lithium-chloride and Diabetes-Mellitus--Type-2

Accumulated evidence suggests that sporadic cases of Alzheimer's disease (AD) make up more than 95% of total AD patients, and diabetes has been implicated as a strong risk factor for the development of AD. Diabetes shares pathological features of AD, such as impaired insulin signaling, increased oxidative stress, increased amyloid-beta (Aβ) production, tauopathy and cerebrovascular complication. Due to shared pathologies between the two diseases, anti-diabetic drugs may be a suitable therapeutic option for AD treatment. In this article, we will discuss the well-known pathologies of AD, including Aβ plaques and tau tangles, as well as other mechanisms shared in AD and diabetes including reactive glia and the breakdown of blood brain barrier in order to evaluate the presence of any potential, indirect or direct links of pre-diabetic conditions to AD pathology. In addition, clinical evidence of high incidence of diabetic patients to the development of AD are described together with application of anti-diabetic medications to AD patients.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Astrocytes; Brain; Cerebrovascular Disorders; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Lithium Chloride; Pioglitazone

We studied antidiabetic effects and cytoprotective activity of two lithium salts (lithium chloride and lithium carbonate) on the model of streptozotocin-induced diabetes mellitus type 2 in Wistar rats. Using the method of β-cells detection with antibodies to insulin, we demonstrated that streptozotocin reduced the number of β-cells and impaired their morphological structure. Both lithium preparations administered to diabetic animals for 28 days in doses of 10 and 8.9 mg/kg, respectively, attenuated the damaging effect of streptozotocin. This cytoprotective effect of lithium salts manifested in weakening of hyperglycemia, polyphagia, polydipsia, and weight loss. A satisfactory correlation between the morphometric data and blood glucose levels was revealed. The mechanisms of the multitarget action of lithium salts are discussed.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Immunohistochemistry; Insulin; Insulin-Secreting Cells; Lithium Carbonate; Lithium Chloride; Liver; Male; Neuroprotective Agents; Rats; Rats, Wistar; Streptozocin

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.

Topics: Albuminuria; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Evaluation, Preclinical; Female; Glycogen Synthase Kinase 3; Hypoglycemic Agents; Kidney; Lithium Chloride; Mice, Obese

A major action of insulin is to regulate the transcription rate of specific genes. The expression of these genes is dramatically altered in type 2 diabetes. For example, the expression of two hepatic genes, glucose-6-phosphatase and PEPCK, is normally inhibited by insulin, but in type 2 diabetes, their expression is insensitive to insulin. An agent that mimics the effect of insulin on the expression of these genes would reduce gluconeogenesis and hepatic glucose output, even in the presence of insulin resistance. The repressive actions of insulin on these genes are dependent on phosphatidylinositol (PI) 3-kinase. However, the molecules that lie between this lipid kinase and the two gene promoters are unknown. Glycogen synthase kinase-3 (GSK-3) is inhibited following activation of PI 3-kinase and protein kinase B. In hepatoma cells, we find that selectively reducing GSK-3 activity strongly reduces the expression of both gluconeogenic genes. The effect is at the level of transcription and is observed with induced or basal gene expression. In addition, GSK-3 inhibition does not result in the subsequent activation of protein kinase B or inhibition of the transcription factor FKHR, which are candidate regulatory molecules for these promoters. Thus, GSK-3 activity is required for basal activity of each promoter. Inhibitors of GSK-3 should therefore reduce hepatic glucose output, as well as increase the synthesis of glycogen from L-glucose. These findings indicate that GSK-3 inhibitors may have greater therapeutic potential for lowering blood glucose levels and treating type 2 diabetes than previously realized.

Topics: Aminophenols; Animals; Blood Glucose; Calcium-Calmodulin-Dependent Protein Kinases; Choline O-Acetyltransferase; Culture Media, Serum-Free; Dexamethasone; Diabetes Mellitus, Type 2; DNA-Binding Proteins; Enzyme Inhibitors; Forkhead Box Protein O1; Forkhead Transcription Factors; Gene Expression Regulation, Enzymologic; Glucose-6-Phosphatase; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Humans; Insulin; Lithium Chloride; Liver Neoplasms, Experimental; Maleimides; Nerve Tissue Proteins; Phosphatidylinositol 3-Kinases; Phosphoenolpyruvate Carboxykinase (GTP); Potassium Chloride; Promoter Regions, Genetic; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Recombinant Proteins; Transcription Factors; Transfection; Tumor Cells, Cultured