Abstract: OBJECTIVE To observe the change of protein expression on PKA/PKC/CaMK Ⅱ phosphorylation signal pathway in the hippocampal tissue of type 2 diabetic rats induced by recurrent severe hypoglycemia and explore the effect of cognitive impairment on the brain. METHODS Forty adult SD rats were randomly divided into 4 groups: control group, diabetes group, recurrent severe hypoglycemia group and diabetes recurrent severe hypoglycemia group. By using STZ method to establish model of type 2 diabetes. The rats in control group and diabetes group were injected with normal saline. The rats in recurrent severe hypoglycemia group and diabetes recurrent severe hypoglycemia group were treated with ordinary insulin continuously for 4 days to present the state of recurrent severe hypoglycemia (<2.0 mmol·L^-1). Western blot method was used to detect the protein phosphorylation expression of PKA/PKC/CaMKⅡ related phosphorylation protein. RESULTS In the rat hippocampus, the protein phosphorylation level of PKA was significant higher in diabetes recurrent severe hypoglycemia group than that in control group(P<0.05). Similarly, the upstream ERK phosphorylation level was also significant higher. PKC, CaMK Ⅱ related protein phosphorylation level showed no significant different between control group and diabetes recurrent severe hypoglycemia group(P>0.05). Compare with diabetes group and recurrent severe hypoglycemia group, PKA, PKC, CaMK Ⅱ related protein phosphorylation level in diabetes recurrent severe hypoglycemia group showed no significant difference(P>0.05). CONCLUSION PKA phosphorylation level was dramatically increased in the hippocampal tissue of type 2 diabetic rats induced recurrent severe hypoglycemia. The change of PKA phosphorylation expression could be used as sensitive biochemical indicators.