1. Imbalanced Insulin Actions in Obesity and Type 2 Diabetes: Key Mouse Models of Insulin Signaling Pathway 
Tetsuya Kubota, Naoto Kubota, Takashi Kadowaki 
Cell Metabolism 
Volume 25, Issue 4, Pages (April 2017)
DOI: /j.cmet
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2. Figure 1
Mechanism Underlying the Impairment of Insulin-Induced Glucose Uptake by the Skeletal Muscle in Obesity
Since downregulation of Irs2 expression in endothelial cells is probably induced by hyperinsulinemia in obese subjects, insulin-mediated Akt and eNOS activations in the fed state are inadequate, and as a result, insulin-induced capillary recruitment, increase of interstitial insulin concentrations, and increase of glucose uptake by the skeletal muscle are impaired in obese subjects. Created based upon Figure 6 in Kubota et al. (2011).
Cell Metabolism  , DOI: ( /j.cmet )
Copyright © 2017 Elsevier Inc. Terms and Conditions

3. Figure 2
Proposed Mechanism Underlying the Selective Insulin Resistance in Type 2 Diabetes
Higher expression levels of Irs1 are observed in the hepatic PV zone than in the hepatic PP zone, while Irs2 expression levels are similar between the two zones. In cases of obesity and type 2 diabetes, while the hepatocyte Irs1 expression levels remain unaffected by the hyperinsulinemia, the expression of Irs2 is downregulated in both the zones. Thus, in the PP zone, where Irs1 is less abundantly expressed and Irs2 expression is downregulated, insulin signaling is impaired despite the hyperinsulinemia, leading to impaired suppression of gluconeogenesis and hyperglycemia. In contrast, in the PV zone, where Irs1 is abundantly expressed via β-catenin activation, insulin signaling is rather stimulated in the presence of hyperinsulinemia despite the downregulation of Irs2, resulting in increased hepatic lipogenesis and steatosis. Reprinted from Kubota et al. (2016).
Cell Metabolism  , DOI: ( /j.cmet )
Copyright © 2017 Elsevier Inc. Terms and Conditions

4. Figure 3
Organ- and Pathway-Specific Imbalanced Insulin Actions in Obesity and Type 2 Diabetes
In chronic energy excessive conditions, sustained hyperinsulinemia observed in obesity consistently reduces the expression levels of Irs2, but not of Irs1, in the endothelial cells, liver, and macrophages, resulting in impaired insulin-induced glucose uptake and suppression of gluconeogenesis. On the other hand, since the expression levels of Irs1 are not decreased, excessive insulin actions are observed in the liver, smooth muscle cells, cancer cells, and adipose tissue, where Irs1 plays a pivotal role in insulin signaling, resulting in increased hepatic lipogenesis, progression of atherosclerosis, cancer, and obesity under conditions of sustained hyperinsulinemia.
Cell Metabolism  , DOI: ( /j.cmet )
Copyright © 2017 Elsevier Inc. Terms and Conditions