Hepatic heat shock proteins in Diabetes and long term diabetic complications

M Brune, NB Nillegoda, B Bukau, PP Nawroth, S Herzig

Research output: Contribution to journalMeeting Abstract

Abstract

Aims: Diabetes mellitus type 2 (DM 2) and its complications include intracellular accumulation of damaged and misfolded proteins, while protective heat shock proteins (HSP) are repressed. We aim to identify HSP-regulated liver-to-periphery signalling pathways effecting the development and progression of long term diabetic complications.

Methods: Livers of DM 2 mice (db/db) were analyzed for expression levels of HSPs. In-vivo reconstitution of HSPs in db/db mice was achieved via hepatocyte-specific adenoviral constructs for Hsp70, DNAJB1 and DNAJA2.

Results: In db/db livers, central HSPs were significantly downregulated (up to -90%). In contrast, the hepatocyte-specific reconstitution of Hsp70 reduced both liver pathology (ALT -40%) and hyperglycaemia (glucose and HbA1c -25%). The simultaneous reconstitution of the cooperating HSPs Hsp70, DNAJB1 and DNAJA2 further improved liver pathology (ALT -67%) and glucose metabolism, including glucose tolerance. Hepatocyte transcriptome analysis revealed protein and amino acid turnover to be involved, and the levels of individual amino acids were increased in both hepatocytes and serum of treated mice. Importantly, hepatic HSP-treatment improved Akt signalling in muscle tissue as well as the thermal nociceptive responsiveness, suggesting a reduced insulin resistance and a reduction of the pre-existing diabetic neuropathy.

Conclusion: The hepatic reconstitution of HSPs cooperating in protein quality control resulted in a profound metabolic improvement in our in vivo model of DM 2, affecting not only parameters of carbohydrate metabolism but also insulin resistance and the long term complication of diabetic neuropathy. Our data indicate that hepatic HSPs regulate systemic signalling pathways which direct the course of diabetes and its long term complications.

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Original languageEnglish
Pages (from-to)31
Number of pages1
JournalDiabetologie und Stoffwechsel
Volume10
DOIs
Publication statusPublished - 2015
Externally publishedYes

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