**10. β-cell therapies and possible targets for prevention of β-cell failure**

The traditionalistic concept of separate T1 and T2DM syndromes has become clouded with knowledge of the involvement of inflammation in T2DM and the metabolic syndrome in T1DM [108]. It is now apparent that treatment modalities that were specifically designed for one form of diabetes may have application in the other. Exercise, weight loss and diet are the most effective strategies to delay T2DM disease development, but similar strategies have shown significant efficacy in T1DM [108,128].

Researchers have targeted TNFα in children with newly diagnosed T1DM and showed that a recombinant TNFR fusion protein preserved c-peptide function, along with enhancing insulin production [82,141]. However, to date, anti-TNFα treatment has failed to improve blood glucose in T2DM patients [90]. Infiltration of cytotoxic T-cells in T1DM has been well charac‐ terised [82]. Therefore, some developing treatment strategies for this precise component of T1DM disease is the generation of T-cell targeted therapy to prevent the destruction of transplanted islets, some of which include introduction of anti-inflammatory Tregs that regulate T-cell activation [89]. Since inflammation has been detected in T2DM, these ap‐ proaches may have similar applications. Directing treatment towards the immunological pathways is quite attractive and recent evidence has suggested that the most promising results involve blockade of IL-1β or NFκB activation [90]. Again, it is noteworthy to highlight that enhanced HSP70 expression has been convincingly demonstrated to protect against obesityinduced insulin-resistance [142], while low HSP70 contents in skeletal muscle of T2DM patients are associated with insulin-resistance [143,144]. Hence, pharmacological (e.g. the hydroxylamine derivative BGP-15, now under clinical trial) as well as physiological (hyper‐ thermic, hot tube) treatments have started to be cogitated as promising therapeutic approaches in T2DM [142,145]. Moreover, physical exercise, which is a powerful antidiabetic intervention, is one of the strongest ways to increase intracellular HSP70 expression in many tissues (for reviews, please see [75,146]), including in pancreatic β-cells (A. Bittencourt et al., manuscript in preparation).

Elevated IL-1β and reduced IL-1Ra is known to correlate with T1DM, but the recent identifi‐ cation of inflammation in T2DM has meant that the IL-1 receptor antagonist (Anakinra), has been trialed in both T2DM and T1DM patients with successful results [77,140,147]. Here, the agent lowered blood glucose, reduced inflammation, improved insulin-sensitivity and secretion. These reports again illustrate the pivotal role played by IL-1β in mediating DM development, and thus clinical trials continue [90].

Salicylate-derivatives, such as salsalate, are also being used in an anti-inflammatory capacity to inhibit the activation of NFκB, although the precise mechanisms of action are not fully understood. These agents have the clear advantages of being orally available and well tolerated. Salsalate has been shown to improve insulin sensitivity and production, increase secretion of the anti-inflammatory cytokine adiponectin, reduce blood glucose and C-reactive protein (CRP) and decrease fatty acid and triglyceride levels [90].

**Abbreviations**

ACC - Acetyl coA carboxylase

AMPK - AMP-activated kinase

Apaf-1 - Apoptosis protease activation factor-1

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

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G-CSP - Granulocyte colony-stimulating factor

GSIS - Glucose-stimulated insulin secretion

GSK3β - Glycogen synthase kinase-3β

iNOS - Inducible nitric oxide synthase

HSF-1 - Heat shock factor-1

HSP70 - Heat shock protein-70

JNK - c-Jun-N-terminal kinase LDH - Lactate dehydrogenase

ME1 - Malic enzyme1

NFκB - Nuclear factor κB

MCFs - Metabolic coupling factors

MIP-1 - Macrophage inflammatory protein-1

NFAT - Nuclear factor of activated T cells

HBP - Hexosamine biochemical pathway

GFAT-1 - Glutamine:fructose-6-phosphate amidotransferase-1

Cp-PGs - Cyclopentenone prostaglandins CPT-1 - Carnitine palmitoyl transferase 1

DHAP - Dihydroxyacetone phosphate

ACL - ATP-citrate lyase

Bcl-2 - B-cell lymphoma-2

ER - Endoplasmic reticulum ETC - Electron transport chain

GABA - γ-aminobutyric acid

GDH - Glutamate dehydrogenase

FasR - Fas receptor

From our own studies we have shown how different amino and fatty acid combinations may affect β-cell metabolism. This proposes the concept of diet manipulation as an additional treatment for hyperglycaemia and lipidaemia in T2 and even T1DM patients. We demonstrat‐ ed the antioxidant activities of arachidonic acid, arginine and glutamine, and this data may suggests that dietary supplementation, high in specific amino or fatty acids, may have favourable effects in DM patients. Given the role of ROS and ER stress in β-cell death, dietary or pharmacological agents that target these pathways may also represent novel treatments for the delay or prevention of DM.
