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Review
. 2000 Aug;106(4):459-65.
doi: 10.1172/JCI10830.

Insights into insulin resistance and type 2 diabetes from knockout mouse models

T Kadowaki  1
Affiliations
Review

Insights into insulin resistance and type 2 diabetes from knockout mouse models

T Kadowaki. J Clin Invest. 2000 Aug.
No abstract available

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Figures

Figure 1
Figure 1
Roles of PPARγ in the adipocyte. In this model, PPARγ acts at two steps to regulate adipocyte size and insulin sensitivity. First, PPARγ promotes the differentiation of pre-adipocytes (P) to normal, insulin-sensitive, small adipocytes (S), a step that can be activated by providing artificial PPARγ agonists, the thiazolidinediones (TZD). PPARγ also plays a critical role in adipocyte hypertrophy and development of insulin resistance under a high-fat diet. In wild-type mice, such a diet promotes adipocyte hypertrophy, which converts small adipocytes (S) into large adipocytes (L). These latter cells, in turn, induce factors such as TNF-α and FFAs, which promote insulin resistance. PPARγ+/– animals therefore enjoy some protection from adipocyte hypertrophy and the development of insulin resistance under a high-fat diet. Adapted from ref. .
Figure 2
Figure 2
Three patterns of response of pancreatic β cells to insulin resistance. (a) In IRS–/– animals, glucose tolerance remains normal in the face of insulin resistance because their β cells (red) proliferate to compensate for reduced insulin responses. (b) In mice lacking both glucokinase and IRS-1 (GK–/–/IRS-1 double knockouts), a similar compensatory β-cell hyperplasia occurs, but the animals develop type 2 diabetes because their β cells (purple) are defective in glucose-stimulated insulin secretion. (c) IRS-2–/– mice, similarly, become overtly diabetic. These animals have functional β cells (red) that are unable to undergo hyperplasia to compensate for insulin resistance. Together, these results indicate that the compensatory response of β cells to insulin resistance plays a crucial role in preventing the development of type 2 diabetes. KO, knockout.
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References

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