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United States Department of Agriculture

Agricultural Research Service

Title: Renal Substrate Exchange and Gluconeogenesis in Normal Postabsorptive Humans

Authors
item Meyer, Christian - UNIV ROCHESTER SCHOOL MED
item Stumvoll, Michael - UNIV ROCHESTER SCHOOL MED
item Dostou, Jean - UNIV ROCHESTER SCHOOL MED
item Welle, Stephen - UNIV ROCHESTER SCHOOL MED
item Haymond, Morey
item Gerich, John - UNIV ROCHESTER SCHOOL MED

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 17, 2001
Publication Date: February 1, 2002
Citation: Meyer,C., Stumvoll,M., Dostou,J., Welle,S., Haymond,M., Gerich,J. 2002. Renal substrate exchange and gluconeogenesis in normal postabsorptive humans. American Journal of Physiology - Endocrinology and Metabolism. 282(2):E428-E434.

Interpretive Summary: The principal findings of the present studies are 1) that in postabsorptive normal humans, lactate is the dominant precursor for both kidney and liver gluconeogenesis, 2) that, on the assumption that 50% of endogenous glucose release was due to gluconeogenesis, the sum of systemic gluconeogenesis from lactate, glycerol, glutamine and alanine, after correction for TCA cycle carbon exchange, could account for nearly all of systemic gluconeogenesis, 3) that the sum of renal gluconeogenesis from these precursors could account for nearly all renal glucose release, 4) that renal gluconeogenesis accounts for nearly 40% of systemic gluconeogenesis, and finally 5) that the kidney is an important organ for lactate and glycerol disposal. In the present studies, with values uncorrected for TCA cycle carbon exchange, systemic lactate gluconeogenesis accounted for approximately 15% of systemic glucose release, whereas systemic gluconeogenesis from glycerol, glutamine, and alanine, each accounted for approximately 5-6% of systemic glucose release, similar to previous reports. By multiplying the isotopically determined rates of systemic gluconeogenesis by 1.33 to correct for an assumed underestimate of 25%, the sum of lactate, glycerol, glutamine, and alanine gluconeogenesis would account for 43% of systemic glucose release. This value is within the range of the contribution of systemic gluconeogenesis to systemic glucose release in postabsorptive humans, estimated with techniques using the mass isotopomer distribution analysis, deuterated water, and MNR measurements of hepatic glycogen depletion. This conclusion is consistent with data indicating that most of the carbons of amino acids originating from proteolysis are transferred through plasma as glutamine and alanine. Regarding kidney gluconeogenesis, we found that lactate was also the most important precursor. It should be pointed out that our data apply only to the postabsorptive state and that the kidney contribution to systemic gluconeogenesis might change under different conditions, i.e. diabetes, hypoglycemia, the post-prandial state, acid-base disorders. That lactate accounted for such a large proportion of kidney glucose release in the present studies is not unexpected. Kidney carbon uptake from lactate, which reflects kidney rates of delivery and kidney fractional extraction, exceeded the sum of kidney carbon uptake from glutamine, alanine and glycerol. Our net kidney balance data for alanine, glycerol, and glutamine are in general agreement with previous reports. It is of note that the proportions of the different substrates taken up by the kidney used for gluconeogenesis were not significantly different from one another. This suggests that renal substrate uptake was the main factor responsible for kidney gluconeogenesis and that there may be no preferential intracellular use of substrates for gluconeogenesis by the kidney. Although kidney uptake accounted for only a small proportion of the systemic disposal of alanine and glutamine, it did account for considerable proportion of systemic lactate and glycerol disposal. This finding may be relevant to the increased propensity of people with chronic renal failure to develop lactic acidosis and hypoglycemia since reduced kidney lactate uptake could lead to lactate accumulation and decreased kidney glucose release.

Technical Abstract: Release of glucose by the kidney in postabsorptive normal humans is generally regarded as being wholly due to gluconeogenesis. Although lactate is the most important systemic gluconeogenic precursor and there is appreciable net renal lactate uptake, renal lactate gluconeogenesis has not yet been investigated. The present studies were therefore undertaken to quantitate the contribution of lactate to renal gluconeogenesis and the role of the kidney in lactate metabolism. We determined systemic and renal lactate conversion to glucose as well as renal lactate net balance, fractional extraction, uptake, and release in 24 postabsorptive humans by use of a combination of isotopic and renal balance techniques. For comparative purposes, accumulated similar data for glutamine, alanine, and glycerol are also reported. Systemic lactate gluconeogenesis (1.97 ± 0.12 µmol·kg-1·min-1) was about threefold greater than that from glycerol, glutamine, and alanine. The sum of gluconeogenesis from these precursors, uncorrected for tricarboxylic acid (TCA) cycle carbon exchange, explained 34% of systemic glucose release. Renal lactate uptake (3.33 ± 0.28 µmol·kg-1·min-1) accounted for nearly 30% of its systemic turnover. Renal gluconeogenesis from lactate (0.78 ± 0.10 µmol·kg-1·min-1) was 3.5, 2.5, and 9.6-fold greater than that from glycerol, glutamine, and alanine. The sum of renal gluconeogenesis from these precursors equaled ~40% of the sum of their systemic gluconeogenesis. When the isotopically determined rates of systemic and renal gluconeogenesis were corrected for TCA cycle carbon exchange, gluconeogenesis from these precursors accounted for 43% of systemic glucose release and 89% of renal glucose release. We conclude that 1) in postabsorptive normal humans, lactate is the dominant precursor for both renal and systemic gluconeogenesis; 2) the kidney is an important organ for lactate disposal; 3) under these conditions, renal glucose release is predominantly, if not exclusively, due to gluconeogenesis; and 4) liver and kidney are similarly important for systemic gluconeogenesis.

Last Modified: 7/23/2014
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