Attenuated suppression of lipolysis explains the increases in triglyceride secretion and concentration associated with basal insulin peglispro relative to insulin glargine treatment in patients with type 1 diabetes

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2018-02, Vol.20 (2), p.419-426
• Main Authors: Johansen, Rakel F., Søndergaard, Esben, Linnebjerg, Helle, Garhyan, Parag, Lam, Eric C. Q., Porksen, Niels, Jacober, Scott J., Nielsen, Søren
• Format: Article
• Language: English
• Subjects: Adipose tissue; Adult; basal insulin; Cross-Over Studies; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - blood; Diabetes Mellitus, Type 1 - drug therapy; Diabetes Mellitus, Type 1 - metabolism; Double-Blind Method; Drug Administration Schedule; drug mechanism; Drug Therapy, Combination - adverse effects; Female; Humans; Hyperglycemia - prevention & control; Hypertriglyceridemia - chemically induced; Hypertriglyceridemia - prevention & control; Hypoglycemia - chemically induced; Hypoglycemia - prevention & control; Hypoglycemic Agents - administration & dosage; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - therapeutic use; Injections, Subcutaneous; Insulin; Insulin - administration & dosage; Insulin - adverse effects; Insulin - therapeutic use; Insulin Glargine - administration & dosage; Insulin Glargine - adverse effects; Insulin Glargine - therapeutic use; Insulin Lispro - administration & dosage; Insulin Lispro - adverse effects; Insulin Lispro - analogs & derivatives; Insulin Lispro - therapeutic use; Lipid peroxidation; Lipolysis; Lipolysis - drug effects; Lipoproteins (very low density); Lipoproteins, VLDL - blood; Lipoproteins, VLDL - metabolism; Liver; Low density lipoprotein; Male; Middle Aged; Oxidation; Palmitic acid; Patients; phase I–II study; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - adverse effects; Polyethylene Glycols - therapeutic use; Secretion; Triglycerides - blood; Triglycerides - metabolism; type 1 diabetes; Young Adult
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.13087

Aims To test the hypothesis that, as well as lowering weight and increasing plasma triglyceride (TG) levels and hepatic fat compared with insulin glargine (GL) in patients with type 1 diabetes, the attenuated peripheral effects of basal insulin peglispro (BIL) may include increased free fatty acid flux to the liver, causing increased very‐low‐density lipoprotein (VLDL)‐TG secretion and lipid oxidation, and decreased TG adipose tissue deposition. Methods In this open‐label, randomized, 2‐period crossover study, 14 patients with type 1 diabetes received once‐daily, individualized, stable BIL or GL doses for 3 weeks. Palmitate flux was assessed using [9,10‐3H]palmitate infusion. VLDL‐TG secretion, clearance and oxidation rate were assessed using primed‐constant infusion of ex vivo labelled [1‐14C]VLDL‐TG, while VLDL‐TG storage rate was assessed using [9,10‐3H]VLDL‐TG bolus injection. Results The VLDL‐TG concentration and secretion rate, and palmitate flux were statistically significantly higher during BIL than during GL treatment (58%, 51% and 35%, respectively). The ratios of least squares (LS) geometric means for VLDL‐TG clearance and oxidation were 0.92 (95% confidence interval [CI] 0.72, 1.17) and 1.31 (95% CI 0.91, 1.90), respectively. The difference in LS means for VLDL‐TG storage rate was −0.36 (95% CI −0.83, 0.12). Conclusions BIL‐treated patients had higher effective lipolysis, VLDL‐TG secretion and VLDL‐TG concentration compared with GL‐treated patients, explaining the increased plasma TG concentrations reported previously. Data support attenuated effects of BIL on lipolysis, in addition to the recently described hepato‐preferential glucodynamic effects.