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

ABSTRACT: 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.

SUBMITTER: de Groot T

PROVIDER: S-EPMC5731748 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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

de Groot Theun T Damen Lars L Kosse Leanne L Alsady Mohammad M Doty Rosalinda R Baumgarten Ruben R Sheehan Susan S van der Vlag Johan J Korstanje Ron R Deen Peter M T PMT

PloS one 20171215 12

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 ...[more]

PMID: 29244860

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Project description:OBJECTIVE:To assess the influence of serum carnosinase (CN1) on the course of diabetic kidney disease (DKD). METHODS:hCN1 transgenic (TG) mice were generated in a BTBROb/Ob genetic background to allow the spontaneous development of DKD in the presence of serum carnosinase. The influence of serum CN1 expression on obesity, hyperglycemia, and renal impairment was assessed. We also studied if aggravation of renal impairment in hCN1 TG BTBROb/Ob mice leads to changes in the renal transcriptome as compared with wild-type BTBROb/Ob mice. RESULTS:hCN1 was detected in the serum and urine of mice from two different hCN1 TG lines. The transgene was expressed in the liver but not in the kidney. High CN1 expression was associated with low plasma and renal carnosine concentrations, even after oral carnosine supplementation. Obese hCN1 transgenic BTBROb/Ob mice displayed significantly higher levels of glycated hemoglobin, glycosuria, proteinuria, and increased albumin-creatinine ratios (1104 ± 696 vs 492.1 ± 282.2 ?g/mg) accompanied by an increased glomerular tuft area and renal corpuscle size. Gene-expression profiling of renal tissue disclosed hierarchical clustering between BTBROb/Wt, BTBROb/Ob, and hCN1 BTBROb/Ob mice. Along with aggravation of the DKD phenotype, 26 altered genes have been found in obese hCN1 transgenic mice; among them claudin-1, thrombospondin-1, nephronectin, and peroxisome proliferator-activated receptor-alpha have been reported to play essential roles in DKD. CONCLUSIONS:Our data support a role for serum carnosinase 1 in the progression of DKD. Whether this is mainly attributed to the changes in renal carnosine concentrations warrants further studies. KEY MESSAGES:Increased carnosinase 1 (CN1) is associated with diabetic kidney disease (DKD). BTBROb/Ob mice with human CN1 develop a more aggravated DKD phenotype. Microarray revealed alterations by CN1 which are not altered by hyperglycemia. These genes have been described to play essential roles in DKD. Inhibiting CN1 could be beneficial in DKD.

Project description:BackgroundGrowing evidence supports the role of gut microbiota in obesity and its related disorders including type 2 diabetes. Ob/ob mice, which are hyperphagic due to leptin deficiency, are commonly used models of obesity and were instrumental in suggesting links between gut microbiota and obesity. Specific changes in their gut microbiota such as decreased microbial diversity and increased Firmicutes to Bacteroidetes ratio have been suggested to contribute to obesity via increased microbiota capacity to harvest energy. However, the differential development of ob/ob mouse gut microbiota compared to wild type microbiota and the role of hyperphagia in their metabolic impairment have not been investigated thoroughly.ResultsWe performed a 10-week long study in ob/ob (n = 12) and wild type control (n = 12) mice fed ad libitum. To differentiate effects of leptin deficiency from hyperphagia, we pair-fed an additional group of ob/ob mice (n = 11) based on the food consumption of control mice. Compared to control mice, ob/ob mice fed ad libitum exhibited compromised glucose metabolism and increased body fat percentage. Pair-fed ob/ob mice exhibited even more compromised glucose metabolism and maintained strikingly similar high body fat percentage at the cost of lean body mass. Acclimatization of the microbiota to our facility took up to 5 weeks. Leptin deficiency impacted gut microbial composition, explaining 18.3% of the variance. Pair-feeding also altered several taxa, although the overall community composition at the end of the study was not significantly different. We found 24 microbial taxa associations with leptin deficiency, notably enrichment of members of Lactobacillus and depletion of Akkermansia muciniphila. Microbial metabolic functions related to energy harvest, including glycan degradation, phosphotransferase systems and ABC transporters, were enriched in the ob/ob mice. Taxa previously reported as relevant for obesity were associated with body weight, including Oscillibacter and Alistipes (both negatively correlated) and Prevotella (positively correlated).ConclusionsLeptin deficiency caused major changes in the mouse gut microbiota composition. Several microbial taxa were associated with body composition. Pair-fed mice maintained a pre-set high proportion of body fat despite reduced calorie intake, and exhibited more compromised glucose metabolism, with major implications for treatment options for genetically obese individuals.

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

Publications

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

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