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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Niacin (nicotinic acid, 3-pyridinecarboxylic acid, a B vitamin) has been used since several decades as lipid-lowering agent; it reduces the level of plasma triglyceride by about 35%, and LDL-cholesterol levels by 10–15%, whereas it increases the concentration of HDL-cholesterol by up to 25% by a so far not precisely known mechanism. Despite these properties, results from recent studies suggest that there are no benefits from niacin therapy concerning prevention of cardiovascular disease events (Krumholz, 2016; Schandelmaier, 2017). Niacin has been withdrawn from many markets (Pedersen, 2016). Acipimox, a derivative of nicotinic acid that also lowers serum lipid levels by reducing the production of VLDL and LDL, has been reported to increase peripheral and hepatic insulin sensitivity (Vestergaard et al., 2017).
PET Imaging of Heart and Skeletal Muscle: An Overview
Published in Robert J. Gropler, David K. Glover, Albert J. Sinusas, Heinrich Taegtmeyer, Cardiovascular Molecular Imaging, 2007
Oral administration of a nicotinic acid or its derivatives have been shown to provide easy approach to stimulate myocardial glucose utilization and improve image quality (9,15). Nicotinic acid inhibits peripheral lipolysis and, thus, reduces plasma FFA concentrations. Acipimox is a very potent nicotinic acid derivative. The FDG image quality has been reported to be comparable with insulin clamping in most of the patients. Importantly, with the exception of flushing, no side effects of acipimox were observed.
Nutrient Interactions and Glucose Homeostasis
Published in Emmanuel Opara, NUTRITION and DIABETES, 2005
As pointed out earlier, fatty-acid oxidation affects glycemic control not only by decreasing peripheral glucose utilization, but also by enhancing gluconeogenesis. Hence, inhibition of lipolysis is an effective strategy to reduce the availability of free fatty acids for oxidation and thus enhance glucose oxidation and decrease blood-glucose levels (19, 21). One of the early attempts to use antilipolytic agent to limit fatty-acid availability and treat type 2 diabetes was made with nicotinic acid. It was found that its inhibitory effect on lipolysis was accompanied by a stimulation of the glucose disposal. It was, however, disappointing to see that although nicotinic acid initially reduced free fatty-acid levels in type 2 diabetes, it was followed by a rebound in free fatty-acid levels that was associated with hyperglycemia and glucosuria (19). Subsequently, an analogue of nicotinic acid, acipimox, was developed, which was more potent and had less of the rebound effect than nicotinic acid (19). To date, acipimox remains an active research interest in the treatment of type 2 diabetes. In a recent experimental study with obese Zucker rats, oral administration of 150 mg/kg of acipimox significantly reduced plasma free fatty-acid (FFA), glucose, and insulin levels, and thus improved glucose tolerance while reducing insulin response (24). Clinical trials with acipimox have also yielded positive effects in the management of type 2 diabetes. In an early double-blind, placebo-controlled trial, hepatic-glucose output (HGO) and fuel use assessed by indirect calorimetry were measured in the basal state and during the last 30 minutes of a hyperglycemic clamp in obese, type 2 diabetics three times thrice during 12 hours. It was found that this protocol of prolonged suppression of lipolysis caused a reduction of fasting blood glucose and HGO while increasing peripheral hepatic sensitivity to insulin in the study subjects (25). The data from this early study were consistent with those from another overnight placebo-controlled study with acipimox (26). In the later study, 250 mg acipimox was administered three times in 12 hours to four different groups of individuals, namely lean control subjects, obese, nondiabetic individuals, obese subjects with impaired glucose tolerance, and patients with type 2 diabetes. It was found that lowering plasma FFA levels reduced insulin resistance/hyperinsulinemia and improved oral glucose tolerance in all groups of the study subjects (26). The observations from these studies of short-term use of acipimox have been confirmed in a randomized, double-blind, placebo-controlled study in which 25 individuals with type 2 diabetes were given 250 mg four times daily, and another 25 received a placebo for one week. The study showed that the treatment with acipimox lowered plasma FFA levels and improved acute-insulin response and insulin-mediated glucose uptake (27). However, in one of the earlier studies, acipimox gave mixed results on suppression of plasma FFA levels and had no effect on hepatic-glucose production (28). The reason for this discrepant observation with acipimox is not clear.
Acipimox inhibits human carbonic anhydrases
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mattia Mori, Claudiu T. Supuran
Acipimox (OlbetamR) 1 is a clinically used drug for the treatment of hyperlipidaemic patients that do not respond to other therapeutic regimens1. The drug exerts its hypolipidemic effect by inhibiting lipolysis as well as the free fatty acid flux to the liver, by reducing the precursor pool size of very low density lipoprotein (VLDL)-triglyceride and inhibiting VLDL synthesis, with the consequent reduction of plasma triglyceride levels and increase of high density lipoprotein (HDL) cholesterol2. The drug also interferes with peroxisomal oxidative activities and enhances autophagy, and for such reasons it was proposed as one of the first therapeutic agents for healthy ageing by Bergamini’s group3. It is known that autophagy plays a crucial role in cell housekeeping processes during fasting, contributing to the removal of altered membranes, mitochondria, as well as other organelles, including peroxisomes, which may explain the antiaging effects of caloric restriction, which in turn can be enhanced by using anti-lipolytic drugs such as acipimox at dosages lower than those used for the treatment of hyperlipidaemia4.
Pro-inflammatory cytokine-induced lipolysis after an episode of acute pancreatitis
Published in Archives of Physiology and Biochemistry, 2018
Sayali A. Pendharkar, Ruma G. Singh, Maxim S. Petrov
Given the findings of this study, we suggest that there are at least two ways to modulate lipid metabolism for therapeutic purposes. First, pro-inflammatory cytokine neutralisation has been demonstrated in pre-clinical studies to effectively improve lipolysis. Evidence from numerous studies (Hotamisligil et al. 1993, Hauner et al.1995, Ren et al.2006, Lorente-Cebrián et al.2012) using either rat models, or cultured 3T3-L1 or human adipocytes, demonstrates that co-incubation of metformin, eicosapentaenoic acid, thiazolidinediones, or glucocorticoids and TNFα results in decreased TNFα-stimulated lipolysis and improved insulin sensitivity and glucose homeostasis (Souza et al.1998, Ren et al.2006, Lee and Fried 2012, Lorente-Cebrián et al.2012). However, whether cytokine blockade affects lipolysis and consequently insulin resistance and glucose homeostasis in humans with impaired glucose homeostasis in general, and in PPDM in particular, remains to be investigated. Second possibility as to how lipid metabolism could be modulated for therapeutic purposes is suppression of lipolysis – long been known to improve insulin-stimulated glucose disposal by enhancing glucose storage as glycogen. Yet, this has been investigated clinically only in the past decade. A study by Lim et al. (2011) recruited ten type 2 diabetes individuals and eight physical activity-, age-, and BMI-matched controls. Isoglycaemic–hyperinsulinaemic clamps with [13C]glucose infusion were performed on all individuals. Glycogen synthesis was measured by 13C magnetic resonance spectroscopy of muscle. All measurements were done in a fasted state and 250 mg of acipimox (a niacin derivative used as a lipid-lowering agent) or placebo was administered in a double-blind manner at baseline and 3 h later. The study showed that suppressed lipolysis increased whole-body glucose uptake with increase in whole-body glucose oxidation rates (as evidenced by increased fasting ATP turnover) but not with increased rate of glucose storage as glycogen (Lim et al.2011). Another study by Girousse et al. (2013) investigated the relationship between white adipose tissue lipolysis and insulin sensitivity in 25 morbidly obese humans who underwent bariatric surgery. Lipolysis and insulin resistance were measured both before and two years after bariatric surgery – findings of which showed that insulin resistance improved with decrease in lipolysis (Girousse et al.2013). Based on the evidence presented in these studies, it appears that suppressing lipolysis contributes to improved insulin resistance and sensitivity, at least in the setting of type 2 diabetes. Future studies are now warranted to determine whether lipolysis suppression may indeed ameliorate glucose derangements in individuals with PPDM.