Obesity-induced diabetes linked to enzyme deficiencies

New research led by scientists at Kanazawa University shows how insulin resistance and endoplasmic reticulum (ER) stress is triggered in the liver of obese people.

The ER is an organelle of cells involved in the synthesis of proteins and lipids in the body. ER stress occurs when protein folding slows or fails. The body then holds an excess of unfolded proteins meaning normal protein actions are interrupted.

It is known that ER stress in the liver is a major factor in triggering insulin resistance and type 2 diabetes in obese people. However, the molecular link between obesity and ER stress are missing.

The research team led by Toshinari Takamura at Kanazawa University have uncovered a critical role of proteasome – the main function of which is to break down damaged proteins - in the development of ER stress and insulin resistance in the liver during obesity. The team first discovered that proteasome function is impaired by 30-40% in the liver of mice with obesity.

To address the significance of proteasome dysfunction in the development of insulin resistance, the research team created proteasome activator (PA28) knockout mice, which showed a 30-40% reduction in proteasome activity relative to wild-type mice, and a subsequent rise in unfolded proteins in the liver. This in turn led to ER stress, together with a significant decrease in insulin signalling. All of these effects were exacerbated by feeding the mice a high-fat diet.

If the liver fails to suppress glucose production due to reduced insulin signalling, type 2 diabetes can occur. However, the reasons why an obese people might suffer from proteasome dysfunction in the liver are as yet unclear. Takamura’s team hope to investigate proteasome further in order to clarify the processes involved.

Publication and Affiliation
Otoda T¹, Takamura T*¹, Misu H¹, Ota T², Murata S³, Hayashi H¹, Takayama H¹, Kikuchi A¹, Kanamori T¹, Shima KR¹, Lan F¹, Takeda T¹, Kurita S¹, Ishikura K¹, Kita Y¹, Iwayama K⁴, Kato K¹, Uno M¹, Takeshita Y¹, Yamamoto M⁵, Tokuyama K⁴, Iseki S⁵, Tanaka K⁶ and Kaneko S¹. Proteasome dysfunction mediates obesity-induced endoplasmic reticulum stress and insulin resistance in the liver. Diabetes. 2013 Mar;62(3):811-24. doi:10.2337/db11-1652. Epub 2012 Dec 3. PubMed PMID: 23209186. Link

Please also refer to Commentaries in Diabetes: Yalcin A, Hotamisligil GS. Impact of ER Protein Homeostasis on Metabolism. Diabetes. 2013 Mar;62(3):691-3. doi: 10.2337/db12-1526. PubMed PMID: 23431011. Link

^1. Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan
^2. Frontier Science Organization, Kanazawa University, Ishikawa, Japan
^3. Laboratory of Protein Metabolism, Department of Integrated Biology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
^4. Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Japan
^5. Department of Histology and Embryology, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan
^6. Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.

*corresponding author, e-mail address: ttakamura@m-kanazawa.jp

ID: 201302H016