c-peptide and Pulmonary-Disease--Chronic-Obstructive

The phosphodiesterase 4 inhibitor roflumilast is a first-in-class antiinflammatory treatment for severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis and a history of frequent exacerbations. In previous clinical studies, a transient and reversible weight decrease was reported with roflumilast, suggesting the systemic actions of this drug may impact metabolism.. Our objective was to investigate the effects of roflumilast on glucose homeostasis and body weight.. We conducted a 12-wk, randomized, double-blind, placebo-controlled multicenter study with outpatients.. Patients (n = 205) with newly diagnosed type 2 diabetes mellitus (DM2) but without COPD were included in the study.. Roflumilast 500 μg or placebo was administered once daily.. We evaluated mean change in blood glycated hemoglobin levels.. We also evaluated mean change from baseline in the postmeal area under the curve (AUC) for a range of metabolic parameters.. Roflumilast was associated with a significantly greater reduction in glycated hemoglobin levels than placebo (least square mean = -0.45%; P < 0.0001) in patients with DM2. In the roflumilast group, postmeal AUC decreased significantly from baseline to last visit for free fatty acids, glycerol, glucose, and glucagon, whereas they slightly increased for C-peptide and insulin. In contrast to roflumilast, the glucagon AUC increased with placebo, and the insulin AUC decreased. Between-treatment analysis revealed statistically significant differences in favor of roflumilast for glucose (P = 0.0082), glycerol (P = 0.0104), and C-peptide levels (P = 0.0033). Patients in both treatment groups lost weight, although the between-treatment difference of the changes from baseline to last visit [-0.7 (0.4) kg] was not statistically significant (P = 0.0584).. Roflumilast lowered glucose levels in patients with newly diagnosed DM2 without COPD, suggesting positive effects on glucose homoeostasis.

Topics: Adult; Aged; Aminopyridines; Area Under Curve; Benzamides; Blood Glucose; Body Weight; C-Peptide; Cyclopropanes; Diabetes Mellitus, Type 2; Double-Blind Method; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glucose; Glycated Hemoglobin; Glycerol; Homeostasis; Humans; Insulin; Male; Middle Aged; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Sample Size

The clinical assessment of new formulations of human insulin is problematic due to the inability to distinguish between endogenous insulin and exogenously administered insulin. The usual methods to surmount the problem of distinguishing between endogenous and exogenous human insulin include evaluation in subjects with no or little endogenous insulin, hyper-insulinemic clamp studies or the administration of somatostatin to suppress endogenous insulin secretion. All of these methods have significant drawbacks. This paper describes a method for C-Peptide correction based upon a mixed effects linear regression of multiple time point sampling of C-Peptide and insulin. This model was able to describe each individual's insulin to C-Peptide relationship using the data from four different phase I clinical trials involving both subjects with and without type 2 diabetes in which insulin and C-Peptide were measured. These studies used hyper-insulinemic euglycemic clamps or meal challenges and subjects received insulin or Glucagon-like peptide 1 (GLP-1). It was possible to determine the exogenously administered insulin concentration from the measured total insulin concentration. A simple statistical technique can be used to determine each individual's insulin to C-Peptide relationship to estimate exogenous and endogenous insulin following the administration of regular human insulin. This technique will simplify the assessment of new formulations of human insulin.

Topics: Biological Availability; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose Clamp Technique; Glucose Tolerance Test; Humans; Hypoglycemic Agents; Insulin; Pulmonary Disease, Chronic Obstructive