Abstract
Glucokinase (GK) plays a critical role in the control of whole-body glucose homeostasis. We investigated the possible effects of a novel glucokinase activator (GKA), HMS5552, to the GK in rats with type 2 diabetes mellitus (T2DM). Male Sprague-Dawley (SD) rats were divided into four groups: control group, diabetic group, low-dose (10 mg/kg) HMS5552-treated diabetic group (HMS-L), and high-dose (30 mg/kg) HMS5552-treated diabetic group (HMS-H). HMS5552 was administered intragastrically to the T2DM rats for one month. The levels of total cholesterol, triglyceride, fasting plasma insulin (FINS), and glucagon (FG) were determined, and an oral glucose tolerance test was performed. The expression patterns of proteins and genes associated with insulin resistance and GK activity were assayed. Compared with diabetic rats, the FINS level was significantly decreased in the HMS5552-treated diabetic rats. HMS5552 treatment significantly lowered the blood glucose levels and improved GK activity and insulin resistance. The immunohistochemistry, western blot, and semiquantitative RT-PCR results further demonstrated the effects of HMS5552 on the liver and pancreas. Our data suggest that the novel GKA, HMS5552, exerts antidiabetic effects on the liver and pancreas by improving GK activity and insulin resistance, which holds promise as a novel drug for the treatment of T2DM patients.
Highlights
Type 2 diabetes mellitus (T2DM), which accounts for approximately 90–95% of the diagnosed cases of diabetes [1], is a major health problem worldwide
We investigated the effects of a novel fourthgeneration glucokinase activator (GKA), HMS5552, which has a structurally novel amino-acid-based chemical scaffold, on the improvements of GK activity and insulin resistance in a rat model of T2DM induced by a high-fat diet and streptozotocin (STZ)
We investigated the mechanism of a novel GKA, HMS5552, which mediates the amelioration of glucose metabolism in a rat model of T2DM induced by STZ combined with a HFD
Summary
Type 2 diabetes mellitus (T2DM), which accounts for approximately 90–95% of the diagnosed cases of diabetes [1], is a major health problem worldwide. The oral therapies that are currently widely used for the treatment of patients with T2DM act mainly by reducing HGP (e.g., biguanides), promoting insulin action (e.g., thiazolidinediones), stimulating insulin release (e.g., sulfonylurea drugs), inhibiting the absorption of intestinal glucose (e.g., α-glucosidase inhibitors), and increasing the endogenous glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) levels (e.g., sitagliptin and saxagliptin) [3]. These therapies, have some notable shortcomings, such as insufficient efficiency, limited tolerability, and significant side-effects [4]. Effective, safe, and novel treatments that target novel pathways are urgently needed to help patients reach and maintain the optimal plasma glucose levels
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