Der Polymorphismus Pro12Ala im Peroxisomenproliferator-Aktivierten Rezeptor γ₂ (PPARγ₂): Betazell-Funktion und Insulinsensitivität

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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