ABSTRACT
AIMS: To compare effects of basal insulin peglispro (BIL), a hepatopreferential insulin, to insulin glargine (glargine) on aminotransferases and liver fat content (LFC) in patients with type 1 and type 2 diabetes (T1D, T2D). MATERIALS AND METHODS: Data from two Phase 2 and five Phase 3 randomized trials comparing BIL and glargine in 1709 T1D and 3662 T2D patients were integrated for analysis of liver laboratory tests. LFC, measured by magnetic resonance imaging (MRI) at baseline, 26 and 52 weeks, was analyzed in 182 T1D patients, 176 insulin-naïve T2D patients and 163 T2D patients previously treated with basal insulin. RESULTS: Alanine aminotransferase (ALT) increased in patients treated with BIL, was higher than in glargine-treated patients at 4-78 weeks (difference at 52 weeks in both T1D and T2D: 7 international units/litre (IU/L), P < .001), and decreased after discontinuation of BIL. More BIL patients had ALT ≥3× upper limit of normal (ULN) than glargine. No patient had ALT ≥3× ULN with bilirubin ≥2× ULN that was considered causally related to BIL. In insulin-naÑve T2D patients, LFC decreased with glargine but was unchanged with BIL. In T1D and T2D patients previously treated with basal insulin, LFC was unchanged with glargine but increased with BIL. In all three populations, LFC was higher after treatment with BIL vs glargine (difference at 52 weeks: 2.2% to 5.3%, all P < .01). CONCLUSIONS: Compared to glargine, patients treated with BIL had higher ALT and LFC at 52-78 weeks. No severe drug-induced liver injury was apparent with BIL treatment for up to 78 weeks.
Subject(s)
Alanine Transaminase/metabolism , Aspartate Aminotransferases/metabolism , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Insulin Glargine/therapeutic use , Insulin Lispro/analogs & derivatives , Liver/metabolism , Polyethylene Glycols/therapeutic use , Adipose Tissue/diagnostic imaging , Adult , Aged , Bilirubin/metabolism , Blood Glucose/metabolism , Cholesterol, HDL/metabolism , Cholesterol, LDL/metabolism , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 2/metabolism , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Drug Therapy, Combination , Female , Glycated Hemoglobin/metabolism , Humans , Hypoglycemia/chemically induced , Insulin Lispro/therapeutic use , Liver/diagnostic imaging , Magnetic Resonance Imaging , Male , Metformin/therapeutic use , Middle Aged , Pioglitazone , Randomized Controlled Trials as Topic , Sulfonylurea Compounds/therapeutic use , Thiazolidinediones/therapeutic use , Triglycerides/metabolismABSTRACT
Recently Zhang et al. cloned a gene that is expressed only in adipose tissue of the mouse. The obese phenotype of the ob/ob mouse is linked to a mutation in the obese gene that results in expression of a truncated inactive protein. Human and rat homologues for this gene are known. Previous experiments predict such a hormone to have a hypothalamic target. Hypothalamic neuropeptide Y stimulates food intake, decreases thermogenesis, and increases plasma insulin and corticosterone levels making it a potential target. Here we express the obese protein in Escherichia coli and find that it suppresses food intake and decreases body weight dramatically when administered to normal and ob/ob mice but not db/db (diabetic) mice, which are thought to lack the appropriate receptor. High-affinity binding was detected in the rat hypothalamus. One mechanism by which this protein regulated food intake and metabolism was inhibition of neuropeptide-Y synthesis and release.