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  Preferential Gq signalling in diabetes: an electrical switch in incretin action and in diabetes progression?

   Radcliffe Department of Medicine

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  Prof P Rorsman  No more applications being accepted  Self-Funded PhD Students Only

About the Project

The progression of type 2 diabetes (T2D) involves development of insulin resistance that is frequently associated with obesity and that is initially compensated by increased insulin secretion from pancreatic β-cells. As insulin resistance increases, β cells eventually fail at which point hyperglycaemia (mild at first) develops leading to a progressive worsening of β-cell function. 

The incretin hormones GIP and GLP-1 (secreted by the endocrine cells of the gut) play a central role in adjusting insulin secretion. Under physiological conditions, GIP plays a particularly important role as it is rapidly released from the duodenum upon food intake. GLP-1 is released with a delay (from the ileum and colon) and therefore does not contribute much to the acute stimulation of insulin secretion. Traditionally, GIP and GLP-1 are thought to use the same (cAMP/PKA-dependent) intracellular signalling pathways but recent data suggest this viewpoint is too simplistic (1). 

In diabetes, the capacity of GIP to stimulate insulin secretion is gradually lost (Nauck MA, Meier JJ. Lancet Diabetes Endocrinol. 4:525–536, 2016). We have recently shown that persistent activation of β-cells (for example, due to chronic hyperglycaemia) cells leads to a switch from Gs to Gq in a major amplifying pathway of insulin secretion. The switch determine the relative insulinotropic effectiveness of GLP-1 and GIP, as GLP-1 can activate both Gq and Gs, while GIP only activates Gs. This observation explains the paradox that whilst GIP represent the physiologically important incretin, only GLP-1-based therapies are effective in patients with beta-cell failure (1). 

The impact of T2D on pancreatic hormone secretion is not restricted to insulin but also includes glucagon and somatostatin (released by the α- and δ-cells of the pancreatic islets) (2,3). Hypersecretion of these two hormones exacerbates the hyperglycaemia resulting from insufficient insulin secretion. The underlying cellular and molecular mechanism have only partially been elucidated. Our studies of α- and δ-cells indicate that hormone release in these cells involves processes similar to those in β-cells (2, 4-6). We therefore hypothesise that the glucagon and somatostatin secretion defects, by analogy to what we have described for β-cells) also result from chronic hyperglycaemia and culminate persistent activation of the α- and δ-cells. 

We believe that the understanding of the physiology and pathophysiology of T2D must include detailed analyses of all the islet cell types and their cross-talk. Our laboratory has a long track record in cell physiological studies of these cells. Our studies involve a wide experimental repertoire that includes biochemical measurements of hormone release, electrophysiology, mouse genetics, advanced optical imaging techniques involving genetically encoded reporters, in vivo physiology and in silico modelling. 

For this project, we will use the Kcnj11fl/fl mouse model (1) and cross them with proglucagon (PG)- or somatostatin (Sst)-cre mice to specifically ablate the ATP-regulated K+ (KATP) channels in α- or δ-cells whilst maintaining normal KATP channel activity in the other islets cells. Previous work suggests that the KATPchannel plays a central role in metabolic regulation of all three types of islet endocrine cell (2,3,6). Closure of the KATP channels leads to membrane depolarization and action potential, culminating in Ca2+ influx and Ca2+-dependent exocytosis of hormone-containing secretory vesicles. Cell-specific ablation of the KATP channels allows us to distinguish between direct effects in α- and δ-cells and more systemic effects of diabetes/hyperglycaemia. Key observations in the mouse models will be confirmed in human pancreatic islets obtained from the OCDEM-based clinical islet isolation and transplantation centre. We have extensive experience of studies on human pancreatic islets (1,6).

Additional supervision will be be provided by Dr Quan Zhang.

For the motivated  student this project is an exceptional opportunity. 

The project provides training in a breadth of techniques: electrophysiology, imaging of multicellular systems, mouse genetics, in vivo physiology and in silico modelling. 

With the training that the project will provide, the successful candidate will be highly employable (like our past students).

The team currently consists of 9 postdoctoral fellows and 2 DPhil students. Our funding comes from the MRC and the Helmsley Trust. 

The student will meet with the principal supervisor on an ad hoc basis but at least twice a month. Daily supervision will be provided by postdoctoral fellows, which will be allocated to the project as it develops. There are weekly lab meeting (by Teams to allow everybody to attend regardless of other commitments). 

More than 30 research students have successfully completed their training under the tutelage of the primary supervisor. 

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Biological Sciences (4) Medicine (26)


1 ODUORI OS, MURAO N, SHIMOMURA K, TAKAHASHI H, ZHANG Q, DOU H, SAKAI S, MINAMI K, CHANCLON B, GUIDA C, KOTHEGALA L, TOLO J, MAEJIMA Y, YOKOI N, MINAMI Y, MIKI T, RORSMAN P & SEINO S. Gs/Gq signaling switch in beta cells defines incretin effectiveness in diabetes. J Clin Invest 130: 6639-6655 (2020).
3 KNUDSEN JG, HAMILTON A, RAMRACHEYA R, TARASOV AI, BRERETON M, HAYTHORNE E, CHIBALINA MV, SPÉGEL P, MULDER H, ZHANG Q, ASHCROFT FM, ADAM J, RORSMAN P. Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production. Cell Metab. 29(2):430-442. (2019).
4 ZHANG Q, RAMRACHEYA R, LAHMANN C, TARASOV A, BENGTSSON M, BRAHA O, BRAUN M, BRERETON M, COLLINS S, GALVANOVSKIS J, et al. Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes. Cell Metab. 18:871-82 (2013)
5 BASCO D, ZHANG Q, SALEHI A, TARASOV A, DOLCI W, HERRERA P, SPILIOTIS I, BERNEY X, TARUSSIO D, RORSMAN P, et al. alpha-cell glucokinase suppresses glucose-regulated glucagon secretion. Nat Commun. 9:546 (2018)
6 RORSMAN P, AND ASHCROFT FM. Pancreatic beta-Cell Electrical Activity and Insulin Secretion: Of Mice and Men. Physiol Rev. 98:117-214 (2018)

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 About the Project