The incidence of insulin resistance and its complications is rising across societies worldwide, making its treatment a significant economic challenge. The disease is multifactorial, and its pathophysiology varies accordingly. Genetic factors, aging, and coexisting diseases are major contributors to its development. Among the coexisting conditions are autoimmune diseases and other conditions requiring treatment with therapeutic agents, some of which can induce insulin resistance. Research indicates that the free radical theory plays a significant role in initiating this complex cycle and in shaping the full clinical picture of diabetes syndrome. In this work, we discuss the pathophysiology of insulin resistance, the role of free radicals in its etiology, and drug treatments for diseases that may contribute to insulin resistance. We also explore the antioxidant effects of vitamin D and oral hypoglycemic agents, as well as their notable adverse effects, including cobalamin (vitamin B12) deficiency. A total of 147 scientific studies, including comprehensive meta-analyses, have been selected to address these questions and have been analyzed and discussed objectively to minimize scientific bias and confusion. This narrative work will help doctors and primary health caregivers envision the dimensions of diabetes syndrome from multiple perspectives and update their knowledge about the significance of vitamin D as an effective tool to combat insulin resistance