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Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double‐blind, placebo‐controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double‐blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6‐year open‐label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg −53.9% [−62.5, −29.3], OCA 50 mg −37.2% [−54.8, −24.6]) compared to placebo (−0.8% [−6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open‐label extension treatment. OCA improved many secondary and exploratory endpoints (including γ‐glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus. Conclusion: OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long‐term clinical outcomes. Pruritus increased dose‐dependently with OCA treatment. Biochemical improvements were observed through 6 years of open‐label extension treatment. (Hepatology 2018;67:1890‐1902).

Consumption of large amounts of coffee has been shown to decrease the incidence of type 2 diabetes. However, the specific compounds and mechanisms responsible for this effect are not known. The aim of this study was to determine the effects of a decaffeinated coffee extract and a synthetic quinide, representative of those found in roasted coffee, 3,4-diferuloyl-1,5-quinolactone, on insulin-stimulated glucose disposal and muscle glucose uptake. Experiments were performed on conscious rats during hyperinsulinemic, euglycemic clamps receiving gastric infusions of saline, a decaffeinated coffee extract (DECAF) (220 mg/kg), or 3,4-diferuloyl-1,5-quinide (DIFEQ) (110 mg/kg). Following treatment, rats received an intravenous bolus of deoxy-[2-3H] glucose to assess muscle glucose uptake (Rg, micromol x 100 g(-1) x min(-1)). Glucose infusions [mg/(kg x min)] required to maintain euglycemia during the tracer period were higher with DIFEQ (14.6 +/- 0.7) than with saline (10.8 +/- 0.7) and DECAF (11.5 +/- 1.1). Despite increased glucose requirements, Rg in skeletal (soleus, gastrocnemius, superficial vastus lateralis) and cardiac muscle were unchanged. DECAF or DIFEQ did not affect heart rate, blood pressure, plasma nonesterified fatty acids or liver aminotransferase activity. These results demonstrate that DIFEQ increases whole-body glucose disposal independently of skeletal muscle Rg.

The aim of the present study was to determine the specific sites of impairment to muscle glucose uptake (MGU) in the insulin-resistant high-fat-fed, conscious C57BL/6J mouse. Wild type (WT) and hexokinase II overexpressing (HK Tg ) mice were fed either a standard diet or high-fat diet and studied at 4 months of age. A carotid artery and jugular veins had catheters chronically implanted for sampling and infusions, respectively, and mice were allowed to recovery for at least 5 days. Mice were fasted for 5 h and underwent a hyperinsulinemic-euglycemic clamp or saline infusion for 120 min. Separate groups of mice were studied during 30-min sedentary or treadmill exercise periods. A bolus of 2-deoxy[ I nsulin resistance induced by high-fat feeding is characterized by a decrease in insulin-stimulated glucose disposal (1-3). The impaired glucose disposal is likely to be due to deficits in one or more of the steps required for skeletal muscle glucose uptake (MGU). Specifically, these steps are 1) delivery of glucose to the muscle membrane, 2) facilitated transport across the muscle membrane, and 3) intracellular phosphorylation to glucose-6-phosphate (G6P) by a hexokinase (HK) isozyme. It is difficult, in the context of the whole animal, to elucidate which sites of the glucose uptake pathway are functionally altered by high-fat feeding. One approach is to alter protein levels by transgenic manipulation and measure the effect on glucose flux. Physiological stimuli can then be applied to better expose perturbations caused by a transgene. For example, overexpressing HK II in skeletal muscle increases glucose phosphorylation capacity and results in increased MGU in high-flux states created by insulin stimulation or exercise in standard diet-fed FVB/ NJ mice but not under basal glucose flux conditions (4).Transgenic manipulation can also isolate sites of impairment to MGU in insulin-resistant states, and high-flux states (e.g., insulin stimulation and exercise) can be used to amplify the signal resulting from such a deficit. In the present study, exercise and insulin were used in combination with HK II overexpression to determine the role of glucose phosphorylation in the impairment of MGU associated with the insulin resistance of the high-fat-fed C57BL/6J mouse (5,6). Previous investigations in the conscious rat have suggested that high-fat feeding leads to a functional impairment in muscle glucose phosphorylation (7). Therefore, it was hypothesized that impaired MGU resulting from high-fat feeding would be exposed in highflux states and could be corrected by HK II overexpression. The unique surgical catheterization used in this study allows for these hypotheses to be tested in the conscious, unrestrained mouse. Determining the site(s) of impairment of MGU manifested by high-fat feeding will provide insight to the pathogenesis of insulin resistance and lead to the identification of potential therapeutic targets. RESEARCH DESIGN AND METHODSAll procedures performed were approved by the Vanderbilt University Animal Care and Us...

Placebo OCA 5-10 mg OCA 1.5-3.0 mg Highlights Novel treatments for PSC are an urgent unmet need. This phase II study evaluated OCA in patients with PSC. OCA 5-10 mg significantly reduced serum ALP levels at 24 weeks. The safety profile of OCA was consistent with previous studies.