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Title: Pathogenesis of A-beta+ ketosis-prone diabetes

item PATEL, SANJEET - Baylor College Of Medicine
item HSU, JEAN - Children'S Nutrition Research Center (CNRC)
item JAHOOR, FAROOK - Children'S Nutrition Research Center (CNRC)
item CORAZA, IVONNE - Baylor College Of Medicine
item BAIN, JAMES - Duke University Medical Center
item STEVENS, ROBERT - Duke University Medical Center
item IYER, DINAKAR - Baylor College Of Medicine
item NALINI, RAMASWAMI - Baylor College Of Medicine
item OZER, KAREM - Baylor College Of Medicine
item HAMPE, CHRISTIANE - University Of Washington
item NEWGARD, CHRISTOPHER - Duke University Medical Center
item BALASUBRAMANYAM, ASHOK - Baylor College Of Medicine

Submitted to: Diabetes
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/19/2012
Publication Date: 3/1/2013
Citation: Patel, S.G., Hsu, J.W., Jahoor, F., Coraza, I., Bain, J.R., Stevens, R.D., Iyer, D., Nalini, R., Ozer, K., Hampe, C.S., Newgard, C.B., Balasubramanyam, A. 2013. Pathogenesis of A-beta+ ketosis-prone diabetes. Diabetes. 62(3):912-922.

Interpretive Summary: Diabetes mellitus is the disease resulting from the inability of the body to produce or respond properly to insulin, a hormone produced by the body and needed to convert glucose to energy. Insulin lowers the blood glucose levels when they become too high. When the blood glucose of patients with diabetes is not entering the cells of their organs and tissues to make energy, they start to break down body fat at a fast rate to provide the cells with an alternative source of energy. This usually leads to a buildup in the blood of a byproduct of fat called ketones and causes the patient's blood to become acidic. This condition is called diabetic ketosis. Its symptoms include fatigue, lethargy, nausea, vomiting, muscle aches, rapid breathing, and coma. Diabetic ketosis mostly results from a severe insulin deficiency, and it has three major features: excessively high blood sugar levels; an overproduction of ketones by the body; and acidosis, meaning that the blood has become too acidic. Insulin deficiency is responsible for all three conditions. So it is not surprising that this condition is mostly seen in patients with type I diabetes, that is patients who do not produce any insulin in their body and have to depend on insulin injections. However, a small number of people with type II diabetes, that is patients who are still making some insulin, also experience ketosis. These patients are called ketosis-prone diabetics. It is a mystery why these patients suffer suddenly from ketosis. To answer this question we studied fat metabolism in these patients. Also some compounds called amino acids that are converted to ketones were studied. It was found that the patients were not breaking down fat at a faster rate as happens during insulin deficiency. Instead, they were not able to convert fat and ketones to energy and this caused a buildup of ketones. Also, they were converting an amino acid called leucine to ketones. So the cause of ketosis in these ketosis-prone diabetic patients was totally different from the usual cause of ketosis in patients with type 1 diabetes, that is, an increase break down of fat.

Technical Abstract: A-beta+ ketosis-prone diabetes (KPD) is an emerging syndrome of obesity, unprovoked ketoacidosis, reversible beta-cell dysfunction, and near-normoglycemic remission. We combined metabolomics with targeted kinetic measurements to investigate its pathophysiology. Fasting plasma fatty acids, acylcarnitines, and amino acids were quantified in 20 KPD patients compared with 19 nondiabetic control subjects. Unique signatures in KPD [higher glutamate but lower glutamine and citrulline concentrations, increased beta-hydroxybutyryl-carnitine, decreased isovaleryl-carnitine (a leucine catabolite), and decreased tricarboxylic acid (TCA) cycle intermediates] generated hypotheses that were tested through stable isotope/mass spectrometry protocols in nine new-onset, stable KPD patients compared with seven nondiabetic control subjects. Free fatty acid flux and acetyl CoA flux and oxidation were similar, but KPD had slower acetyl CoA conversion to beta-hydroxybutyrate; higher fasting beta-hydroxybutyrate concentration; slower beta-hydroxybutyrate oxidation; faster leucine oxidative decarboxylation; accelerated glutamine conversion to glutamate without increase in glutamate carbon oxidation; and slower citrulline flux, with diminished glutamine amide-nitrogen transfer to citrulline. The confluence of metabolomic and kinetic data indicate a distinctive pathogenic sequence: impaired ketone oxidation and fatty acid utilization for energy, leading to accelerated leucine catabolism and transamination of a-ketoglutarate to glutamate, with impaired TCA anaplerosis of glutamate carbon. They highlight a novel process of defective energy production and ketosis in A-beta+ KPD.