title: Treatment of diabetic rats with insulin or a synthetic insulin receptor agonist peptide leads to divergent metabolic responses.
abstract: In addition to lowering of blood glucose, treatment with insulin also induces lipid synthesis and storage. Patients with type 2 diabetes often suffer from lipid-related comorbidities including dyslipidemia, obesity, and fatty liver disease. We examined here in two separate studies changes in lipid dynamics in Zucker diabetic fatty (ZDF) rats, in response to 7 days of treatment with either insulin or the insulin receptor agonist peptide S597. In concert with blood glucose normalization, the treated rats displayed large increases in hepatic de novo lipid synthesis and deposition of newly synthesized lipids in adipose tissue depots, accompanied by weight gain and expansion of adipose depots. In both treatment groups, heavy water labeling revealed that after 2 h (study A), de novo lipogenesis was responsible for 80% of newly stored hepatic triglyceride (TG)-palmitate, and after 5 days (study B), ∼60% of newly deposited TG-palmitate in adipose tissues originated from this pathway. Interestingly, in both studies, treatment with the insulin mimetic peptide resulted in significantly lower blood TG levels, plasma TG production rates, and hepatic de novo synthesized fatty acid in plasma TG compared with insulin. There were no differences in plasma TG turnover (clearance rate) in response to either treatment, consistent with differential actions on the liver. These results show that in ZDF rats, treatment with a synthetic insulin-receptor-activating peptide or with insulin to lower blood glucose is accompanied by different effects on hepatic lipid anabolism and blood TG profiles.
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA Department of Insulin Biology, Novo Nordisk, Maaloev, Denmark.
authors.forename: Henriette
authors.initials: H
authors.lastname: Frikke-Schmidt
authors.affiliation: Department of Insulin Biology, Novo Nordisk, Maaloev, Denmark.
authors.forename: Thomas Å
authors.initials: TÅ
authors.lastname: Pedersen
authors.affiliation: Department of Insulin Pharmacology, Novo Nordisk, Maaloev, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Fledelius
authors.affiliation: Department of Insulin Biology, Novo Nordisk, Maaloev, Denmark.
authors.forename: Grith S
authors.initials: GS
authors.lastname: Olsen
authors.affiliation: Department of Insulin Pharmacology, Novo Nordisk, Maaloev, Denmark.
authors.forename: Stephan D
authors.initials: SD
authors.lastname: Bouman
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA.
authors.forename: Mark
authors.initials: M
authors.lastname: Fitch
authors.affiliation: Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA KineMed, Inc., Emeryville, CA march@berkeley.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Hellerstein
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010455:Peptides / Q000627:therapeutic use; D051381:Rats; D011972:Receptor, Insulin / Q000819:agonists*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D010455:Peptides; C530074:S597 peptide; D011972:Receptor, Insulin