Background: Increasing body weight is a risk factor for development of insulin resistance (IR) and type 2 diabetes mellitus (T2DM). Aim: We aimed to determine the relationship between insulin, C-peptide, leptin, cortisol, growth hormone (GH) and adiposity in obese and subjects with T2DM as data regarding this issue are still controversial. Study Design: Cross sectional study. Methodology: this study included 60 patients with T2DM, 60 obese non-diabetics and 30 healthy controls. Anthropometric parameters, glycemic and lipid profiles, insulin, C-peptide, leptin, cortisol and GH were measured. Results: Serum C-peptide (P=0.025, P=0.030, P=0.021), insulin (P=0.0001 for all) and leptin Original Research Article Hamed et al.; BJMMR, 12(2): 1-12, 2016; Article no.BJMMR.21457 2 (P=0.001, P=0.02, P=0.0001) were higher in obese (n=22) and non-obese diabetics (n=38) and obese non-diabetics versus controls. Cortisol was higher in obese non-diabetics versus obese (P=0.017) and non-obese (P=0.007) diabetics and controls (P=0.0001). GH was higher in obese non-diabetics versus obese diabetics (P=0.031). IR was reported in obese (72.70%) and nonobese (71.00%) diabetics and obese non-diabetics (38.30%). Central obesity was reported in obese (59.10%) and non-obese (34.20%) diabetics and obese non-diabetics (45.00%). In obese diabetics, a positive correlation was reported between leptin with C-peptide (P=0.001). In nonobese diabetics, positive correlations were reported between IR and cortisol (P=0.025) and waist/hip ratio (WHR) with insulin (P=0.029) but a negative correlation was reported between glycosylated hemoglobin (HBAIc) and leptin (P=0.047). In obese non-diabetics, positive correlations were reported between leptin with HbA1c (P=0.01) and cortisol (P=0.003), WHR with insulin (P=0.0001) and cortisol with leptin (P=0.003). Conclusion: The association of insulin and leptin resistances and hypercortisolemia with obesity supports the notion that the regulatory defects of blood glucose and obesity are associated with long-term metabolic complications.