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
- 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
- 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
- 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
- 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
- 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
- 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
- 8
Watson R T, Pessin J E.
Intracellular organization of insulin signaling and GLUT4 translocation.
Recent Prog Horm Res.
2001;
56
175-193
- 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
- 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
- 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
- 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
- 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
- 14
Barroso I.
Genetics of Type 2 diabetes.
Diabet Med.
2005;
22
517-535
- 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
- 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
- 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
- 18
Sorisky A.
Molecular links between obesity and cardiovascular disease.
Am J Ther.
2002;
9
516-521
- 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
- 20
Lopez-Miranda J, Perez-Martinez P, Marin C. et al .
Dietary fat, genes and insulin sensitivity.
J Mol Med.
2007;
85
209-222
- 21
Van Gaal L F, Mertens I L, De Block C E.
Mechanisms linking obesity with cardiovascular disease.
Nature.
2006;
444
875-880
- 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
- 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
- 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
- 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
- 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
- 27 Hauner H, Buchholz G, Hamann A. et al .Deutsche Adipositas Gesellschaft: Evidenzbasierte
Leitlinie. Prävention und Therapie der Adipositas. 2006
- 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
- 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
- 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
- 31
Rosen E D, Spiegelman B M.
PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth.
J Biol Chem.
2001;
276
37731-37734
- 32
Guan Y, Breyer M D.
Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in
renal disease.
Kidney Int.
2001;
60
14-30
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 53
Pagotto U, Pasquali R.
Fighting obesity and associated risk factors by antagonising cannabinoid type 1 receptors.
Lancet.
2005;
365
1363-1364
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
PD Dr. Marcus Quinkler
Klinische Endokrinologie, Innere Medizin mit Schwerpunkt Gastroenterologie, Hepatologie
und Endokrinologie, Campus Mitte, Charité Universitätsmedizin Berlin
Schumannstraße 20/21
10117 Berlin
Phone: (++ 49)-30-450514152
Fax: (++ 49)-30-450514952
Email: marcus.quinkler@charite.de