Niclosamide ethanolamine–induced mild mitochondrial uncoupling improves diabetic symptoms in mice

Abstract

Type 2 diabetes (T2D) has reached an epidemic level globally. Most current treatments ameliorate the hyperglycemic symptom but are not effective in correcting the underlying cause. One important causal factor of T2D is ectopic accumulation of lipid in organs such as liver and muscle. Mitochondrial uncoupling, which reduces cellular energy efficiency and increases lipid oxidation, represents an appealing therapeutic strategy. The challenge, however, is to discover safe mitochondrial uncouplers for practical use. Niclosamide is an FDA approved anthelmintic drug that uncouples mitochondria of parasitic worms. Here we show that niclosamide ethanolamine salt (NEN) uncouples mammalian mitochondria at upper nanomolar concentrations. Oral NEN increases energy expenditure and lipid metabolism in mice. It is efficacious in preventing and treating high-fat diet (HFD) induced hepatic steatosis and insulin resistance. Moreover, it improves glycemic control and delays disease progression of the db/db mice. Given the well- documented safety profile of NEN, our study provides a potentially practical pharmacological embodiment of a new strategy for treating T2D.

Screening a Commercial Library of Pharmacologically Active Small Molecules against Staphylococcus aureus Biofilms

“…The antimicrobial activity of some derivatives and analogues of niclosamide has been documented (27,28). It has received increased attention in recent years due to its anticancer activity (29) and antidiabetic activity (30), highlighting its potential as a candidate for repurposing. The typical dosage is 2 g taken orally every 2 to 7 days, as required.…”

The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux

“…(126)(127)(128). Proof-of-concept studies in rodent models of NALFD and T2D demonstrate that mildly increasing hepatic mitochondrial inefficiency can safely reverse hypertriglyceridemia, ectopic lipid-induced (DAG/nPKC) liver and muscle insulin resistance, steatohepatitis, liver fibrosis, and diabetes, offering a novel therapeutic target for T2D and nonalcoholic steatohepatitis (NASH) (81,118,129). This knowledge and understanding gained over the past several decades into the pathogenesis of insulin resistance may avert the looming epidemics of diabetes and NAFLD/NASH and ensure a healthier future for subsequent generations (130).…”

Hepatic glucose and lipid metabolism

“…To date, hepatic Krebs cycle fluxes have been assayed by measuring the flow and distribution of carbon-labelled tracers through its constituent metabolite pools and into biosynthetic products such as glucose. Initial studies using 14 C tracers and laborious metabolite carbon-by-carbon degradation methods for obtaining positional labelling information were fundamental in describing the principal carbon flows through the hepatic Krebs cycle [15][16][17] and provided the foundations for developing stable isotope 13 C tracers whose distributions can be analysed more conveniently and in greater detail by MS and NMR methods. While positron emission tomography (PET) has also been used to measure hepatic fatty acid oxidation in humans using Ex vivo analysis involves 13 C NMR or gas chromatographymass spectrometry (GC-MS) measurements of circulating or excreted metabolites that can be traced back to the hepatic Krebs cycle (Fig.…”

“…Thus, the antihyperglycaemic actions of metformin have been explained through blockade of respiration redox reactions via inhibition of mitochondrial glycerol-3-phosphate dehydrogenase [11] and by direct inhibition of complex I and ATP synthase [12]. Compounds or formulations that reduce energy generation through mild mitochondrial uncoupling have also been shown to improve glucose intolerance and reverse steatosis [13,14] and have been proposed as a new class of glucose-lowering medications. In this setting, uncoupling agents have an additional advantage over respiration blockers in that they also accelerate fatty acid oxidation, thereby promoting the clearance of excess fat as well as reducing gluconeogenesis.…”