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CONTEXT: Circulating lactate concentration is an important determinant of exercise tolerance. OBJECTIVE: To determine the role of hyperglycemia on lactate metabolism during exercise in type 1 diabetes (T1D). DESIGN: Protocol involved compared T1D participants and participants without diabetes (ND) at euglycemia [5.5mM] or hyperglycemia [9.2mM] in random order in T1D and at euglycemia in ND. SETTING: Clinical Research Unit, University of Virginia, Charlottesville, VA. PARTICIPANTS: 7 T1D and 7 ND. INTERVENTION: [1-13C] lactate infusion, exercise at 65% VO2max, euglycemia and hyperglycemia visits. MAIN OUTCOME MEASURE: Lactate turnover before, during and after 60 min of exercise at 65% VO2max. RESULTS: A two-compartment model with loss only from the peripheral compartment described lactate kinetics. Volume of distribution of the accessible compartment was similar between T1D and ND (p=0.76) and concordant to plasma volume (â¼40ml/kg). Circulating lactate concentrations were higher (p<0.001) in T1D participants during exercise at hyperglycemia than euglycemia. Exercise induced lactate appearance did not differ (p=0.13) between hyperglycemia and euglycemia. However, lactate clearance was lower (p=0.03) during hyperglycemia than euglycemia in T1D. There were no differences in any of the above parameters between T1D and ND during euglycemia. CONCLUSIONS: Hyperglycemia modulates lactate metabolism during exercise by lowering lactate clearance leading to higher circulating lactate concentrations in T1D. This novel observation implies that exercise during hyperglycemia can lead to higher circulating lactate concentrations thus increasing the likelihood of reaching the lactate threshold sooner in T1D, and has high translational relevance for both providers and recreationally active people with Type 1 diabetes.
RESUMO
BACKGROUND: Glucagon serves as an important regulatory hormone for regulating blood glucose concentration with tight feedback control exerted by insulin and glucose. There are critical gaps in our understanding of glucagon kinetics, pancreatic α cell function and intra-islet feedback network that are disrupted in type 1 diabetes. This is important for translational research applications of evolving dual-hormone (insulin + glucagon) closed-loop artificial pancreas algorithms and their usage in type 1 diabetes. Thus, it is important to accurately measure glucagon kinetics in vivo and to develop robust models of glucose-insulin-glucagon interplay that could inform next generation of artificial pancreas algorithms. METHODS: Here, we describe the administration of novel 13C15N heavy isotope-containing glucagon tracers-FF glucagon [(Phe 6 13C9,15N; Phe 22 13C9,15N)] and FFLA glucagon [(Phe 6 13C9,15N; Phe 22 13C9,15N; Leu 14 13C6,15N; Ala 19 13C3)] followed by anti-glucagon antibody-based enrichment and LC-MS/MS based-targeted assays using high-resolution mass spectrometry to determine levels of infused glucagon in plasma samples. The optimized assay results were applied for measurement of glucagon turnover in subjects with and without type 1 diabetes infused with isotopically labeled glucagon tracers. RESULTS: The limit of quantitation was found to be 1.56 pg/ml using stable isotope-labeled glucagon as an internal standard. Intra and inter-assay variability was < 6% and < 16%, respectively, for FF glucagon while it was < 5% and < 23%, respectively, for FFLA glucagon. Further, we carried out a novel isotope dilution technique using glucagon tracers for studying glucagon kinetics in type 1 diabetes. CONCLUSIONS: The methods described in this study for simultaneous detection and quantitation of glucagon tracers have clinical utility for investigating glucagon kinetics in vivo in humans.