Obese patients with ketosis-prone type 2 diabetes (“A-β+ KPD”) have increased catabolism of the ketogenic amino acids leucine/isoleucine (Leu/Ile) and impaired ketone oxidation when stable and normoglycemic (Patel et al, Diabetes 2013). We performed comparative serum metabolomics on patients at presentation with hyperglycemic crisis without (N = 29) or with (N = 73) DKA compared to healthy controls (N = 17). The diabetic groups included normal weight and overweight/obese subgroups. DKA patients had higher plasma cortisol and catecholamines and lower C-peptide than the other groups. Three metabolite patterns distinguished the DKA patients from the other groups: 1) Elevated levels of Leu/Ile and of their respective ketoacids, no difference in isovaleryl carnitine (C5) but markedly lower ratio of C5 to C2 (acetyl carnitine) - implying accelerated shunting of Leu/Ile into their catabolic pathways but impaired oxidation because defective TCA cycle activity restrains acetyl CoA entry and metabolism. These changes were most pronounced in obese DKA patients, recapitulating the pattern of A-β+ KPD patients when stable; 2) Markedly decreased levels of glutamate, ammonia and many non-essential amino acids including citrulline, in the presence of increased glutamine, suggesting a defect in glutaminase activity; 3) Low levels of 3-methyl histidine, suggesting a surprising decrease in muscle protein breakdown. The pattern of amino acids and their metabolites among the DKA (especially obese) patients indicate that both increased ketone production from Leu/Ile and their blunted oxidation contribute to the proclivity to develop DKA; elevated leucine and low citrulline could contribute to beta cell dysfunction via mTOR hyperactivity and diminished intracellular arginine availability. Thus serum metabolomic profiling during an acute DKA episode helps define a unique pathophysiology underlying the phenotype of obese ketosis-prone T2D.
J.W. Hsu: None. P. Mehta: None. K.R. Keene: None. S.N. Mulukutla: None. E.I. Caducoy: None. W. Peacock: None. A. Balasubramanyam: None. F. Jahoor: None.
National Institutes of Health (R01DK101411)