Paracrine signalling in alpha cells and the integration of mechanisms that control glucagon secretion

Introduction

Diabetes is a common disease affecting millions of patients worldwide. The disease is characterised by hyperglycaemia, caused by reduced insulin signalling and release. Recent findings suggest that the hormone glucagon also plays a critical role.

Role of Glucagon

Glucagon is a counterregulatory hormone released from alpha cells in pancreatic islets to increase hepatic glucose production. Diabetic and obese patients suffer from hyperglucagonaemia, which leads to inappropriate hepatic glucose production.

Regulation of Glucagon Secretion

Glucagon secretion is regulated by intrinsic and paracrine mechanisms.

Intrinsic Regulation

The intrinsic regulation relies on the effect of glucose on metabolism.

Paracrine Regulation

The paracrine regulation depends on the secretion of hormones from neighbouring beta and delta cells. Paracrine signalling from insulin and somatostatin inhibits glucagon secretion through:

1. Activation of Protein kinase B
2. Inhibition of Protein kinase A

This leads to lower electrical and exocytotic activity. Both kinases regulate transcription and metabolism in other tissues.

Hypothesis

I suggest that paracrine signalling also affects alpha cell metabolism to regulate glucagon secretion. My recent work shows that alpha cells rely on fatty acids for ATP production and that the mechanism by which glucose inhibits glucagon secretion requires glucose to lower fatty acid oxidation.

Project Objectives

In this project, I will:

1. Investigate whether insulin and somatostatin signalling regulate metabolism and ATP production in alpha cells.
2. Identify the underlying kinase signalling.
3. Explore the role of hyperglucagonaemia in diabetes.

Methodology

To understand the effect of insulin and somatostatin on alpha cell function and glucagon secretion, I will use dynamic measurements of:

• Kinase signalling
• ATP levels
• Membrane potential
• Calcium in mouse and human islets

Combining this with genetically modified animal models, we will have the unique opportunity to study if dysfunction of both paracrine and intrinsic regulation of glucagon secretion is required for the development of hyperglucagonaemia in diabetes.