Meglumine Exerts Protective Effects against Features of Metabolic Syndrome and Type II Diabetes

Abstract

Metabolic syndrome, diabetes and diabetes complications pose a growing medical challenge worldwide, accentuating the need of safe and effective strategies for their clinical management. Here we present preclinical evidence that the sorbitol derivative meglumine (N-methyl-D-glucamine) can safely protect against several features of metabolic syndrome and diabetes, as well as elicit enhancement in muscle stamina. Meglumine is a compound routinely used as an approved excipient to improve drug absorption that has not been ascribed any direct biological effects in vivo. Normal mice (SV129) administered 18 mM meglumine orally for six weeks did not display any gastrointestinal or other observable adverse effects, but had a marked effect on enhancing muscle stamina and at longer times in limiting weight gain. In the established KK.Cg-Ay/J model of non-insulin dependent diabetes, oral administration of meglumine significantly improved glycemic control and significantly lowered levels of plasma and liver triglycerides. Compared to untreated control animals, meglumine reduced apparent diabetic nephropathy. Sorbitol can improve blood glucose uptake by liver and muscle in a manner associated with upregulation of the AMPK-related enzyme SNARK, but with undesirable gastrointestinal side effects not seen with meglumine. In murine myoblasts, we found that meglumine increased steady-state SNARK levels in a dose-dependent manner more potently than sorbitol. Taken together, these findings provide support for the clinical evaluation of meglumine as a low-cost, safe supplement offering the potential to improve muscle function, limit metabolic syndrome and reduce diabetic complications.

Sucrose nonfermenting AMPK‐related kinase (SNARK) regulates exercise‐stimulated and ischemia‐stimulated glucose transport in the heart

“…SNARK has been shown to play an important role in the regulation of glucose uptake in skeletal muscle, 14 and some studies have suggested that SNARK may regulate whole body metabolic homeostasis. 10,22 Accordingly, the current study was designed to determine whether SNARK is part of the mechanism that regulates glucose transport in the heart. Our results show that SNARK is expressed in mouse hearts and HL1 cardiomyocytes, and that treadmill exercise and ischemia, stimuli that increase glucose transport in the heart, also increase SNARK phosphorylation at the Thr 208 site that controls SNARK enzymatic activity.…”

“…Despite the importance of cardiac glucose metabolism in the prevention and recovery from heart disease, there are still many questions regarding the mechanisms that regulate glucose uptake in the heart. SNARK has been shown to play an important role in the regulation of glucose uptake in skeletal muscle [Koh et al], and some studies have suggested that SNARK may regulate whole body metabolic homeostasis [Bravo-Nuevo A MA, 2014; Tsuchihara et al, 2008]. Accordingly, the current study was designed to determine whether SNARK is part of the mechanism that regulates glucose transport in the heart.…”

“…In recent years the AMP-activated protein kinase (AMPK) and its upstream kinase LKB1 have been suggested to be components of a cellular signaling pathway that regulates glucose transport in the heart through an insulin-independent mechanism [Arad et al, 2007; Bravo-Nuevo A MA, 2014; Huang et al, 2013; Ikeda et al, 2009; Jessen et al. ; Sakamoto et al, 2006; Xing et al, 2003].…”

“…; Sakamoto et al, 2006; Xing et al, 2003]. Transgenic mice expressing an inactive AMPK catalytic subunit in the heart have an inability to augment glucose uptake during low-flow ischemia [Bravo-Nuevo A MA, 2014; Xing et al, 2003] and these hearts develop left ventricular dysfunction manifested by an early and more rapid increase in left ventricular end-diastolic pressure [Xing et al, 2003]. While there is a clear cardiac phenotype in AMPK inactive transgenic mice, knockout of LKB1 in the heart results in an even more severe phenotype [Ikeda et al, 2009; Jessen et al.…”

How extracellular sodium replacement affects the conduction velocity distribution of rats’ peripheral nerves

“…N-methyl-D-glucamine (megulamine; NMG) is an agent used mostly as a benign excipient or vehicle of a drug in pharmacology to improve drug absorption. It also offers the potential for improved muscle function and reduction in metabolic syndrome and diabetes mellitus complications by sys-temic administration with no observable adverse effects [1]. However, in electrophysiological in vitro applications, when used as a component of a replacement medium, it mimics the presence of an Na + compound and blocks Na + currents in the cell membrane [2,3].…”