Objective: Obesity is associated with insulin resistance and hyperinsulinemia which is considered to be a core component in the pathophysiology of obesity related co-morbidities. As yet it is unknown if insulin resistance and hyperinsulinemia already develop during weight gain within the normal range. Methods: In 10 healthy male subjects the effect of intentional weight gain by 2 BMI-points was examined on insulin. C-peptide and glucose levels following a meal, 75g glucose and a two-step hyperglycemic clamp increasing plasma glucose by 1.38 and 2.75mmol/l, respectively. Results: Baseline insulin, C-peptide and glucose concentrations were significantly higher after weight gain from BMI 21.8kg/m² to 23.8kg/m² within 4.5 months. Calculations of insulin-secretion and clearance indicate that reduced insulin clearance contributes more to post weight gain basal hyperinsulinemia than insulin secretion. Following oral or i.v.-stimulation insulin concentrations were significantly higher post weight gain during all three test conditions while C-peptide and glucose levels did not differ. Calculations of insulin secretion and clearance demonstrated that higher stimulated insulin concentrations are entirely due to clearance but not secretion. Despite significantly higher insulin levels the rate of i.v.-glucose required to maintain the defined elevation of glucose levels was either identical (1.38mmol/l) or even significantly lower (2.75mmol/l) following weight gain. Conclusion: The present study demonstrates for the first time that insulin resistance develops already during weight gain within the normal range of body weight. The associated basal and stimulated hyperinsulinemia is the result of differentiated changes of insulin secretion and clearance, respectively.