In today's modern world, the recent dramatic increase in the number of patients with type 2 diabetes indicates an unchecked global epidemic is at hand. In 2011 the U.S. Centers for Disease Control and Prevention estimated that about 8.3% of the American population (25.8 million people) had diabetes while 7 million were unaware of it. [1]

Digestion and Diabetes

Type 2 Diabetes, AMPK, Biomarker Preservation Reagents, Leptin Signaling, Type 2 Diabetes, Anti-diabeteic compounds, P32/98 Biomarker, obesity Diagnostic Applications, diabetes Protein Biomarkers

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Signaling Pathways in Diabetes & Obesity

Glucose is the fundamental fuel required by the cells in the body and is supplied, in part, through the process of digesting the foods we eat.  During digestion, the hormone insulin is released by beta-cells produced in the Islets of Langerhans in the pancreas. Insulin acts like a cellular key allowing the passage of glucose to move from the bloodstream into the cells of the body. In patients with type 2 diabetes, the amount of insulin produced by beta-cells is often insufficient because patients simply do not produce enough insulin. Another important hormone of the pancreas is called Glucagon. Glucagon is synthesized and released in α-cells also located in the pancreas. When Glucose levels are low, and metabolic fuel is needed to avoid hypoglycemia, Glucagon stimulates the pancreas to release Glucose stored in the body as Glycogen [2].

A closer look at the substances from the intestinal track revealed the presence of two important incretin hormones in the regulation of glucose. These hormones include GIP (gastric inhibitory polypeptide), released from K cells in the duodenum, and GLP-1 (glucagon-like peptide 1), released from L cells from ileum and colon. In the pancreas, both incretins are released in response to insulin.

New Tools for Type 2 Diabetes Research

Thanks to leaps in the medical research surrounding diabetes care, science's understanding of the disease have led to a new arsenal of drugs known as DPP-4 inhibitors, or more commonly as gliptins. The FDA has approved, in total, five gliptin compounds, allowing doctors to provide a more focused strategy in the treatment of type 2 diabetes. The studies reveal this: DPP-4 inhibitors are associated with insulin enrichment at the cellular level and increased circulating levels of GIP and GLP-1 [3]. Both GIP and GLP-1 are physiological substrates for DPP-4 and serve as important prandial stimulators of insulin secretion and regulators of blood glucose. These two incretin hormones are responsible for more than 50% of nutrient-stimulated insulin secretion [4]. Recent research suggests one benefit of increased levels of GIP and GLP-1: they slow the emptying of the stomach without causing weight gain or hypoglycemia [5].

But how do DPP-4 gliptin compounds trigger insulin secretion in the first place?

The answer appears to involve regulating the activity of naturally occurring NHE3 (Na+/H+ exchangers) membrane receptors responsible for cell signaling. Interestingly, five different ion membrane exchangers have been found in a variety of tissues, and primarily in the pancreas, intestines, and kidneys. DPP-4 inhibitors affect metabolic cell-signaling pathways by blocking the primary catalytic site of DPP-4, which would otherwise inactivate GIP and GLP-1 [6].

Diagnostic Applications

The first reported DPP-4 inhibitor was P32/98 (di-[2S,3S]-2-amino-3-methyl-pentanoic-1,3-thiazolidine fumarate) from Merck. It is a specific competitive inhibitor and uses isoleucine thiazolidide as the primary substrate to inactivate DPP-4. In animal studies, P32/98 showed positive effects on glycemic control due to it's ability to hydrolyze Glucose-dependent GIP and GLP-1, making it an important tool for diabetes researchers. [7]

 Structure of P32/98 Biomarker

 P32/98 Diagnostic Biomarker, AMPK, Biomarker Preservation Reagents, Leptin Signaling, Type 2 Diabetes, Anti-diabeteic compounds, P32/98 Biomarker, obesity Diagnostic Applications, diabetes Protein Biomarkers

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Researchers at the American Diabetes Association have also found that the P32/98 selective inhibitor can be used as biomarkers for diagnostic testing or as vehicles to transport proteins or for protein preservation. Furthermore, because this product preserves key protein biomarkers, it enables them to be detected and utilized in diagnostic applications, and also used in cell cultures (1-10nM), or in vivo (10 mg/Kg orally) [8].

The pharmacological and toxicological properties of this product have not been fully investigated. Exercise caution in use and handling. This product must not be used in humans.

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REFERENCES

[1] Diabetes Public Health Resource, 2011 Diabetes Fact Sheet.http://www.cdc.gov/diabetes/pubs/estimates11.htm#2

[2] Biochemistry. by Jeremy M Berg, John L Tymoczko, and Lubert Stryer; W H Freedman, 5th edition, 2002. Page 843-859.

[3] Dipeptidyl Peptidase-4 Inhibition and the Treatment of Type 2 Diabetes: Preclinical Biology and Mechanisms of Action. http://www.medscape.com/viewarticle/559076_7

[4] [8] Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats.http://www.ncbi.nlm.nih.gov/pubmed/11916911

[5] Dipeptidyl peptidase IV (DPP IV) inhibitors: a newly emerging drug class for the treatment of type 2 diabetes.http://dvr.sagepub.com/content/3/3/159.full.pdf

[6] Role of dipeptidyl peptidase IV in regulating activity of Na+/H+ exchanger isoform NHE3 in proximal tubule cells.http://ajpcell.physiology.org/content/ajpcell/287/5/C1238.full.pdf

[7] Development of dipeptidyl peptidase-4 inhibitors. http://en.wikipedia.org/wiki/Development_of_dipeptidyl_peptidase-4_inhibitors

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    DPP IV Inhibitor, NVP DPP 728
    D-2295

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