Liver or kidney: Who has the oar in the gluconeogenesis boat and when?

Abstract

Gluconeogenesis is an endogenous process of glucose production from non-carbohydrate carbon substrates. Both the liver and kidneys express the key enzymes necessary for endogenous glucose production and its export into circulation. We would be remiss to add that more recently gluconeogenesis has been described in the small intestine, especially under high-protein, low-carbohydrate diets. The contribution of the liver glucose release, the net glucose flux, towards systemic glucose is already well known. The liver is, in most instances, the primary bulk contributor due to the sheer size of the organ (on average, over 1 kg). The contribution of the kidney (at just over 100 g each) to endogenous glucose production is often under-appreciated, especially on a weight basis. Glucose is released from the liver through the process of glycogenolysis and gluconeogenesis. Renal glucose release is almost exclusively due to gluconeogenesis, which occurs in only a fraction of the cells in that organ (proximal tubule cells). Thus, the efficiency of glucose production from other carbon sources may be superior in the kidney relative to the liver or at least on the level. In both these tissues, gluconeogenesis regulation is under tight hormonal control and depends on the availability of substrates. Liver and renal gluconeogenesis are differentially regulated under various pathological conditions. The impact of one source vs the other changes, based on post-prandial state, acid-base balance, hormonal status, and other less understood factors. Which organ has the oar (is more influential) in driving systemic glucose homeostasis is still in-conclusive and likely changes with the daily rhythms of life. We reviewed the literature on the differences in gluconeogenesis regulation between the kidneys and the liver to gain an insight into who drives the systemic glucose levels under various physiological and pathological conditions.

Keywords: Gluconeogenesis in the kidney and liver; Diabetes; Hormonal regulation; Metabolic acidosis; Insulin resistance; Net glucose metabolism

Core Tip: The liver and kidneys have an essential role in regulating glucose homeostasis through gluconeogenesis. However, the two tissues prefer different substrates. The contribution of kidney vs liver gluconeogenesis may vary under certain physiological and pathological conditions. However, increased gluconeogenesis in the liver and kidneys contributes to hyperglycemia in the pathogenic stage of type 2 diabetes mellitus. While in the case of metabolic acidosis, which develops in response to diabetes, gluconeogenesis induction occurs exclusively in the kidneys. Nevertheless, the two organs often compensate for each other by inter-organ coordination to maintain glucose and energy homeostasis.