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Title: Arginine metabolism is altered in adults with A-B + ketosis-prone diabetes

Author
item MULUKUTLA, SURYA - Baylor College Of Medicine
item HSU, JEAN - Children'S Nutrition Research Center (CNRC)
item GABA, RUCHI - Baylor College Of Medicine
item BOHREN, KURT - Children'S Nutrition Research Center (CNRC)
item GUTHIKONDA, ANU - Baylor College Of Medicine
item IYER, DINAKAR - Baylor College Of Medicine
item AJAMI, NADIM - Baylor College Of Medicine
item PETROSINO, JOSEPH - Baylor College Of Medicine
item HAMPE, CHRISTIANE - University Of Washington
item RAM, NALINI - Baylor College Of Medicine
item JAHOOR, FAROOK - Children'S Nutrition Research Center (CNRC)
item BALASUBRAMANYAM, ASHOK - Baylor College Of Medicine

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/31/2017
Publication Date: 2/27/2018
Citation: Mulukutla, S.N., Hsu, J.W., Gaba, R., Bohren, K.M., Guthikonda, A., Iyer, D., Ajami, N.J., Petrosino, J.F., Hampe, C.S., Ram, N., Jahoor, F., Balasubramanyam, A. 2018. Arginine metabolism is altered in adults with A-B + ketosis-prone diabetes. Journal of Nutrition. 148(2):185-193. https://doi.org/10.1093/jn/nxx032.
DOI: https://doi.org/10.1093/jn/nxx032

Interpretive Summary: There is now a new set of individuals with type 2 diabetes who lose their ability to make insulin and release it in their blood. Insulin is a compound that is needed by most organs and muscles in the body to take up glucose (sugar) from the blood and use it to make energy or to store it. When there is no insulin the blood sugar rises very high because it cannot get into the body's organs and muscles. The person starts breaking down body fat and sending it to these organs and muscles to make energy. When this happens some of the fat is broken down to a substance called ketone and as ketone level rises in the blood it makes the individual's blood turn acidic causing then to become sick eventually becoming unconscious. At this point the individual is usually taken to the emergency room and treated with insulin to bring down the blood sugar by sending it into the body's organs and muscles. Soon the individual recovers and most will have to be treated with insulin for the rest of their life. However, this new set of type 2 diabetes patients gradually start making insulin and releasing it into their blood like a normal healthy person. We wanted to find out why this happens in these individuals. In an earlier study we noticed that they had low levels of a compound called arginine in their blood suggesting that they were not making enough of it or that they were using more of it than normal healthy persons. Insulin is usually made in an organ called the pancreas by some cells called beta cells. Arginine is needed by beta cells to make insulin and to release it in the blood. Therefore, it is possible that this set of diabetes patients stopped making insulin because their supply of arginine was low. In this study we wanted to find out the relationship between blood arginine and insulin secretion in these patients and to compare their values to those of normal healthy persons. We found that when their blood sugar is normal these patients needed more arginine compared to healthy persons. When their blood sugar was high however, they did not have enough arginine to increase insulin secretion. When they were given extra arginine in their blood, their insulin secretion increased like in normal healthy persons.

Technical Abstract: A-B + ketosis-prone diabetes (KPD) is a subset of type 2 diabetes in which patients have severe but reversible B cell dysfunction of unknown etiology. Plasma metabolomic analysis indicates that abnormal arginine metabolism may be involved. The objective of this study was to determine the relation between gut microbiome and arginine metabolism and the relation between arginine availability and B cell function in KPD patients compared with control participants. Kinetics of arginine and related metabolites were measured with stable isotope tracers, and insulin secretory responses to arginine and glucose were determined under euglycemic and hyperglycemic conditions in 6 KPD patients and 6 age-, gender-, and body mass index–matched control participants. Glucose potentiation of arginine-induced insulin secretion was performed in a different set of 6 KPD and 3 control participants. Arginine availability was higher in KPD patients during euglycemia [53.5 +/- 4.3 (mean +/- SEM) compared with 40.3 +/- 2.4 umol / kg lean body mass (LBM) -1 / h-1, P = 0.03] but declined more in response to hyperglycemia (delta 10.15 +/- 2.6 compared with delta 3.20 +/- 1.3 umol / kg LBM-1 / h-1, P = 0.041). During hyperglycemia, ornithine flux was not different between groups but after an arginine bolus, plasma ornithine AUC trended higher in KPD patients (3360 +/- 294 compared with 2584 +/- 259 min / umol / L-1, P = 0.08). In both euglycemia and hyperglycemia, the first-phase insulin responses to glucose stimulation were lower in KPD patients (euglycemic insulin AUC 282 +/- 108 compared with 926 +/- 257 min / uU / mL-1, P = 0.02; hyperglycemic insulin AUC 358 +/- 79 compared with 866 +/- 292 min / uU / mL-1, P = 0.05), but exogenous arginine restored first-phase insulin secretion in KPD patients to the level of control participants. Compared with control participants, KPD patients have increased arginine availability in the euglycemic state, indicating a higher requirement. This is compromised during hyperglycemia, with an inadequate supply of arginine to sustain metabolic functions such as insulin secretion. Exogenous arginine administration restores a normal insulin secretory response.