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Glimepiride Administered in Chow Reversibly Impairs Glucose Tolerance in Mice 时间:2018-11-08 13:15 来源:未知作者:admin 点击: 次 Abstract:Sulfonylureas are a class of antidiabetes medications prescribed to millions of individuals worldwide. Rodents have been used extensively to study sulfonylureas in the laboratory. Here, we report the results of studies treating mice with a sulfonylurea (glimepiride) in order to understand how the drug affects glucose homeostasis and tolerance. We tested the effect of glimepiride on fasting blood glucose, glucose tolerance, and insulin secretion, using glimepiride sourced from a local pharmacy. We also examined the effect on glucagon, gluconeogenesis, and insulin sensitivity. Unexpectedly, glimepiride exposure in mice was associated with fasting hyperglycemia, glucose intolerance, and decreased insulin. There was no change in circulating glucagon levels or gluconeogenesis. The effect was dose-dependent, took effect by two weeks, and was reversed within three weeks after removal. Glimepiride elicited the same effects in all strains evaluated: four wild-type strains, as well as the transgenic Grn−/− and diabetic db/db mice. Our findings suggest that the use of glimepiride as a hypoglycemic agent in mice should proceed with caution and may have broader implications about mouse models as a proxy to study the human pharmacopeia.
1. Introduction
The potassium (K+) channel subtype, the “KATP channel,” and its orthologs are expressed in a range of species and have many functions. When KATP channels are present in the plasma membrane, K+ ions are pumped out, thus establishing an ion gradient. Inhibition of KATP channels induces membrane depolarization and activation of voltage-gated calcium channels. The KATP channel is also responsive to the ATP/ADP ratio, thus working as a “metabolic sensor” [1]. The channel contains a regulatory subunit, composed of the ABCC8 or ABCC9 (ATP-binding cassette, subfamily C members 8 and 9) gene products referred to as sulfonylurea receptor 1 and 2 (SUR1 and SUR2) proteins [2], respectively.
SUR1 and SUR2 are so named because an important drug class, the sulfonylureas, bind to, and block, activity. In the pancreas, sulfonylureas stimulate insulin secretion, leading to their use as oral antidiabetes medication, prescribed worldwide to millions of individuals [3]. Multiple generations of sulfonylurea drugs have been used in the human pharmacopoeia, alone and in drug combinations, varying in their specificity, activity, and impact on human subjects, with much of the variation unexplained to date. Because there has been suggestion that sulfonylurea drugs may have deleterious effects for some persons, this is a topical biomedical issue [4].
Understanding the characteristics of SUR proteins has been a focal point among researchers for decades. The two SUR paralogs are well-conserved across species: protein sequence homology between human and zebrafish SUR2 is ~70% [1]. One reason for evolutionary conservation is that they play phylogenetically durable roles, including metabolism, stress response, and regulation of blood vessel function [2, 5–9]. SUR1 and SUR2 allelic variants are associated with human diseases, including congenital diabetes, heart disease, and CNS disorders [6]. SUR1 function is best understood in the vertebrate pancreas and central neuronal tissue, as a regulator of insulin secretion and neuronal excitability.
Rodent studies are a common experimental context in which to study SUR physiology and pharmacology. A PubMed search combining “Sulf/phonylurea” and "rat/mouse" returns over 5400 published papers. However, there has been some indication that the pharmacological effect of sulfonylureas seen in humans differs appreciably from that seen in rodents in lab experiments. It is important to understand such a discrepancy, both for relevance to experimental models and for understanding the pharmacobiology of drugs commonly used in humans.
Here, we report the results of studies using the orally-administered sulfonylurea drug glimepiride (tradename Amaryl™) in six different mouse strains, in order to understand how the drug affects glucose homeostasis and tolerance. We used glimepiride sourced from a local pharmacy for comparison to human clinical use. Contrary to expectations, glimepiride exposure was associated with increased blood glucose levels and impaired glucose tolerance in all strains tested, both of which were reversible after several weeks wash-out.