The invention relates to the use of isoform-specific fructokinase (ketohexokinase) (KHK) inhibitors alone or in combination with various agents to both prevent and treat a wide variety of diseases including, but not limited to, sugar craving, obesity, features of metabolic syndrome (including insulin resistance, hypertriglyceridemia, hypertension, and fatty liver), polyuria, proximal tubular injury, and diabetic kidney disease.