Insulin-resistant Individuals Research Articles

Association of Glutathione Peroxidase 3 (GPx3) and miR-196a with Carbohydrate Metabolism Disorders in the Elderly.

The escalating prevalence of carbohydrate metabolism disorders (CMDs) prompts the need for early diagnosis and effective markers for their prediction. Hyperglycemia, the primary indicator of CMDs including prediabetes and type 2 diabetes mellitus (T2DM), leads to overproduction of reactive oxygen species (ROS) and oxidative stress (OxS). This condition, resulting from chronic hyperglycemia and insufficient antioxidant defense, causes damage to biomolecules, triggering diabetes complications. Additionally, aging itself can serve as a source of OxS due to the weakening of antioxidant defense mechanisms. Notably, previous research indicates that miR-196a, by downregulating glutathione peroxidase 3 (GPx3), contributes to insulin resistance (IR). Additionally, a GPx3 decrease is observed in overweight/obese and insulin-resistant individuals and in the elderly population. This study investigates plasma GPx3 levels and miR-196a expression as potential CMD risk indicators. We used ELISA to measure GPx3 and qRT-PCR for miR-196a expression, supplemented by multivariate linear regression and receiver operating characteristic (ROC) analysis. Our findings included a significant GPx3 reduction in the CMD patients (n = 126), especially in the T2DM patients (n = 51), and a decreasing trend in the prediabetes group (n = 37). miR-196a expression, although higher in the CMD and T2DM groups than in the controls, was not statistically significant, potentially due to the small sample size. In the individuals with CMD, GPx3 levels exhibited a negative correlation with the mass of adipose tissue, muscle, and total body water, while miR-196a positively correlated with fat mass. In the CMD group, the analysis revealed a weak negative correlation between glucose and GPx3 levels. ROC analysis indicated a 5.2-fold increased CMD risk with GPx3 below 419.501 ng/mL. Logistic regression suggested that each 100 ng/mL GPx3 increase corresponded to a roughly 20% lower CMD risk (OR = 0.998; 95% CI: 0.996-0.999; p = 0.031). These results support the potential of GPx3 as a biomarker for CMD, particularly in T2DM, and the lack of a significant decline in GPx3 levels in prediabetic individuals suggests that it may not serve reliably as an early indicator of CMDs, warranting further large-scale validation.

Association between antioxidant metabolites and N-terminal fragment brain natriuretic peptides in insulin-resistant individuals.

Oxidative stress plays a pivotal role in the development of metabolic syndrome, including heart failure and insulin resistance. The N-terminal fragment of brain natriuretic peptide (NT-proBNP) has been associated with heightened oxidative stress in heart failure patients. Yet, its correlation with insulin resistance remains poorly understood. Our objective is to investigate the association between oxidative stress markers and NT-proBNP levels in insulin-resistant individuals. In this cross-sectional study involving 393 participants from the Qatar Biobank, clinical and metabolic data were collected, and the association between NT-proBNP and 72 oxidative stress metabolites was compared between insulin-sensitive and insulin-resistant individuals. Our results showed significantly lower NT-proBNP levels in insulin-resistant individuals (median = 17 pg/ml; interquartile range = 10.3-29) when compared to their insulin-sensitive counterparts (median = 31 pg/ml; interquartile range = 19-57). Moreover, we revealed notable associations between NT-proBNP levels and antioxidant metabolic pathways, particularly those related to glutathione metabolism, in insulin-resistant, but not insulin-sensitive individuals. The significant decrease in NT-proBNP observed in individuals with insulin resistance may be attributed to a direct or indirect enhancement in glutathione production, which is regarded as a compensatory mechanism against oxidative stress. This study could advance our understanding of the interplay between oxidative stress during insulin resistance and cardiovascular risk, which could lead to novel therapeutic approaches for managing cardiovascular diseases. Further investigations are needed to assess the practical utility of these potential metabolites and understand the causal nature of their association with NT-proBNP in the etiology of insulin resistance.

Short, frequent, light-intensity walking activity improves postprandial vascular-inflammatory biomarkers in people with type 1 diabetes: The SIT-LESS randomized controlled trial.

To examine the effect of interrupting prolonged sitting with short, frequent, light-intensity activity on postprandial cardiovascular markers in people with type 1 diabetes (T1D). In a randomized crossover trial, 32 adults with T1D (mean ± SD age 28 ± 5 years, glycated haemoglobin 67.9 ± 12.6 mmol/mol, 17 women) completed two 7-h laboratory visits separated by >7 days. Participants either remained seated for 7 h (SIT) or interrupted sitting with 3-min bouts of self-paced walking at 30-min intervals commencing 1 h after each meal (SIT-LESS). Physical activity, insulin regimen, experimental start times, and meal consumption were standardized during each arm. Plasma levels of interleukin (IL)-1β, tumour necrosis factor (TNF)-α, plasminogen activator inhibitor (PAI)-1 and fibrinogen were sampled at baseline, 3.5 and 7 h, and assessed for within- and between-group effects using a repeated measures ANOVA. The estimated glucose disposal rate was used to determine the insulin resistance status. Vascular-inflammatory parameters were comparable between SIT and SIT-LESS at baseline (p > .05). TNF-α, IL-1β, PAI-1 and fibrinogen increased over time under SIT, whereas these rises were attenuated under SIT-LESS (p < .001). Specifically, over the 7 h under SIT, postprandial increases were detected in TNF-α, IL-1β, PAI-1 and fibrinogen (+67%, +49%, +49% and +62%, respectively; p < .001 for all). Conversely, the SIT-LESS group showed no change in IL-1β (-9%; p > .50), whereas reductions were observed in TNF-α, PAI-1 and fibrinogen (-22%, -42% and -44%, respectively; p < .001 for all). The intervention showed enhanced effects in insulin-resistant individuals with T1D. Interrupting prolonged sitting with light-intensity activity ameliorates postprandial increases in vascular-inflammatory markers in T1D. The trial was prospectively registered (ISRCTN13641847).

Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease

To understand the dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune, and clinical markers of microbiomes from four body sites in 86 participants over 6 years. We found that microbiome stability and individuality are body-site specific and heavily influenced by the host. The stool and oral microbiome are more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. We identify individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlate across body sites, suggesting systemic dynamics influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals show altered microbial stability and associations among microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease.

Interactions among insulin resistance, epigenetics, and donor sex in gene expression regulation of iPSC-derived myoblasts.

About 25% of people in the general population are insulin resistant, increasing the risk for type 2 diabetes (T2D) and metabolic disease. Transcriptomic analysis of induced pluripotent stem cells differentiated into myoblasts (iMyos) from insulin-resistant (I-Res) versus insulin-sensitive (I-Sen) nondiabetic individuals revealed that 306 genes increased and 271 genes decreased in expression in iMyos from I-Res donors with differences of 2-fold or more. Over 30 of the genes changed in I-Res iMyos were associated with T2D by SNPs and were functionally linked to insulin action and control of metabolism. Interestingly, we also identified more than 1,500 differences in gene expression that were dependent on the sex of the cell donor, some of which modified the insulin resistance effects. Many of these sex differences were associated with increased DNA methylation in cells from female donors and were reversed by 5-azacytidine. By contrast, the insulin sensitivity differences were not reversed and thus appear to reflect genetic or methylation-independent epigenetic effects.

CytogeneticsRapid Resolution of Medically Relevant Polyunsaturated, Very Long-, Odd-, and Branched-Chain Fatty Acid Methyl Esters

Abstract Fatty acids play an important role in human health and disease. Nearly 100 years ago, the Burrs demonstrated that polyunsaturated fatty acids (PUFAs) were essential for development; subsequent work uncovered the role of PUFAs as precursors to important signaling molecules such as prostaglandins, leukotrienes, and thromboxanes. Very long chain fatty acids (VLCFAs) originally sparked interest over 40 years ago for being elevated in humans with peroxisomal disorders. More recent studies have shown that VLCFAs are elevated in healthy human controls, compared to their diabetic counterparts. In a similar vein, odd chain fatty acids (OCFAs) and branched-chain fatty acids (BCFAs) of the iso and anteiso variety are higher in humans with insulin sensitivity than in insulin resistant individuals. These families of fatty acids are most frequently analyzed as their fatty acid methyl esters (FAMEs) by gas chromatography (GC). Regrettably, even recently published methods resolving BCFAs from their linear correlates have run-times in excess of an hour and, in some cases, over 100 minutes. Objective: The goal of this study was to decrease the GC run-time for the analysis of FAMEs relevant to human health and disease. Methods: Baseline resolution of FAMEs required careful combination of the right gas chromatograph, column dimensions, stationary phase, carrier gas, and temperature programming. Results: We cleanly resolved the FAMEs of all common polyunsaturated, very long-, odd-, and branched-chain fatty acids with baseline separation in only ~15 minutes – a 4-fold improvement over many existing methods. Conclusion: This method will significantly improve analysis of fatty acids in health and disease, especially in large-scale, clinical studies, by quartering the run time necessary to resolve PUFAs, VLCFAs, OCFAs, and BCFAs.

ZFYVE28 mediates insulin resistance by promoting phosphorylated insulin receptor degradation via increasing late endosomes production

Insulin resistance is associated with many pathological conditions, and an in-depth understanding of the mechanisms involved is necessary to improve insulin sensitivity. Here, we show that ZFYVE28 expression is decreased in insulin-sensitive obese individuals but increased in insulin-resistant individuals. Insulin signaling inhibits ZFYVE28 expression by inhibiting NOTCH1 via the RAS/ERK pathway, whereas ZFYVE28 expression is elevated due to impaired insulin signaling in insulin resistance. While Zfyve28 overexpression impairs insulin sensitivity and causes lipid accumulation, Zfyve28 knockout in mice can significantly improve insulin sensitivity and other indicators associated with insulin resistance. Mechanistically, ZFYVE28 colocalizes with early endosomes via the FYVE domain, which inhibits the generation of recycling endosomes but promotes the conversion of early to late endosomes, ultimately promoting phosphorylated insulin receptor degradation. This effect disappears with deletion of the FYVE domain. Overall, in this study, we reveal that ZFYVE28 is involved in insulin resistance by promoting phosphorylated insulin receptor degradation, and ZFYVE28 may be a potential therapeutic target to improve insulin sensitivity.

OR18-03 Peripheral But Not Hepatic Insulin Resistance Associates With Adverse Vascular And Metabolic Health In Type 1 Diabetes: A Possible Target For Adjunctive Therapy

Abstract Disclosure: J.R. Snaith: None. N. Olsen: None. G. Kowalski: None. C. Bruce: None. J. Holmes-Walker: None. J.R. Greenfield: None. Insulin resistance in type 1 diabetes (T1D) is a cardiometabolic risk factor that is potentially targetable with adjunctive therapy. Prior studies of metformin in T1D have yielded mixed results. Whether liver and/or muscle insulin resistance is a prerequisite for metformin’s action in adults with T1D is unknown. The INTIMET study recruited 40 adults with T1D (age 37.4±8.8 years, HbA1c 7.5±0.9%, diabetes duration 22.9±8.8 years, BMI 26.4±0.9 kg/m2) and 20 age- and BMI-matched controls without diabetes. Subjects with T1D were randomized to metformin extended-release 1500mg daily or placebo for 26 weeks. Two-step hyperinsulinemic euglycemic clamps (low-dose 20 mU/m2/min, high-dose 60 mU/m2/min insulin) using 6,6-2H2-glucose tracers assessed liver (basal glucose rate of appearance [B-Ra] and low-dose endogenous glucose production [L-EGP]; primary outcomes) and muscle (high-dose glucose infusion rate [GIR]; secondary outcome) insulin resistance at t=0 in all subjects and at t=26 weeks in T1D. Dual-energy x-ray absorptiometry was used to measure fat free mass and visceral adipose tissue (VAT). Applanation tonometry was used to measure arterial stiffness (AIx, augmentation index). Adults with T1D and controls had similar B-Ra (18.2±5.1 vs 18.3±2.2 mmol/kgFFM/min; p=0.87). However, T1D were insulin-resistant at the liver (L-EGP 5.9±2.2 vs 3.6±1.7 mmol/kgFFM/min; p&amp;lt;0.001) and at muscle (GIR 62±20 vs 88±18 µmol/min·kgFFM; p&amp;lt;0.001). Despite these differences, VAT was comparable. In all subjects, baseline GIR correlated with L-EGP (r=-0.343; p=0.008), VAT (r=-0.269; p=0.039) and BMI (r=-0.304; p=0.019). In contrast, baseline L-EGP did not relate to VAT (r=0.060; p=0.653) or BMI (r=0.173; p=0.189). Adults with T1D had borderline higher AIx than controls (11.2±11.4 vs 4.7±13.1%, p=0.05). In the whole group, GIR was associated with LogAIx (r=-0.258, p=0.048), but L-EGP was not (r=0.154; p=0.246). In T1D, HbA1c correlated with GIR (r=-0.329; p=0.041) but L-EGP did not (r=0.307; p=0.057). After 26 weeks, there was no difference between metformin vs placebo-treated T1D subjects in HbA1c and weight, or B-Ra, L-EGP or GIR using generalised linear regression adjusted for age and baseline B-Ra, L-EGP and GIR. In these models, baseline GIR inversely predicted L-EGP (p=0.027) and directly predicted GIR (p&amp;lt;0.001) at 26 weeks. Adults with T1D exhibited greater liver and muscle insulin resistance, and higher arterial stiffness, which was not improved with metformin. Muscle but not liver insulin resistance related to BMI, VAT, HbA1c and AIx. Baseline muscle insulin resistance predicted muscle and hepatic insulin resistance at 26 weeks, irrespective of metformin treatment. This study highlights 1) the importance of muscle but not liver insulin resistance in T1D and 2) the need to identify muscle insulin resistant T1D individuals to enable interventions that improve vascular and metabolic outcomes. Presentation: Saturday, June 17, 2023

The tissue-specific metabolic effects of the PPARα agonist ciprofibrate in insulin-resistant male individuals: a double-blind, randomized, placebo-controlled crossover study.

Insulin resistance is characterized by ectopic fat accumulation leading to cardiac diastolic dysfunction and nonalcoholic fatty liver disease. The objective of this study was to determine whether treatment with the peroxisome proliferator-activated receptor-α (PPARα) agonist ciprofibrate has direct effects on cardiac and hepatic metabolism and can improve insulin sensitivity and cardiac function in insulin-resistant volunteers. Ten insulin-resistant male volunteers received 100 mg/d of ciprofibrate and placebo for 5 weeks in a randomized double-blind crossover study. Insulin-stimulated metabolic rate of glucose (MRgluc) was measured using dynamic 18 F-fluorodeoxyglucose-positron emission tomography(18 F-FDG-PET). Additionally, cardiac function, whole-body insulin sensitivity, intrahepatic lipid content, skeletal muscle gene expression, 24-hour blood pressure, and substrate metabolism were measured. Whole-body insulin sensitivity, energy metabolism, and body composition were unchanged after ciprofibrate treatment. Ciprofibrate treatment decreased insulin-stimulated hepatic MRgluc and increased hepatic lipid content. Myocardial net MRgluc tended to decrease after ciprofibrate treatment, but ciprofibrate treatment had no effect on cardiac function and cardiac energy status. In addition, no changes in PPAR-related gene expression in muscle were found. Ciprofibrate treatment increased hepatic lipid accumulation and lowered MRgluc, without affecting whole-body insulin sensitivity. Furthermore, parameters of cardiac function or cardiac energy status were not altered upon ciprofibrate treatment.

Association of Glycosylated Hemoglobin Levels with Insulin Resistance in Adolescent among Medical Students Ain Shams University

Abstract Background Insulin resistance is a common pathway for the development of glucose metabolism disorders and high blood pressure, all of which are components of the metabolic syndrome. The earlier onset of obesity may cause a longer period of insulin resistance, which may explain the concomitant earlier onset of impaired glucose tolerance in young obese people and adolescents so insulin resistance has been implicated as risk factor for metabolic disorders and it is of real importance to develop simple test that can be used in routine clinical setting for identifying insulin resistant individuals in advance so HOMA-IR(Homeostatic Model Assessment for Insulin Resistance) and HbA1c (glycated haemoglobin) screening to identify young at high risk for insulin resistance and diabetes at an early stage. The study aimed to evaluate the association of HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) and HbA1c levels in overweight and nonoverweight young medical students to assess insulin resistance, a condition that can cause diabetes mellitus and metabolic syndrome in earlier life. Subject and Methods The study was systematic random sample was conducted between 40 overweight and 40 non-overweight students (80 in total). All cases were subjected to history taking, clinical examination and laboratory investigations included HOMA-IR and HbA1c. Results Regarding HOMA-IR in present study they illustrated statistically significant difference between groups with higher levels in overweighed group than for normal weight group.HOMA-IR ≥2.5 was represent (17.5%)of normal weight group and (45.0%) of overweighed group with statistically significant difference. N statistically significant difference regarding Glucose (mg/dl) level for normal and overweighed group. The relation was statistically significant regarding Insulin (mIU/ml) level as it was higher in overweighed group than normal group. Regarding HbA1c% in present study; there is no statistically significant difference between normal group compared to obese group that range within normal values with higher result in obese group. Our study found statistically significant association between HOMA-IR&amp;lt;2.5 and (glucose and insulin), in both groups and for HbA1c in obese group. Also statistically significant positive correlation between HOMA-IR and HbA1c% in all patients. Conclusion Obesity is significantly associated with higher levels of fasting insulin, and HOMA-IR values in adolescents. There is a positive correlation between HbA1c and HOMA-IR

Plasma proteomic signatures of a direct measure of insulin sensitivity in two population cohorts.

The euglycaemic-hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC. We measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained (R2). A standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R2 0.444 [0.391, 0.497]; ULSAM to RISC R2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2. A plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences.

The Metabolic Switch of Physical Activity in Non-Obese Insulin Resistant Individuals.

Healthy non-obese insulin resistant (IR) individuals are at higher risk of metabolic syndrome. The metabolic signature of the increased risk was previously determined. Physical activity can lower the risk of insulin resistance, but the underlying metabolic pathways remain to be determined. In this study, the common and unique metabolic signatures of insulin sensitive (IS) and IR individuals in active and sedentary individuals were determined. Data from 305 young, aged 20-30, non-obese participants from Qatar biobank, were analyzed. The homeostatic model assessment of insulin resistance (HOMA-IR) and physical activity questionnaires were utilized to classify participants into four groups: Active Insulin Sensitive (ISA, n = 30), Active Insulin Resistant (IRA, n = 20), Sedentary Insulin Sensitive (ISS, n = 21) and Sedentary Insulin Resistant (SIR, n = 23). Differences in the levels of 1000 metabolites between insulin sensitive and insulin resistant individuals in both active and sedentary groups were compared using orthogonal partial least square discriminate analysis (OPLS-DA) and linear models. The study indicated significant differences in fatty acids between individuals with insulin sensitivity and insulin resistance who engaged in physical activity, including monohydroxy, dicarboxylate, medium and long chain, mono and polyunsaturated fatty acids. On the other hand, the sedentary group showed changes in carbohydrates, specifically glucose and pyruvate. Both groups exhibited alterations in 1-carboxyethylphenylalanine. The study revealed different metabolic signature in insulin resistant individuals depending on their physical activity status. Specifically, the active group showed changes in lipid metabolism, while the sedentary group showed alterations in glucose metabolism. These metabolic discrepancies demonstrate the beneficial impact of moderate physical activity on high risk insulin resistant healthy non-obese individuals by flipping their metabolic pathways from glucose based to fat based, ultimately leading to improved health outcomes. The results of this study carry significant implications for the prevention and treatment of metabolic syndrome in non-obese individuals.

Transcriptomic Analysis from Normal Glucose Tolerance to T2D of Obese Individuals Using Bioinformatic Tools

Understanding the role of white adipose tissue (WAT) in the occurrence and progression of metabolic syndrome is of considerable interest; among the metabolic syndromes are obesity and type 2 diabetes (T2D). Insulin resistance is a key factor in the development of T2D. When the target cells become resistant to insulin, the pancreas responds by producing more insulin to try to lower blood glucose. Over time, this can lead to a state of hyperinsulinemia (high levels of insulin in the blood), which can further exacerbate insulin resistance and contribute to the development of T2D. In order to understand the difference between healthy and unhealthy obese individuals, we have used published transcriptomic profiling to compare differences between the WAT obtained from obese diabetics and subjects who are obese with normal glucose tolerance and insulin resistance. The identification of aberrantly expressed messenger RNA (mRNA) and the resulting molecular interactions and signaling networks is essential for a better understanding of the progression from normal glucose-tolerant obese individuals to obese diabetics. Computational analyses using Ingenuity Pathway Analysis (IPA) identified multiple activated signaling networks in obesity progression from insulin-resistant and normal glucose-tolerant (IR-NGT) individuals to those with T2D. The pathways affected are: Tumor Necrosis Factor (TNF), Extracellular signal-Regulated protein Kinase 1/2 ERK1/2, Interleukin 1 A (IL1A), Protein kinase C (Pkcs), Convertase C5, Vascular endothelial growth factor (Vegf), REL-associated protein (RELA), Interleukin1/1 B (IL1/1B), Triggering receptor expressed on myeloid cells (TREM1) and Nuclear factor KB1 (NFKB1) networks, while functional annotation highlighted Liver X Receptor (LXR) activation, phagosome formation, tumor microenvironment pathway, LPS/IL-1 mediated inhibition of RXR function, TREM1 signaling and IL-6 signaling. Together, by conducting a thorough bioinformatics study of protein-coding RNAs, prospective targets could be exploited to clarify the molecular pathways underlying the development of obesity-related type 2 diabetes.

Physiological and molecular mechanisms of cold-induced improvements in glucose homeostasis in humans beyond brown adipose tissue.

Exposure to low ambient temperatures has previously been demonstrated to markedly improve glucose homeostasis in both rodents and humans. Although the brown adipose tissue is key in mediating these beneficial effects in rodents, its contribution appears more limited in humans. Hence, the exact tissues and underlying mechanisms that mediate cold-induced improvements in glucose homeostasis in humans remain to be fully established. In this review, we evaluated the response of the main organs involved in glucose metabolism (i.e. pancreas, liver, (white) adipose tissue, and skeletal muscle) to cold exposure and discuss their potential contribution to cold-induced improvements in glucose homeostasis in humans. We here show that cold exposure has widespread effects on metabolic organs involved in glucose regulation. Nevertheless, cold-induced improvements in glucose homeostasis appear primarily mediated via adaptations within the skeletal muscle and (presumably) white adipose tissue. Since the underlying mechanisms remain elusive, future studies should be aimed at pinpointing the exact physiological and molecular mechanisms involved in humans. Nonetheless, cold exposure holds great promise as a novel, additive lifestyle approach to improve glucose homeostasis in insulin resistant individuals. Parts of this graphical abstract were created using (modified) images from Servier Medical Art, licensed under the Creative Commons Attribution 3.0 Unported License. TG = thermogenesis, TAG = triacylglycerol, FFA = free fatty acid, SLN = sarcolipin, UCP3 = uncoupling protein 3, β2-AR = beta-2 adrenergic receptor, SNS = sympathetic nervous system.

Altered glucose-dependent secretion of glucagon and ACTH is associated with insulin resistance, assessed by population analysis.

This study aimed to characterize how the dysregulation of counter-regulatory hormones can contribute to insulin resistance and potentially to diabetes. Therefore, we investigated the association between insulin sensitivity and the glucose- and insulin-dependent secretion of glucagon, adrenocorticotropic hormone (ACTH), and cortisol in non-diabetic individuals using a population model analysis. Data, from hyperinsulinemic-hypoglycemic clamps, were pooled for analysis, including 52 individuals with a wide range of insulin resistance (reflected by glucose infusion rate 20-60 min; GIR20-60min). Glucagon secretion was suppressed by glucose and, to a lesser extent, insulin. The GIR20-60min and BMI were identified as predictors of the insulin effect on glucagon. At normoglycemia (5 mmol/L), a 90% suppression of glucagon was achieved at insulin concentrations of 16.3 and 43.4 µU/mL in individuals belonging to the highest and lowest quantiles of insulin sensitivity, respectively. Insulin resistance of glucagon secretion explained the elevated fasting glucagon for individuals with a low GIR20-60min. ACTH secretion was suppressed by glucose and not affected by insulin. The GIR20-60min was superior to other measures as a predictor of glucose-dependent ACTH secretion, with 90% suppression of ACTH secretion by glucose at 3.1 and 3.5 mmol/L for insulin-sensitive and insulin-resistant individuals, respectively. This difference may appear small but shifts the suppression range into normoglycemia for individuals with insulin resistance, thus, leading to earlier and greater ACTH/cortisol response when the glucose falls. Based on modeling of pooled glucose-clamp data, insulin resistance was associated with generally elevated glucagon and a potentiated cortisol-axis response to hypoglycemia, and over time both hormonal pathways may therefore contribute to dysglycemia and possibly type 2 diabetes.

Acute Effects of Insulin Infusion on Kidney Hemodynamic Function in People With Type 2 Diabetes and Normal Kidney Function

Acute Effects of Insulin Infusion on Kidney Hemodynamic Function in People With Type 2 Diabetes and Normal Kidney Function

Effects of the sodium-glucose cotransporter 2 inhibitor dapagliflozin on substrate metabolism in prediabetic insulin resistant individuals: A randomized, double-blind crossover trial

Aims/hypothesisSodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment in type 2 diabetes mellitus patients results in glucosuria, causing an energy loss, and triggers beneficial metabolic adaptations. It is so far unknown if SGLT2i exerts beneficial metabolic effects in prediabetic insulin resistant individuals, yet this is of interest since SGLT2is also reduce the risk for progression of heart failure and chronic kidney disease in patients without diabetes. MethodsFourteen prediabetic insulin resistant individuals (BMI: 30.3 ± 2.1 kg/m2; age: 66.3 ± 6.2 years) underwent 2-weeks of treatment with dapagliflozin (10 mg/day) or placebo in a randomized, placebo-controlled, cross-over design. Outcome parameters include 24-hour and nocturnal substrate oxidation, and twenty-four-hour blood substrate and insulin levels. Hepatic glycogen and lipid content/composition were measured by MRS. Muscle biopsies were taken to measure mitochondrial oxidative capacity and glycogen and lipid content. ResultsDapagliflozin treatment resulted in a urinary glucose excretion of 36 g/24-h, leading to a negative energy and fat balance. Dapagliflozin treatment resulted in a higher 24-hour and nocturnal fat oxidation (p = 0.043 and p = 0.039, respectively), and a lower 24-hour carbohydrate oxidation (p = 0.048). Twenty-four-hour plasma glucose levels were lower (AUC; p = 0.016), while 24-hour free fatty acids and nocturnal β-hydroxybutyrate levels were higher (AUC; p = 0.002 and p = 0.012, respectively) after dapagliflozin compared to placebo. Maximal mitochondrial oxidative capacity was higher after dapagliflozin treatment (dapagliflozin: 87.6 ± 5.4, placebo: 78.1 ± 5.5 pmol/mg/s, p = 0.007). Hepatic glycogen and lipid content were not significantly changed by dapagliflozin compared to placebo. However, muscle glycogen levels were numerically higher in the afternoon in individuals on placebo (morning: 332.9 ± 27.9, afternoon: 368.8 ± 13.1 nmol/mg), while numerically lower in the afternoon on dapagliflozin treatment (morning: 371.7 ± 22.8, afternoon: 340.5 ± 24.3 nmol/mg). Conclusions/interpretationDapagliflozin treatment of prediabetic insulin resistant individuals for 14 days resulted in significant metabolic adaptations in whole-body and skeletal muscle substrate metabolism despite being weight neutral. Dapagliflozin improved fat oxidation and ex vivo skeletal muscle mitochondrial oxidative capacity, mimicking the effects of calorie restriction. Trial registrationClinicalTrials.gov NCT03721874.

Machine learning-derived gut microbiome signature predicts fatty liver disease in the presence of insulin resistance

A simple predictive biomarker for fatty liver disease is required for individuals with insulin resistance. Here, we developed a supervised machine learning-based classifier for fatty liver disease using fecal 16S rDNA sequencing data. Based on the Kangbuk Samsung Hospital cohort (n = 777), we generated a random forest classifier to predict fatty liver diseases in individuals with or without insulin resistance (n = 166 and n = 611, respectively). The model performance was evaluated based on metrics, including accuracy, area under receiver operating curve (AUROC), kappa, and F1-score. The developed classifier for fatty liver diseases performed better in individuals with insulin resistance (AUROC = 0.77). We further optimized the classifiers using genetic algorithm. The improved classifier for insulin resistance, consisting of ten microbial genera, presented an advanced classification (AUROC = 0.93), whereas the improved classifier for insulin-sensitive individuals failed to distinguish participants with fatty liver diseases from the healthy. The classifier for individuals with insulin resistance was comparable or superior to previous methods predicting fatty liver diseases (accuracy = 0.83, kappa = 0.50, F1-score = 0.89), such as the fatty liver index. We identified the ten genera as a core set from the human gut microbiome, which could be a diagnostic biomarker of fatty liver diseases for insulin resistant individuals. Collectively, these findings indicate that the machine learning classifier for fatty liver diseases in the presence of insulin resistance is comparable or superior to commonly used methods.

Associations of Betatrophin/ANGPTL8 with Septic Dyslipidemia in Human Peritonitis: An Explorative Analysis.

Sepsis is defined by life-threatening organ dysfunction mediated by the host's response to infection. This can result in septic dyslipidemia, which is involved in the neutralization of pathogen-related lipids. Knowledge of the regulatory mechanisms of septic dyslipidemia is incomplete. The cytokine betatrophin/Angiopoietin-like protein 8 (ANGPTL8) plays a role in the regulation of triacylglyceride metabolism, though its function in septic dyslipidemia remains unknown. Sixty-six patients were enrolled in a cross-sectional study. Circulating concentrations and adipose tissue (AT) mRNA expression of betatrophin/ANGPTL8 were studied in patients suffering from peritoneal sepsis. Insulin-resistant individuals and subjects without metabolic derangement/systemic inflammation were enrolled as controls. All underwent open abdominal surgery. Circulating betatrophin/ANGPTL8 was analyzed by an enzyme-linked immunosorbent assay and AT mRNA expression levels were assessed by real-time PCR. Standard laboratory analyses including lipid electrophoresis were evaluated. Sepsis patients showed pronounced septic dyslipidemia (p &lt; 0.05 for all major lipid classes). Despite comparable betatrophin/ANGPTL8 mRNA expression in AT (p = 0.24), we found significantly increased circulating betatrophin/ANGPTL8 with septic dyslipidemia (p = 0.009). Expression levels of betatrophin/ANGPTL8 in AT correlated with circulating concentrations in both control groups (r = 0.61; p = 0.008 and r = 0.43; p = 0.034), while this association was undetectable in sepsis. After stratification, betatrophin/ANGPTL8 remained associated with hypertriacylglyceridemia (p &lt; 0.05).

Association of α-Dicarbonyls and Advanced Glycation End Products with Insulin Resistance in Non-Diabetic Young Subjects: A Case-Control Study.

α-Dicarbonyls and advanced glycation end products (AGEs) may contribute to the pathogenesis of insulin resistance by a variety of mechanisms. To investigate whether young insulin-resistant subjects present markers of increased dicarbonyl stress, we determined serum α-dicarbonyls-methylglyoxal, glyoxal, 3-deoxyglucosone; their derived free- and protein-bound, and urinary AGEs using the UPLC/MS-MS method; soluble receptors for AGEs (sRAGE), and cardiometabolic risk markers in 142 (49% females) insulin resistant (Quantitative Insulin Sensitivity Check Index (QUICKI) ≤ 0.319) and 167 (47% females) age-, and waist-to-height ratio-matched insulin-sensitive controls aged 16-to-22 years. The between-group comparison was performed using the two-factor (sex, presence/absence of insulin resistance) analysis of variance; multiple regression via the orthogonal projection to latent structures model. In comparison with their insulin-sensitive peers, young healthy insulin-resistant individuals without diabetes manifest alterations throughout the α-dicarbonyls-AGEs-sRAGE axis, dominated by higher 3-deoxyglucosone levels. Variables of α-dicarbonyls-AGEs-sRAGE axis were associated with insulin sensitivity independently from cardiometabolic risk markers, and sex-specifically. Cleaved RAGE associates with QUICKI only in males; while multiple α-dicarbonyls and AGEs independently associate with QUICKI particularly in females, who displayed a more advantageous cardiometabolic profile compared with males. Further studies are needed to elucidate whether interventions alleviating dicarbonyl stress ameliorate insulin resistance.