Phosphoenolpyruvate carboxykinase in urine exosomes reflect impairment in renal gluconeogenesis in early insulin resistance and diabetes

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 318; no. 3; pp. F720 - F731
• Main Authors: Sharma, Rajni, Kumari, Manju, Prakash, Prem, Gupta, Sushil, Tiwari, Swasti
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.03.2020
• Subjects: Acidosis; Ammonium chloride; Blood glucose; Diabetes; Diabetes mellitus; Drinking water; Enzymatic activity; Enzyme activity; Enzymes; Exosomes; Fructose; Gluconeogenesis; Glucose; Hyperglycemia; Insulin; Insulin resistance; Kidneys; Proteins; Proximal tubules; Sensitivity; Sucrose; Sugar; Urine; extracellular vesicles; fructose 1,6-bisphosphatase; glucose 6-phosphatase; diabetes; insulin resistance
• ISSN: 1931-857X; 0363-6119; 1522-1466; 1522-1466; 1522-1490
• DOI: 10.1152/ajprenal.00507.2019

Impaired insulin-induced suppression of renal gluconeogenesis could be a risk for hyperglycemia. Diabetes is associated with elevated renal gluconeogenesis; however, its regulation in early insulin resistance is unclear in humans. A noninvasive marker of renal gluconeogenesis would be helpful. Here, we show that human urine exosomes (uE) contain three gluconeogenic enzymes: phosphoenolpyruvate carboxykinase (PEPCK), fructose 1,6-bisphosphatase, and glucose 6-phosphatase. Their protein levels were positively associated with whole body insulin sensitivity. PEPCK protein in uE exhibited a meal-induced suppression. However, subjects with lower insulin sensitivity had blunted meal-induced suppression. Also, uE from subjects with prediabetes and diabetic rats had higher PEPCK relative to nondiabetic controls. Moreover, uE-PEPCK was higher in drug-naïve subjects with diabetes relative to drug-treated subjects with diabetes. To determine whether increased renal gluconeogenesis is associated with hyperglycemia or PEPCK expression in uE, acidosis was induced in rats by 0.28 M NH 4 Cl with 0.5% sucrose in drinking water. Control rats were maintained on 0.5% sucrose. At the seventh day posttreatment, gluconeogenic enzyme activity in the kidneys, but not in the liver, was higher in acidotic rats. These rats had elevated PEPCK in their uE and a significant rise in blood glucose relative to controls. The induction of gluconeogenesis in human proximal tubule cells increased PEPCK expression in both human proximal tubules and human proximal tubule-secreted exosomes in the media. Overall, gluconeogenic enzymes are detectable in human uE. Elevated PEPCK and its blunted meal-induced suppression in human urine exosomes are associated with diabetes and early insulin resistance.