Adipozite Dışındaki İnsülin Direnci Belirleyicileri: Normal Ağırlıktaki Yetişkinlerde Çok Değişkenli Bir Analiz

Öz

İnsülin direnci (IR), Tip 2 diabetes mellitusun patogenezinin merkezinde bulunan  önemli bir mekanizmadır ve genellikle obeziteye bağlı inflamasyonla bağlantılıdır. Ancak IR, normal kilolu bireylerde de görülebilir; bu durum metabolik obez normal kilolu fenotipi olarak bilinir. Bu çalışmanın amacı, obez olmayan popülasyonlarda IR'yi tespit etmek için rutin hematolojik parametrelerin, kombine inflamasyon indekslerine kıyasla öngörü değerini belirlemektir. Bu retrospektif kesitsel çalışmaya 305 normal kilolu yetişkin (vücut kitle indeksi < 25 kg/m²) dahil edildi. Çalışmada IR için kesim değeri olarak 2,5 kullanılmıştır. Parametreler, tek değişkenli ve hiyerarşik çok değişkenli lojistik regresyon kullanılarak analiz edildi. Yaş, cinsiyet ve vücut kitle indeksi (VKİ) için ayarlanmış paralel modeller, bireysel lökosit alt tiplerini değerlendirmek için kullanıldı. Ayırt edici performans, alıcı çalışma karakteristiği (ROC) eğrisi analizi ile değerlendirildi. IR, 93 (%30,5) katılımcıda saptandı. IR olan grupta, VKİ, glikoz, trigliseritler, HbA1c ve beyaz kan hücresi (WBC) sayılarında anlamlı olarak daha yüksek değerler saptandı (p < 0,05). Çok değişkenli analizde, WBC sayısı inflamasyonun tek bağımsız belirleyicisi olarak saptandı (OR = 1,946, p < 0,001). WBC sayısı, panimmün inflamasyon değeri (AUC = 0,510) gibi bireysel alt tiplere ve bileşik indekslere kıyasla daha iyi açıklayıcı güç (Nagelkerke R2 = 0,196) ve ayırt edici performans (AUC = 0,725) gösterdi. Nihai çok değişkenli model 0,736 AUC değerine ulaştı. Normal kilolu yetişkinlerde, IR, oran bazlı indekslerden ziyade mutlak WBC sayılarının yansıttığı genel sistemik inflamasyon ile daha belirgin bir ilişki sergilemektedir. WBC sayısının günlük pratikte obez olmayan bireylerde erken metabolik risk tanımlaması için ucuz, pratik bir biyobelirteç olarak akılda tutulması faydalı bir yaklaşımdır.

Anahtar Kelimeler

• : İnsülin direnci
• Beyaz kan hücresi sayısı
• Enflamasyon
• Sistemik bağışıklık indeksleri
• Panimmün inflamasyon değeri.

Determinants of Insulin Resistance Beyond Adiposity: A Multivariable Analysis in Normal-Weight Adults

Öz

Insulin resistance (IR) is a key pathogenic mechanism in Type 2 Diabetes Mellitus, often linked to obesity-related inflammation. However, IR can also occur in individuals with normal weight, a condition known as the metabolically obese normal-weight phenotype. This study assesses the predictive value of routine hematological parameters compared to combined inflammation indices for detecting IR in non-obese populations. This retrospective cross-sectional study included 305 normal-weight adults (body mass index < 25 kg/m²). IR was defined by a Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) threshold of 2.5. Parameters were analyzed using univariate and hierarchical multivariable logistic regression. Parallel models, adjusted for age, sex, and body mass index (BMI), were used to assess individual leukocyte subtypes. Discriminatory performance was evaluated through Receiver Operating Characteristic (ROC) curve analysis. IR was found in 93 (30.5%) participants. The IR+ group exhibited significantly higher BMI, glucose, triglycerides, HbA1c, and white blood cell (WBC) counts (p < 0.05). Multivariable analysis identified WBC count as the only independent predictor of inflammation (OR = 1.946, p < 0.001). WBC count showed better explanatory power (Nagelkerke R2 = 0.196) and discriminatory ability (AUC = 0.725) compared to individual subtypes and composite indices, like the panimmune inflammation value (AUC = 0.510). The final multivariable model achieved an AUC of 0.736. In normal-weight adults, IR appears to exhibit a more pronounced association with generalized systemic inflammation reflected by absolute WBC counts rather than ratio-based indices. WBC count serves as a practical marker for early metabolic risk identification in non-obese individuals.

Anahtar Kelimeler

• Insulin resistance
• White blood cell count
• Inflammation
• Systemic immune indices
• Panimmune inflammation value.

Kaynakça

1. 1. Park HM, Lee HS, Lee YJ, Lee JH. The triglyceride-glucose index is a more powerful surrogate marker for predicting the prevalence and incidence of type 2 diabetes mellitus than the homeostatic model assessment of insulin resistance. Diabetes Res Clin Pract. 2021;180:109042.
2. 2. Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773–95.
3. 3. Lee SH, Park SY, Choi CS. Insulin Resistance: From Mechanisms to Therapeutic Strategies. Diabetes Metab J. 2022;46(1):15–37.
4. 4. Tahapary DL, Pratisthita LB, Fitri NA, Marcella C, Wafa S, Kurniawan F, et al. Challenges in the diagnosis of insulin resistance: Focusing on the role of HOMA-IR and Tryglyceride/glucose index. Diabetes Metab Syndr. 2022;16(8):102581.
5. 5. Lee CH, Shih AZ, Woo YC, Fong CH, Leung OY, Janus E, et al. Optimal Cut-Offs of Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) to Identify Dysglycemia and Type 2 Diabetes Mellitus: A 15-Year Prospective Study in Chinese. PLoS One. 2016;11(9):e0163424.
6. 6. Esteghamati A, Ashraf, H., Khalilzadeh, O., Zandieh, A., Nakhjavani, M., Rashidi, A., Haghazali, M., & Asgari, F. Optimal cut-off of homeostasis model assessment of insulin resistance (HOMA-IR) for the diagnosis of metabolic syndrome: third national surveillance of risk factors of non-communicable diseases in Iran. Nutrition & metabolism. 2010;7(26).
7. 7. Gomez-Casado G, Jimenez-Gonzalez A, Rodriguez-Munoz A, Tinahones FJ, Gonzalez-Mesa E, Murri M, et al. Neutrophils as indicators of obesity-associated inflammation: A systematic review and meta-analysis. Obes Rev. 2025;26(3):e13868.
8. 8. Amin MN, Hussain MS, Sarwar MS, Rahman Moghal MM, Das A, Hossain MZ, et al. How the association between obesity and inflammation may lead to insulin resistance and cancer. Diabetes Metab Syndr. 2019;13(2):1213–24.

9. 9. Islam MM, Satici MO, Eroglu SE. Unraveling the clinical significance and prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, systemic inflammation response index, and delta neutrophil index: An extensive literature review. Turk J Emerg Med. 2024;24(1):8–19.
10. 10. Zhao Q, Liu X, Xu J, Rao X, Liu M. Association of systemic immunity-inflammation index with type 2 diabetes and insulin resistance in NHANES 2005-2018. Sci Rep. 2024;14(1):30133.
11. 11. WHO. Obesity and overweight [Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.
12. 12. Yamada C, Mitsuhashi T, Hiratsuka N, Inabe F, Araida N, Takahashi E. Optimal reference interval for homeostasis model assessment of insulin resistance in a Japanese population. J Diabetes Investig. 2011;2(5):373–6.
13. 13. Nattino G, Pennell ML, Lemeshow S. Assessing the goodness of fit of logistic regression models in large samples: A modification of the Hosmer-Lemeshow test. Biometrics. 2020;76(2):549–60.
14. 14. Hotamisligil GS. Inflammation and endoplasmic reticulum stress in obesity and diabetes. Int J Obes (Lond). 2008;32 Suppl 7(Suppl 7):S52–4.
15. 15. Bluher M. Metabolically Healthy Obesity. Endocr Rev. 2020;41(3).
16. 16. Nakanishi N, Sato, M., Shirai, K., Nakajima, K., Murakami, S., Takatorige, T., Suzuki, K., & Tatara, K. Associations between white blood cell count and features of the metabolic syndrome in Japanese male office workers. Industrial health. 2002;40(3):273–7.
17. 17. Garcia-Escobar A, Vera-Vera S, Tebar-Marquez D, Rivero-Santana B, Jurado-Roman A, Jimenez-Valero S, et al. Neutrophil-to-lymphocyte ratio an inflammatory biomarker, and prognostic marker in heart failure, cardiovascular disease and chronic inflammatory diseases: New insights for a potential predictor of anti-cytokine therapy responsiveness. Microvasc Res. 2023;150:104598.
18. 18. Cupp MA, Cariolou M, Tzoulaki I, Aune D, Evangelou E, Berlanga-Taylor AJ. Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies. BMC Med. 2020;18(1):360.
19. 19. Dziedzic EA, Gasior JS, Tuzimek A, Paleczny J, Junka A, Dabrowski M, et al. Investigation of the Associations of Novel Inflammatory Biomarkers-Systemic Inflammatory Index (SII) and Systemic Inflammatory Response Index (SIRI)-With the Severity of Coronary Artery Disease and Acute Coronary Syndrome Occurrence. Int J Mol Sci. 2022;23(17).
20. 20. Zhu Q, Dai L. Prognostic implications of systemic immune-inflammation index and systemic inflammation response index in hemodialysis patients. BMC Nephrol. 2025;26(1):322.
21. 21. Balta S, Cakar M, Demirkol S, Arslan Z, Akhan M. Higher neutrophil to lymhocyte ratio in patients with metabolic syndrome. Clin Appl Thromb Hemost. 2013;19(5):579.
22. 22. Mohammadian Khonsari N, Baygi F, Tabatabaei-Malazy O, Mohammadpoor Nami S, Ehsani A, Asadi S, et al. Association of normal weight obesity phenotype with inflammatory markers: A systematic review and meta-analysis. Front Immunol. 2023;14:1044178.
23. 23. He HM, Zhang L, Qiu N, Zhou ZT, Zhang K, Li Y, et al. Insulin resistance in school-aged girls with overweight and obesity is strongly associated with elevated white blood cell count and absolute neutrophil count. Front Endocrinol (Lausanne). 2022;13:1041761.