Dipeptidyl Peptidase IV (DPP-IV) Test

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DPP-IV: A Key Enzyme In Food Sensitivities And Virtually All Human Physiology

Dipeptidyl Peptidase IV or DPP-IV is a critical enzyme that regulates a wide variety of physiological processes including eating, digestion, immune function, pain perception, growth, infection, and many others. This enzyme which is present in all organs and the blood starts or stops these processes by removing a two amino acid peptide from a variety of peptides and proteins from the free amino end of these molecules. Thus, growth hormone releasing factor (GHRF), which is secreted by the hypothalamus, stimulates the pituitary gland to release growth hormone until DPP-IV removes two amino acids from GHRF to inactivate it. Substance P, a nine amino acid peptide, mediates the perception of pain when released from injured tissue and continues to provoke pain until DPP-IV removes two amino acids from substance P, terminating the pain perception.


The function of DPP-IV has been a major target of new drugs called DPP-IV inhibitors that have been developed to control adult onset diabetes. These new oral drugs such as Januvia® (sitagliptin), Galvus® (vildagliptin), Onglyza® (saxagliptin), Tradjenta® (linagliptin),and many others are inhibitors of DPP-IV that cause persistence of peptides normally broken down by DPP-IV such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), that potentiate the effects of insulin and even increase the growth of insulin-producing cells in the pancreas. However, these DPP-IV inhibitors used to treat diabetes also cause the persistence of pain mediators usually deactivated by DPP-IV such as substance P. Therefore, it is not surprising that patients whose rheumatoid arthritis was under control, report severe joint pain, sometimes within one day of using these anti-diabetic drugs. Furthermore, stopping these drugs terminates pain and re-institution of the drug causes pain to return. Since substance P is a major factor in increasing anxiety, it is reasonable that these drugs may also lead to increased anxiety. A 2014 review found increased risk of heart failure with saxagliptin and alogliptin, prompting the FDA in 2016 to add warnings to the relevant drug labels. A 2018 meta-analysis showed that use of DPP-IV inhibitors was associated with a 58% increased risk of developing acute pancreatitis compared with placebo or no treatment. Since very low serum DPP-IV values are associated with suicidal depression, it would be wise to advise any patient using these diabetes drugs of this potential side effect.