Type 2 diabetes mellitus (T2DM) is a prevalent disease in the elderly for which current treatments are unsatisfactory. It is a chronic, age-related degenerative disorder that is a leading cause of morbidity and mortality in the elderly, and has attained epidemic proportion, with in excess of 171 afflicted worldwide (Wild et al., Diabetes Care 27, 104753, 2004). A variety of risk factors have been implicated in the development of T2DM (Gtz et al., Cell Mol Life Sci. 66, 1321-5, 2009;Jin &Patti, Clin Sci (Lond). 116, 99-111, 2009), including a genetic predisposition, age, oxidative stress, obesity, diet, and physical inactivity. By comparison, several of these same factors appear to be involved in neurodegenerative disorders, such as Alzheimer's disease (AD), the most common form of dementia (Reddy et al., J Alzheimers Dis. 16, 763-774, 2009;Luchsinger &Gustafson, J Alzheimers Dis. 16, 693-704, 2009. Interestingly, a number of well-designed epidemiological studies have established a link between these two diseases, together with others, including Parkinson's disease (PD) and stroke, identifying T2DM as a risk factor for developing various chronic and acute neurodegenerative disorders (Toro et al., J Alzheimers Dis. 16:687-91, 2009;Craft. Curr Alzheimer Res. 4, 147-52, 2007). The pancreas and brain are both highly insulin sensitive tissues. T2DM and AD, together with other neurological conditions. share several clinical and biochemical features, particularly important amongst these is an impaired insulin signaling, suggesting overlapping pathogenic mechanisms. Hence, an effective treatment strategy in one disease could have potential value in the other. A recent effective treatment strategy in T2DM is the use of incretin-based therapies based on the insulinotropic actions of the endogenous peptide, glucagon-like peptide-1 (GLP-1), utilizing the long-acting analog exendin-4 (Ex-4) (Lovshin &Drucker, Nat Rev Endocrinol. 5, 262-9, 2009). The acute actions of GLP-1 and receptor (R) agonists on beta-cells include stimulation of glucose-dependent insulin release, augmentation of insulin biosynthesis and stimulation of insulin gene transcription. Chronic actions include stimulation of beta-cell proliferation, induction of islet neogenesis and inhibition of beta-cell apoptosis that, together, promote expansion of beta-cell mass and the normalization of insulin signaling (Drucker, Lancet. 372(9645), 1240-50, 2008, Lovshin &Drucker ibid, 2008). Ex-4 has been reported to readily enter the brain (Kastin et al., Int J Obes Relat Metab Disord 27, 313-8, 2003), where the GLP-1R is expressed widely (Perry &Greig, Trends Pharmacol Sci. 24, 377-83, 2003) and its activation results in multiple biological responses. GLP-1R stimulation in brain is classically allied to regulation of appetite and satiety (Lovshin &Drucker ibid, 2008). More recently, however, it has been associated with neurotrophic (Perry et al., J Pharmacol Exp Ther 300, 95866, 2002) and neuroprotective actions in both cellular and in vivo models of acute and chronic neurodegenerative conditions (Perry et al., J Pharmacol Exp Ther. 302, 881-8., 2002;Perry et al., J Neurosci Res. 72, 603-12, 2003), including stroke, AD, PD and Huntingtons disease (HD) (Li et al., PNAS 106, 1285-90, 2009;Li et al., J Alz Dis. 19:1205-19, 2010;Harkavyi et al., J Neuroinflam. 21, 519, 2008;Martin et al., Diabetes 58, 318-328, 2009;Bertilsson et al., J Neurosci Res 86, 32638, 2008). Our target for drug design is the glucagon-like peptide-1 (GLP-1) receptor (R). GLP-1 is secreted from the gut in response to food and is a potent secretagogue that binds to the GLP-1R on pancreatic beta-cells to induce glucose-dependent insulin secretion, thereby controling plasma glucose levels. We are developing long-acting GLP-1 analogues (collaborators: Drs. Egan, Mattson). This research aided in the development of the peptide exendin-4 (Ex-4) into clinical studies in type 2 diabetes. Novel chimeric peptides that combine the best features of GLP-1 and Ex-4 have also been designed and are under preclinical assessment in a variety models (Wang et al., J Clin Invest. 99:2883-9, 1997, DeOre et al., J Gerontol A Biol Sci Med Sci. 52:B245-9, 1997;Greig et al., Diabetologia. 42:45-50, 1999;Szayna et al., Endocrinol 141:1936-41, 2000;Doyle et al., Endocrinol 142:4462-8, 2001;Doyle et al., Regul Pept. 114:153-8, 2003;Doyle et al., Endocrine. 27:1-9, 2005). We are characterizing the role of the GLP-1R stimulation in the nervous system, as it is found present in brain and peripheral nerve. Our collaborative studies were the first to define that GLP-1 analogues possess neurotrophic properties and protect neuronal cells from a wide variety of lethal insults. Neuroprotection in cell culture translated to in vivo studies in classical rodent neurodegeneration models, which include AD, stroke, PD, HD, ALS, traumatic brain injury and peripheral neuropathy (Perry et al., Exp Neurol 203: 293-301, 2007;Li et al., PNAS 106, 1285-90, 2009;Li et al., J Alz Dis. 19:1205-19, 2010, Li et al., PLoS One.;7(2):e32008, 2012;Salcedo et al., Br J Pharmacol. 166:1586-99, 2012;Tweedie et al., Exp Neurol. 239:170-82, 2013;Rachmany et al., Age 2013 E-online;Tweedie et al., Neurobiol Dis. 54:1-11, 2013). Current studies are focused on selecting agents for clinical assessment and defining mechanisms underpinning the neurotrophic/neuroprotective actions (Li et al., J Neurochem 113: 621-31, 2010). Additional research is focused on optimizing the translation of Ex-4 for the treatment of neurodegenerative disorders, and defining which specific disorders are most likely to have a clinical response - in this regard, the long-acting GLP-1 receptor agonist exendin-4 is in a current clinical trial in MCI/early AD (Collaborators: Drs. Kapogiannis, Egan, Mattson) and other clinbical trials in different disorders are in current planning (Collaborators: Drs. Hoffer;Chiang, Wang, Pick). An alternate approach is to augment the levels of endogenous incretins available within the body by inhibiting their metabolism and, thereby, elevating their levels. In this regard, GLP-1 and the incretin, glucose-dependent insulinotropic polypeptide (GIP) are released following food ingestion and bind to their receptors on pancreatic beta cells to induce insulin secretion. Receptors for these endogenous peptides are found throughout the body, including the brain - which both GLP-1 and GIP can readily enter. The presence of the metabolizing serine protease enzyme, dipeptidyl peptidase-4 (DPP-4), results in the rapid clearance of both incretins. Current studies are assessing the utility of selective and well tolerated DPP-4 inhibitors in cellular and preclinical animal studies to elevate available GLP-1 and GIP levels in plasma and brain to a level at which they provide neurotrophic and neuroprotective actions for the treatment of neurodegenerative disorders. On going studies are in preclinical stages to aid the rapid repurposing of DPP-4 inhibitors towards neurological disorders currently lacking effective pharmacological treatment where this drug class could prove highly beneficial (Collaborators: Drs. Wang, Hoffer, Tones, Zaleska).
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