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Type 2 diabetes occurs as a result of insulin resistance and dysfunction in insulin signaling. Controlling hyperglycemia and activation of insulin signaling are important in the management of type 2 diabetes. This study aimed to evaluate the effect of genistein and Momordica charantia L. fruit (MCF) on oxidative stress, markers of inflammation, and their role in proglucagon and insulin receptor messenger RNA (mRNA) expression by real-time PCR in diabetic rats. Thirty-five albino rats were divided into 7 groups ( n  = 5). Group I (non-diabetic) and group II (diabetic control) were treated with distilled water, and groups III and IV received 250 mg/kg and 500 mg/kg lyophilized MCF, respectively. Groups V and VI received 10 mg/kg and 20 mg/kg genistein, respectively, while group VII received 500 mg/kg metformin. The administration lasted for 28 days. MCF and genistein significantly reduced interleukin (IL)-1β and tumor necrosis factor alpha (TNF-α) levels, which were elevated in the serum of diabetic rats. Treatment with MCF and genistein significantly increased the expression of proglucagon mRNA in the small intestine and insulin receptor mRNA in the liver of diabetic rats. In conclusion, MCF and genistein ameliorate type 2 diabetes complications by preventing the loss of insulin-positive cells, inhibiting IL-1β and TNF-α, and upregulating proglucagon and insulin receptor mRNA expression. Novelty: MCF and genistein have an inhibitory effect on diabetic induced IL-1β and TNF-α production. MCF and genistein upregulate proglucagon and insulin receptor mRNA expression.