulated with heating and is reported to promote insulin sensitivity in metabolically active tissues, in part via inhibition of JNK activity. Accordingly, we further hypothesized that, in individuals with T2D, 7 days of passive heat treatment via hot water immersion to waist level would improve leg blood flow responses to an oral glucose load (i.e., endogenous insulin stimulation) via induction of endothelial HSP72. In contrast, we found that: 1) endothelial insulin resistance in T2D mice and humans was not associated with reduced HSP72 in aortas and venous endothelial cells, respectively; 2) after passive heat treatment, improved leg blood flow responses to an oral glucose load did not parallel with increased endothelial HSP72; and 3) downregulation of HSP72 (via small-interfering RNA) or upregulation of HSP72 (via heating) in cultured endothelial cells did not impair or enhance insulin signaling, respectively, nor was JNK activity altered. Collectively, these findings do not support the hypothesis that reduced HSP72 is a key driver of endothelial insulin resistance in T2D but provide novel evidence that lower-body heating may be an effective strategy for improving leg blood flow responses to glucose ingestion-induced hyperinsulinemia.

Protocol Standardization of Microbiome Studies—Daunting but Necessary

Protocol Standardization of Microbiome Studies—Daunting but Necessary

Gut-Microbial Metabolites, Probiotics and Their Roles in Type 2 Diabetes.

Type 2 diabetes (T2D) is a worldwide prevalent metabolic disorder defined by high blood glucose levels due to insulin resistance (IR) and impaired insulin secretion. Understanding the mechanism of insulin action is of great importance to the continuing development of novel therapeutic strategies for the treatment of T2D. Disturbances of gut microbiota have been widely found in T2D patients and contribute to the development of IR. In the present article, we reviewed the pathological role of gut microbial metabolites including gaseous products, branched-chain amino acids (BCAAs) products, aromatic amino acids (AAAs) products, bile acids (BA) products, choline products and bacterial toxins in regulating insulin sensitivity in T2D. Following that, we summarized probiotics-based therapeutic strategy for the treatment of T2D with a focus on modulating gut microbiota in both animal and human studies. These results indicate that gut-microbial metabolites are involved in the pathogenesis of T2D and supplementation of probiotics could be beneficial to alleviate IR in T2D via modulation of gut microbiota.

The effects of resveratrol supplementation in patients with type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease: an umbrella review of meta-analyses of randomized controlled trials

Uncertainty remains about the estimates of the effects for resveratrol supplementation, including the certainty of the evidence for each estimate and the magnitude of the observed impact based on the minimal important difference. We aimed to provide an overview of the effects of resveratrol supplementation, in comparison to control groups, for the management of cardiometabolic risk factors in patients with type 2 diabetes (T2D), metabolic syndrome (MetS), and nonalcoholic fatty liver disease (NAFLD). PubMed, Scopus, and ISI Web of Science were searched from inception to May 2021. For each meta-analysis, the mean difference and its 95% CI were recalculated using a random-effects model. The certainty of evidence was rated using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. We identified 11 meta-analyses corresponding to 29 outcomes in 1476 individuals with T2D, 17 meta-analyses reporting 26 outcomes in 727 participants with the MetS, and 10 meta-analyses reporting 24 outcomes in 271 patients with NAFLD. Resveratrol supplementation had beneficial effects on some outcomes such as blood pressure, lipid profile, glycemic control, and insulin resistance in T2D, waist circumference in MetS, and body-weight and inflammation markers in NAFLD; however, for almost all outcomes, the magnitude of the effect was trivial, the certainty of evidence was very low to low, or the number of trials was too few. In the case of glycated hemoglobin (HbA1c), there was evidence that resveratrol can exert favorable and clinically important effects in the short term (<12 wk; mean difference: -1.05%, 95% CI: -2.09%, -0.02%; n=6; GRADE=moderate). Current evidence does not support supplementation with resveratrol for the management of cardiometabolic risk factors in patients with T2D, MetS, and NAFLD. In the case of HbA1c, subject to the limitations such as short-term follow-up and small sample size, there was a clinically important effect. The protocol of the present systematic review was registered in Open Science Framework (https://osf.io/ake85; registration doi: 10.17605/OSF.IO/AKE85).

Genetic variants associated with beta-cell function and insulin sensitivity potentially influence bile acid metabolites and gestational diabetes mellitus in a Chinese population

IntroductionTo investigate associations between genetic variants related to beta-cell (BC) dysfunction or insulin resistance (IR) in type 2 diabetes (T2D) and bile acids (BAs), as well as the risk of...

Effects of physical exercise on memory in type 2 diabetes: a brief review.

Type 2 diabetes (T2D) is a metabolic disorder that can lead to memory impairment. T2D main features are insulin resistance and hyperglycemia. Physical exercise is a non-pharmacological intervention that can regulate glycemic levels and fight insulin resistance in T2D, but whether it influences memory has been discussed. There are 2 main types of physical exercise: aerobic exercise and resistance exercise. Here, we review about the consequences of different physical exercise protocols on memory in diabetic subjects and animal models of T2D. Physical exercise, aerobic or resistance training, most of the times, is a capable agent to prevent and treat memory loss on diabetic subjects and animal models of T2D. However, whether aerobic and resistance training combined improve memory in subjects with T2D remains controversial. Regarding animal models of T2D, aerobic and resistance training have been showed to be capable to prevent and treat memory loss. Acute and chronic protocols of exercise, generally, induce positive physiological responses and adaptations in T2D, such as a better glucose control. The ideal physical exercise protocol that will produce the best benefits to diabetic subjects and to animal models of T2D has not been described yet. A variety of combination between intensity, volume, frequency, and duration of the physical exercise protocol on future studies is necessary to both diabetic subjects and animal models of T2D to determine the best protocol that will induce more benefits on memory in T2D.

Insight into type 2 diabetes impaired exercising mitochondrial oxidative flux: is it blood flow, mitochondria, or neither?

Insight into type 2 diabetes impaired exercising mitochondrial oxidative flux: is it blood flow, mitochondria, or neither?

Association of adiponectin &amp; leptin with insulin resistance in type-2 diabetes

Indian phenotype having greater abdominal adiposity, higher waist circumference (WC) &amp; lower body mass index (BMI), thereby making the indians more prone to diabetes and it’s complications. Type-2 diabetes mellitus (T2DM) worldwide known for its morbidity and mortality. Recent studies have demonstrated that the abnormal levels of adipocytokines (Adiponectin, leptin) may contribute to Insulin resistance (IR) and T2DM.The present study aimed to analyze circulatory levels of Adiponectin &amp; Leptin with Insulin Resistance in study subjects compared with control subject &amp; Type-2 diabetes mellitus (T2DM).A total 120 T2DM patients and 120 healthy subjects aged between 30 and 60 years who were Non-diabetic, Non-hypertensive and having no family history of hypertension visiting to Medicine OPD were included in study. Parameters such as age, sex, anthropometric measures and biochemical indicators like fasting and postprandial blood sugar, lipid profile, adiponectin, leptin, fasting insulin, HOMA-IR &amp; systolic and diastolic blood pressure were determined &amp; compared with control subjects.Adiponectin levels were reported significantly lower in T2DM group whereas Leptin levels were significantly higher in T2DM group compared to non-diabetics group (P ≤ 0.001) in both genders.Adiponectin &amp; Leptin levels are used as an important clinical biomarkers for T2DM and obesity. IR, Adiponectin and Leptin can be used as cut off to predict the occurrence of T2DM.

Circulating resistin levels in relation with insulin resistance, inflammatory and endothelial dysfunction markers in patients with type 2 diabetes and impaired fasting glucose

BackgroundResistin is an adipose tissue secreted protein link with the mechanism involved in the pathophysiology of insulin resistance. Aim of the workThis study aims to investigate the potential role of resistin in insulin resistance in relation with inflammatory markers and endothelial dysfunction markers in impaired fasting glucose (IFG) and type 2 diabetes (T2D). Patients and MethodsThis pilot study assess the relation of resistin with insulin resistance (HOMA-IR), adipokines (adiponectin, leptin), inflammatory markers [tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), interleukin-6 (IL-6)] and endothelial dysfunction markers [vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1)] cross-sectionally using serum samples obtained from 64 participants; controls (n=29), IFG (n=20) and T2D (n=15). The levels of biomarker were measured by using Randox Evidence biochip analyzer. Statistical analyses were performed by SPSS 21.0 software. ResultsResistin levels in IFG and T2D groups were higher compared to control group. A positive correlation was detected between serum resistin levels with HOMA-IR (p= 0.02), inflammatory markers; TNF-α (p=<0.001), IL-6 (p=0.007) and endothelial dysfunction marker; VCAM-1 (p=0.02) in T2D group. In IFG group, resistin showed a significant positive correlation with IL-6 (p= 0.03). ConclusionThe present study demonstrates the involvement of inflammation and endothelial dysfunction in relation with resistin linked insulin resistance in T2D. The promising insulin resistance biomarker-resistin- among people at high risk to develop type 2 diabetes mellitus and add significant contribution to this highly prevalent population .

Metabolic and Molecular Mechanisms of Macrophage Polarisation and Adipose Tissue Insulin Resistance.

Inflammation plays a key role in the development and progression of type-2 diabetes (T2D), a disease characterised by peripheral insulin resistance and systemic glucolipotoxicity. Visceral adipose tissue (AT) is the main source of inflammation early in the disease course. Macrophages are innate immune cells that populate all peripheral tissues, including AT. Dysregulated AT macrophage (ATM) responses to microenvironmental changes are at the root of aberrant inflammation and development of insulin resistance, locally and systemically. The inflammatory activation of macrophages is regulated at multiple levels: cell surface receptor stimulation, intracellular signalling, transcriptional and metabolic levels. This review will cover the main mechanisms involved in AT inflammation and insulin resistance in T2D. First, we will describe the physiological and pathological changes in AT that lead to inflammation and insulin resistance. We will next focus on the transcriptional and metabolic mechanisms described that lead to the activation of ATMs. We will discuss more novel metabolic mechanisms that influence macrophage polarisation in other disease or tissue contexts that may be relevant to future work in insulin resistance and T2D.

Relationship of metabolic syndrome defined by IDF or revised NCEP ATP III with glycemic control among Malaysians with Type 2 Diabetes

BackgroundThe chronic complications of Type 2 Diabetes (T2D) such as macrovascular disease is amplified with the increase in the number of metabolic syndrome (MetS) risk factors. This research aims to study the relationship of MetS, diagnosed by the International Diabetes Federation (IDF) or revised National Cholesterol Education Programs Adult Treatment Panel III (NCEP ATP III) criteria, with glycemic control, fasting blood glucose (FBG), glycated hemoglobin (HbA1c), C-peptide, and insulin resistance in T2D patients.MethodsThe study is a cross-sectional observational study which, involved 485 T2D patients who are receiving treatment at the University Kebangsaan Malaysia Medical Center (UKMMC), Kuala Lumpur, Malaysia. The MetS among the T2D patients was diagnosed based on IDF and revised NCEP ATP III criteria. C-peptide and HbA1c levels were determined by an automated quantitative immunoassay analyzer and high-performance liquid chromatography, respectively. The MetS factors; FBG, triglyceride, and high-density lipoprotein cholesterol were measured by spectrophotometer.ResultsApplication of the IDF and revised NCEP ATP III criteria respectively resulted in 73% and 85% of the T2D subjects being diagnosed with MetS. The concordance of these criteria in diagnosing MetS among T2D patients was low (κ = 0.33, P < 0.001). Both IDF and revised NCEP ATP III criteria indicated that T2D patients with 5 MetS factors had higher insulin resistance (P = 2.1 × 10−13; 1.4 × 10−11), C-peptide (P = 1.21 × 10−13; 4.1 × 10−11), FBG (P = 0.01; 0.021), and HbA1c (P = 0.039; 0.018) than those T2D patients without MetS, respectively.ConclusionAlthough there is a low concordance between IDF and revised NCEP ATP III criteria in the diagnosis of MetS among T2D patients, both criteria showed that T2D patients with 5 MetS factors had higher insulin resistance, C-peptide, FBG, and HbA1c.

High-intensity resistance training induces changes in cognitive function, but not in locomotor activity or anxious behavior in rats induced to type 2 diabetes

Type 2 diabetes (T2D) is a metabolic disorder that can lead to cognitive decline through impairment of insulin signaling. Resistance training, a type of physical exercise, is a non-pharmacological approach used to improve insulin resistance in T2D. The aim of our study was to evaluate the effects of high-intensity resistance training (HIRT) over cognitive function, locomotor activity, and anxious behavior in rats induced to T2D. Thirty young adult male wistar rats were distributed into 3 groups (n = 10): Control; dexamethasone (D); and dexamethasone + exercise (DE), that performed the HIRT during 4 weeks. Blood glucose, water intake, and total body fat were measured. Locomotor activity, and anxious behavior where evaluated through the open field task. Cognitive function was assessed through the novel object recognition task. Insulin resistance and neuronal death were evaluated through western blot analysis. Rats induced to T2D had higher blood glucose levels, and consumed more water when compared to control group, but DE had better blood glucose levels than D. Total body fat was reduced in DE compared to D. Locomotor activity, and anxious behavior were not significantly altered. T2D rats which performed HIRT maintained cognitive function, while those induced to T2D that did not exercise developed cognitive decline. DE group showed a reduction in the inhibition of the activation of hippocampal IRS-1 and higher expression of GSk3β phosphorylated in serine compared to D group, revealing insulin signaling impairment, and neuronal death were identified in the hippocampus of D group. Lifestyle intervention through the regular practice of HIRT plays a fundamental role in the treatment of T2D preventing cognitive decline.

298-OR: Disruption of Multiple Cell-Autonomous Protein Phosphorylation Networks Underlies Muscle Insulin Resistance in Type 2 Diabetes

Skeletal muscle insulin resistance is the earliest defect in type 2 diabetes (T2D), however, whether this represents a cell-autonomous defect or is secondary to changes in hormones and other circulating factors in vivo is unclear. To identify primary drivers of skeletal muscle insulin resistance in T2D without interference of these systemic factors, we have developed a “disease-in-a-dish” model by differentiating induced pluripotent stem cells (iPSCs) from T2D patients and controls into skeletal myoblasts (iMyos) and studied their function in vitro (n=8 subjects per group). We find that T2D iMyos retain multiple features of in vivo insulin resistance including altered insulin signaling downstream of the IRS/AKT pathway, impaired insulin-stimulated glucose uptake, and reduced mitochondrial oxidation. More importantly, using global phosphoproteomics we identify nearly 1,000 phosphorylation sites that were significantly increased or decreased (FDR &amp;lt; 0.05) by T2D status. While many of the observed signaling defects in T2D iMyos occurred inside the classical insulin signaling pathway and included dysregulation of Akt, mTOR and forkhead box transcription factors, over 85% of these changes occurred in basal protein phosphorylation. These included phosphorylation of proteins in many pathways not typically involved in insulin resistance, such as mRNA splicing and processing, gene transcription, chromatin remodeling and cytoskeleton dynamics. Motif analysis revealed enrichment of a multiplicity of kinases including ROCK, mTOR/S6K and PKCs with potential targets involved in insulin action, cytoskeleton and cell cycle, without changes in total protein content. This broad dysregulated phosphorylation network reveals a new dimension in the complexity of the cell-autonomous mechanisms underlying insulin resistance in T2D, as well as new targets for therapy or prevention of the disease. Disclosure T.M. Batista: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker’s Bureau; Self; Merck Sharp &amp; Dohme Corp. J.R. Zierath: None. M. Mann: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences. Consultant; Self; AntriaBio, Flagship Pioneering, Sana-Cobalt. Funding National Institutes of Health (R01DK031036, R01DK033201); Swedish Research Council (2015-00165); Novo Nordisk Foundation (NNF18CC0034900)

Exposure to adropin improves insulin‐induced dilation in arteries from type 2 diabetic mice

Vascular insulin resistance is a hallmark of type 2 diabetes (T2D) and blunting of insulin‐induced dilation is its primary manifestation. Importantly, in T2D, reduced insulin‐induced dilation and blood flow to skeletal muscle significantly limits glucose uptake and contributes to impaired glucose control. However, the mechanisms underlying vascular insulin resistance in T2D remain largely unknown. Adropin is a peptide primarily secreted by the liver and brain, recently shown to regulate energy homeostasis as well as to promote systemic insulin sensitivity. Notably, circulating levels of adropin are decreased in T2D, which may contribute to impairments in vascular insulin signaling. Herein we tested the hypothesis that arterial exposure to adropin improves vascular insulin sensitivity, particularly in T2D. To test this hypothesis, femoral arteries from ~12‐week old db/db (n=5) and genetic control (db+/−, n=5) male mice were incubated with adropin (50 ng/mL) or vehicle for 24 hours and vasomotor responses to acetylcholine, insulin, and sodium nitroprusside (SNP) assessed thereafter via pressure myography. Consistent with our hypothesis, we show that treatment of femoral arteries from db/db mice with adropin improves insulin‐induced dilation (P&lt;0.05), an effect that is not observed in db+/− control mice (P&gt;0.05). Adropin exposure did not alter acetylcholine and SNP‐induced dilation of femoral arteries in either db/db or db+/− mice (P&gt;0.05). These findings support the notion that adropin deficiency may contribute to vascular insulin resistance in T2D.

ADAM17 Cleaves the Insulin Receptor Ectodomain on Endothelial Cells and Induces Vascular Insulin Resistance

Despite efforts to reduce the incidence of type 2 diabetes (T2D) and its cardiovascular consequences, T2D‐associated cardiovascular mortality continues to rise in the US and worldwide. The presence of a pro‐inflammatory state and microvascular insulin resistance are hallmarks of T2D that contribute to cardiovascular disease. The former is associated with increased activity of ADAM17, an enzyme that cleaves the ectodomain of multiple transmembrane proteins, while the latter is characterized by decreased insulin‐induced vasodilatory responses. However, the specific mechanisms, including the potential role(s) of ADAM17, underlying vascular insulin resistance in T2D, remain unknown. We hypothesize that in T2D, increased expression and activation of ADAM17 sheds the insulin receptor ectodomain (IRα) from endothelial cells and thus impairs insulin‐induced vasodilation. We tested this hypothesis using isolated small visceral arteries from T2D and non‐T2D subjects undergoing bariatric surgery and cultured human endothelial cells. Results indicate that arteries from subjects with T2D exhibit increased ADAM17 expression, reduced presence of TIMP3 (the endogenous inhibitor of ADAM17), decreased extracellular IRα, and impaired insulin‐induced vasodilation in comparison with arteries from non‐T2D subjects (P&lt;0.05). In vitro, ADAM17 cleaved insulin receptor recombinant proteins at a specific extracellular site of the IRβ subunit (p&lt;0.05). Exposure of endothelial cells to the PKC activator, PMA, increased the shedding activity of ADAM17 (P&lt;0.05) and decreased the presence of IRα on cell surfaces occupied by ADAM17, as observed using super‐resolution microscopy. Moreover, pharmacological inhibition of ADAM17 with TAPI‐0 rescued PMA‐induced impairments in insulin signaling in endothelial cells and insulin‐stimulated vasodilation in human small visceral arteries (P&lt;0.05). Collectively, these findings suggest that ADAM17‐mediated shedding of IR ectodomains from the endothelial surface impairs insulin‐mediated vasodilation. Therefore, inhibition of ADAM17 sheddase activity should be considered a potential new therapeutic strategy to restore vascular insulin sensitivity in T2D.Support or Funding InformationResearch support: National Institutes of Health grants: R01 HL137769 (JP), R01 HL088105 (LM‐L).