Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2016

Overexpression of the Unfolded Protein Response Gene Herpud1 leads to impaired insulin secretion but protection from high fat induced glucose intolerance (#96)

Amy Huang 1 , Diane Vue 1 , Nicole Wong 1 , Sof Andrikopoulos 1
  1. University of Melbourne, Heidelberg, Vic, Australia

Islet β-cell dysfunction in the presence of insulin resistance is the key defect causing hyperglycaemia in type 2 diabetes.  While many mechanisms have been investigated including glucose toxicity, lipotoxicity, oxidative and endoplasmic reticulum stress, it is still not clear what causes islet β-cell dysfunction.  Furthermore, there may be interaction between oxidative and endoplasmic reticulum stress, such that the damage to the cell is amplified. Herpud1 is a gene that encodes for the unfolded protein response (UPR) protein called Herp, which we have previously associated with impaired insulin secretion.  Herp is involved in the early UPR response and may be protective against further cellular damage.  To further understand the role of Herp in insulin secretion, we generated β-cell specific Herpud1 transgenic mice that have a four-fold increase in β-cell Herp compared with littermate controls. On a chow diet, β-cell Herp transgenic mice had normal body weights but fasting hyperglycaemia associated with impaired insulin secretion following an intravenous glucose tolerance test (IVGTT).  Following a high fat diet for 8 weeks, β-cell Herp transgenic mice similar body weights and fasting plasma glucose levels and were protected from the insulin hypersecretion following an IVGTT seen in the littermate controls. In vitro isolated islet studies showed that while high fat exposure reduced glucose-mediated insulin secretion in control mice, β-cell Herp transgenic mice secreted comparable insulin amounts to the control non-fat exposed islets.  The data suggest that overexpression of the URP protein Herp can impair insulin secretion and that following high fat exposure this defect is no longer observed.  The data support a role of the UPR in the protection against fat-induced impairments in insulin secretion and may identify Herp as a potential target to improve β-cell function in type 2 diabetes.