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Nonalcoholic fatty liver disease (NAFLD) ranges in severity from steatosis to NASH. NASH, which is characterized by steatosis, ballooning, inflammation (NAFLD Activity Score [NAS]), and frequently fibrosis, can progress to cirrhosis and hepatocellular carcinoma. Despite the unmet medical needs of NASH leading to end stage liver disease and increased risk for cardiovascular death, there are no approved treatments to date. In clinical trials, pioglitazone treatment (6-24 months) has led to NASH resolution and/or reduction in fibrosis. We developed a cynomolgus monkey (cyno) model of NASH by feeding a high fat/cholesterol diet for 2+ years and demonstrated accelerated disease progression by adding fructose to this diet. A total of 31 obese (mean±SD, 10.4±1.8 kg), insulin resistant (HOMA-IR: 29±32) cynos with NASH were used. Histological assessments of liver biopsies were used to characterize disease progression and response to therapy and compared to human studies. Baseline NAS of 5.6±0.9 was similar to those in NASH patients, whereas baseline fibrosis scores of 1.2±0.5 were slightly lower than values of ∼2 typically enrolled in Phase 2 trials. Cynos were treated daily with vehicle (n=10) or pioglitazone (3 mg/kg; n=21) for 6 months. Drug exposures 24 hours post-dose averaged 233±145 ng/mL, similar to that seen in humans (∼200 ng/mL) dosed with 45 mg. Adiponectin, a biomarker for PPARγ activation, increased ∼2-fold in treated cynos. NAS improvement (a decrease in NAS of ≥2 with changes in 2 or more components of NAS) was seen in 30% of treated cynos (p=0.08). No vehicle animals showed NAS improvement. Treated cynos showed significant decreases in ballooning, trends in decreases (p=0.07) in steatosis and inflammation, but no change in fibrosis whereas vehicle animals showed no changes or worsening. We have validated and benchmarked a novel cyno model for NASH that has characteristics similar to human pathology and responds to a treatment known to improve NASH in clinical trials. Disclosure R. Camacho: Employee; Self; Janssen Pharmaceuticals, Inc. D. Polidori: Employee; Self; Janssen Research and Development. Stock/Shareholder; Self; Janssen Research and Development. T. Chen: Employee; Self; Janssen Pharmaceuticals, Inc. B. Gao: Employee; Self; Janssen Pharmaceuticals, Inc. P. Wong: Employee; Self; Johnson & Johnson. Stock/Shareholder; Self; Merck & Co., Inc. J.A. Gabriel: Employee; Self; Kunming Biomed International (KBI). E. Zhu: None. T. Wang: None. A.R. Nawrocki: Employee; Self; Janssen Pharmaceuticals, Inc.

African Americans (AAs) tend to have higher plasma insulin concentrations than European Americans (EAs); the increased insulin concentrations have been attributed to increased secretion and/or decreased insulin clearance by liver or other tissues. This work characterizes the contributions of hepatic versus extrahepatic insulin degradation related to ethnic differences between AAs and EAs. By using a recently developed mathematical model that uses insulin and C-peptide measurements from the insulin-modified, frequently sampled intravenous glucose tolerance test (FSIGT), we estimated hepatic versus extrahepatic insulin clearance in 29 EA and 18 AA healthy women. During the first 20 min of the FSIGT, plasma insulin was approximately twice as high in AAs as in EAs. In contrast, insulin was similar in AAs and EAs after the 20–25 min intravenous insulin infusion. Hepatic insulin first-pass extraction was two-thirds lower in AAs versus EAs in the overnight-fasted state. In contrast, extrahepatic insulin clearance was not lower in AAs than in EAs. The difference in insulin degradation between AAs and EAs can be attributed totally to liver clearance. The mechanism underlying reduced insulin degradation in AAs remains to be clarified, as does the relative importance of reduced liver clearance to increased risk for type 2 diabetes.

Insulin clearance is a highly variable and important factor that affects circulating insulin concentrations. We developed a novel model-based method to estimate both hepatic and extrahepatic insulin clearance using plasma insulin and C-peptide profiles obtained from the insulin-modified frequently sampled intravenous glucose tolerance test. Data from 100 African immigrants without diabetes (mean age 38 years, body weight 81.7 kg, fasting plasma glucose concentration 83 mg/dL, and fasting insulin concentration 37 pmol/L) were used. Endogenous insulin secretion (calculated by C-peptide deconvolution) and insulin infusion rates were used as inputs to a new two-compartment model of insulin kinetics and hepatic and extrahepatic clearance parameters were estimated. Good agreement between modeled and measured plasma insulin profiles was observed (mean normalized root mean square error 6.8%), and considerable intersubject variability in parameters of insulin clearance among individuals was identified (the mean [interquartile range] for hepatic extraction was 25.8% [32.7%], and for extrahepatic insulin clearance was 20.7 mL/kg/min [11.7 mL/kg/min]). Parameters of insulin clearance were correlated with measures of insulin sensitivity and acute insulin response to glucose. The method described appears promising for future research aimed at characterizing variability in insulin clearance and the mechanisms involved in the regulation of insulin clearance.

African American (AA) adult women (AAw) have 1/3 the hepatic insulin extraction as European American adult women (EAw). Lower hepatic (but not extrahepatic) insulin clearance in AAw contributes to hyperinsulinemia. Our aim was to examine whether hepatic insulin clearance impairment exists in AA since childhood. If so, genetic factors might explain ethnic differences in insulin clearance. The FSIGT was performed on 203 children [55 AAc, 88 EAc, 60 HAc (Hispanic American), ages 7-13 years, mean BMI = 19 kg/m2, basal plasma glucose = 99 mg/dL, insulin = 78 pM, C-peptide = 511 pM]. Data were analyzed with a recent mathematical model providing individual estimates of both hepatic fractional insulin extraction (FEL) and extrahepatic insulin clearance (CLP). Results are presented as mean (SD). Two-way ANOVA and ANCOVA were done: sex and ethnicity were used as groups for both the analysis, while age, Tanner stage and body fat from DXA were the covariates. FEL is lower in AAc (19% (20%)) than EAc (33% (20%)), p = 0.0007). Adjusting for the covariates, ethnicity was still associated with lower FEL in AAc vs. EAc (p = 0.0012); sex had a slight but significant effect (FEL=24% (10%) in boys vs. 29% (10%) in girls, p = 0.04). FEL in HAc (28% (21%)) was not significantly different than either AAc or EAc (p>0.05), with or without covariates correction. No correlation between FEL and age was found in these children. Unlike FEL, CLP was not impacted by ethnicity or sex; similar values were observed among the three groups [27 (12), 21 (12), and 24 (28) mL/kg/min for AAc, HAc, and EAc, respectively; p > 0.05]. As the between-group differences in FEL are seen early in childhood, this suggests genetic factors likely contribute to those, rather than lifestyle, that might have a less evident effect at that age, instead. Playing a more important role than previously realized, the reduced insulin degradation would lead to hyperinsulinemia, insulin resistance, and possibly greater risk for type 2 diabetes in AA, compared to other ethnic groups. Disclosure F. Piccinini: None. D. Polidori: Employee; Self; Janssen Research & Development. Stock/Shareholder; Self; Janssen Research & Development. B. Gower: None. J.R. Fernandez: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S.