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Purpose Roflumilast (Daliresp, Daxas) is a FDA-approved phosphodiesterase 4 (PDE4) inhibitor for the treatment of moderate-to-severe chronic obstructive pulmonary disease. In mice and in limited human studies, this oral medication can cause weight loss and improve insulin sensitivity. We set out to determine the mechanism of its effect on insulin sensitivity. Patients and methods Eight adults with overweight/obesity and prediabetes received roflumilast for 6 weeks. Before and after roflumilast, subjects underwent tests of insulin sensitivity, mixed meal test, body composition, markers of inflammation, and mitochondria function. Dietary intake and physical activity were also assessed. Our primary outcome was the change in peripheral insulin sensitivity, as assessed by the hyper-insulinemic euglycemic clamp. Results This study was underpowered for the primary outcome. Pre- and post-roflumilast mean peripheral insulin sensitivity were 48.7 and 70.0 mg/g fat free mass/minute, respectively, ( P -value=0.18), respectively. Among the mixed meal variables, roflumilast altered glucagon-like peptide 1 (GLP-1) hormone the most, although the average effect was not statistically significant ( P =0.18). Roflumilast induced a trend toward significance in 1) decreased energy intake (from 11,095 KJ to 8,4555 KJ, P =0.07), 2) decreased fat mass (from 34.53 to 32.97 kg, P =0.06), 3) decreased total and LDL cholesterol ( P =0.06 for both variables), and 4) increased plasma free fatty acids (from 0.40 to 0.50 mEq/L, P =0.09) The interval changes in adiposity and free fatty acid were significantly associated with the subject’s age ( P -value range= <0.001 to 0.02 for the correlations). Inflammatory and adhesion markers, though unchanged, significantly correlated with one another and with incretin hormones only after roflumilast. Conclusion We demonstrate, for the first time in humans, increasing percentage of fat mass loss from roflumilast with increasing age in adults with prediabetes and overweight/obesity. We also demonstrate novel associations among roflumilast-induced changes in incretin hormones, inflammatory markers, peripheral insulin sensitivity, and adiposity. We conclude that roflumilast’s early effects on insulin sensitivity is indirect and likely mediated through roflumilast’s prioritization of lipid over glucose handling. Clinical trials registration NCT01862029.

Pancreatic β‐cell dysfunction because of reduced β‐cell mass and function is a primary determinant in the progression of diabetes. Increase in β‐cell mass and compensatory hyperinsulinaemia is frequently associated with insulin‐resistant states. Although the humoral factors mediating this compensatory response are unknown, serpinB1, a protease inhibitor, has recently been proposed to be one such factor. In this study, we examine the relationships between plasma serpinB1, insulin sensitivity, and pancreatic β‐cell function in non‐diabetic individuals. 117 subjects (women, n = 50, men, n = 67; age= 37.6 ± 10.8; BMI=31.1 ± 7.7 kg/m2) underwent an insulin‐modified frequently sampled intravenous glucose tolerance test (FSIVGTT) at the NIH Clinical Research Center. Acute insulin response (AIR) and insulin sensitivity index (SI) were obtained from the FSIVGTT with MINMOD analysis. The Quantitative Insulin Sensitivity Check Index (QUICKI) was calculated from fasting insulin and glucose values. Plasma serpinB1 levels were measured using an ELISA assay. Simple linear correlation analyses were performed to evaluate the relationship between serpinB1 and measures of insulin sensitivity and β‐cell function. Circulating serpinB1 levels were unrelated to age, sex, race, BMI, or percent body fat. SI but not AIR significantly correlated with circulating serpinB1 levels (r = 0.23, P < 0.05). QUICKI tended to positively correlate with serpinB1 (r = 0.16, P = 0.09). Circulating serpinB1 is directly associated with insulin sensitivity but not β‐cell function in non‐diabetic adults. Whether this modest association plays a role in insulin sensitivity in humans remains to be clarified.

Purpose: Current reference methods for measuring glucose effectiveness (GE) are the somatostatin pancreatic glucose clamp and minimal model analysis of frequently sampled intravenous glucose tolerance test (FSIVGTT), both of which are laborious and not feasible in large epidemiological studies. Consequently, surrogate indices derived from an oral glucose tolerance test (OGTT) to measure GE (oGE) have been proposed and used in many studies. However, the predictive accuracy of these surrogates has not been formally validated. In this study, we used a calibration model analysis to evaluate the accuracy of surrogate indices to predict GE from the reference FSIVGTT (Sg MM ).Methods: Subjects (n=123, mean age 48 ±11 years; BMI 35.9±7.3 kg/m 2 ) with varying glucose tolerance (NGT, n=37; IFG/IGT, n=78; and T2DM, n=8) underwent FSIVGTT and OGTT on two separate days. Predictive accuracy was assessed by both root mean squared error (RMSE) of prediction and leave-one-out cross-validation-type RMSE of prediction (CVPE).Results: As expected, insulin sensitivity, Sg MM , and oGE were reduced in subjects with T2DM and IFG/IGT when compared with NGT. Simple linear regression analyses revealed a modest but significant relationship between oGE and Sg MM (r=0.25, p<0.001). However, using calibration model, measured Sg MM and predicted Sg MM derived from oGE were modestly correlated (r = 0.21, p<0.05) with the best fit line suggesting poor predictive accuracy. There were no significant differences in CVPE and RMSE among the surrogates, suggesting similar predictive ability.