PhD Study : Exploiting crosstalk between the pancreas, bone and muscle for the treatment of diabetes

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Summary

Studies in our laboratory have already highlighted an important physiological link between the pancreas and bone [Mabilleau et al. 2016]. It has been demonstrated that osteocalcin (OC), a peptide hormone expressed in osteoblast bone cells and secreted into the circulation, regulates glucose homeostasis by stimulating insulin secretion directly from pancreatic beta-cells [Faienza et al. 2015]. In agreement, OC deficient mice have reduced beta-cell mass and decreased insulin sensitivity [Lee et al. 2007], whereas subcutaneous infusion of OC in mice enhances glucose tolerance and improves insulin sensitivity [Ferron et al. 2008].

Furthermore, recent studies with a myokine peptide hormone named irisin, have highlighted similar important crosstalk between muscle and the pancreas [Chen et al. 2016]. Thus, irisin has a direct impact on insulin resistance [Chen et al. 2016], and treatment of diabetic mice with irisin improved insulin secretion and glucose homeostasis [Duan et al. 2016], as well as glucose utilisation [Xin et al. 2016]. Taken together, it is clear that an important pancreas-bone-muscle loop exists, that could offer novel treatment opportunities for the treatment of diabetes. Initially, it is important to fully understand the degradation profile of OC and irisin in plasma, with a view to deterring the degradation profile of the peptides and creating longer-acting OC and irisin analogues. Such stable OC and irisin analogues would then have potential therapeutic use for diabetes.

Importantly, our laboratory has a wealth of experience in the generation of novel and stable peptide hormones that possess antidiabetic promise [Irwin & Flatt 2015]. Taken together, uncovering the mechanisms involved in the pancreas-bone-muscle loop, and the importance of OC and irisin in this respect, should help reveal novel therapeutic strategies for the treatment of diabetes.

The core objectives of this research project are:

*Determine degradation profile of osteocalcin and irisin

*Design and characterise novel stable and long-acting osteocalcin and irisin based peptides

*Assess the in vitro enzymatic stability and biological actions of novel peptides.

*Determine effects of peptides on human and rodent pancreatic beta-cell proliferation and apoptosis

*Establish in vivo gluco-regulatory and insulin secretory actions of novel peptides

*Assess beneficial effects of novel peptides alone, and in combination with established anti-diabetic drugs, in animal models with different aetiologies of type 2 diabetes.

A wide range of methods are required for this study including peptide synthesis, HPLC purification of peptides, mass-spectrometry, in vitro insulin secretion studies, PCR and Western blot, longer term in vitro culturing, assessment of markers of proliferation and apoptosis, in vitro radio-receptor binding studies, animal studies in normal rodents as well as rodent models of obesity-diabetes, tissue gene expression studies, blood biochemistry assessments, DXA scanning and measurement of body fat, indirect calorimetry measurements, behavioural analysis and use of assays including ELISA and RIA technologies. This will provide excellent training in a wide variety of important research techniques.

Applicants should note that Bench fees of £3500.00 per annum are required.

References

1. Chen N, Li Q, Liu J, Jia S. Irisin, an exercise-induced myokine as a metabolic regulator: an updated narrative review. Diabetes Metab Res Rev. 2016 Jan;32(1):51-9.

2. Duan H, Ma B, Ma X, Wang H, Ni Z, Wang B, Li X, Jiang P, Umar M, Li M. Anti-diabetic activity of recombinant irisin in STZ-induced insulin-deficient diabetic mice. Int J Biol Macromol. 2016 Mar;84:457-63.

3. Faienza MF, Luce V, Ventura A, Colaianni G, Colucci S, Cavallo L, Grano M, Brunetti G. Skeleton and glucose metabolism: a bone-pancreas loop. Int J Endocrinol. 2015;2015:758148.

4. Ferron M, Hinoi E, Karsenty G, Ducy P. Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice. Proc Natl Acad Sci U S A. 2008 Apr 1;105(13):5266-70.

5. Xin C, Liu J, Zhang J, Zhu D, Wang H, Xiong L, Lee Y, Ye J, Lian K, Xu C, Zhang L, Wang Q, Liu Y, Tao L. Irisin improves fatty acid oxidation and glucose utilization in type 2 diabetes by regulating the AMPK signaling pathway. Int J Obes (Lond). 2016 Mar;40(3):443-51.

6. Irwin N, Flatt PR. New perspectives on exploitation of incretin peptides for the treatment of diabetes and related disorders. World J Diabetes. 2015 Nov 10;6(15):1285-95.

7. Mabilleau G, Perrot R, Mieczkowska A, Boni S, Flatt PR, Irwin N, Chappard D. Glucose-dependent insulinotropic polypeptide (GIP) dose-dependently reduces osteoclast differentiation and resorption. Bone. 2016 Oct;91:102-12.

Essential criteria

Applicants should hold, or expect to obtain, a First or Upper Second Class Honours Degree in a subject relevant to the proposed area of study.

We may also consider applications from those who hold equivalent qualifications, for example, a Lower Second Class Honours Degree plus a Master’s Degree with Distinction.

In exceptional circumstances, the University may consider a portfolio of evidence from applicants who have appropriate professional experience which is equivalent to the learning outcomes of an Honours degree in lieu of academic qualifications.

Sound understanding of subject area as evidenced by a comprehensive research proposal

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.