Pancreatic islet cell biology

Development and function of pancreatic beta cells:

Diabetes1We are interested in understanding the changes in beta cell gene expression that occur during the functional maturation of pancreatic beta cells during their development, and the influences of hormones and environmental factors, particularly diet, on the development and function of the endocrine pancreas.

Pancreatic islets respond poorly to stimulators of insulin secretion in fetal or neonatal life, but secretory responses mature during development concomitant with upregulation of major components of glucose sensing and exocytosis.  Our studies have shown that IA-2, a secretory granule protein that is a major target of autoimmunity in Type 1 diabetes, is an important regulator of beta cell secretory granule content and insulin secretion. IA-2 is poorly expressed in fetal life, but is up-regulated after birth, in parallel with increases in islet insulin secretion in response to glucose.

The early post natal period is important for establishing immunological self tolerance and environmental factors that regulate islet protein expression during this period may influence tolerance induction. We have shown that maternal high fat diet can influence the expansion and maturation of pancreatic islets and studies in somatostatin knockout mice have implicated transforming growth factor beta signalling in this process.  

These studies will aid our understanding of how early exposure to environmental factors can influence the growth, development and function of the pancreatic islet and influence susceptibility to Type 1 and Type 2 diabetes later in life.

 

Cell communication in pancreatic beta cell function

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Photo: Time lapse of glucose-induced changes in cytosolic calcium measured using fura-2 microfluorimetry in from an engineered pancreatic pseudoislet. 

The idea that the functional unit of insulin secretion is the pancreatic islet is reinforced by evidence that glucose-induced oscillations of [Ca2+]i are synchronous in clusters of beta-cells, whereas individual cells show varied and asynchronous changes in [Ca2+]i with very different thresholds for stimulation by glucose.

In accordance with this, dispersed pancreatic beta-cells exhibit a wide range of thresholds for stimulation by glucose. Dispersed islet cells tend to re-aggregate on prolonged culture in vitro and re-aggregated cells are more responsive, and suggest that functional coupling between cells is critical for efficient and appropriate insulin release.

Several theories have been proposed to explain the synchronous and cooperative activity of islets when compared to non-cooperative events in isolated individual beta-cells including; the presence of other endocrine cells in islets, increased concentration of a diffusible transmitter and activity of gap-junctions.

It has been suggested that cell adhesion molecules may also be important in regulating both islet architecture and insulin secretion from beta-cells. We are currently examining the impact that the calcium-sensing receptor (CaSR) has on E-cadherin mediated cell-cell adhesion, improved cell-to-cell communication and insulin secretion. 

Key References

Lobner K, Steinbrenner H, Roberts GA, Ling Z, Huang GC, Piquer S, Pipeleers DG, Seissler J, Christie MR (2002) Different regulated expression of the tyrosine phosphatase-like proteins IA-2 and phogrin by glucose and insulin in pancreatic islets: relationship to development of insulin secretory responses in early life.  Diabetes 51: 2982-2988

Richardson CC, Hussain K, Jones PM, Persaud S, Lobner K, Boehm A, Clark A, Christie MR (2007) Low levels of glucose transporters and K+ATP channels in human pancreatic beta cells early in development. Diabetologia 50 :1000-1005

Foot VL, Richardson CC, Jefferson W, Taylor PD, Christie MR (2010) Islets in early life are resistant to detrimental effects of a high-fat maternal diet; a study in rats.  Horm Metab Res  44: 923-929

Richardson CC, To K, Foot VL, Hauge-Evans AC, Carmignac D, Christie MR (2015) Increased perinatal remodelling of the pancreas in somatostatin-deficient mice: potential role of transforming growth factor-beta signalling in regulating beta cell growth in early life. Horm Metab Res 47: 56-63

Hills C.E., Younis M.Y.G., Bennett J., Siamantouras E., Liu K-K., Squires P.E.(2012) Calcium-sensing receptor activation increases cell-cell adhesion and β-cell function. Cell Physiol Biochem, 30, 575-586.

Squires, P.E., Jones, P.M., Younis M.Y.G, Hills, C.E. (2014) 'The calcium-sensing receptor and beta-cell function.' The pancreatic beta-cell. Vitamins & Hormones 95, 249-267.

Siamantouras E., Hills C.E., Younis M.Y.G., Squires P.E., Liu K-K. (2014) Quantitative investigation of calcimimetic R568 on beta-cell adhesion and mechanics using AFM single-cell force spectroscopy. FEBS Letters 588 1178 – 1183

Funding

All research is funded by Diabetes UK

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Freemasons donated £50,000 to Diabetes UK for Type 1 'vaccine' research within the University of Lincoln

School of Life Sciences, University of Lincoln, Brayford Pool, Lincoln. LN6 7TS 

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