Molecular signaling mechanisms of renal gluconeogenesis in nondiabetic and diabetic conditions

Abstract

The kidneys are as involved as the liver in gluconeogenesis which can significantly contribute to hyperglycemia in the diabetic condition. Substantial evidence has demonstrated the overexpression of rate‐limiting gluconeogenic enzymes, especially phosphoenolpyruvate carboxykinase and glucose 6 phosphatase, and the accelerated glucose release both in the isolated proximal tubular cells and in the kidneys of diabetic animal models and diabetic patients. The aim of this review is to provide an insight into the mechanisms that accelerate renal gluconeogenesis in the diabetic conditions and the therapeutic approaches that could affect this process in the kidney. Increase in gluconeogenic substrates, reduced insulin concentration or insulin resistance, downregulation of insulin receptors and insulin signaling, oxidative stress, and inappropriate activation of the renin–angiotensin system are likely to participate in enhancing renal gluconeogenesis in the diabetic milieu. Several studies have suggested that controlling glucose metabolism at the renal level favors effective overall glycemic control in both type 1 and type 2 diabetes. Therefore, renal gluconeogenesis may be a promising target for effective glycemic control as a therapeutic strategy in diabetes.

Acid Loading Unmasks Glucose Homeostatic Instability in Proximal-Tubule-Targeted Insulin/Insulin-Like-Growth-Factor-1 Receptor Dual Knockout Mice

“…There was a trend (p = 0.067) for increased glucose producing capacity of PT due to Insr/Igf1r deletion. This agreed with our previous findings in mice with solely PT IR deletion [35], and supports other work showing insulin down-regulates gluconeogenesis in both liver and kidney [2,7,8,13]. This may be particularly relevant to metabolic syndrome, where insulin receptor expression is reduced in kidney [36] and insulin receptor resistance is common.…”

“…Liver, kidney, and intestine work in concert to regulate blood glucose levels during fed and fasted states; thus impairment in the processes in one of these organs, such as during metabolic acidosis, can offset balance, leading to episodes of hypo and hyperglycemia [1,2]. For over ½ century it has been known that metabolic acidosis or NH 4 Cl loading (in animals) increases the capacity of the kidney to produce glucose [3].…”

“…Glucose is synthesized in the PT primarily from amino acid precursors via activation of gluconeogenic enzymes. Ratelimiting (unidirectional) enzymes in this cascade include glucose-6-phosphatase (G6P), fructose-bisphosphatase (FBP1), and phosphoenolpyruvate carboxykinase (PEPCK) [2,6].…”

“…Insulin downregulates gluconeogenesis in liver and kidney [2,7,8]. In fact, recent studies suggest kidney may be more sensitive than liver to hormonal down-regulation [9].…”

Continuous glucose monitoring during pregnancy in healthy mice

“…Non-prandial glucose excursions could originate from several sources. The liver, kidney, skeletal muscle and the intestine have the capacity for glycogenolysis and/or gluconeogenesis and might increase the glucose level in plasma independent from an eating episode [18][19][20] . Detailed telemetric measurements also allow a precise assessment of glucose variability indicators.…”