The metabolic footprint of compromised insulin sensitivity under fasting and hyperinsulinemic-euglycemic clamp conditions in an Arab population

Halama, Anna; Suleiman, Noor; Kuliński, Michał; Bettahi, Ilham; Hassoun, Shaimaa; Alkasem, Meis; Abdalhakam, Ibrahem; Iskandarani, Ahmad; Samra, Tareq A.; Atkin, Stephen L.; Suhre, Karsten; Abou‐Samra, Abdul Badi

doi:10.1038/s41598-020-73723-8

Cited by 5 publications

(7 citation statements)

References 48 publications

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“…Diabetes-specific alterations of protein and metabolite levels have previously been described in different populations [42][43][44][45] . To validate the metabolomic and proteomic data in QBB and its ability to characterize T2D participants, we investigated omics-associations with T2D.…”

Section: Resultsmentioning

confidence: 93%

Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population

Zaghlool

Halama

Stephan

et al. 2022

Preprint

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Background. Type 2 diabetes (T2D) has a heterogeneous etiology which is increasingly recognized to influence the risk of complications and choice of treatment. A data driven cluster analysis in four separate European populations of patients with type 2 diabetes identified four subtypes of severe insulin dependent (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) (Ahlqvist et al., Lancet Diabetes Endocrinology, 2018). Our aim was to extend this classification to the Arab population of Qatar and characterize the biological processes that differentiate these subtypes in relation to metabolomic and proteomic signatures. Methods. The Ahlqvist et al. subtype clustering approach was applied to 631 individuals with T2D from the Qatar Biobank (QBB) and validated in an independent set of 420 participants from the same population. The association between blood metabolites (n=1,159) and protein levels (n=1,305) with each cluster were established. Findings. The four subtypes of T2D were reproduced and validated in the population of Qatar. Cluster-specific metabolomic and proteomic associations revealed subtype-specific molecular processes. Activation of the complement system with many features of autoimmune diabetes and reduced 1,5-anhydroglucitol (1,5-AG) characterized SIDD, with evidence of impaired insulin signaling in SIRD, elevated leptin and fatty acid binding protein in MOD, whilst MARD appeared to be the healthiest subgroup. Interpretation. We have replicated the four T2D clusters in an Arab population and identified distinct metabolic and proteomic signatures, providing insights into underlying etiology with the potential to deploy subtype-specific treatment options.

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Section: Resultsmentioning

confidence: 93%

Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population

Zaghlool

Halama

Stephan

et al. 2022

Preprint

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“…The study subjects were selected from among a cohort of 60 subjects previously described [ 20 , 21 ]. The subjects were young adult, normoglycemic (normal fasting glucose and normal response to 75 g oral glucose tolerance test), healthy (no medication and no chronic diseases), and with body mass index below 28.…”

Section: Methodsmentioning

confidence: 99%

iPSCs derived from insulin resistant offspring of type 2 diabetic patients show increased oxidative stress and lactate secretion

et al. 2022

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Background The genetic factors associated with insulin resistance (IR) are not well understood. Clinical studies on first-degree relatives of type 2 diabetic (T2D) patients, which have the highest genetic predisposition to T2D, have given insights into the role of IR in T2D pathogenesis. Induced pluripotent stem cells (iPSCs) are excellent tools for disease modeling as they can retain the genetic imprint of the disease. Therefore, in this study, we aimed to investigate the genetic perturbations associated with insulin resistance (IR) in the offspring of T2D parents using patient-specific iPSCs. Methods We generated iPSCs from IR individuals (IR-iPSCs) that were offspring of T2D parents as well as from insulin-sensitive (IS-iPSCs) individuals. We then performed transcriptomics to identify key dysregulated gene networks in the IR-iPSCs in comparison to IS-iPSCs and functionally validated them. Results Transcriptomics on IR-iPSCs revealed dysregulated gene networks and biological processes indicating that they carry the genetic defects associated with IR that may lead to T2D. The IR-iPSCs had increased lactate secretion and a higher phosphorylation of AKT upon stimulation with insulin. IR-iPSCs have increased cellular oxidative stress indicated by a high production of reactive oxygen species and higher susceptibility to H2O2 -induced apoptosis. Conclusions IR-iPSCs generated from offspring of diabetic patients confirm that oxidative stress and increased lactate secretion, associated with IR, are inherited in this population, and may place them at a high risk of T2D. Overall, our IR-iPSC model can be employed for T2D modeling and drug screening studies that target genetic perturbations associated with IR in individuals with a high risk for T2D.

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“…We have recently reported that insulin sensitivity, measured by HIEC, varied widely among euglycemic young healthy men (15) and correlated with circulating metabolomic signatures (16). The goal of the present study was to evaluate the altered expression pattern of skeletal muscle proteins associated with reduced insulin sensitivity in muscle biopsies taken at the basal state and during insulin infusion, at the end of the insulin clamp, when both glycemia and glucose infusion have stabilized.…”

Section: Introductionmentioning

confidence: 93%

“…As previously reported (16), the subjects were admitted to the research study unit at 7 a.m., after 10-12 h of overnight fasting, and a baseline muscle biopsy was obtained before the clamp study. Three polyethylene catheters were inserted in the antecubital fossa and back of the hand veins, enabling insulin/ dextrose infusions, blood glucose measurements, and blood sampling.…”

Section: Hyperinsulinemic Euglycemic Clampmentioning

confidence: 99%

“…Similar to previous studies, the duration of the HIEC procedure was 120 min (17-19). Insulin sensitivity, as reflected by the wholebody glucose disposal rate (M-value, milligram of glucose infused per kilogram of body weight per minute), was computed after the stabilization of glycemia and of infusion rate during the last 60 min of the euglycemic clamp; this showed a wide variation ranging from 2 to 20 (16). Muscle biopsies were quick-frozen in liquid nitrogen.…”

Section: Hyperinsulinemic Euglycemic Clampmentioning

confidence: 99%

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Differences in protein expression, at the basal state and at 2 h of insulin infusion, in muscle biopsies from healthy Arab men with high or low insulin sensitivity measured by hyperinsulinemic euglycemic clamp

Bettahi

Krishnankutty²,

Jaganjac³

et al. 2023

Front. Endocrinol.

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BackgroundSkeletal muscle is the main site for insulin-dependent glucose disposal. The hyperinsulinemic euglycemic clamp (HIEC) is the gold standard for the assessment of insulin sensitivity (IS). We have previously shown that insulin sensitivity, measured by HIEC, varied widely among a group of 60 young healthy men with normoglycemia. The aim of this study was to correlate the proteomic profile of skeletal muscles to insulin sensitivity.MethodsMuscle biopsies from 16 subjects having the highest (M ≥ 13; n = 8, HIS) and lowest (M ¾ 6, n = 8, LIS) IS were obtained at baseline and during insulin infusion after stabilization of the blood glucose level and glucose infusion rate at the end of the HIEC. The samples were processed using a quantitative proteomic analysis approach.ResultsAt baseline, 924 proteins were identified in the HIS and LIS groups. Among the 924 proteins detected in both groups, three were suppressed and three were increased significantly in the LIS subjects compared with the HIS subjects. Following insulin infusion, 835 proteins were detected in both groups. Among the 835 proteins, two showed differential responsiveness to insulin; ATP5F1 protein was decreased, and MYLK2 was higher in the LIS group compared with that in the HIS group. Our data suggest that alteration in mitochondrial proteins and an increased number of proteins involved in fast-twitch fiber correlate to insulin sensitivity in healthy young Arab men.ConclusionsThese results suggest a change in a small number of differentially expressed proteins. A possible reason for this small change could be our study cohorts representing a homogeneous and healthy population. Additionally, we show differences in protein levels from skeletal muscle in low and high insulin sensitivity groups. Therefore, these differences may represent early events for the development of insulin resistance, pre-diabetes, and type 2 diabetes.

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The metabolic footprint of compromised insulin sensitivity under fasting and hyperinsulinemic-euglycemic clamp conditions in an Arab population

Cited by 5 publications

References 48 publications

Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population

Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population

iPSCs derived from insulin resistant offspring of type 2 diabetic patients show increased oxidative stress and lactate secretion

Differences in protein expression, at the basal state and at 2 h of insulin infusion, in muscle biopsies from healthy Arab men with high or low insulin sensitivity measured by hyperinsulinemic euglycemic clamp

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