The Mode of Action of the Antidiabetic Drug Glimepiride-Beyond Insulin Secretion

Abstract

During the past 10 years a multitude of clinical and observational studies have confirmed the efficacy of the antidiabetic drug, glimepiride, in lowering fasting and postprandial blood glucose in lean and obese type 2 diabetic patients even after a single administration per day, only, as well as its high safety and patient's compliance. Additional findings obtained in these studies suggested a number of clinical advantages compared to other sulfonylurea drugs on the market (e.g. glibenclamide), in particular, the lower risk for hypoglycemia, weight gain and atherosclerotic vascular disease as well as the less pronounced hyperinsulinemia. Studies investigating the molecular basis underlying the clinical profile of glimepiride provide strong evidence for multiple molecular targets/mechanisms for the blood glucose-lowering effect of glimepiride operating at both pancreatic ß-cells and extrapancreatic cells. (i) Interaction with the sulfonylurea receptor, SUR, at the ß-cell plasma membrane triggers insulin release. (ii) Interaction with lipid rafts, DIGs, at the plasma membrane of adipose and muscle cells induces the insulin-mimetic activity via the activation of a glycosylphosphatidylinositol-specific phospholipase, redistribution of signaling components and positive cross-talk downstream to the insulin signaling cascade. (iii) Interference with additional molecular mechanisms in extrapancreatic cells (e.g. regulation of adipocytokine release from and differentiation of adipocytes), relying on or independent of SUR and DIGs, contributes to the insulin-sensitizing activity of glimepiride. Differences in the engagement of these targets/mechanisms between glimepiride and glibenclamide are compatible with the more favorable blood glucose-lowering profile and the lower risk for weight gain, hypoglycemic incidences and cardiovascular side effects. The molecular and clinical findings with glimepiride raise doubts that the potential of sulfonylureas for the therapy of type 2 diabetic patients has already been fully explored and feeds the hope for more efficient and nevertheless safe antidiabetic drugs derived from this "old" pharmacophore class in the future.

Inhibition of lipolysis by adiposomes containing glycosylphosphatidylinositol-anchored Gce1 protein in rat adipocytes

“…The improvement in sensitivity of adipocytes toward H 2 O 2 -, glimepiride-and palmitate-induced lipolysis inhibition by ADIP as is reflected in two-to four-fold reduced IC 50 -values (Figure 1) may be of physiological and therapeutic relevance in humans. These IC 50 -values are within the range of the total plasma concentrations measured for H 2 O 2 during stress, glimepiride during anti-diabetic therapy (Müller, 2005) and fatty acids during starvation. The present study in combination with the previous one (Müller et al, in press) suggests that the transfer of GPI-proteins, such as Gce1 and CD73, from donor cells, such as large adipocytes, via microvesicles and/ or exosomes, such as ADIP, to plasma membrane DIGs and their subsequent translocation to LD of acceptor cells, such as small adipocytes, can transmit physiological signals, such as the regulation of lipid metabolism, in paracrine fashion between neighbouring cells within a tissue depot (e.g.…”

Personalized Prognosis and Diagnosis of Type 2 Diabetes – Vision or Fiction?

“…While common variants in glucokinase do not influence type 2 diabetes risk per se, they have a clear impact on fasting glucose levels within the population. In any case, the genotype-phenotype relationships revealed by these gene discovery efforts will highlight the pathways involved as prime candidates for beneficial therapeutic or preventative manipulation, a view reinforced by the fact that at least two of the genes involved in both monogenic and multifactorial forms of diabetes (PPARG, KCNJ11) encode the targets of the two major classes of the currently available antidiabetic drugs, the thiazolidinediones and sulfonylureas, with the most widely used representatives rosiglitazone and glimepiride [37] . The corresponding gene products, transcription factor PPAR ␥ in adipose cells and the SUR1 subunit of the K ATP in pancreatic beta cells, play critical roles in the insulin-stimulated whole-body glucose utilization and the glucosestimulated insulin secretion, respectively.…”

“…It is a major challenge to establish how to use analogous knowledge from the identification of predisposing polymorphisms of genes, proteins and metabolites for common diseases such as type 2 diabetes, to improve patient care. In the future, systems biology will be the prerequisite for an earlier and more reliable diagnosis, prognosis and therapy, tailored to the individual pathogenic mechanism and thereby justify the hopes commonly associated with personalized medicine in the public [37,[48][49][50][51][52][53] . No doubt, this necessitates a broad understanding of the putative personal consequences and advantages of systems biology-based diagnosis in the public, which will critically depend on corresponding individualized therapeutic options.…”

Oral Protein Therapy for the Future – Transport of Glycolipid-Modified Proteins: Vision or Fiction

“…The GPI anchor is susceptible to cleavage by special types of serum phospholipases C or D [81][82][83][84] . They operate in constitutive or regulated fashion during a number of physiological (for example insulin action [85] ) and pharmacological (for example glimepiride action [86,87] ) processes or are used for the experimental release of the (hydrophilic) protein moiety from the membrane or cell surface for the diagnosis of GPI anchorage ( fig. 4 ) [88] .…”