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Aktuelle Ernährungsmedizin 2008; 33(2): 62-69
DOI: 10.1055/s-2007-986314
Übersicht

© Georg Thieme Verlag KG Stuttgart · New York

Verbesserung der Insulinsensitivität - Möglichkeiten und Grenzen der Pharmakotherapie

Improvement of Insulin Sensitivity - Strategies and Limitations of PharmacotherapyT.  Kienitz1 , M.  Quinkler1
  • 1Klinische Endokrinologie, Campus Mitte, Charité Universitätsmedizin Berlin
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Publication History

Publication Date:
26 March 2008 (online)

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Zusammenfassung

Hintergrund Sprechen Zielorgane vermindert auf Insulin an, so spricht man von Insulinresistenz. Kann dieser Zustand von den pankreatischen β-Zellen über eine Mehrproduktion von Insulin nicht mehr kompensiert werden, so kann sich ein Diabetes mellitus Typ 2 entwickeln. Des Weiteren ist die Insulinresistenz selbst eigenständiger Risikofaktor für die Entwicklung kardiovaskulärer Erkrankungen. Goldstandard zur genauen Bewertung der Insulinsensitivität ist der euglykämische-hyperinsulinämische Glukose-Clamp, der in der klinischen Routine jedoch kaum Bedeutung besitzt. Ziel Dieser Artikel fasst medikamentöse Strategien in der Behandlung der Insulinresistenz zusammen und stellt sie konventionellen Therapieressourcen gegenüber. Ergebnisse Als Therapeutika stehen Metformin und Thiazolidindione zur Verfügung. Über Orlistat kann die Resorption von Fettsäuren und damit einer der wichtigsten Einflussfaktoren bei der Entwicklung der Insulinresistenz vermindert werden. Seit Neuestem bieten außerdem Modulatoren des Endocannabinoid- sowie des Inkretinsystems vielversprechende Ansätze zur Behandlung der Insulinresistenz. Schlussfolgerung Obgleich inzwischen vielfältige Medikamente zur Verbesserung der Insulinsensitivität zur Verfügung stehen, müssen zukünftige Studien zeigen, inwiefern diese besonders langfristig einen Vorteil gegenüber traditionellen Ansätzen darstellen.

Abstract

Background Insulin resistance is defined as diminished response of peripheral tissue towards insulin. If pancreatic β-cells cannot compensate this condition by means of an increase in insulin secretion, diabetes mellitus type 2 may develop. Furthermore, insulin resistance itself is a risk factor for cardiovascular complications. Gold standard for the assessment of insulin sensitivity is the euglycemic-hyperinsulinemic glucose clamp, which does not play a role in clinical routine, though. AIM This review provides an overview of pharmacological strategies in the treatment of insulin resistance and compares them to conventional therapy resources. Results Metformin and thiazolidinediones are able to improve insulin sensitivity. In addition, Orlistat decreases enteral resorption of fatty acids and through this mechanism influences insulin resistance. Lately, modulators of the endocannabinoid as well as incretin system have been developed and appear as promising new classes of antidiabetic agents. Conclusion Although several pharmacological agents have been developed to improve insulin sensitivity, future studies will have to evaluate their role in comparison to traditional therapy resources, especially as long-term effects are concerned.

Schlüsselwörter

Insulinresistenz - Diagnose - Therapie - Insulinsensitivität - Inkretine

Key words

insulin resistance - diagnosis - therapy - insulin sensitizer - incretins

Literatur

  • 1 Kahn S E, Hull R L, Utzschneider K M. Mechanisms linking obesity to insulin resistance and type 2 diabetes.  Nature. 2006;  444 840-846
    CrossrefPubMedGoogle Scholar
  • 2 Butler A E, Janson J, Soeller W C. et al . Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid.  Diabetes. 2003;  52 2304-2314
    CrossrefPubMedGoogle Scholar
  • 3 Kloppel G, Lohr M, Habich K. et al . Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited.  Surv Synth Pathol Res. 1985;  4 110-125
    PubMedGoogle Scholar
  • 4 Weyer C, Hanson K, Bogardus C. et al . Long-term changes in insulin action and insulin secretion associated with gain, loss, regain and maintenance of body weight.  Diabetologia. 2000;  43 36-46
    CrossrefPubMedGoogle Scholar
  • 5 Despres J P, Lamarche B, Mauriege P. et al . Hyperinsulinemia as an independent risk factor for ischemic heart disease.  N Engl J Med. 1996;  334 952-957
    CrossrefPubMedGoogle Scholar
  • 6 Paolisso G, Howard B V. Role of non-esterified fatty acids in the pathogenesis of type 2 diabetes mellitus.  Diabet Med. 1998;  15 360-366
    CrossrefPubMedGoogle Scholar
  • 7 Vettor R, Fabris R, Serra R. et al . Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle.  Int J Obes Relat Metab Disord. 2002;  26 838-847
    CrossrefPubMedGoogle Scholar
  • 8 Watson R T, Pessin J E. Intracellular organization of insulin signaling and GLUT4 translocation.  Recent Prog Horm Res. 2001;  56 175-193
    CrossrefPubMedGoogle Scholar
  • 9 Itani S I, Ruderman N B, Schmieder F. et al . Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha.  Diabetes. 2002;  51 2005-2011
    CrossrefPubMedGoogle Scholar
  • 10 Ferrannini E, Camastra S. Relationship between impaired glucose tolerance, non-insulin-dependent diabetes mellitus and obesity.  Eur J Clin Invest. 1998;  28, Suppl 2 3-6, discussion 6 - 7
    CrossrefPubMedGoogle Scholar
  • 11 Smith S R, Lovejoy J C, Greenway F. et al . Contributions of total body fat, abdominal subcutaneous adipose tissue compartments, and visceral adipose tissue to the metabolic complications of obesity.  Metabolism. 2001;  50 425-435
    CrossrefPubMedGoogle Scholar
  • 12 Knowler W C, Barrett-Connor E, Fowler S E. et al . Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.  N Engl J Med. 2002;  346 393-403
    CrossrefPubMedGoogle Scholar
  • 13 Andrulionyte L, Zacharova J, Chiasson J L. et al . Common polymorphisms of the PPAR-gamma2 (Pro12Ala) and PGC-1alpha (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial.  Diabetologia. 2004;  47 2176-2184
    CrossrefPubMedGoogle Scholar
  • 14 Barroso I. Genetics of Type 2 diabetes.  Diabet Med. 2005;  22 517-535
    CrossrefPubMedGoogle Scholar
  • 15 Le Fur S, Fradin D, Boileau P. et al . Association of Kir6.2 and INS VNTR variants with glucose homeostasis in young obese.  Physiol Genomics. 2005;  22 398-401
    PubMedGoogle Scholar
  • 16 Muller Y L, Infante A M, Hanson R L. et al . Variants in hepatocyte nuclear factor 4alpha are modestly associated with type 2 diabetes in Pima Indians.  Diabetes. 2005;  54 3035-3039
    CrossrefPubMedGoogle Scholar
  • 17 Grant S F, Thorleifsson G, Reynisdottir I. et al . Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.  Nat Genet. 2006;  38 320-323
    CrossrefPubMedGoogle Scholar
  • 18 Sorisky A. Molecular links between obesity and cardiovascular disease.  Am J Ther. 2002;  9 516-521
    CrossrefPubMedGoogle Scholar
  • 19 Lamounier-Zepter V, Ehrhart-Bornstein M, Bornstein S R. Insulin resistance in hypertension and cardiovascular disease.  Best Pract Res Clin Endocrinol Metab. 2006;  20 355-367
    CrossrefPubMedGoogle Scholar
  • 20 Lopez-Miranda J, Perez-Martinez P, Marin C. et al . Dietary fat, genes and insulin sensitivity.  J Mol Med. 2007;  85 209-222
    PubMedGoogle Scholar
  • 21 Van Gaal L F, Mertens I L, De Block C E. Mechanisms linking obesity with cardiovascular disease.  Nature. 2006;  444 875-880
    CrossrefPubMedGoogle Scholar
  • 22 Matthews D R, Hosker J P, Rudenski A S. et al . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
    Google Scholar
  • 23 Katz A, Nambi S S, Mather K. et al . Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.  J Clin Endocrinol Metab. 2000;  85 2402-2410
    CrossrefPubMedGoogle Scholar
  • 24 Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) . Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).  JAMA. 2001;  285 2486-2497
    CrossrefPubMedGoogle Scholar
  • 25 McAuley K A, Williams S M, Mann J I. et al . Diagnosing insulin resistance in the general population.  Diabetes Care. 2001;  24 460-464
    CrossrefPubMedGoogle Scholar
  • 26 Stern S E, Williams K, Ferrannini E. et al . Identification of individuals with insulin resistance using routine clinical measurements.  Diabetes. 2005;  54 333-339
    CrossrefPubMedGoogle Scholar
  • 27 Hauner H, Buchholz G, Hamann A. et al .Deutsche Adipositas Gesellschaft: Evidenzbasierte Leitlinie. Prävention und Therapie der Adipositas. 2006
    Google Scholar
  • 28 Natali A, Ferrannini E. Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review.  Diabetologia. 2006;  49 434-441
    CrossrefPubMedGoogle Scholar
  • 29 Kahn S E, Haffner S M, Heise M A. et al . Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.  N Engl J Med. 2006;  355 2427-2443
    CrossrefPubMedGoogle Scholar
  • 30 UK Prospective Diabetes Study (UKPDS) Group . Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).  Lancet. 1998;  352 854-865
    CrossrefPubMedGoogle Scholar
  • 31 Rosen E D, Spiegelman B M. PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth.  J Biol Chem. 2001;  276 37731-37734
    PubMedGoogle Scholar
  • 32 Guan Y, Breyer M D. Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in renal disease.  Kidney Int. 2001;  60 14-30
    CrossrefPubMedGoogle Scholar
  • 33 Gurnell M, Savage D B, Chatterjee V K. et al . The metabolic syndrome: peroxisome proliferator-activated receptor gamma and its therapeutic modulation.  J Clin Endocrinol Metab. 2003;  88 2412-2421
    CrossrefPubMedGoogle Scholar
  • 34 Ristow M, Muller-Wieland D, Pfeiffer A. et al . Obesity associated with a mutation in a genetic regulator of adipocyte differentiation.  N Engl J Med. 1998;  339 953-959
    CrossrefPubMedGoogle Scholar
  • 35 Orio Jr. F, Matarese G, Di Biase S. et al . Exon 6 and 2 peroxisome proliferator-activated receptor-gamma polymorphisms in polycystic ovary syndrome.  J Clin Endocrinol Metab. 2003;  88 5887-5892
    CrossrefPubMedGoogle Scholar
  • 36 Rosenberg D E, Jabbour S A, Goldstein B J. Insulin resistance, diabetes and cardiovascular risk: approaches to treatment.  Diabetes Obes Metab. 2005;  7 642-653
    CrossrefPubMedGoogle Scholar
  • 37 Gerstein H C, Yusuf S, Bosch J. et al . Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.  Lancet. 2006;  368 1096-1105
    CrossrefPubMedGoogle Scholar
  • 38 Nissen S E, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes.  N Engl J Med. 2007;  356 2457-2471
    CrossrefPubMedGoogle Scholar
  • 39 Home P D, Pocock S J, Beck-Nielsen H. et al . Rosiglitazone evaluated for cardiovascular outcomes - an interim analysis.  N Engl J Med. 2007;  357 28-38
    CrossrefPubMedGoogle Scholar
  • 40 Erdmann E, Dormandy J A, Charbonnel B. et al . The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study.  J Am Coll Cardiol. 2007;  49 1772-1780
    CrossrefPubMedGoogle Scholar
  • 41 Drent M L, van der Veen E A. Lipase inhibition: a novel concept in the treatment of obesity.  Int J Obes Relat Metab Disord. 1993;  17 241-244
    PubMedGoogle Scholar
  • 42 Torgerson J S, Hauptman J, Boldrin M N. et al . XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.  Diabetes Care. 2004;  27 155-161
    Google Scholar
  • 43 Padwal R, Li S K, Lau D C. Long-term pharmacotherapy for overweight and obesity: a systematic review and meta-analysis of randomized controlled trials.  Int J Obes Relat Metab Disord. 2003;  27 1437-1446
    CrossrefPubMedGoogle Scholar
  • 44 Sjostrom L, Rissanen A, Andersen T. et al . Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group.  Lancet. 1998;  352 167-172
    CrossrefPubMedGoogle Scholar
  • 45 De Petrocellis L, Cascio M G, Di Marzo V. The endocannabinoid system: a general view and latest additions.  Br J Pharmacol. 2004;  141 765-774
    CrossrefPubMedGoogle Scholar
  • 46 Van Gaal L F, Rissanen A M, Scheen A J. et al . Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study.  Lancet. 2005;  365 1389-1397
    CrossrefPubMedGoogle Scholar
  • 47 Di Marzo V, Goparaju S K, Wang L. et al . Leptin-regulated endocannabinoids are involved in maintaining food intake.  Nature. 2001;  410 822-825
    CrossrefPubMedGoogle Scholar
  • 48 Ravinet Trillou C, Arnone M, Delgorge C. et al . Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice.  Am J Physiol Regul Integr Comp Physiol. 2003;  284 R345-353
    CrossrefPubMedGoogle Scholar
  • 49 Cota D, Marsicano G, Tschop M. et al . The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis.  J Clin Invest. 2003;  112 423-431
    CrossrefPubMedGoogle Scholar
  • 50 Liu Y L, Connoley I P, Wilson C A. et al . Effects of the cannabinoid CB1 receptor antagonist SR141716 on oxygen consumption and soleus muscle glucose uptake in Lep(ob)/Lep(ob) mice.  Int J Obes (Lond). 2005;  29 183-187
    CrossrefPubMedGoogle Scholar
  • 51 Osei-Hyiaman D, DePetrillo M, Pacher P. et al . Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity.  J Clin Invest. 2005;  115 1298-1305
    PubMedGoogle Scholar
  • 52 Gomez R, Navarro M, Ferrer B. et al . A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding.  J Neurosci. 2002;  22 9612-9617
    PubMedGoogle Scholar
  • 53 Pagotto U, Pasquali R. Fighting obesity and associated risk factors by antagonising cannabinoid type 1 receptors.  Lancet. 2005;  365 1363-1364
    CrossrefPubMedGoogle Scholar
  • 54 Pi-Sunyer F X, Aronne L J, Heshmati H M. et al . Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial.  JAMA. 2006;  295 761-775
    CrossrefPubMedGoogle Scholar
  • 55 Hollander P. Endocannabinoid blockade for improving glycemic control and lipids in patients with type 2 diabetes mellitus.  Am J Med. 2007;  120 S18-28; discussion S29 - 32
    PubMedGoogle Scholar
  • 56 Drucker D J, Nauck M A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.  Lancet. 2006;  368 1696-1705
    CrossrefPubMedGoogle Scholar
  • 57 Nauck M A, Homberger E, Siegel E G. et al . Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses.  J Clin Endocrinol Metab. 1986;  63 492-498
    CrossrefPubMedGoogle Scholar
  • 58 Toft-Nielsen M B, Damholt M B, Madsbad S. et al . Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients.  J Clin Endocrinol Metab. 2001;  86 3717-3723
    CrossrefPubMedGoogle Scholar
  • 59 Buse J B, Henry R R, Han J. et al . Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes.  Diabetes Care. 2004;  27 2628-2635
    CrossrefPubMedGoogle Scholar
  • 60 DeFronzo R A, Ratner R E, Han J. et al . Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.  Diabetes Care. 2005;  28 1092-1100
    CrossrefPubMedGoogle Scholar
  • 61 Kendall D M, Riddle M C, Rosenstock J. et al . Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea.  Diabetes Care. 2005;  28 1083-1091
    CrossrefPubMedGoogle Scholar
  • 62 Heine R J, Van Gaal L F, Johns D. et al . Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial.  Ann Intern Med. 2005;  143 559-569
    CrossrefPubMedGoogle Scholar
  • 63 Gallwitz B. Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data.  Int J Clin Pract. 2006;  60 1654-1661
    CrossrefPubMedGoogle Scholar

PD Dr. Marcus Quinkler

Klinische Endokrinologie, Innere Medizin mit Schwerpunkt Gastroenterologie, Hepatologie und Endokrinologie, Campus Mitte, Charité Universitätsmedizin Berlin

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10117 Berlin

Phone: (++ 49)-30-450514152

Fax: (++ 49)-30-450514952

Email: marcus.quinkler@charite.de

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