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therapies for type 2 diabetes; particularly new therapies that provide safety and

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tolerability advantages over existing agents. The hyperglycemia type 2 diabetes is a

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consequence of both resistance to the biologic effects of Insulin and a deficit in

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production of Insulin in sufficient quantities to overcome this Insulin resistance. Nearly,

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all of the available therapies for type 2 diabetes address one or both of these

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pathophysiologic mechanisms. As we will see, Saxagliptin addresses both the deficit in

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Insulin protection by pancreatic beta cell and over-production of glucose by the liver, by

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modulating production of glucagon by the pancreatic alpha cell. An understanding of the

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incretin effect is essential to understanding the mechanisms of action for Saxagliptin.

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A1c over time, most likely due to progressive failure of the pancreatic beta cell. Thus,

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patients with type 2 diabetes who are well controlled today are likely to need new

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therapies in the future to maintain glycemic control. Unfortunately, type 2 diabetes is

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becoming more prevalent in younger age groups. This will likely increase the need for

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new therapies as younger patients face more years of progressive decline of beta cell

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function.

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difference in the Insulin response to an oral glucose challenge versus an intravenous

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glucose challenge. For a given level of plasma glucose the Insulin response is

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approximately 70% higher for oral versus intravenous administration of glucose. This is

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known as the incretin effect. This observation led to the discovery of small peptides that

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are secreted by neuroendocrine cells in the intestine. The two major incretin peptides,

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Glucagon-like peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide

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Type 2 diabetes is a progressive disease characterized by an increase in

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In summary, there are substantial unmet medical needs to provide new

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A series of studies by other investigators have demonstrated an important

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