The periphery

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The triad of β-cell, muscle, and liver related defects as important features in the pathophysiology of T2DM, has expanded to defects in several other specific organ systems, including the CNS as discussed in this review. There are now agents available that can target multiple pathophysiological mechanisms in T2DM. For instance, thiazolidinediones (TZDs) are known as potent insulin sensitizers that act not only at the level of the liver, but also in muscle and adipose tissue. TZDs are PPARγ agonists, and in the liver they inhibit the increased rate of hepatic gluconeogenesis responsible for the elevated rate of basal hepatic glucose production in T2DM (Gastaldelli et al., 2006a; Gastaldelli et al., 2006b). In both muscle and adipose tissue, TZDs have been shown to act as potent insulin sensitizers  (Miyazaki et al., 2003; Miyazaki et al., 2001), whereas in the pancreas they are thought to improve and maintain β-cell function (Gastaldelli et al., 2007).

It is now thought that β-cell dysfunction occurs much earlier in the pathogenesis of T2DM than initially believed (DeFronzo, 2010; Gastaldelli et al., 2004). Accordingly, it may prove most beneficial, with respect to glycemic control, when therapeutic interventions for T2DM are aimed at delaying β-cell failure. In contrast to the protective effects of TZDs on β-cells, over a 15-year course of study (Group, 1998a, b), and using the insulin secretion/insulin resistance index as a standard for determining  β-cell function (DeFronzo, 2010), neither sulfonylureas nor metformin are believed to exert similar protective effects. Sulfonylureas act primarily by increasing insulin secretion by β-cells, whereas the most important effect of metformin is inhibition of hepatic gluconeogenesis. Using TZDs as a therapeutic intervention, it has been reported that there is a significant reduction in the progression from impaired glucose tolerance to overt T2DM (DeFronzo, 2010). This reduction appeared to be a result of protective effects on the β-cell, as well as increased tissue sensitivity to insulin. Similar to TZDs, metformin is known to have pleiotropic effects and is widely used as the first line of treatment in T2DM. However, a recent report by Chen and colleagues suggests that prescription of this antidiabetic drug should be considered carefully (Chen et al., 2009). Their research showed that in monotherapy, metformin significantly increases production of the AD associated Aβ peptides. This effect appeared to be mediated by a transcriptional upregulation of β-secretase (BACE1), which has a role in the proteolytic cleavage of APP. They also reported that even though insulin and metformin display opposing effects on Aβ generation, in combined use, metformin enhances insulin’s effect in reducing Aβ levels (Chen et al., 2009). This combinatory effect may involve the interplay of their antagonizing effects on BACE1 transcription and on APP processing. Although the combination of insulin and metformin may result in a beneficial effect in treating both T2DM and in mitigating AD progression in elderly, these findings raise the concern of potential side effects of metformin alone, potentially even accelerating AD clinical manifestation in patients with T2DM.

In addition to TZDs, a relatively new class of antidiabetics, i.e. incretins, have also been shown to improve β-cell function and maintain durability of glycemic control (Bunck et al., 2009). Incretins refer to the collection of glucagon-like peptide-1 (GLP-1) receptor agonists, whereas dipeptidyl peptidase 4 (DPP-4) inhibitors have an important role in regulating their degradation. Physiologically, GLP-1 is secreted in response to a meal and has a pivotal role in the stimulation of glucose-dependent insulin secretion, whereas DPP-4 is a catalytic enzyme involved in the breakdown of GLP-1. The recognition that impairments in the incretin response and particularly in GLP-1 activity, may contribute to dysregulation of insulin and glucagon secretion, has resulted in the development of an incretin family of therapeutic agents. A number of GLP-1 receptor agonists are currently in clinical development. One of these agents, liraglutide, a once-daily human GLP-1 analogue, has recently received US Food and Drug Adminstration (FDA) approval. Data from studies on liraglutide and a similar drug, exenatide, suggest that GLP-1 receptor agonists slow the progression of β-cell failure, which should lead to long-term sustained glucose control. DPP-4 inhibitors act by inhibiting DPP-4 and thereby GLP-1 breakdown, subsequently increasing endogenous levels of GLP-1 and maintaining β-cell function.

With the development of new antihyperglycemic drugs, it is clear that combination therapy targeting the fundamental defects that underlie T2DM is both a viable and rational approach for managing patients early in the course of their disease. As longer-acting drug derivatives are developed, many of the challenges of patient care may be addressed. Additionally, weight gain with TZD usage can be prevented by combining therapy with exenatide. This combination is likely to be highly effective as exenatide and TZDs preserve β-cell function, while the TZDs are also highly potent insulin sensitizers. Taken together, future therapeutic regimens must involve drugs with different mechanisms of action to target the multiple contributors of disease progression.

In line with the view that preservation of pancreatic β-cells may be the best therapeutic strategy to prevent/inhibit the progression to/of T2DM, it is also important to consider hIAPP cytotoxic effects on β-cells. There has been considerable progress in the field of hIAPP induced β-cell damage via membrane permeabilization. Nevertheless, the exact mechanisms leading to cytotoxic membrane permeabilization remain to be elucidated. Contradicting reports on cytotoxicity and membrane interactions of hIAPP species may be the result of ‘mixed’ hIAPP samples (Engel, 2009). Due to often rapid and uncontrollable aggregation of amyloidogenic proteins and peptides, the possibility of dissociation and re-association of molecules within the fibril population (Carulla et al., 2005), or the recently proposed lipid-induced fibril dissociation into soluble amyloid protofibrils (Martins et al., 2008), it is difficult to obtain a structurally uniform sample of either monomers, oligomers or fibrils. Many of the membrane permeability assays are performed under conditions distinct from the membrane conditions found in vivo, which currently still makes extrapolation of data obtained by using model-membrane systems towards physiological β-cell membranes difficult. Morphology and structure from in vivo produced hIAPP oligomers and fibrils would provide valuable insights in the physiological relevance of the molecular species and processes that have now mostly been obtained using synthetic peptides and in vitro conditions. As hIAPP toxicity may constitute an important event leading to death of insulin producing β-cells, development of inhibitors targeting hIAPP-induced cytotoxic processes may prove to be extremely beneficial, especially in combination with insulin sensitizers or incretins.