Medicine (Austin & Northern Health) - Research Publications
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ItemNarrow-leafed lupin (Lupinus angustifolius L.) β-conglutin proteins modulate the insulin signaling pathway as potential type 2 diabetes treatment and inflammatory-related disease amelioration(WILEY, 2017-05)SCOPE: We have investigated the potential use of β-conglutin protein isoforms from narrow-leafed lupin (Lupinus angustifolius L.) as a diabetes treatment. METHODS AND RESULTS: We produced purified recombinant β1-, β2-, β3-, β4-, and β6-conglutin proteins and showed that β1, β3, and β6 could bind to insulin. To assess β-conglutin proteins modulatory effect on insulin activation meditated kinases, whole blood and peripheral blood mononuclear cell cultures from type 2 diabetes (T2D) and healthy control subjects (C) were incubated with conglutin proteins. The treatment of peripheral blood mononuclear cells from T2D patients with β1, β3, and β6 proteins increased up to threefold mRNA and protein levels of genes important in insulin signaling pathways, namely insulin receptor substrate 1/p85/AKT/glucose transporter type 4. This was accompanied by a comparable fold-change decrease in the mRNA expression level of pro-inflammatory genes (iNOS and IL-1β) and proteins compared to healthy controls. The β2 and β4 isoforms had no effect on the insulin signaling pathway. However, these β-conglutin proteins elicited pro-inflammatory effects since levels of mRNA and proteins of inducible nitric oxide synthase and IL 1 beta were increased. CONCLUSION: Our results raise the possibility of using these particular β-conglutin proteins in the prevention and treatment of diabetes, as well as their potential as anti-inflammatory molecules.
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ItemA novel mechanism regulating insulin secretion involving Herpud1 in mice(SPRINGER, 2013-07)AIMS/HYPOTHESIS: Type 2 diabetes results from beta cell dysfunction after prolonged physiological stress, which causes oversecretion of insulin. We recently found that insulin hypersecretion is mediated by at least two genes. Among mouse models of type 2 diabetes, the DBA/2 mouse strain is more susceptible to diabetes than is the C57BL/6J (B6J) strain. One distinctive feature of the DBA/2 mouse is that it hypersecretes insulin, independent of changes in insulin sensitivity; we identified Nnt as a gene responsible for this trait. METHODS: To identify the other gene(s) affecting insulin hypersecretion, we tested a panel of recombinant inbred BXD strains, which have different combinations of B6 and DBA/2 alleles. RESULTS: We found that 25% of the BXD strains hypersecreted insulin in response to glucose. Microarray profiling of islets from high- and low-secretor strains showed that at least four genes were differentially expressed. One gene was consistently underexpressed in islets from both DBA/2 and the high-secretor BXD strains. This gene (Herpud1 or Herp) encodes the 54 kDa endoplasmic reticulum stress-inducible protein (HERP) that resides in the integral endoplasmic reticulum membrane. To test directly whether Herpud1 can interact with Nnt, Herpud1 was either knocked down or overexpressed in MIN6 cells. These results showed that when Herpud1 was suppressed, Nnt expression was reduced, while overexpression of Herpud1 led to increased Nnt expression. Furthermore, Herpud1 suppression resulted in significantly decreased glucose-stimulated insulin secretion in the DBA/2 islets but not B6J islets. CONCLUSIONS/INTERPRETATION: We conclude that Herpud1 regulates insulin secretion via control of Nnt expression.