**The Impact of Inflammation on Pancreatic β-Cell Metabolism, Function and Failure in T1DM and T2DM: Commonalities and Differences**

Philip Newsholme, Kevin Keane, Paulo I Homem de Bittencourt Jr. and Mauricio Krause

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55349

**1. Introduction**

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Type 1 diabetes mellitus (T1DM) is a chronically progressive autoimmune disease that affects approximately 1% of the population in the developed world. This adverse immune response is induced and promoted by the interaction of both genetic and environmental factors. In contrast, in type 2 diabetes mellitus (T2DM), insulin-resistance coupled with reduced insulin output appears to be the major cause of hyperglycaemia (affecting approximately 6% of the population). Although the aetiology of diabetes may differ from T1DM to T2DM, a common feature associated with both types is the failure of pancreatic β-cells in the islets of Langerhans, thus causing a reduction in insulin secretion, cell mass and ultimately apoptotic death. However, the impact and time-course of pancreatic β-cell death, which may appear very different in T1 and T2DM, may be related through common molecular mechanisms.

Glucose-stimulated insulin secretion (GSIS) is central to the physiological control of metabolic fuel homeostasis, and its impairment is a hallmark of pancreatic β-cell failure in T2DM. β-Cells are often referred to as "fuel sensors" as they continually monitor and respond to dietary nutrients, under the modulation of additional neuro-hormonal and immunological signals, in order to secrete insulin to best meet the needs of the organism. Therefore, β-cell dysfunction and death in diabetes leads to hyperglycaemia and its complications. An intriguing charac‐ teristic of the pancreatic β-cells is their similarity to immune cells: 1) they can release cytokines; 2) they strongly respond to cytokines from other cells and tissues; 3) their function is dependent on the production of reactive oxygen (ROS) and nitrogen species (RNS); 4) they express high

© 2013 Newsholme et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

levels of pro-inflammatory proteins such as nuclear transcription factor κB (NFκB), inducible nitric oxide synthase (iNOS), NADPH oxidase (NOX), Toll-like receptors (TLR) and other proteins in response to immune signals, but also to metabolic challenge. However and in contrast to professional immunoinflammatory cells, such as macrophages or neutrophils, the β-cell is fragile when subjected to immune attack and is highly vulnerable to oxidative stress.

β-cell plasma membrane transporter proteins GLUT1 and GLUT2, actively transport free glucose molecules inside the cell where glycolysis can be initiated to create the nucleotide ATP (Fig. 1). Consequently, intracellular metabolism of glucose by glycolysis, and further metab‐ olism of pyruvate via the downstream tricarboxylic acid (TCA) cycle, leads to elevated NADH, FADH2 and ultimately ATP levels [4]. The increased intracellular ATP:ADP ratio closes

The Impact of Inflammation on Pancreatic β-Cell Metabolism, Function and Failure in T1DM and T2DM…

and a subsequent opening of membrane-bound voltage activated Ca2+ channels. A rapid influx of calcium ions is promoted, causing the exocytosis of insulin through fusion of the insulin containing vesicles with the plasma membrane via VAMP (vesicle-associated membrane protein) and SNARE (soluble NH2-ethylmaleimide-sensitive fusion protein attachment protein receptor) association [5]. This specific process of insulin secretion is known as KATPdependent GSIS, and since ATP generation is critical, the metabolic control points of glycolysis, the TCA cycle and oxidative phosphorylation (*i.e.* activity of metabolic enzymes such as hexokinase, phosphofructokinase, pyruvate kinase, pyruvate dehydrogenase, pyruvate carboxylase, glutamate dehydrogenase and mitochondrial redox-shuttles) have a significant

**Figure 1.** Mechanisms of nutrient and amino acid stimulated insulin secretion. Glucose metabolism is essential for stimulation of insulin secretion. The mechanisms by which amino acids enhance insulin secretion are understood to primarily rely on (a) direct depolarization of the plasma membrane (e.g. cationic amino acid, L-arginine); (b) metabo‐ lism (e.g. alanine, glutamine, leucine); and (c) co-transport with Na+ and cell membrane depolarization (e.g. alanine). Notably, rapid partial oxidation may also initially increase both the cellular content of ATP (impacting on K+ATP chan‐ nel closure prompting membrane depolarization) and other stimulus secretion coupling factors. In the absence of glu‐ cose, fatty acids may be metabolised to generate ATP and maintain basal levels of insulin secretion. Adapted from [3].

However, there also remains the possibility that KATP-independent GSIS can occur in the βcell, although the exact methodology is still not fully understood. KATP-independent GSIS has been illustrated in studies utilising diazoxide to maintain K+ channels in the open position [6]

channels, resulting in plasma membrane depolarisation

http://dx.doi.org/10.5772/55349

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membrane-bound ATP-sensitive K+

impact on regulation of insulin release.

In this chapter, we intend to review the mechanisms of insulin secretion in response to a wide variety of metabolic stimuli, the 'immune-like' characteristics of the pancreatic β-cells with respect to metabolism, secretion and cell defence, the similarities between β-cell failure/death in T1DM and T2DM and finally, to suggest novel targets for the treatment of diabetes.
