Hintergrund und Fragestellung: Der
Peroxisomenproliferator-Aktivierte Rezeptor (PPAR) ist ein zentraler
Regulator des Lipid- und Glucosestoffwechsels. Für einen
weitverbreiteten Polymorphismus (Pro12Ala in PPARγ2 ,
Prävalenz ca. 25 %) wurde eine Assoziation
mit einem verminderten Typ-2-Diabetesrisiko gezeigt. Zur Krankheitsentstehung
des Typ-2-Diabetes mellitus tragen generell sowohl die
Betazelldysfunktion als auch die Insulinresistenz bei. Deshalb war
das Ziel der vorliegenden Studie, die Mechanismen zu untersuchen,
durch die das Alanin-Allel dieses Polymorphismus zum reduzierten
Typ-2-Diabetesrisiko beiträgt.
Patienten und Methodik: Wir untersuchten 51 Personen
ohne (Pro/Pro) und 26 Personen mit diesem Polymorphismus
(X/Ala) (beide Gruppen nicht diabetisch) mit einem modifizierten
hyperglykämischen Clamp, der die Bestimmung sowohl der
Insulinsekretion (als Antwort auf Glukose, GLP-1 und Arginin) als auch
der Insulinsensitivität zulässt.
Ergebnisse: Keine der verschiedenen
Phasen der Insulinsekretion war zwischen den beiden Genotypen signifikant
unterschiedlich (alle p-Werte > 0,13). Im Gegensatz dazu
war die Insulinsensitivität bei der X/Ala-Gruppe
signifikant höher (0,19±0,03 U) als bei der Pro/Pro-Gruppe
(0,14±0,01U, p = 0,04). In einer
zweidimensionalen Auswertung von Insulinsensitivität und
Sekretion zeigten die homozygoten Alanin-Träger die günstigste
Konstellation.
Folgerung: Zusammenfassend zeigen diese
gleichzeitig gewonnen Daten zur Insulinsekretion und Insulinsensitivität,
dass die Senkung des Typ-2-Diabetesrisikos durch das Alanin-Allel höchstwahrscheinlich
auf einer verbesserten Insulinsensitivität beruht.
Pro12Ala polymorphism in peroxisome
proliferator-activated receptorg2 (PPARg2): beta-cell function and
insulin sensitivity
Background and objective: The peroxisome proliferator-activated
receptor isoform γ (PPARγ) is a key regulator
in lipid and glucose homoeostasis. A common polymorphism (Pro12Ala
in PPARγ2 , prevalence ca. 25 %)
was shown to be associated with a decreased risk of type 2 diabetes.
Generally, both beta-cell dysfunction and insulin resistance contribute
to the development of type 2 diabetes. Therefore, the aim of the
present study was to assess the mechanism by which the Ala allele
of this polymorphism contributes to the reduced risk for type 2
diabetes.
Patients and methods: We studied 51 subjects without
(Pro/Pro) and 26 subjects with this polymorphisms (X/Ala)
(both groups non-diabetic) by a modified hyperglycaemic clamp which
permitted determination of both insulin secretion (in response to
glucose, GLP-1 and arginine) and insulin sensitivity.
Results: None of the various phases
of insulin secretion was significantly different between the 2 genotype
groups (all p values > 0.13). In contrast, insulin sensitivity
was significantly greater in X/Ala (0.19±0.03
U) compared to Pro/Pro (0.14±0.01U, p = 0.04). In
a two-dimensional assessment of insulin sensitivity and secretion,
the homozygous alanine carriers appeared to have the most favourable
constellation.
Conclusion: These simultaneously obtained
data for insulin secretion and sensitivity strongly suggest that
the mechanism by which the Ala allele contributes to a risk reduction
for type 2 diabetes most likely involves an increase in insulin
sensitivity.
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Korrespondenz
Dr. med. Michael Stumvoll
Medizinische Universitätsklinik
Otfried-Müller-Straße 10
72076 Tübingen
Phone: 07071/2980390
Fax: 07071/292784