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Background and purpose Analogues of fibroblast growth factor 21 (FGF21) demonstrate diverse metabolic benefits in preclinical models of type 2 diabetes, dyslipidaemia, and non-alcoholic steatohepatitis (NASH), but clinical responses with different analogues are inconsistent. Efruxifermin is an Fc-FGF21 fusion protein with prolonged half-life and enhanced receptor affinity compared to native human FGF21. Efruxifermin is in clinical trials for the treatment of NASH. Experimental approach Efruxifermin was administered weekly to male and female Sprague Dawley rats for 4 or 26 weeks. Body and organ weights, macro- and microscopic pathology, clinical chemistry, blood cytology, and serum and urine biomarkers were analysed to characterise the pharmacodynamics of efruxifermin, and to investigate potential nonclinical toxicities following chronic administration of supra-pharmacological doses of efruxifermin. Key results Efruxifermin significantly reduced body weight gain after 4 and 26 weeks, despite increasing food intake. Changes in tissue pathology, clinical chemistry and serum biomarkers generally appeared to be associated with weight loss, except for a significant decrease in urine volume in both males and females without perturbed electrolyte balance. Markers of sympathetic activation, urinary corticosterone, and ratio of adrenal-to-body weight were unchanged. Conclusion and implications Efruxifermin attenuated body weight gain, consistent with other FGF21 analogues. In contrast to at least one other FGF21 analogue, efruxifermin decreased rather than increased urine volume. The absence of an increase in sympathetic tone in rats mirrors the unchanged salivary cortisol and systemic blood pressure following efruxifermin treatment in humans.

The rising global prevalence of obesity, metabolic syndrome, and type 2 diabetes has driven a sharp increase in non-alcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in the liver. Approximately one-sixth of the NAFLD population progresses to non-alcoholic steatohepatitis (NASH) with liver inflammation, hepatocyte injury and cell death, liver fibrosis and cirrhosis. NASH is one of the leading causes of liver transplant, and an increasingly common cause of hepatocellular carcinoma (HCC), underscoring the need for intervention. The complex pathophysiology of NASH, and a predicted prevalence of 3–5% of the adult population worldwide, has prompted drug development programs aimed at multiple targets across all stages of the disease. Currently, there are no approved therapeutics. Liver-related morbidity and mortality are highest in more advanced fibrotic NASH, which has led to an early focus on anti-fibrotic approaches to prevent progression to cirrhosis and HCC. Due to limited clinical efficacy, anti-fibrotic approaches have been superseded by mechanisms that target the underlying driver of NASH pathogenesis, namely steatosis, which drives hepatocyte injury and downstream inflammation and fibrosis. Among this wave of therapeutic mechanisms targeting the underlying pathogenesis of NASH, the hormone fibroblast growth factor 21 (FGF21) holds considerable promise; it decreases liver fat and hepatocyte injury while suppressing inflammation and fibrosis across multiple preclinical studies. In this review, we summarize preclinical and clinical data from studies with FGF21 and FGF21 analogs, in the context of the pathophysiology of NASH and underlying metabolic diseases.

Summary Experimental fibroblast growth factor 21 (FGF21) analogs can improve lipid profiles in patients with metabolic diseases. However, their effects on markers of insulin sensitivity appear to be minimal, potentially because of insufficient exposure. Systemic drug levels vary from sub-pharmacological to demonstrating pharmacodynamic effects but with dose-limiting adverse events. Here we report results from a phase 1 multiple ascending dose study of AKR-001, an Fc-FGF21 fusion protein engineered for sustained systemic pharmacologic exposure, in individuals with type 2 diabetes. With a half-life of 3–3.5 days, the peak-to-trough ratio under steady-state conditions is approximately 2 following QW dosing. AKR-001 appears to demonstrate pharmacodynamic effects on serum markers of insulin sensitivity and acceptable tolerability up to and including 70 mg QW. Positive trends in lipoprotein profile, including triglycerides, non-high-density lipoprotein (non-HDL) cholesterol, HDL-C, and apolipoproteins B and C3 are consistent with other FGF21 analogs. AKR-001’s clinical profile supports further evaluation as a treatment for metabolic diseases., Graphical Abstract, Highlights AKR-001 is an Fc-FGF21 analog with stabilized N- and C-terminal domains of FGF21 AKR-001 dosed once weekly modulates markers of insulin sensitivity in T2D patients AKR-001 exhibits positive trends in markers of lipid metabolism AKR-001 has acceptable tolerability, supporting ongoing clinical development, FGF21 ameliorates metabolic disease in animal models but has modest effects in humans. Kaufman et al. report the pharmacokinetic, pharmacodynamic, and safety data from a phase 1 multiple ascending dose study in T2DM of AKR-001, a long-acting FGF21 analog. They show that AKR-001 exhibits positive trends in various metabolic markers.

Diabetic nephropathy remains an area of high unmet medical need, with current therapies that slow down, but do not prevent, the progression of disease. A reduced phosphorylation state of adenosine monophosphate-activated protein kinase (AMPK) has been correlated with diminished kidney function in both humans and animal models of renal disease. Here, we describe the identification of novel, potent, small molecule activators of AMPK that selectively activate AMPK heterotrimers containing the β1 subunit. After confirming that human and rodent kidney predominately express AMPK β1, we explore the effects of pharmacological activation of AMPK in the ZSF1 rat model of diabetic nephropathy. Chronic administration of these direct activators elevates the phosphorylation of AMPK in the kidney, without impacting blood glucose levels, and reduces the progression of proteinuria to a greater degree than the current standard of care, angiotensin-converting enzyme inhibitor ramipril. Further analyses of urine biomarkers and kidney tissue gene expression reveal AMPK activation leads to the modulation of multiple pathways implicated in kidney injury, including cellular hypertrophy, fibrosis, and oxidative stress. These results support the need for further investigation into the potential beneficial effects of AMPK activation in kidney disease.

The continuous, longitudinal nature of accelerometry monitoring is well-suited to capturing the regular 24-hour oscillations in human activity across the day, the cumulative effect of our circadian rhythm and behavior. Disruption of the circadian rhythm in turn disrupts rest-activity rhythms. Although circadian disruption is a major feature of Parkinson's disease (PD), rest-activity rhythms and their relationship with disease severity have not been well characterized in PD. 13 PD participants (Hoehn & Yahr Stage [HY significant associations between MDS-UPDRS scores and activity levels were observed only in the unadjusted model. These findings demonstrate that continuous actigraphy is capable of detecting rest-activity disruption in PD, and provides preliminary evidence that rest-activity rhythms are associated with motor symptom severity and H&Y Stage.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that downregulates low-density lipoprotein (LDL) receptor (LDL-R) levels on the surface of hepatocytes, resulting in decreased clearance of LDL-cholesterol (LDL-C). Phenotypic screening of a small-molecule compound collection was used to identify an inhibitor of PCSK9 secretion, (R)-N-(isoquinolin-1-yl)-3-(4-methoxyphenyl)-N-(piperidin-3-yl)propanamide (R-IMPP), which was shown to stimulate uptake of LDL-C in hepatoma cells by increasing LDL-R levels, without altering levels of secreted transferrin. Systematic investigation of the mode of action revealed that R-IMPP did not decrease PCSK9 transcription or increase PCSK9 degradation, but instead caused transcript-dependent inhibition of PCSK9 translation. In support of this surprising mechanism of action, we found that R-IMPP was able to selectively bind to human, but not E. coli, ribosomes. This study opens a new avenue for the development of drugs that modulate the activity of target proteins by mechanisms involving inhibition of eukaryotic translation.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a key role in regulating the levels of plasma low density lipoprotein cholesterol (LDL-C). Here we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation. The mechanism of action employed by PF-06446846 reveals a previously unexpected tunability of the human ribosome, which allows small molecules to specifically block translation of individual transcripts.One Sentence SummaryA small-molecule PCSK9 inhibitor targets the human ribosome and selectively prevents PCSK9 synthesis.

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/Open Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention. US National Institutes of Health (NIH) Training 5-T32-GM007748-33 Doris Duke Charitable Foundation 2006087 Fulbright Diabetes UK Fellowship BDA 11/0004348 Broad Institute from Pfizer, Inc. NIH U01 DK085501 U01 DK085524 U01 DK085545 U01 DK085584 Swedish Research Council Dnr 521-2010-3490 Dnr 349-2006-237 European Research Council (ERC) GENETARGET T2D GA269045 ENGAGE 2007-201413 CEED3 2008-223211 Sigrid Juselius Foundation Folkh lsan Research Foundation ERC AdG 293574 Research Council of Norway 197064/V50 KG Jebsen Foundation University of Bergen Western Norway Health Authority Lundbeck Foundation Novo Nordisk Foundation Wellcome Trust WT098017 WT064890 WT090532 WT090367 WT098381 Uppsala University Swedish Research Council and the Swedish Heart- Lung Foundation Academy of Finland 124243 102318 123885 139635 Finnish Heart Foundation Finnish Diabetes Foundation, Tekes 1510/31/06 Commission of the European Community HEALTH-F2-2007-201681 Ministry of Education and Culture of Finland European Commission Framework Programme 6 Integrated Project LSHM-CT-2004-005272 City of Kuopio and Social Insurance Institution of Finland Finnish Foundation for Cardiovascular Disease NIH/NIDDK U01-DK085545 National Heart, Lung, and Blood Institute (NHLBI) National Institute on Minority Health and Health Disparities N01 HC-95170 N01 HC-95171 N01 HC-95172 European Union Seventh Framework Programme, DIAPREPP Swedish Child Diabetes Foundation (Barndiabetesfonden) 5U01DK085526 DK088389 U54HG003067 R01DK072193 R01DK062370 Z01HG000024 info:eu-repo/grantAgreement/EC/FP7/202013

Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders1–7 – and who consequently may have increased disease risk. However, previous studies of rare variants in phenotypically extreme individuals have ascertainment bias and may demonstrate inflated effect size estimates8–12. We sequenced seven genes for maturity-onset diabetes of the young (MODY)13 in well-phenotyped population samples14,15 (n=4,003). Rare variants were filtered according to prediction criteria used to identify disease-causing mutations: i) previously-reported in MODY, and ii) stringent de novo thresholds satisfied (rare, conserved, protein damaging). Approximately 1.5% and 0.5% of randomly selected Framingham and Jackson Heart Study individuals carried variants from these two classes, respectively. However, the vast majority of carriers remained euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a significant fraction of individuals as at risk for MODY or other Mendelian diseases.

Dietary inclusion of salbutamol (3 ppm), a β2-adrenergic agonist, to growing pigs fed either a normal or a high level of dietary protein from 25 to 90 kg body weight, resulted in a pronounced increase in the protein accretion rate of skeletal muscles. This effect was two-fold higher when pigs were fed the high level compared to the normal level of dietary protein (16 vs. 7%). Histochemical analysis of slow-twitch (ST) and fast-twitch fibres (FTa and FTb) of biopsy samples taken either in vivo by a biopsy needle or post mortem from M. longissimus dorsi (LD) and M. biceps femoris (BF) demonstrated an increase in the relative area of the muscles occupied by FTb fibres. This was mainly due to a reduced frequency of the smaller FTa fibres and an increased frequency of the larger FTb fibres, which indicates an FTa to FTb fibre type conversion induced by salbutamol. In BF, a reduction in the frequency of and the relative area occupied by ST fibres was also found. The changes had already occured at 45 kg...

Dietary inclusion of salbutamol (3 ppm), a β2-adrenergic agonist, to growing pigs from 25 to 90 kg body weight reduced the activities of citrate synthetase (CS) (P