Evidence has shown the presence of D-amino acids (D-AAs), unusual cell-to-cell signaling molecules, in the pancreatic islets of rodents and humans. In particular, D-alanine (D-Ala) and serine racemase, the enzyme that converts L- to D-serine (D-Ser), colocalize within insulin-producing beta cells. Both D-Ala and D-Ser function as co-agonists of the N-methyl-D-aspartate (NMDA) receptor, which is also present in islets and modulates insulin release, suggesting potential autocrine or paracrine signaling role of these compounds. Here, we investigated the relationship between the endogenous levels of D-AAs and islet regulation of glucose homeostasis. The glucose-stimulated D-AA profiles in the rat islets revealed that the L-AA forms were released from the pancreatic islets in a dose-dependent manner. Interestingly, we observed between a 20% and 45% reduction of D-Ala and D-Ser levels, respectively, in islets after the stimulation which appears to be independent of the extracellular glucose levels. In addition to islets, significant D-AAs were detected in the surrounding acinar tissue; only D-Ala was abundant at high percentage of 11.6 ± 1.5% to total Ala in the tissue, while other D-AAs were not measured at high levels. As beta cells appear not to be able to synthesize their own D-Ala, this suggests that the D-Ala detected in these cells can be supplied by nearby acinar tissue. We also have measured the D-Ser percentages in healthy and type 2 diabetes (T2D)-affected islets received from the Human Pancreas Analysis Program (UPenn). Preliminary results revealed the lower D-Ser level in the T2D-affected islets compared to healthy islets. We are continuing to accumulate more data to determine the potential correlation of D-AAs, including D-Ala and D-Ser, to diabetes progression. The continued characterization of endogenous D-AAs levels will shed light on their roles in islet normal and pathological functions.
C.J. Lee: None. A. Patel: None. D. Lee: None. S. Rubakhin: None. J.V. Sweedler: None.
American Diabetes Association/Pathway to Stop Diabetes (1-18-VSN-19 to J.V.S.)