|
1
|
Suleiman N, Alkasem M, Hassoun S, Abdalhakam I, Bettahi I, Mir F, Ramanjaneya M, Jerobin J, Iskandarani A, Samra TA, Chandra P, Skarulis M, Abou-Samra AB. Insulin sensitivity variations in apparently healthy Arab male subjects: correlation with insulin and C peptide. BMJ Open Diabetes Res Care 2021; 9:9/2/e002039. [PMID: 34785564 PMCID: PMC8596034 DOI: 10.1136/bmjdrc-2020-002039] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION Decreased insulin sensitivity occurs early in type 2 diabetes (T2D). T2D is highly prevalent in the Middle East and North Africa regions. This study assessed the variations in insulin sensitivity in normal apparently healthy subjects and the levels of adiponectin, adipsin and inflammatory markers. RESEARCH DESIGN AND METHODS A total of 60 participants (aged 18-45, body mass index <28) with a normal oral glucose tolerance test (OGTT) completed hyperinsulinemic-euglycemic clamp (40 mU/m2/min) and body composition test by dual-energy X-ray absorptiometry scan. Blood samples were assayed for glucose, insulin, C peptide, inflammatory markers, oxidative stress markers, adiponectin and adipsin. RESULTS The subjects showed wide variations in the whole-body glucose disposal rate (M value) from 2 to 20 mg/kg/min and were divided into three groups: most responsive (M>12 mg/kg/min, n=17), least responsive (M≤6 mg/kg/min, n=14) and intermediate responsive (M=6.1-12 mg/kg/min, n=29). Insulin and C peptide responses to OGTT were highest among the least insulin sensitive group. Triglycerides, cholesterol, alanine transaminase (ALT) and albumin levels were higher in the least responsive group compared with the other groups. Among the inflammatory markers, C reactive protein (CRP) was highest in the least sensitivity group compared with the other groups; however, there were no differences in the level of soluble receptor for advanced glycation end products and Tumor Necrosis Factor Receptor Superfamily 1B (TNFRS1B). Plasma levels of insulin sensitivity markers, adiponectin and adipsin, and oxidative stress markers, oxidized low-density lipoprotein, total antioxidant capacity and glutathione peroxidase 1, were similar between the groups. CONCLUSIONS A wide range in insulin sensitivity and significant differences in triglycerides, cholesterol, ALT and CRP concentrations were observed despite the fact that the study subjects were homogenous in terms of age, gender and ethnic background, and all had normal screening comprehensive chemistry and normal glucose response to OGTT. The striking differences in insulin sensitivity reflect differences in genetic predisposition and/or environmental exposure. The low insulin sensitivity status associated with increased insulin level may represent an early stage of metabolic abnormality.
Collapse
Affiliation(s)
- Noor Suleiman
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
| | - Meis Alkasem
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
| | - Shaimaa Hassoun
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
| | | | - Ilham Bettahi
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
- Interim Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Fayaz Mir
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
- Interim Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Manjunath Ramanjaneya
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
- Interim Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Jayakumar Jerobin
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
- Interim Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Ahmad Iskandarani
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
- Interim Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Tareq A Samra
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
- Interim Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Prem Chandra
- Medical Research Center, Hamad Medical Corporation, Doha, Qatar
| | - Monica Skarulis
- Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
| | | |
Collapse
|
|
2
|
O'Reilly CL, Uranga S, Fluckey JD. Culprits or consequences: Understanding the metabolic dysregulation of muscle in diabetes. World J Biol Chem 2021; 12:70-86. [PMID: 34630911 PMCID: PMC8473417 DOI: 10.4331/wjbc.v12.i5.70] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 06/21/2021] [Accepted: 08/03/2021] [Indexed: 02/06/2023] Open
Abstract
The prevalence of type 2 diabetes (T2D) continues to rise despite the amount of research dedicated to finding the culprits of this debilitating disease. Skeletal muscle is arguably the most important contributor to glucose disposal making it a clear target in insulin resistance and T2D research. Within skeletal muscle there is a clear link to metabolic dysregulation during the progression of T2D but the determination of culprits vs consequences of the disease has been elusive. Emerging evidence in skeletal muscle implicates influential cross talk between a key anabolic regulatory protein, the mammalian target of rapamycin (mTOR) and its associated complexes (mTORC1 and mTORC2), and the well-described canonical signaling for insulin-stimulated glucose uptake. This new understanding of cellular signaling crosstalk has blurred the lines of what is a culprit and what is a consequence with regard to insulin resistance. Here, we briefly review the most recent understanding of insulin signaling in skeletal muscle, and how anabolic responses favoring anabolism directly impact cellular glucose disposal. This review highlights key cross-over interactions between protein and glucose regulatory pathways and the implications this may have for the design of new therapeutic targets for the control of glucoregulatory function in skeletal muscle.
Collapse
Affiliation(s)
| | - Selina Uranga
- Health and Kinesiology, Texas A&M University, TX 77843, United States
| | - James D Fluckey
- Health and Kinesiology, Texas A&M University, TX 77843, United States
| |
Collapse
|
|
3
|
Saande CJ, Steffes MA, Webb JL, Valentine RJ, Rowling MJ, Schalinske KL. Whole Egg Consumption Impairs Insulin Sensitivity in a Rat Model of Obesity and Type 2 Diabetes. Curr Dev Nutr 2019; 3:nzz015. [PMID: 31008440 PMCID: PMC6462456 DOI: 10.1093/cdn/nzz015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 02/20/2019] [Accepted: 03/06/2019] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND The literature regarding the relation between egg consumption and type 2 diabetes (T2D) is inconsistent and there is limited evidence pertaining to the impact of egg consumption on measures of insulin sensitivity. OBJECTIVES The aim of this study was to investigate the effect of dietary whole egg on metabolic biomarkers of insulin resistance in T2D rats. METHODS Male Zucker diabetic fatty (ZDF) rats (n = 12; 6 wk of age) and age-matched lean controls (n = 12) were randomly assigned to be fed a casein- or whole egg-based diet. At week 5 of dietary treatment, an insulin tolerance test (ITT) was performed on all rats and blood glucose was measured by glucometer. After 7 wk of dietary treatment, rats were anesthetized and whole blood was collected via a tail vein bleed. Following sedation, the extensor digitorum longus muscle was removed before and after an intraperitoneal insulin injection, and insulin signaling in skeletal muscle was analyzed by Western blot. Serum glucose and insulin were analyzed by ELISA for calculation of the homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS Mean ITT blood glucose over the course of 60 min was 32% higher in ZDF rats fed the whole egg-based diet than in ZDF rats fed the casein-based diet. Furthermore, whole egg consumption increased fasting blood glucose by 35% in ZDF rats. Insulin-stimulated phosphorylation of key proteins in the insulin signaling pathway did not differ in skeletal muscle of ZDF rats fed casein- and whole egg-based diets. In lean rats, no differences were observed in insulin tolerance, HOMA-IR and skeletal muscle insulin signaling, regardless of experimental dietary treatment. CONCLUSIONS These data suggest that whole body insulin sensitivity may be impaired by whole egg consumption in T2D rats, although no changes were observed in skeletal muscle insulin signaling that could explain this finding.
Collapse
Affiliation(s)
- Cassondra J Saande
- Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011
- Interdepartmental Graduate Program in Nutritional Sciences, Iowa State University, Ames, IA 50011
| | - Megan A Steffes
- Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011
| | - Joseph L Webb
- Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011
- Interdepartmental Graduate Program in Nutritional Sciences, Iowa State University, Ames, IA 50011
| | - Rudy J Valentine
- Interdepartmental Graduate Program in Nutritional Sciences, Iowa State University, Ames, IA 50011
- Department of Kinesiology, Iowa State University, Ames, IA, 50011
| | - Matthew J Rowling
- Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011
- Interdepartmental Graduate Program in Nutritional Sciences, Iowa State University, Ames, IA 50011
| | - Kevin L Schalinske
- Department of Food Science and Human Nutrition, Iowa State University, Ames, IA 50011
- Interdepartmental Graduate Program in Nutritional Sciences, Iowa State University, Ames, IA 50011
| |
Collapse
|
|
4
|
Fazakerley DJ, Krycer JR, Kearney AL, Hocking SL, James DE. Muscle and adipose tissue insulin resistance: malady without mechanism? J Lipid Res 2018; 60:1720-1732. [PMID: 30054342 DOI: 10.1194/jlr.r087510] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 07/25/2018] [Indexed: 12/14/2022] Open
Abstract
Insulin resistance is a major risk factor for numerous diseases, including type 2 diabetes and cardiovascular disease. These disorders have dramatically increased in incidence with modern life, suggesting that excess nutrients and obesity are major causes of "common" insulin resistance. Despite considerable effort, the mechanisms that contribute to common insulin resistance are not resolved. There is universal agreement that extracellular perturbations, such as nutrient excess, hyperinsulinemia, glucocorticoids, or inflammation, trigger intracellular stress in key metabolic target tissues, such as muscle and adipose tissue, and this impairs the ability of insulin to initiate its normal metabolic actions in these cells. Here, we present evidence that the impairment in insulin action is independent of proximal elements of the insulin signaling pathway and is likely specific to the glucoregulatory branch of insulin signaling. We propose that many intracellular stress pathways act in concert to increase mitochondrial reactive oxygen species to trigger insulin resistance. We speculate that this may be a physiological pathway to conserve glucose during specific states, such as fasting, and that, in the presence of chronic nutrient excess, this pathway ultimately leads to disease. This review highlights key points in this pathway that require further research effort.
Collapse
Affiliation(s)
- Daniel J Fazakerley
- School of Life and Environmental Sciences, Central Clinical School, University of Sydney, Camperdown, New South Wales, Australia
| | - James R Krycer
- School of Life and Environmental Sciences, Central Clinical School, University of Sydney, Camperdown, New South Wales, Australia
| | - Alison L Kearney
- School of Life and Environmental Sciences, Central Clinical School, University of Sydney, Camperdown, New South Wales, Australia
| | - Samantha L Hocking
- Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
| | - David E James
- School of Life and Environmental Sciences, Central Clinical School, University of Sydney, Camperdown, New South Wales, Australia .,Faculty of Medicine and Health, Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia
| |
Collapse
|
|
5
|
Ma GS, Lopez-Sanchez I, Aznar N, Kalogriopoulos N, Pedram S, Midde K, Ciaraldi TP, Henry RR, Ghosh P. Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity. Mol Biol Cell 2015; 26:4209-23. [PMID: 26378251 PMCID: PMC4642855 DOI: 10.1091/mbc.e15-08-0553] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 09/11/2015] [Indexed: 11/11/2022] Open
Abstract
A long-held tenet in the field of diabetes is that the tipping point between insulin sensitivity and resistance resides at the level of insulin receptor/insulin receptor substrate–adaptor complexes. Here it is shown that activation of Gαi by GIV/Girdin is a decisive event within the metabolic insulin signaling cascade that reversibly orchestrates insulin sensitivity or resistance. Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles.
Collapse
Affiliation(s)
- Gary S Ma
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093
| | - Inmaculada Lopez-Sanchez
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093
| | - Nicolas Aznar
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093
| | - Nicholas Kalogriopoulos
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093
| | - Shabnam Pedram
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093
| | - Krishna Midde
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093
| | - Theodore P Ciaraldi
- Department of Veterans Affairs, VA San Diego Healthcare System, San Diego, CA 92161
| | - Robert R Henry
- Department of Veterans Affairs, VA San Diego Healthcare System, San Diego, CA 92161
| | - Pradipta Ghosh
- Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093 Department of Veterans Affairs, VA San Diego Healthcare System, San Diego, CA 92161 Department of Cell and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093
| |
Collapse
|
|
6
|
Abstract
The phenotype of many regulatory circuits in which mutations can cause complex, polygenic diseases is to some extent robust to DNA mutations that affect circuit components. Here I demonstrate how such mutational robustness can prevent the discovery of genetic disease determinants. To make my case, I use a mathematical model of the insulin signaling pathway implicated in type 2 diabetes, whose signaling output is governed by 15 genetically determined parameters. Using multiple complementary measures of a parameter's importance for this phenotype, I show that any one disease determinant that is crucial in one genetic background will be virtually irrelevant in other backgrounds. In an evolving population that drifts through the parameter space of this or other robust circuits through DNA mutations, the genetic changes that can cause disease will vary randomly over time. I call this phenomenon causal drift. It means that mutations causing disease in one (human or non-human) population may have no effect in another population, and vice versa. Causal drift casts doubt on our ability to infer the molecular mechanisms of complex diseases from non-human model organisms.
Collapse
Affiliation(s)
- Andreas Wagner
- University of Zurich, Institute for Evolutionary Biology and Environmental Studies, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
- The Swiss Institute of Bioinformatics, Lausanne, Switzerland
- The Santa Fe Institute, Santa Fe, New Mexico
- * E-mail:
| |
Collapse
|
|
7
|
Ramalingam L, Oh E, Thurmond DC. Novel roles for insulin receptor (IR) in adipocytes and skeletal muscle cells via new and unexpected substrates. Cell Mol Life Sci 2013; 70:2815-34. [PMID: 23052216 PMCID: PMC3556358 DOI: 10.1007/s00018-012-1176-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Revised: 08/21/2012] [Accepted: 09/18/2012] [Indexed: 01/30/2023]
Abstract
The insulin signaling pathway regulates whole-body glucose homeostasis by transducing extracellular signals from the insulin receptor (IR) to downstream intracellular targets, thus coordinating a multitude of biological functions. Dysregulation of IR or its signal transduction is associated with insulin resistance, which may culminate in type 2 diabetes. Following initial stimulation of IR, insulin signaling diverges into different pathways, activating multiple substrates that have roles in various metabolic and cellular processes. The integration of multiple pathways arising from IR activation continues to expand as new IR substrates are identified and characterized. Accordingly, our review will focus on roles for IR substrates as they pertain to three primary areas: metabolism/glucose uptake, mitogenesis/growth, and aging/longevity. While IR functions in a seemingly pleiotropic manner in many cell types, through these three main roles in fat and skeletal muscle cells, IR multi-tasks to regulate whole-body glucose homeostasis to impact healthspan and lifespan.
Collapse
Affiliation(s)
- Latha Ramalingam
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN USA
| | - Eunjin Oh
- Department of Pediatrics, Herman B Wells Center, Indiana University School of Medicine, Indianapolis, IN USA
| | - Debbie C. Thurmond
- Departments of Pediatrics, Biochemistry and Molecular Biology, and Cellular and Integrative Physiology, Herman B Wells Center, Indiana University School of Medicine, 635 Barnhill Drive MS 2031, Indianapolis, IN 46202 USA
| |
Collapse
|
|
8
|
Antidiabetic Activity of Polysaccharides from Tuberous Root of Liriope spicata var. prolifera in KKAy Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2013; 2013:349790. [PMID: 23762123 PMCID: PMC3677662 DOI: 10.1155/2013/349790] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Revised: 03/13/2013] [Accepted: 04/18/2013] [Indexed: 11/18/2022]
Abstract
Tuberous root of Liriope spicata var. prolifera has been widely used as a traditional Chinese medicine for the treatment of diabetes. The present study investigated the antidiabetic effect and the potential mechanisms of two new polysaccharides (LSP1, LSP2) and the total polysaccharides (TLSP), isolated from the tuberous roots. Upon the intragastric administration in obese insulin-resistant diabetic KKAy mice for 28 days, TLSP, LSP1, and LSP2 all caused a remarkable decrease of fasting blood glucose and significant improvement of insulin resistance and serum lipid metabolism in diabetic mice. In addition, liver histological analysis showed that TLSP, LSP1, and LSP2 significantly ameliorated the hepatocyte hypertrophy and decreased the lipid accumulation in the mice liver. Further experiments suggested that TLSP, LSP1, and LSP2 effectively inhibited hepatic gluconeogenesis and increased hepatic glycolysis and hepatic glycogen content. Furthermore, the mechanistic analysis showed the increased expression of insulin-receptor α subunit, insulin-receptor substrate-1, phosphatidylinositol 3-kinase, and peroxisome proliferators-activated receptors γ. These results suggested that TLSP, LSP1, and LSP2 manifest strong antidiabetic activity, therefore hold a great promise for therapeutic application in diabetic therapy and other related metabolic disorders.
Collapse
|
|
9
|
Andreozzi F, Procopio C, Greco A, Mannino GC, Miele C, Raciti GA, Iadicicco C, Beguinot F, Pontiroli AE, Hribal ML, Folli F, Sesti G. Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance. Diabetologia 2011; 54:1879-87. [PMID: 21461637 DOI: 10.1007/s00125-011-2116-6] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2010] [Accepted: 02/17/2011] [Indexed: 10/18/2022]
Abstract
AIMS/HYPOTHESIS We determined the contribution to insulin resistance of the PH domain leucine-rich repeat protein phosphatase (PHLPP), which dephosphorylates Akt at Ser473, inhibiting its activity. We measured the abundance of PHLPP in fat and skeletal muscle from obese participants. To study the effect of PHLPP on insulin signalling, PHLPP (also known as PHLPP1) was overexpressed in HepG2 and L6 cells. METHODS Subcutaneous fat samples were obtained from 82 morbidly obese and ten non-obese participants. Skeletal muscle samples were obtained from 12 obese and eight non-obese participants. Quantification of PHLPP-1 in human tissues was performed by immunoblotting. The functional consequences of recombinant PHLPP1 overexpression in hepatoma HepG2 cells and L6 myoblasts were investigated. RESULTS Of the 82 obese participants, 31 had normal fasting glucose, 33 impaired fasting glucose and 18 type 2 diabetes. PHLPP-1 abundance was twofold higher in the three obese groups than in non-obese participants (p = 0.004). No differences were observed between obese participants with normal fasting glucose, impaired fasting glucose or type 2 diabetes. PHLPP-1 abundance was correlated with basal Akt Ser473 phosphorylation (r = -0.48; p = 0.001), BMI (r = 0.44; p < 0.0001), insulin (r = 0.35; p < 0.0001) and HOMA (r = 0.38; p < 0.0001). PHLPP-1 abundance was twofold higher in the skeletal muscle of 12 obese participants than in that of eight non-obese participants (p < 0.0001). Insulin treatment of HepG2 cells resulted in a dose- and time-dependent upregulation of PHLPP-1. Overexpression of PHLPP1 in HepG2 cells and L6 myoblasts resulted in impaired insulin signalling involving Akt/glycogen synthase kinase 3, glycogen synthesis and glucose transport. CONCLUSIONS/INTERPRETATION Increased abundance of PHLPP-1, production of which is regulated by insulin, may represent a new molecular defect in insulin-resistant states such as obesity.
Collapse
Affiliation(s)
- F Andreozzi
- Department of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, Viale Europa, 88100 Catanzaro, Italy
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Pathogenesis of insulin resistance in skeletal muscle. J Biomed Biotechnol 2010; 2010:476279. [PMID: 20445742 PMCID: PMC2860140 DOI: 10.1155/2010/476279] [Citation(s) in RCA: 395] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2009] [Accepted: 01/20/2010] [Indexed: 12/16/2022] Open
Abstract
Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Recent studies have reported a mitochondrial defect in oxidative phosphorylation in skeletal muscle in variety of insulin resistant states. In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle.
Collapse
|
|
11
|
Thompson LH, Kim HT, Ma Y, Kokorina NA, Messina JL. Acute, muscle-type specific insulin resistance following injury. Mol Med 2008; 14:715-23. [PMID: 19009015 DOI: 10.2119/2008-00081.thompson] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2008] [Accepted: 09/19/2008] [Indexed: 01/04/2023] Open
Abstract
Acute insulin resistance can develop following critical illness and severe injury, and the mortality of critically ill patients can be reduced by intensive insulin therapy. Thus, compensating for the insulin resistance in the clinical care setting is important. However, the molecular mechanisms that lead to the development of acute injury/infection-associated insulin resistance are unknown, and the development of acute insulin resistance is much less studied than chronic disease-associated insulin resistance. An animal model of injury and blood loss was utilized to determine whether acute skeletal muscle insulin resistance develops following injury, and surgical trauma in the absence of hemorrhage had little effect on insulin-mediated signaling. However, following hemorrhage, there was an almost complete loss of insulin-induced Akt phosphorylation in triceps, and severely decreased tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1. The severity of insulin resistance was similar in triceps and extensor digitorum longus muscles, but was more modest in diaphragm, and there was little change in insulin signaling in cardiac muscle following hemorrhage. Since skeletal muscle is an important insulin target tissue and accounts for much of insulin-induced glucose disposal, it is important to determine its role in injury/infection-induced hyperglycemia. This is the first report of an acute development of skeletal muscle insulin signaling defects. The presented data indicates that the defects in insulin signaling occurred rapidly, were reversible and more severe in some skeletal muscles, and did not occur in cardiac muscle.
Collapse
Affiliation(s)
- LaWanda H Thompson
- Department of Pathology, Division of Molecular and Cellular Pathology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA
| | | | | | | | | |
Collapse
|
|
12
|
Tjønna AE, Lee SJ, Rognmo Ø, Stølen T, Bye A, Haram PM, Loennechen JP, Al-Share QY, Skogvoll E, Slørdahl SA, Kemi OJ, Najjar SM, Wisløff U. Aerobic interval training versus continuous moderate exercise as a treatment for the metabolic syndrome: a pilot study. Circulation 2008; 118:346-54. [PMID: 18606913 PMCID: PMC2777731 DOI: 10.1161/circulationaha.108.772822] [Citation(s) in RCA: 777] [Impact Index Per Article: 45.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Individuals with the metabolic syndrome are 3 times more likely to die of heart disease than healthy counterparts. Exercise training reduces several of the symptoms of the syndrome, but the exercise intensity that yields the maximal beneficial adaptations is in dispute. We compared moderate and high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with the metabolic syndrome. METHODS AND RESULTS Thirty-two metabolic syndrome patients (age, 52.3+/-3.7 years; maximal oxygen uptake [o(2)max], 34 mL x kg(-1) x min(-1)) were randomized to equal volumes of either moderate continuous moderate exercise (CME; 70% of highest measured heart rate [Hfmax]) or aerobic interval training (AIT; 90% of Hfmax) 3 times a week for 16 weeks or to a control group. o(2)max increased more after AIT than CME (35% versus 16%; P<0.01) and was associated with removal of more risk factors that constitute the metabolic syndrome (number of factors: AIT, 5.9 before versus 4.0 after; P<0.01; CME, 5.7 before versus 5.0 after; group difference, P<0.05). AIT was superior to CME in enhancing endothelial function (9% versus 5%; P<0.001), insulin signaling in fat and skeletal muscle, skeletal muscle biogenesis, and excitation-contraction coupling and in reducing blood glucose and lipogenesis in adipose tissue. The 2 exercise programs were equally effective at lowering mean arterial blood pressure and reducing body weight (-2.3 and -3.6 kg in AIT and CME, respectively) and fat. CONCLUSIONS Exercise intensity was an important factor for improving aerobic capacity and reversing the risk factors of the metabolic syndrome. These findings may have important implications for exercise training in rehabilitation programs and future studies.
Collapse
Affiliation(s)
- Arnt Erik Tjønna
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Sang Jun Lee
- Department of Physiology and Pharmacology, the University of Toledo College of Medicine, OH, USA
| | - Øivind Rognmo
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Tomas Stølen
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Anja Bye
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Per Magnus Haram
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
| | - Jan Pål Loennechen
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Cardiology, St. Olav's Hospital, Trondheim, Norway, N-7006 Trondheim, Norway
| | - Qusay Y. Al-Share
- Department of Physiology and Pharmacology, the University of Toledo College of Medicine, OH, USA
| | - Eirik Skogvoll
- Unit for Applied Clinical Research, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Anaesthesia and Emergency Medicine, St. Olav's University Hospital, Trondheim, Norway
| | - Stig A. Slørdahl
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Cardiology, St. Olav's Hospital, Trondheim, Norway, N-7006 Trondheim, Norway
| | - Ole J. Kemi
- Institute of Biomedical and life Sciences, University of Glasgow, UK
| | - Sonia M. Najjar
- Department of Physiology and Pharmacology, the University of Toledo College of Medicine, OH, USA
| | - Ulrik Wisløff
- Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Cardiology, St. Olav's Hospital, Trondheim, Norway, N-7006 Trondheim, Norway
| |
Collapse
|
|
13
|
Goldfine ID, Maddux BA, Youngren JF, Reaven G, Accili D, Trischitta V, Vigneri R, Frittitta L. The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities. Endocr Rev 2008; 29:62-75. [PMID: 18199690 PMCID: PMC2244935 DOI: 10.1210/er.2007-0004] [Citation(s) in RCA: 100] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Insulin resistance is a major feature of most patients with type 2 diabetes mellitus (T2D). A number of laboratories have observed that PC-1 (membrane [corrected] glycoprotein plasma cell antigen 1; also termed [corrected] ectonucleotide pyrophosphatase phosphodiesterase 1 or ENPP1) [corrected] is either overexpressed or overactive in muscle, adipose tissue, fibroblasts, and other tissues of insulin-resistant individuals, both nondiabetic and diabetic. Moreover, PC-1 (ENPP1) overexpression [corrected] in cultured cells in vitro and in transgenic mice in vivo, [corrected] impairs insulin stimulation of insulin receptor (IR) activation and downstream signaling. PC-1 binds to the connecting domain of the IR alpha-subunit that is located in residues 485-599. The connecting domain transmits insulin binding in the alpha-subunit to activation of tyrosine kinase activation in the beta-subunit. When PC-1 is overexpressed, it inhibits insulin [corrected]induced IR beta-subunit tyrosine kinase activity. In addition, a polymorphism of PC-1 (K121Q) in various ethnic populations is closely associated with insulin resistance, T2D, and cardio [corrected] and nephrovascular diseases. The product of this polymorphism has a 2- to 3-fold increased binding affinity for the IR and is more potent than the wild-type PC-1 protein (K121K) in inhibiting the IR. These data suggest therefore that PC-1 is a candidate protein that may play a role in human insulin resistance and T2D by its overexpression, its overactivity, or both.
Collapse
Affiliation(s)
- Ira D Goldfine
- Department of Medicine and Diabetes Center, University of California San Francisco, San Francisco, California 94143, USA.
| | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Affiliation(s)
- Ying Leng
- Department of Surgical Sciences, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden
| | | | | |
Collapse
|
|
15
|
Abstract
Insulin is a key hormone regulating the control of metabolism and the maintenance of normoglycaemia and normolipidaemia. Insulin acts by binding to its cell surface receptor, thus activating the receptor's intrinsic tyrosine kinase activity, resulting in receptor autophosphorylation and phosphorylation of several substrates. Tyrosine phosphorylated residues on the receptor itself and on subsequently bound receptor substrates provide docking sites for downstream signalling molecules, including adapters, protein serine/threonine kinases, phosphoinositide kinases and exchange factors. Collectively, those molecules orchestrate the numerous insulin-mediated physiological responses. A clear picture is emerging of the way in which insulin elicits several intracellular signalling pathways to mediate its physiologic functions. A further challenge, being pursued by several laboratories, is to understand the molecular mechanisms that underlie insulin action at the peripheral level, deregulation of which ultimately leads to hyperglycaemia and Type 2 diabetes. We review how circulating factors such as insulin itself, TNF-alpha, interleukins, fatty acids and glycation products influence insulin action through insulin signalling molecules themselves or through other pathways ultimately impinging on the insulin-signalling pathway. Understanding how the mechanism by which molecular insulin action is modulated by these factors will potentially provide new targets for pharmacological agents, to enable the control of altered glucose and lipid metabolism and diabetes.
Collapse
Affiliation(s)
- L Pirola
- INSERM Unit 145, Faculty of Medicine, Nice, France
| | | | | |
Collapse
|
|
16
|
Koistinen HA, Chibalin AV, Zierath JR. Aberrant p38 mitogen-activated protein kinase signalling in skeletal muscle from Type 2 diabetic patients. Diabetologia 2003; 46:1324-8. [PMID: 12937895 DOI: 10.1007/s00125-003-1196-3] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2003] [Revised: 06/25/2003] [Indexed: 01/16/2023]
Abstract
AIMS/HYPOTHESIS p38 mitogen activated protein kinase (MAPK) is generally thought to facilitate signal transduction to genomic, rather than metabolic responses. However, recent evidence implicates a role for p38 MAPK in the regulation of glucose transport; a site of insulin resistance in Type 2 diabetes. Thus we determined p38 MAPK protein expression and phosphorylation in skeletal muscle from Type 2 diabetic patients and non-diabetic subjects. METHODS In vitro effects of insulin (120 nmol/l) or AICAR (1 mmol/l) on p38 MAPK expression and phosphorylation were determined in skeletal muscle from non-diabetic (n=6) and Type 2 diabetic (n=9) subjects. RESULTS p38 MAPK protein expression was similar between Type 2 diabetic patients and non-diabetic subjects. Insulin exposure increased p38 MAPK phosphorylation in non-diabetic, but not in Type 2 diabetic patients. In contrast, basal phosphorylation of p38 MAPK was increased in skeletal muscle from Type 2 diabetic patients. CONCLUSION/INTERPRETATION Insulin increases p38 MAPK phosphorylation in skeletal muscle from non-diabetic subjects, but not in Type 2 diabetic patients. However, basal p38 MAPK phosphorylation is increased in skeletal muscle from Type 2 diabetic patients. Thus, aberrant p38 MAPK signalling might contribute to the pathogenesis of insulin resistance.
Collapse
Affiliation(s)
- H A Koistinen
- Department of Surgical Sciences, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden
| | | | | |
Collapse
|
|
17
|
Bouzakri K, Roques M, Gual P, Espinosa S, Guebre-Egziabher F, Riou JP, Laville M, Le Marchand-Brustel Y, Tanti JF, Vidal H. Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes 2003; 52:1319-25. [PMID: 12765939 DOI: 10.2337/diabetes.52.6.1319] [Citation(s) in RCA: 224] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
To understand better the defects in the proximal steps of insulin signaling during type 2 diabetes, we used differentiated human skeletal muscle cells in primary culture. When compared with cells from control subjects, myotubes established from patients with type 2 diabetes presented the same defects as those previously evidenced in vivo in muscle biopsies, including defective stimulation of phosphatidylinositol (PI) 3-kinase activity, decreased association of PI 3-kinase with insulin receptor substrate (IRS)-1 and reduced IRS-1 tyrosine phosphorylation during insulin stimulation. In contrast to IRS-1, the signaling through IRS-2 was not altered. Investigating the causes of the reduced tyrosine phosphorylation of IRS-1, we found a more than twofold increase in the basal phosphorylation of IRS-1 on serine 636 in myotubes from patients with diabetes. Concomitantly, there was a higher basal mitogen-activated protein kinase (MAPK) activity in these cells, and inhibition of the MAPKs with PD98059 strongly reduced the level of serine 636 phosphorylation. These results suggest that IRS-1 phosphorylation on serine 636 might be involved in the reduced phosphorylation of IRS-1 on tyrosine and in the subsequent alteration of insulin-induced PI 3-kinase activation. Moreover, increased MAPK activity seems to play a role in the phosphorylation of IRS-1 on serine residue in human muscle cells.
Collapse
Affiliation(s)
- Karim Bouzakri
- INSERM U449 and CRNHL, IFR 62, R. Laennec Medical Faculty, F-69370 Lyon Cedex 08, France
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Huang C, Somwar R, Patel N, Niu W, Török D, Klip A. Sustained exposure of L6 myotubes to high glucose and insulin decreases insulin-stimulated GLUT4 translocation but upregulates GLUT4 activity. Diabetes 2002; 51:2090-8. [PMID: 12086937 DOI: 10.2337/diabetes.51.7.2090] [Citation(s) in RCA: 116] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Hyperglycemia and hyperinsulinemia are cardinal features of acquired insulin resistance. In adipose cell cultures, high glucose and insulin cause insulin resistance of glucose uptake, but because of altered GLUT4 expression and contribution of GLUT1 to glucose uptake, the basis of insulin resistance could not be ascertained. Here we show that GLUT4 determines glucose uptake in L6 myotubes stably overexpressing myc-tagged GLUT4. Preincubation for 24 h with high glucose and insulin (high Glc/Ins) reduced insulin-stimulated GLUT4 translocation by 50%, without affecting GLUT4 expression. Insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation, phosphatidylinositol 3-kinase activation, and Akt phosphorylation also diminished, as did insulin-mediated glucose uptake. However, basal glucose uptake rose by 40% without any gain in surface GLUT4. High Glc/Ins elevated basal p38 mitogen-activated protein kinase (MAPK) phosphorylation and activity, and a short inhibition of p38 MAPK with SB202190 corrected the rise in basal glucose uptake, suggesting that p38 MAPK activity contributes to this rise. We propose that in a cellular model of skeletal muscle, chronic exposure to high Glc/Ins reduced the acute, insulin-elicited GLUT4 translocation. In addition, basal state GLUT4 activity was augmented to partially compensate for the translocation defect, resulting in a more robust glucose uptake than what would be predicted from the amount of cell surface GLUT4 alone.
Collapse
Affiliation(s)
- Carol Huang
- Programme in Cell Biology, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8
| | | | | | | | | | | |
Collapse
|
|
19
|
Stefan N, Vozarova B, Funahashi T, Matsuzawa Y, Weyer C, Lindsay RS, Youngren JF, Havel PJ, Pratley RE, Bogardus C, Tataranni PA. Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes 2002; 51:1884-8. [PMID: 12031977 DOI: 10.2337/diabetes.51.6.1884] [Citation(s) in RCA: 414] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Adiponectin, the most abundant adipose-specific protein, has been found to be negatively associated with degree of adiposity and positively associated with insulin sensitivity in Pima Indians and other populations. Moreover, adiponectin administration to rodents has been shown to increase insulin-induced tyrosine phosphorylation of the insulin receptor (IR) and also increase whole-body insulin sensitivity. To further characterize the relationship between plasma adiponectin concentration and insulin sensitivity in humans, we examined 1) the cross-sectional association between plasma adiponectin concentration and skeletal muscle IR tyrosine phosphorylation and 2) the prospective effect of plasma adiponectin concentration at baseline on change in insulin sensitivity. Fasting plasma adiponectin concentration, body composition (hydrodensitometry or dual energy X-ray absorptiometry), insulin sensitivity (insulin-stimulated glucose disposal, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) were measured in 55 Pima Indians (47 men and 8 women, aged 31 +/- 8 years, body fat 29 +/- 8% [mean +/- SD]; 50 with normal glucose tolerance, 3 with impaired glucose tolerance, and 2 with diabetes). Group 1 (19 subjects) underwent skeletal muscle biopsies for the measurement of basal and insulin-stimulated tyrosine phosphorylation of the IR (stimulated by 100 nmol/l insulin). The fold increase after insulin stimulation was calculated as the ratio between maximal and basal phosphorylation. Group 2 (38 subjects) had follow-up measurements of insulin-stimulated glucose disposal. Cross-sectionally, plasma adiponectin concentration was positively associated with insulin-stimulated glucose disposal (r = 0.58, P < 0.0001) and negatively associated with percent body fat (r = -0.62, P < 0.0001) in the whole group. In group 1 plasma adiponectin was negatively associated with the basal (r = -0.65, P = 0.003) and positively associated with the fold increase in IR tyrosine phosphorylation (r = 0.69, P = 0.001) before and after the adjustment for percent body fat (r = -0.58, P = 0.01 and r = 0.54, P = 0.02, respectively). Longitudinally, after adjustment for age, sex, and percent body fat, low plasma adiponectin concentration at baseline was associated with a decrease in insulin sensitivity (P = 0.04). In conclusion, our cross-sectional data suggest a role of physiological concentration of fasting plasma adiponectin in the regulation of skeletal muscle IR tyrosine phosphorylation. Prospectively, low plasma adiponectin concentration at baseline precedes a decrease in insulin sensitivity. Our data indicate that adiponectin plays an important role in regulation of insulin sensitivity in humans.
Collapse
Affiliation(s)
- Norbert Stefan
- Clinical Diabetes and Nutrition Section, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Vollenweider P, Ménard B, Nicod P. Insulin resistance, defective insulin receptor substrate 2-associated phosphatidylinositol-3' kinase activation, and impaired atypical protein kinase C (zeta/lambda) activation in myotubes from obese patients with impaired glucose tolerance. Diabetes 2002; 51:1052-9. [PMID: 11916925 DOI: 10.2337/diabetes.51.4.1052] [Citation(s) in RCA: 92] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Impaired glucose tolerance (IGT) is characterized by insulin resistance. Recently, defects in the insulin-signaling cascade have been implicated in the pathogenesis of insulin resistance. To study insulin signaling in IGT, we used human skeletal muscle cells in primary culture from patients with IGT and control subjects. In these cultured myotubes, we assessed insulin-induced 2-deoxyglucose uptake and early steps of the metabolic insulin-signaling cascade. Myotubes in culture from patients with IGT had insulin-induced glucose uptake that was roughly 30-50% less than that from control subjects. This insulin resistance was associated with impaired insulin receptor substrate (IRS)-2-associated phosphatidylinositol 3' (PI3) kinase activation and IRS-2 tyrosine phosphorylation as well as significantly decreased protein kinase C (PKC)-zeta/lambda activation in response to insulin. IRS-1- associated PI3 kinase activation and insulin receptor autophosphorylation were comparable in the two groups. Protein expression levels for the insulin receptor, IRS-1, IRS-2, the p85 regulatory subunit of PI3 kinase, Akt, PKC-zeta/lambda, GLUT1, and GLUT4 were also similar in the two groups. In conclusion, myotubes from patients with IGT have impaired insulin-induced glucose uptake. This is associated with impaired IRS-2-associated PI3 kinase activation and PKC-zeta/lambda activation. Our results suggest that these defects may contribute to insulin resistance in IGT patients.
Collapse
Affiliation(s)
- Peter Vollenweider
- Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
| | | | | |
Collapse
|
|
21
|
Storgaard H, Song XM, Jensen CB, Madsbad S, Björnholm M, Vaag A, Zierath JR. Insulin signal transduction in skeletal muscle from glucose-intolerant relatives of type 2 diabetic patients [corrected]. Diabetes 2001; 50:2770-8. [PMID: 11723060 DOI: 10.2337/diabetes.50.12.2770] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
To determine whether defects in the insulin signal transduction cascade are present in skeletal muscle from prediabetic individuals, we excised biopsies from eight glucose-intolerant male first-degree relatives of patients with type 2 diabetes (IGT relatives) and nine matched control subjects before and during a euglycemic-hyperinsulinemic clamp. IGT relatives were insulin-resistant in oxidative and nonoxidative pathways for glucose metabolism. In vivo insulin infusion increased skeletal muscle insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation (P = 0.01) and phosphatidylinositide 3-kinase (PI 3-kinase) activity (phosphotyrosine and IRS-1 associated) in control subjects (P < 0.02) but not in IGT relatives (NS). The incremental increase in insulin action on IRS-1 tyrosine phosphorylation was lower in IGT relatives versus control subjects (P < 0.05). The incremental defects in signal transduction noted for IRS-1 and PI 3-kinase may be attributed to elevated basal phosphorylation/activity of these parameters, because absolute phosphorylation/activity under insulin-stimulated conditions was similar between IGT relatives and control subjects. Insulin increased Akt serine phosphorylation in control subjects and IGT relatives, with a tendency for reduced phosphorylation in IGT relatives (P = 0.12). In conclusion, aberrant phosphorylation/activity of IRS-1, PI 3-kinase, and Akt is observed in skeletal muscle from relatives of patients with type 2 diabetes with IGT. However, the elevated basal activity of these signaling intermediates and the lack of a strong correlation between these parameters to glucose metabolism suggests that other defects of insulin signal transduction and/or downstream components of glucose metabolism may play a greater role in the development of insulin resistance in skeletal muscle from relatives of patients with type 2 diabetes.
Collapse
Affiliation(s)
- H Storgaard
- Department of Endocrinology, Hvidovre Hospital and Clinical Trial Unit, University of Copenhagen, Copenhagen, Denmark
| | | | | | | | | | | | | |
Collapse
|
|
22
|
Mari A, Pacini G, Murphy E, Ludvik B, Nolan JJ. A model-based method for assessing insulin sensitivity from the oral glucose tolerance test. Diabetes Care 2001; 24:539-48. [PMID: 11289482 DOI: 10.2337/diacare.24.3.539] [Citation(s) in RCA: 599] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Available insulin sensitivity (IS) methods based on the oral glucose tolerance test (OGTT) are empirical. We used a glucose-insulin model to derive an OGTT-based IS (oral glucose insulin sensitivity [OGIS]) index, which predicts glucose clearance in a glucose clamp. We validated OGIS against clamp data. RESEARCH DESIGN AND METHODS OGIS requires glucose and insulin concentrations from a 75-g OGTT at 0, 2, and 3 h (3-h OGTT) or at 0, 1.5, and 2 h (2-h OGTT). The formula includes six constants optimized to match the clamp results. For this purpose, 15 lean nondiabetic subjects (BMI < 25 kg/m2), 38 obese nondiabetic subjects (BMI > 25 kg/m2), and 38 subjects with type 2 diabetes randomly underwent an OGTT and a 120 mU x min(-1) x m(-2) insulin infusion euglycemic clamp. Glucose clearance (Cl CLAMP), calculated as the ratio of glucose infusion to concentration during the last hour of the clamp, was compared with OGIS. OGIS was also tested on an independent group of 13 subjects with impaired glucose tolerance (IGT). RESULTS OGIS and Cl CLAMP were correlated in the whole group (R = 0.77, P < 0.0001), in the subgroups (lean: R = 0.59; obese: R = 0.73; type 2 diabetes: R = 0.49; P < 0.02), and in the independent IGT group (R = 0.65, P < 0.02). Reproducibility of OGIS and Cl CLAMP were similar (coefficients of variation: OGIS 7.1%, Cl CLAMP 6.4%). OGIS was as effective as Cl CLAMP in discriminating between groups (for OGIS, lean vs. obese: 440 +/- 16 vs. 362 +/- 11 ml x min(-1) x m(-2), p < 0.001; lean vs. type 2 diabetes: 440 +/- 16 vs. 239 +/- 7, P < 0.0001; obese vs. type 2 diabetes: 362 +/- 11 vs. 239 +/- 7, P < 0.0001; results were similar for Cl CLAMP). The relationships between IS and BMI, fasting plasma insulin, and insulin secretion (calculated from the OGTT insulin concentration) were examined. OGIS yielded results similar to Cl CLAMP and fully consistent with established physiological principles. The performance of the index for the 3-h and 2-h OGTT was similar. CONCLUSIONS OGIS is an index of IS in good agreement with the clamp. Because of its simplicity (only three blood samples required), this method has potential use for clinical investigation including large-scale epidemiological studies.
Collapse
Affiliation(s)
- A Mari
- Institute of Systems Science and Biomedical Engineering, National Research Council, Padova, Italy.
| | | | | | | | | |
Collapse
|
|
23
|
Zhou Q, Dolan PL, Dohm GL. Dephosphorylation increases insulin-stimulated receptor kinase activity in skeletal muscle of obese Zucker rats. Mol Cell Biochem 1999; 194:209-16. [PMID: 10391142 DOI: 10.1023/a:1006942831223] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Serine/threonine phosphorylation of insulin receptor has been implicated in the development of insulin resistance. To investigate whether dephosphorylation of serine/threonine residues of the insulin receptor may restore the decreased insulin-stimulated receptor tyrosine kinase activity in skeletal muscle of obese Zucker rats, insulin receptor tyrosine kinase activity was measured before and after alkaline phosphatase treatment. Compared to lean controls, insulin-stimulated glucose transport was depressed by 61% (p < 0.05) in obese Zucker rats. The insulin receptor and insulin receptor substrate-1 contents were decreased by 14% (p < 0.05) and 16% (p < 0.05), respectively, in skeletal muscle of obese Zucker rats. In vivo insulin-induced tyrosine phosphorylation of insulin receptor and insulin receptor substrate-1 was depressed by 82% (p < 0.05) and 86% (p < 0.05), respectively. In the meantime, in vitro insulin-stimulated receptor tyrosine kinase activity in obese rats was decreased by 39% (p < 0.05). Dephosphorylation of the insulin receptor by prior alkaline phosphatase treatment increased insulin-stimulated receptor tyrosine kinase activity in both lean and obese Zucker rats, but the increase was three times greater in obese Zucker rats (p < 0.05). These findings suggest that excessive serine/threonine phosphorylation of the insulin receptor in obese Zucker rats may be a cause for insulin resistance in skeletal muscle.
Collapse
Affiliation(s)
- Q Zhou
- Department of Biochemistry, East Carolina University School of Medicine, Greenville, North Carolina 27858, USA
| | | | | |
Collapse
|
|
24
|
Frittitta L, Youngren J, Vigneri R, Maddux BA, Trischitta V, Goldfine ID. PC-1 content in skeletal muscle of non-obese, non-diabetic subjects: relationship to insulin receptor tyrosine kinase and whole body insulin sensitivity. Diabetologia 1996; 39:1190-5. [PMID: 8897006 DOI: 10.1007/bf02658505] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Insulin sensitivity varies widely in non-obese, non-diabetic subjects, and we have previously reported that in vivo insulin action correlates with in vitro insulin stimulated insulin receptor tyrosine-kinase activity in skeletal muscle. Plasma membrane glyco-protein PC-1 content is elevated in fibroblasts of insulin-resistant subjects, and expression of PC-1 cDNA in cultured cells reduces both insulin receptor tyrosine-kinase activity and the biological actions of insulin. In the present study we investigated non-obese, non-diabetic subjects and found a significant negative correlation between muscle PC-1 content and both in vivo insulin action as measured by the intravenous insulin tolerance test (r = -0.51, p = 0.035) and the sensitivity (ED50) of in vitro insulin stimulation of insulin receptor tyrosine-kinase activity (r = 0.66, p = 0.027). These studies indicate, therefore, that increased muscle PC-1 content is associated with reduced insulin action both in vivo and in vitro. Moreover, they suggest a possible role for PC-1 in regulating insulin receptor function in human skeletal muscle.
Collapse
Affiliation(s)
- L Frittitta
- Istituto di Medicina Interna e Malattie Endocrine e Metaboliche, Università di Catania, Ospedale Garibaldi, Italy
| | | | | | | | | | | |
Collapse
|
|
25
|
Kroder G, Bossenmaier B, Kellerer M, Capp E, Stoyanov B, Mühlhöfer A, Berti L, Horikoshi H, Ullrich A, Häring H. Tumor necrosis factor-alpha- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signaling. J Clin Invest 1996; 97:1471-7. [PMID: 8617880 PMCID: PMC507207 DOI: 10.1172/jci118569] [Citation(s) in RCA: 150] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Inhibition of insulin receptor signaling by high glucose levels and by TNF-alpha was recently observed in different cell systems. The aim of the present study was to characterize the mechanism of TNF-alpha-induced insulin receptor inhibition and to compare the consequences of TNF-alpha- and hyperglycemia-induced insulin receptor inhibition for signal transduction downstream from the IR. TNF-alpha (0.5-10 nM) and high glucose (25 mM) showed similar rapid kinetics of inhibition (5-10 min, > 50%) of insulin receptor autophosphorylation in NIH3T3 cells overexpressing the human insulin receptor. TNF-alpha effects were completely prevented by the phosphotyrosine phosphatase (PTPase) inhibitors orthovanadate (40 microM) and phenylarsenoxide (35 microM), but they were unaffected by the protein kinase C (PKC) inhibitor H7 (0.1 mM), the phosphatidylinositol-3 kinase inhibitor wortmannin (5 microM), and the thiazolidindione troglitazone (CS045) (2 microgram/ml). In contrast, glucose effects were prevented by PKC inhibitors and CS045 but unaffected by PTPase inhibitors and wortmannin. To assess effects on downstream signaling, tyrosine phosphorylation of the following substrate proteins of the insulin receptor was determined: insulin receptor substrate-1, the coupling protein Shc, focal adhesion kinase (FAK125), and unidentified proteins of 130 kD, 60 kD. Hyperglycemia (25 mM glucose) and TNF-alpha showed analogous (> 50% inhibition) effects on tyrosine phosphorylation of insulin receptor substrate-1, Shc, p60, and p44, whereas opposite effects were observed for tyrosine phosphorylation of FAK125, which is dephosphorylated after insulin stimulation. Whereas TNF-alpha did not prevent insulin-induced dephosphorylation of FAK125, 25 mM glucose blocked this insulin effect completely. In summary, the data suggest that TNF-alpha and high glucose modulate insulin receptor-signaling through different mechanisms: (a) TNF-alpha modulates insulin receptor signals by PTPase activation, whereas glucose acts through activation of PKC. (b) Differences in modulation of the insulin receptor signaling cascade are found with TNF-alpha and high glucose: Hyperglycemia-induced insulin receptor inhibition blocks both insulin receptor-dependent tyrosine phosphorylation and dephosphorylation of insulin receptor substrate proteins. In contrast, TNF-alpha blocks only substrate phosphorylation, and it does not block insulin-induced substrate dephosphorylation. The different effects on FAK125 regulation allow the speculation that long-term cell effects related to FAK125 activity might develop in a different way in hyperglycemia- and TNF-alpha-dependent insulin resistance.
Collapse
Affiliation(s)
- G Kroder
- IV Abteilung Medizinische Klinik und Poliklinik, Eberhard-Karls Universität, Tubingen, Germany
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Kellerer M, Coghlan M, Capp E, Mühlhöfer A, Kroder G, Mosthaf L, Galante P, Siddle K, Häring HU. Mechanism of insulin receptor kinase inhibition in non-insulin-dependent diabetes mellitus patients. Phosphorylation of serine 1327 or threonine 1348 is unaltered. J Clin Invest 1995; 96:6-11. [PMID: 7615833 PMCID: PMC185166 DOI: 10.1172/jci118073] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
The tyrosine kinase activity of insulin receptor isolated from the skeletal muscle of NIDDM patients has previously been found to be decreased compared with the activity of receptor from nondiabetic subjects but the mechanism underlying this defect is unknown. Phosphorylation of receptor serine/threonine residues has been proposed to exert an inhibitory influence on receptor tyrosine kinase activity and Ser 1327 and Thr 1348 have been identified as specific sites of phosphorylation in the insulin receptor COOH terminal domain. To address the potential negative regulatory role of phosphorylation of these residues in vivo, we assessed the extent of phosphorylation of each site in insulin receptor isolated from the skeletal muscle of 12 NIDDM patients and 13 nondiabetic, control subjects. Phosphorylation of Ser 1327 and Thr 1348 was determined using antibodies that specifically recognize insulin receptor phosphorylated at these sites. In addition, a phosphotyrosine-specific antibody was used to monitor receptor tyrosine phosphorylation. The extent of insulin-induced tyrosine autophosphorylation was decreased in receptor isolated from diabetic versus nondiabetic muscle, thus confirming earlier reports. In contrast, there was no significant difference in the extent of phosphorylation of either Ser 1327 or Thr 1348 in receptor isolated from diabetic or nondiabetic muscle as assessed by immunoprecipitation (Ser 1327: 5.6 +/- 1.6% diabetics vs. 4.7 +/- 2.0% control; Thr 1348: 3.8 +/- 1.0% diabetics vs. 3.2 +/- 1.2% control). Moreover, within each group there was no correlation between the level of tyrosine kinase activity and the extent of serine/threonine phosphorylation. It is concluded that the stoichiometry of serine/threonine phosphorylation of insulin receptor in vivo is low, and that increased phosphorylation of Ser 1327 or Thr 1348 is not responsible for the decreased insulin receptor tyrosine kinase activity observed in the skeletal muscle of NIDDM patients.
Collapse
Affiliation(s)
- M Kellerer
- Institut für Diabetesforschung, München, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|