HF feeding produces insulin resistance independently of aldosterone. Somatostatin-modified hyperinsulinaemic–euglycaemic clamps were used to abolish baseline differences in insulin secretion between wild-type and As−/− mice during HF feeding. Before the clamp, plasma C-peptide (a, basal) and insulin (b, basal) varied among groups at basal time points (white circle, normal chow wild-type; white triangle, normal chow As−/−; black circle, HF-fed wild-type; black triangle, HF-fed As−/−). Somatostatin suppressed endogenous insulin secretion, demonstrated by C-peptide in all groups (a, end), and equivalent plasma insulin was achieved between genotypes (b, End). Blood glucose was maintained at 6.9 mmol/l (125 mg/dl) (c). HF feeding significantly decreased insulin sensitivity in both wild-type and As−/− mice, demonstrated by the GIR required to maintain euglycaemia (d). ***p≤0.001