Comprehensive study on human pancreatic β-cell regulatory mechanism

Professor Yoshifumi Saisho of the Division of Nephrology, Endocrinology and Metabolism, Keio University School of Medicine, Japan. Saisho’s work focuses on beta cells and their central importance to T2DM. He believes that current research, diagnosis and treatment are too glucose-centric. That is to say, the focus is on glucose and insulin levels instead of the biological underpinning of these factors - the beta cells. Beta cells detect blood glucose levels and manufacture insulin accordingly. In those with T2DM, the beta cells become increasingly overworked and eventually start to lose mass, or in other words die, and become dysfunctional. Saisho believes a switch to uncovering more about beta cells in T2DM is necessary to help our chances of reducing the disease burden, both on individuals and on healthcare systems. Beta cells are found in the pancreas and make, store and secrete insulin. They sense glucose levels through the initiation of glycolysis - the first step in the cell’s core metabolic pathway - caused by the diffusion of glucose through pores in the cell membrane. The increase in ATP results in a downstream accumulation of potassium ions and therefore a potential difference. This leads to an activation of voltage-gated channels, increasing the cellular calcium levels which, in turn, forces intracellular vesicles containing insulin to release their cargo into the bloodstream. In those with T2DM, the beta are constantly detecting high blood glucose levels and therefore increase their production of insulin to counteract this. Essentially, their workload increases. The cells cannot withstand this higher workload for long and begin to lose functionality. In addition to losing functionality, many cells also begin to die. The mechanism behind this is unknown, though many ideas have been proposed. However, it has been shown that loss of cells occurs through increased cell death rather than a loss of ability to replicate and regenerate. Crucially, studies show there is already a 50 per cent loss of functionality (either through death or loss of ability to function properly) in beta cells by diagnosis. Saisho believes such findings are key to catching T2DM earlier and finding more ways to reverse its progression. This is because they show that the actual disease physiology occurs much earlier than the point of diagnosis. Those who show elevated blood glucose levels below the threshold for T2DM either have impaired fasting glycaemia (IFG) and/or impaired glucose tolerance (IGT). They are monitored and told to improve diets and health, but are not investigated further biologically. However, it is most likely that this is actually the key point at which to target beta cells and where the majority of their loss occurs.