Disertasi

Pengaruh pajanan diet tinggi lemak terhadap resistensi insulin,profil metabolik, dan respons imun subyek normoglikemidengan riwayat orang tua diabetes mellitus tipe 2 = Impact of a 5-day high fat diet on insulin resistace, metabolicprofiles, and immune responsses of first degree relatives of type2 diabetes mellitus patients.

Latar belakang. Subyek sehat dengan riwayat orang tua diabetes melitus tipe 2 [firstdegree relatives of type 2 diabetes mellitus patients (FDR T2DM)] diketahui memilikipenanda resistensi insulin (RI) dan inflamasi relatif lebih tinggi dibanding subyek nonFDR T2DM sehingga lebih rentan mengembangkan penyakit RI bila terpajan lingkungandengan pola makan tinggi lemak [high fat diet (HFD)]. Namun demikian, studi mengenaidampak buruk HFD terhadap subyek sehat FDR masih memerlukan eksplorasi lebihlanjut. Studi ini bertujuan untuk mengetahui apakah subyek pria Indonesia sehat denganriwayat FDR T2DM lebih rentan terhadap dampak buruk pajanan HFD dibanding subyeknon-FDR berdasarkan perubahan pada parameter metabolik dan respons imun yangdihasilkan.Metode. Duapuluh delapan subyek non FDR dan 27 subyek FDR T2DM dengan kisaranusia dan indeks massa tubuh (IMT) serupa menjalani perlakuan HFD berupa penambahankrim susu sebanyak 250 mL ke dalam menu harian mereka selama lima hari berturutturut. Pengambilan data asupan makanan, profil metabolik, dan kadar sitokin dilakukanpada sebelum dan sesudah perlakuan HFD untuk kemudian dibandingkan besaranperubahan yang terjadi antar kelompok.Hasil. Pajanan HFD mengakibatkan penurunan sensitivitas tubuh terhadap insulin sertapeningkatan kadar kolesterol yang cenderung sama di kedua kelompok. Pajanan HFDtidak menimbulkan perubahan bermakna kadar sitokin pro- dan anti inflamasi serta profilsel monosit CD14+CD16++ di kedua kelompok. Namun, dampak proinflamasi berupapeningkatan rasio TNF-α/IL-10 ditemukan lebih besar secara bermakna terjadi padakelompok FDR dibanding non-FDR (p=0,001). Nilai odds rasio subyek FDR untukmengalami respons proinflamasi tersebut adalah 7-kali lebih besar dibanding non-FDRdan meningkat menjadi 25-kali pada kategori IMT ≥25. Lebih lanjut, pada subgrup FDRdengan IMT ≥25 tersebut ditemukan adanya korelasi bermakna antara penurunankemampuan inhibisi IL-10 sel imun dengan peningkatan kadar TNF-α pada kondisi HFD(R=-0,92; p=0,001). Selain itu, subgrup tersebut juga menunjukkan korelasi kuat antarapenurunan kemampuan inhibisi IL-10 dengan peningkatan ukuran lingkar pinggang (R=-0,78; p=0,02).Kesimpulan. Subyek sehat dengan riwayat FDR T2DM, terutama yang memiliki IMT≥25, memberikan respons proinflamasi lebih tinggi secara bermakna dibanding non-FDRpada lingkungan HFD. Respons proinflamasi terhadap HFD berkorelasi denganpeningkatan ukuran lingkar pinggang dan diduga terjadi melalui mekanisme penurunankemampuan inhibisi IL-10 sel-sel imun.
Kata kunci: anak kandung pasien diabetes, lingkar pinggang, resistensi insulin, TNF- α,IL-10


Background. Healthy non-diabetic first-degree relatives (FDR) of type 2 diabetesmellitus (T2DM) patients have been reported to have relatively higher insulin resistance(IR) and inflammatory markers compared to population without family history of T2DM.This chararcteristic predispose them to progress into IR-associated diseases whenexposed to HFD environment. However, studies regarding the adverse metabolic effectof HFD on healthy FDR subjects have yielded mixed results. This study aimed toinvestigate whether healthy FDR T2DM of Indonesian males living in urban area aremore susceptible to the adverse effects of high fat diet (HFD) than the non-FDR males,based on changes in their metabolic and immune responsse parameters.Method. Twenty-seven normoglycemic and normotensive FDR males and 28 age-andbody mass index (BMI) matched of healthy non-FDR males underwent a 5-days HFDchallenge. Dietary intake data, metabolic profiles, and plasma cytokine levels weremeasured before and after the HFD intervention.Results. The HFD intervention reduced body sensitivity to insulin and causing increasein cholesterol levels in both group similarly. There were no significant changes wereobserved in the levels of pro- and anti-inflammatory cytokines as well as the theCD14+CD16++ cells in both groups. However, there was a significant increase in plasmaTNF-α/IL-10 ratio observed in the FDR group compared to the non-FDR (p=0.001). Theodds ratio for FDR subjects to experience this pro-inflammatory responsse was 7 timesas likely as the non-FDR and it increased to 25 times at the BMI ≥25 category. This FDRBMI ≥25 subgroup demonstrated a significant negative correlation between the inhibitionability of IL-10 and plasma TNF-α level following HFD intervention (R=-0.92; p=0.001).Furthermore, this subgroup also showed a strong correlation between decreased IL-10inhibition ability and increased waist circumference (R=-0.78; p=0.02).Conclusion. Within similar HFD environment, healthy FDR T2DM subjects, particularlythose with BMI ≥25, demonstrated a significantly higher proinflammatory response thannon-FDR. Increase in waist circumference accompanied with decreased in IL-10inhibitory ability of immune cells were proposed as the underlying mechanism of thisHFD-related proinflammatory response.
Keywords: first-degree relatives of diabetes patient, waist circumference, insulinresistance, TNF-α, IL-10