Central Obesity, Type 2 Diabetes and Insulin: Exploring a Pathway Full of Thorns

Overview

Journal Arch Med Sci

Specialty General Medicine

Date 2015 Jul 15

PMID 26170839

Citations 67

Authors

Georgios S Papaetis

Panagiotis Papakyriakou

Themistoklis N Panagiotou

Affiliations

Soon will be listed here.

Abstract

The prevalence of type 2 diabetes (T2D) is rapidly increasing. This is strongly related to the contemporary lifestyle changes that have resulted in increased rates of overweight individuals and obesity. Central (intra-abdominal) obesity is observed in the majority of patients with T2D. It is associated with insulin resistance, mainly at the level of skeletal muscle, adipose tissue and liver. The discovery of macrophage infiltration in the abdominal adipose tissue and the unbalanced production of adipocyte cytokines (adipokines) was an essential step towards novel research perspectives for a better understanding of the molecular mechanisms governing the development of insulin resistance. Furthermore, in an obese state, the increased cellular uptake of non-esterified fatty acids is exacerbated without any subsequent β-oxidation. This in turn contributes to the accumulation of intermediate lipid metabolites that cause defects in the insulin signaling pathway. This paper examines the possible cellular mechanisms that connect central obesity with defects in the insulin pathway. It discusses the discrepancies observed from studies organized in cell cultures, animal models and humans. Finally, it emphasizes the need for therapeutic strategies in order to achieve weight reduction in overweight and obese patients with T2D.

Citing Articles

Normal-weight central obesity and cardiometabolic disorders among Aboriginal and Torres Strait Islander Australians.

Ahmed K, Mondal U, Huda M, Aychiluhm S, Newman J, Thapa S BMC Med. 2025; 23(1):106.

PMID: 39984922 PMC: 11846202. DOI: 10.1186/s12916-025-03942-1.

Lipid Deposition in Skeletal Muscle Tissues and Its Correlation with Intra-Abdominal Fat: A Pilot Investigation in Type 2 Diabetes Mellitus.

Sarma M, Saucedo A, Sadananthan S, Darwin C, Felker E, Raman S Metabolites. 2025; 15(1).

PMID: 39852368 PMC: 11767081. DOI: 10.3390/metabo15010025.

A comparison between lipid-based vs. glycemic-based insulin sensitivity indices for the association with abnormal ECG findings and 20-year mortality among older adults.

Moshkovits Y, Goldman A, Chetrit A, Moshkovitz Shrem H, Dankner R Cardiovasc Diabetol. 2024; 23(1):438.

PMID: 39696234 PMC: 11656852. DOI: 10.1186/s12933-024-02533-3.

The value of lipid accumulation products in predicting type 2 diabetes mellitus: a cross-sectional study on elderlies over 65 in Shanghai.

Li T, Yan S, Sun D, Wu Y, Liang H, Zheng Q J Diabetes Metab Disord. 2024; 23(1):1223-1231.

PMID: 38932880 PMC: 11196563. DOI: 10.1007/s40200-024-01414-6.

Insulin degludec in pregestational diabetes: evidence and perspectives.

Papaetis G, Mikellidis K Arch Med Sci Atheroscler Dis. 2024; 9:e86-e93.

PMID: 38846058 PMC: 11155466. DOI: 10.5114/amsad/188092.

References

Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S . Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002; 8(11):1288-95. DOI: 10.1038/nm788. View

Gao Z, Zhang X, Zuberi A, Hwang D, Quon M, Lefevre M . Inhibition of insulin sensitivity by free fatty acids requires activation of multiple serine kinases in 3T3-L1 adipocytes. Mol Endocrinol. 2004; 18(8):2024-34. DOI: 10.1210/me.2003-0383. View

Davidson J . Advances in therapy for type 2 diabetes: GLP-1 receptor agonists and DPP-4 inhibitors. Cleve Clin J Med. 2009; 76 Suppl 5:S28-38. DOI: 10.3949/ccjm.76.s5.05. View

Wang C, Mao X, Wang L, Liu M, Wetzel M, Guan K . Adiponectin sensitizes insulin signaling by reducing p70 S6 kinase-mediated serine phosphorylation of IRS-1. J Biol Chem. 2007; 282(11):7991-6. DOI: 10.1074/jbc.M700098200. View

Alessi M, Juhan-Vague I . Contribution of PAI-1 in cardiovascular pathology. Arch Mal Coeur Vaiss. 2004; 97(6):673-8. View

Hansen D, Dendale P, Beelen M, Jonkers R, Mullens A, Corluy L . Plasma adipokine and inflammatory marker concentrations are altered in obese, as opposed to non-obese, type 2 diabetes patients. Eur J Appl Physiol. 2010; 109(3):397-404. PMC: 2874484. DOI: 10.1007/s00421-010-1362-5. View

Graham T, Yang Q, Bluher M, Hammarstedt A, Ciaraldi T, Henry R . Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med. 2006; 354(24):2552-63. DOI: 10.1056/NEJMoa054862. View

Qi Y, Nie Z, Lee Y, Singhal N, Scherer P, Lazar M . Loss of resistin improves glucose homeostasis in leptin deficiency. Diabetes. 2006; 55(11):3083-90. DOI: 10.2337/db05-0615. View

Gill R, Sharma A, Al-Adra D, Birch D, Karmali S . The impact of bariatric surgery in patients with type-2 diabetes mellitus. Curr Diabetes Rev. 2011; 7(3):185-9. DOI: 10.2174/157339911795843087. View

10.

Thogersen A, Jansson J, Boman K, Nilsson T, Weinehall L, Huhtasaari F . High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation. 1998; 98(21):2241-7. DOI: 10.1161/01.cir.98.21.2241. View

11.

Hotamisligil G, Shargill N, Spiegelman B . Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993; 259(5091):87-91. DOI: 10.1126/science.7678183. View

12.

Rahmouni K, Morgan D, Morgan G, Mark A, Haynes W . Role of selective leptin resistance in diet-induced obesity hypertension. Diabetes. 2005; 54(7):2012-8. DOI: 10.2337/diabetes.54.7.2012. View

13.

Paquot N, Castillo M, Lefebvre P, Scheen A . No increased insulin sensitivity after a single intravenous administration of a recombinant human tumor necrosis factor receptor: Fc fusion protein in obese insulin-resistant patients. J Clin Endocrinol Metab. 2000; 85(3):1316-9. DOI: 10.1210/jcem.85.3.6417. View

14.

Hauner H, Petruschke T, Gries F . Endothelin-1 inhibits the adipose differentiation of cultured human adipocyte precursor cells. Metabolism. 1994; 43(2):227-32. DOI: 10.1016/0026-0495(94)90250-x. View

15.

Charbonneau A, Marette A . Inducible nitric oxide synthase induction underlies lipid-induced hepatic insulin resistance in mice: potential role of tyrosine nitration of insulin signaling proteins. Diabetes. 2010; 59(4):861-71. PMC: 2844834. DOI: 10.2337/db09-1238. View

16.

Gerhardt C, Romero I, Cancello R, Camoin L, Strosberg A . Chemokines control fat accumulation and leptin secretion by cultured human adipocytes. Mol Cell Endocrinol. 2001; 175(1-2):81-92. DOI: 10.1016/s0303-7207(01)00394-x. View

17.

Festa A, DAgostino Jr R, Mykkanen L, Tracy R, Zaccaro D, Hales C . Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance. The Insulin Resistance Atherosclerosis Study (IRAS). Arterioscler Thromb Vasc Biol. 1999; 19(3):562-8. DOI: 10.1161/01.atv.19.3.562. View

18.

Hristova M, Aloe L . Metabolic syndrome--neurotrophic hypothesis. Med Hypotheses. 2005; 66(3):545-9. DOI: 10.1016/j.mehy.2005.08.055. View

19.

van Loon B, Kluft C, Radder J, Blankenstein M, Meinders A . The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance. Metabolism. 1993; 42(8):945-9. DOI: 10.1016/0026-0495(93)90005-9. View

20.

Steinberg H, Tarshoby M, Monestel R, Hook G, Cronin J, Johnson A . Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997; 100(5):1230-9. PMC: 508300. DOI: 10.1172/JCI119636. View