Lithium reduces blood glucose levels, but aggravates albuminuria in BTBR-ob/ob mice

• Published in: PloS one Vol. 12; no. 12; p. e0189485
• Main Authors: de Groot, Theun, Damen, Lars, Kosse, Leanne, Alsady, Mohammad, Doty, Rosalinda, Baumgarten, Ruben, Sheehan, Susan, van der Vlag, Johan, Korstanje, Ron, Deen, Peter M T
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.12.2017; Public Library of Science (PLoS)
• Subjects: Adipose tissue; Albumin; Albuminuria; Albuminuria - drug therapy; Albuminuria - etiology; Animal models; Animals; Biology and Life Sciences; Blood; Blood Glucose; Body weight; Care and treatment; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetic nephropathies; Diabetic Nephropathies - blood; Diabetic Nephropathies - prevention & control; Diabetic nephropathy; Drug Evaluation, Preclinical; Fasting; Female; Glomerular filtration rate; Glucose; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 - metabolism; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Immunoglobulin G; Inhibition; Injury prevention; Insulin; Insulin resistance; Kidney - drug effects; Kidney - enzymology; Kidney - pathology; Kidney diseases; Kidneys; Kinases; Laboratories; Laboratory testing; Lithium; Lithium chloride; Lithium Chloride - pharmacology; Lithium Chloride - therapeutic use; Lithium compounds; Medicine and Health Sciences; Mice; Mice, Obese; Muscles; Nephrology; Nephropathy; Phosphorylation; Physical Sciences; Physiology; Research and Analysis Methods; Rodents; Urine; United States > US; Maine
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0189485

Glycogen synthase kinase 3 (GSK3) plays an important role in the development of diabetes mellitus and renal injury. GSK3 inhibition increases glucose uptake in insulin-insensitive muscle and adipose tissue, while it reduces albuminuria and glomerulosclerosis in acute kidney injury. The effect of chronic GSK3 inhibition in diabetic nephropathy is not known. We tested the effect of lithium, the only clinical GSK3 inhibitor, on the development of diabetes mellitus and kidney injury in a mouse model of diabetic nephropathy. Twelve-week old female BTBR-ob/ob mice were treated for 12 weeks with 0, 10 and 40 mmol LiCl/kg after which the development of diabetes and diabetic nephropathy were analysed. In comparison to BTBR-WT mice, ob/ob mice demonstrated elevated bodyweight, increased blood glucose/insulin levels, urinary albumin and immunoglobulin G levels, glomerulosclerosis, reduced nephrin abundance and a damaged proximal tubule brush border. The lithium-10 and -40 diets did not affect body weight and resulted in blood lithium levels of respectively <0.25 mM and 0.48 mM. The Li-40 diet fully rescued the elevated non-fasting blood glucose levels. Importantly, glomerular filtration rate was not affected by lithium, while urine albumin and immunoglobulin G content were further elevated. While lithium did not worsen the glomerulosclerosis, proximal tubule function seemed affected by lithium, as urinary NGAL levels were significantly increased. These results demonstrate that lithium attenuates non-fasting blood glucose levels in diabetic mice, but aggravates urinary albumin and immunoglobulin G content, possibly resulting from proximal tubule dysfunction.