Insulin resistance, the key mechanism in Type 2 diabetes mellitus (T2DM) is also associated with the deregulation of other glucose homeostasis pathways, such as the growth hormone (GH)-IGF-I system. In this review, we summarize the endocrine and renal GH-IGF axis changes in db/db mice, a model of T2DM, and compare it with the nonobese diabetic mouse model of T1DM. In the latter, elevated circulating GH levels (associated with kidney disease) could be ameliorated with the use of GH antagonists. Contrary to that, in the obese db/db mice, serum GH and IGF-I levels are decreased and tissue levels of IGF-binding protein 1 (Igfbp1) are increased. The latter hinted again for the known inverse correlation between insulin and Igfbp1 and was mediated by changes in the transcription factor phosphorylated forkhead box O1 in obese animals. In addition, the decrease in circulating IGF-I and GH levels causes a state of low free and active IGF-I, which may further impair tissue viability (including pancreatic β-cells). Thus, further GH inhibition to modulate complications in T2DM is not indicated, but the therapeutic role of IGF-1 in this disease remains to be determined.