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The Role of Glutamine in Human Carbohydrate Metabolism in Kidney and Other Tissues

Oct 20, 2014

Glutamine is the most abundant amino acid in the human body and is involved in more metabolic processes than any other amino acid. Recent studies using isotopic and balance techniques have greatly advanced the understanding of glutamine metabolism in humans and its role in glucose metabolism in the kidney and other tissues….

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There is now evidence that in post-absorptive humans, glutamine is an important glucose precursor and makes a significant contribution to the addition of new carbon to the glucose carbon pool. It appears that glutamine is predominantly a renal gluconeogenic substrate, whereas alanine gluconeogenesis is essentially confined to the liver.

As shown recently, renal gluconeogenesis contributes 20 to 25% to whole-body glucose production. Moreover, glutamine has been shown not only to stimulate net muscle glycogen storage but also to stimulate gluconeogenesis in normal humans.

In humans with type 2 diabetes, conversion of glutamine to glucose is increased (more so than that of alanine). The available evidence on the hormonal regulation of glutamine gluconeogenesis in kidney and liver and its alterations under pathological conditions are just starting to be understood….

It has always been thought that the liver is the exclusive site of glucose production in humans in the post-absorptive state, however the human liver and kidneys release approximately equal amounts of glucose via gluconeogenesis in the post-absorptive state. In the postprandial state, while overall endogenous glucose release decreases substantially, renal gluconeogenesis actually increases by approximately two-fold. Following meal ingestion, glucose utilization by the kidney increases. Increased glucose uptake into the kidney may be implicated in diabetic nephropathy. Normally each day, ∼ 180 g of glucose is filtered by the kidneys; almost all of this is reabsorbed by means of sodium glucose cotransporter 2 (SGLT2), expressed in the proximal tubules. However, the capacity of SGLT2 to reabsorb glucose from the renal tubules is finite and when plasma glucose concentrations exceed a threshold, glucose begins to appear in the urine. Renal glucose release is stimulated by epinephrine and is inhibited by insulin. Handling of glucose by the kidney is altered in type 2 diabetes mellitus (T2DM): renal gluconeogenesis and renal glucose uptake are increased in both the post-absorptive and postprandial states, and renal glucose reabsorption is also increased Since renal glucose release is almost exclusively due to gluconeogenesis, it seems that the kidney is as important gluconeogenic organ as the liver.

It is also interesting to note that the hormone insulin exerts an effect on glutamine in the kidneys.

In humans during euglycemic-hyperinsulinemic clamp experiments, systemic glucose production, which represents the sum of hepatic plus renal, decreases virtually to zero. This strongly suggests that insulin suppresses renal and hepatic gluconeogenesis from all substrates in humans. Infusion of insulin in normal volunteers, which increased arterial insulin levels from 36 to 219 pm suppressed systemic glutamine gluconeogenesis by 50%. The fact that glutamine gluconeogenesis in the liver was reduced by approximately 25%, whereas that in kidney was reduced by almost 75%, suggests that renal glutamine gluconeogenesis is more sensitive to insulin than hepatic gluconeogenesis. This could mean that our patients who lose first phase insulin release capabilities will have much more glucose in the blood stream in postprandial times.

In type 2 patients it may be that the reduction in glutamine oxidation could be due to increased plasma free fatty acids (FFA) and glucose levels usually associated with type 2 diabetes. Free fatty acids and glucose, in view of the prevailing hyperglycemia, could have substituted for glutamine as an oxidative fuel in certain tissues making more available for gluconeogenesis and therefore increased blood glucose levels.

Therefore in diabetes patients not only do the SGLT-2 receptors play an important roll in glucose excursions, but glutamine generated gluconeogenesis must be considered in the role of the kidneys and may lead to new medications for treatment.


Role of glutamine in human carbohydrate metabolism in kidney and other tissues


Medizinische Klinik, Eberhard-Karls-Universität, Tübingen, Germany; Dipartimento di Medicina Interna, Università di Perugia, Perugia, Italy; and University of Rochester School of Medicine, Rochester, New York, USA

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