While it is uncertain whether these alterations also involve modified incretin responses, within the framework of obesity, MetS and the use of hydrochlorothiazide for treating hypertension associated with these conditions, these findings suggest an intriguing hypothesis: that overweight or overnutrition might amplify the metabolic effects of these diuretics by inhibiting NCC and/or other targets in β-cells and in metabolically active tissues but independently of insulin secretion. This evidence concerns the gene INS and obesity due to melanocortin 4 receptor deficiency.