Mustafa YAMAN, Halime UĞUR, Cemalettin KİŞMİROĞLU, İsmail BELLİ, Bahtiyar ÖZGÜR

Aşırı Beslenmeye Bağlı Oluşan İnsülin Direncinin BiyokimyasalGelişimi ve AMP-ile Aktive Edilmiş Protein Kinaz (AMPK)’ınFonksiyonu

Aşırı beslenme ve obezitenin, insülin direnci, diyabet, hipertansiyon, kardiyovasküler hastalıklar ve kanser gibi birçok kronik hastalığaneden olduğu bilinmektedir. İnsülin direnci, glikozun kas ve diğer dokulara taşınmasında hücrelerin insülininin etkisine yanıt vermeyeteneğinin azalması olarak tanımlanır. Obezitenin gelişmesiyle birlikte yağ dokusundan salınan esterlenmemiş yağ asitleri, gliserol veproinflamatuar sitokinler insülin direncine neden olur. Özellikle MCP-1 ve TNF-α gibi sitokin ve kemokinler adipositlerdetrigliseridlerin hidrolizine neden olur. Ortaya çıkan serbest yağ asitleri dolaşım yoluyla kas, karaciğer ve beta hücrelerine taşınır veDAG, TAG ve seramid olarak depolanır. Bu yağ asitleri türevlerinin birikimi hem IRS’yi bloke ederek insülin direncine, hemde hücreiçi enerji sensörü olan AMPK’nin aktivasyonunun azalmasına neden olur. AMPK’nin aktivasyonunun azalması sonucu glukoz taşıyıcıproteininin translokasyonu azalır ve insülin direnci gelişir. Bunun yanında, AMPK’nin aktivasyonunun azalması dokularda lipitbirikimine, hücresel işlev bozukluklarına ve birçok kronik hastalığın gelişmesine neden olur. Egzersizin yanında metformin, AICARve TZDs gibi bazı farmasötik ilaçların hem lipit birikimini azalttığı hem de AMPK’nin aktivasyonunu artırarak insülin direnciniengellediği bildirilmiştir.

Biochemical Development of Insulin Resistance due to Excess Nutrition and the Function of AMP-Activated Protein Kinase (AMPK)

Overnutrition and obesity are known to cause many chronic diseases such as insulin resistance, diabetes, and cancer. Insulin resistanceis defined as a decrease in the ability of cells to respond to the effect of insulin in the transport of glucose to muscle and other tissues.With the development of obesity, nonesterified fatty acids, glycerol, hormones, pro-inflammatory cytokines released from adipose tissueare known to play a role in the development of insulin resistance. Especially cytokines and chemokines such as MCP-1 and TNFα causehydrolysis of triglycerides in adipocytes, causing high levels of free fatty acids in circulation. These free fatty acids are then stored bythe muscle and liver and beta cells again as DAG, TAG, and ceramide, blocking the IRS receptor causing its resistance. In addition, asa result of excessive fat nutrition, the accumulation of toxic lipid derivatives causes the inactivation of the intracellular energy sensorAMPK. Depending on the inactivation of AMPK, the glucose carrier protein (GLUT4) translocation decreases, and insulin resistanceimproves. Also, reduced activation of AMPK causes lipid accumulation in tissues, cellular dysfunctions, and, consequently, manychronic diseases. In addition to exercise, it is seen that some pharmaceutical drugs such as metformin, AICAR, and TZDs both reducelipid accumulation and increase the activation of AMPK and prevent insulin resistance.

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