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To determine the therapeutic effects of adrenomedullin (ADM) on vascular calcification and related molecular mechanism in fructose-induced insulin resistance rats.Rats received ordinary drinking water or 10% fructose in drinking water for 12 weeks and subcutaneous injection of normal saline or ADM (3.6 μg kg−1) twice a day for the last 4 weeks. Levels of ADM, calcitonin receptor-like receptors (CRLR), receptor activity-modifying proteins (RAMP) as well as calcium content, alkaline phosphatase (ALP) activity, osteoblastic and contractile smooth muscle markers in aortic media were measured.The levels of ADM, CRLR, RAMP2 and RAMP3 in aortic media were increased in fructose-fed rats. ADM treatment attenuated the fructose-induced insulin resistance, increased blood pressure, fasting glucose, insulin, triglycerides and cholesterol levels. It improved VSMCs proliferation and disordered arrangement and hyperplasia of elastic fibres in fructose-fed rats. Calcium deposits, calcium content and ALP activity in the aortic media were increased in fructose-fed rats, which were attenuated by ADM treatment. The osteoblastic markers such as osteopontin (OPN), bone morphogenetic protein 2 (BMP2) proteins and core binding factor alpha-1 (Cbfα-1) protein and mRNA expressions were increased in fructose-fed rats. ADM treatment increased the OPN protein expression, but reduced the BMP2 protein, Cbfα-1 protein and mRNA expression. Contractile smooth muscle markers such as α-actin and smooth muscle 22α (SM-22α) were downregulated in fructose-fed rats, which were recovered by ADM treatment.Administration of ADM attenuates insulin resistance, calcium deposition and osteogenic transdifferentiation in aortic media in fructose-fed rats.