Urinary Magnesium Regulation by Mucin-1 and Uromodulin - An Unexpected Role in the Development of Type 2 Diabetes Mellitus
Abstract
Diabetes mellitus is the seventh most common cause of death. The vast majority of diabetic patients have type 2 diabetes mellitus (T2DM). In the United States, T2DM affects 28 million people and more than 80 million are at risk for T2DM. T2DM causes long-term complications of multiple organs such as the eyes, kidneys, and cardiovascular and nervous systems, resulting in an economic burden of over US $320 billion annually. Therefore, early identification of at-risk individuals and timely treatment initiation to reduce the risk of complications are necessary. The causes for T2DM are diverse including lifestyle, diet, weight, and genetic predisposition. In addition, low serum magnesium levels were identified as a long overlooked risk factor doubling the risk of T2DM. Low magnesium levels and urinary magnesium wasting are common problems affecting 30% of T2DM patients. The cause for urinary magnesium wasting is unclear. While low magnesium is a T2DM risk factor, magnesium therapy improves diabetic control. Magnesium regulation in humans is not well understood. The kidney is a major regulator of human magnesium balance, and urinary magnesium loss contributes to low serum magnesium concentration. In the kidney, a magnesium channel called TRPM6 determines the amount of urinary magnesium excretion. We found that two common proteins in human urine, Mucin-1 (MUC1) and Uromodulin (UMOD), increase the number of TRPM6 channels and improve magnesium reabsorption in the kidney. Genetic variations among humans determine how much MUC1 and UMOD are secreted in the urine. We discovered that mice lacking UMOD lost more magnesium in the urine and developed abnormal glucose handling when fed with a low magnesium diet. It is still unclear how low magnesium contributes to T2DM. We found that TRPM6 binds to a member of the insulin signaling family called insulin receptor substrate 4 (IRS4), which is needed for TRPM6 stimulation and so provides a novel link between magnesium and glucose homeostasis. Our hypothesis is that MUC1 and UMOD are secreted into urine and enhance TRPM6 channels, thereby increasing magnesium reabsorption by the kidney. We found that UMOD is secreted more in low magnesium states. Humans carrying genetic variations that reduce urinary MUC1 or UMOD secretion may not be able to respond to low serum magnesium concentrations resulting in a low magnesium state, which renders these individuals to become at-risk patients for T2DM. Genetic predisposition to excrete less MUC1 and UMOD in urine, low serum magnesium, and high magnesium losses in urine may represent novel risk factors for T2DM. Additionally, we propose that IRS4 enhances renal Mg2+ absorption by TRPM6 stimulation and may also affect glucose metabolism by the IRS4-TRPM6 relationship. In the first aim of this proposal, we will test the biological mechanism how MUC1 modifies TRPM6, if specific TRPM6 channel modifications are needed, and if MUC1 and UMOD work together in TRPM6 regulation. In the second aim, we will test the significance of MUC1, UMOD, and TRPM6 for magnesium balance and glucose homeostasis in mice lacking the corresponding genes. To induce T2DM, animals will be fed with a high-fat diet and challenged with a low magnesium diet. To demonstrate the beneficial effect of magnesium, we will then feed mice with a high-fat, high magnesium diet, and glucose homeostasis will be tested. Different possible causes contributing to T2DM due to low magnesium will be evaluated. In the third aim, we will confirm TRPM6-IRS4 protein interaction. In mice lacking IRS4, we will study renal magnesium and glucose homeostasis at baseline and when fed a high-fat diet with low or high magnesium. The results of this project will be applicable and impactful for patients with T2DM: (1) We study if urinary magnesium loss is a sensitive marker for T2DM risk to identify early at-risk-individuals. (2) As individuals with low urinary MUC1 and UMOD may be unab
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910205
Entities
People
- M. Wolf
Organizations
- United States Army
- University of Texas Southwestern Medical Center