Recombinant human insulin-like growth factor-I treatment inhibits gluconeogenesis in a transgenic mouse model of type 2 diabetes mellitus

Patricia Pennisi, Oksana Gavrilova, Jennifer Setser-Portas, William Jou, Stefania Santopietro, David Clemmons, Shoshana Yakar, Derek LeRoith

Research output: Contribution to journalArticle

Abstract

IGF-I and insulin are structurally related polypeptides that mediate a similar pattern of biological effects via receptors that display considerably homology. Administration of recombinant human IGF-I (rhIGF-I) has been proven to improve glucose control and liver and muscle insulin sensitivity in patients with type 2 diabetes mellitus (DM). The effect of rhIGF-I treatment was evaluated in a mouse model of type 2 DM (MKR mouse), which expresses a dominant-negative form of the human IGF-I receptor under the control of the muscle creatine kinase promoter specifically in skeletal muscle. MKR mice have impaired IGF-I and insulin signaling in skeletal muscle, leading to severe insulin resistance in muscle, liver, and fat, developing type 2 DM at 5 wk of age. Six-week-old MKR mice were treated with either saline or rhIGF-I for 3 wk. Blood glucose levels were decreased in response to rhIGF-I treatment in MKR mice. rhIGF-I treatment also increased body weight in MKR with concomitant changes in body composition such as a decrease in fat mass and an increase in lean body mass. Insulin, fatty acid, and triglyceride levels were not affected by rhIGF-I, nor were insulin or glucose tolerance in MKR mice. Hyperinsulinemic-euglycemic clamp analysis demonstrated no improvement in overall insulin sensitivity. Pyruvate and glutamine tolerance tests proved that there was a decrease in the rate of glucose appearance in MKR mice treated with rhIGF-I, suggesting a reduction in the gluconeogenic capacity of liver, kidney, and small intestine. Taken together these results demonstrate that the improvement of the hyperglycemia was achieved by inhibition of gluconeogenesis rather than an improvement in insulin sensitivity. Also, these results suggest that a functional IGF-I receptor in skeletal muscle is required for IGF-I to improve insulin sensitivity in this mouse model of type 2 DM.

Original languageEnglish (US)
Pages (from-to)2619-2630
Number of pages12
JournalEndocrinology
Volume147
Issue number6
DOIs
StatePublished - Jun 2006

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Gluconeogenesis
Insulin-Like Growth Factor I
Type 2 Diabetes Mellitus
Transgenic Mice
Insulin Resistance
Insulin
Therapeutics
IGF Type 1 Receptor
Skeletal Muscle
Glucose
Liver
Fats
MM Form Creatine Kinase
Muscles
Glucose Clamp Technique
Body Composition
Glutamine
Pyruvic Acid
Hyperglycemia
Small Intestine

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Pennisi, P., Gavrilova, O., Setser-Portas, J., Jou, W., Santopietro, S., Clemmons, D., ... LeRoith, D. (2006). Recombinant human insulin-like growth factor-I treatment inhibits gluconeogenesis in a transgenic mouse model of type 2 diabetes mellitus. Endocrinology, 147(6), 2619-2630. https://doi.org/10.1210/en.2005-1556

Recombinant human insulin-like growth factor-I treatment inhibits gluconeogenesis in a transgenic mouse model of type 2 diabetes mellitus. / Pennisi, Patricia; Gavrilova, Oksana; Setser-Portas, Jennifer; Jou, William; Santopietro, Stefania; Clemmons, David; Yakar, Shoshana; LeRoith, Derek.

In: Endocrinology, Vol. 147, No. 6, 06.2006, p. 2619-2630.

Research output: Contribution to journalArticle

Pennisi, P, Gavrilova, O, Setser-Portas, J, Jou, W, Santopietro, S, Clemmons, D, Yakar, S & LeRoith, D 2006, 'Recombinant human insulin-like growth factor-I treatment inhibits gluconeogenesis in a transgenic mouse model of type 2 diabetes mellitus', Endocrinology, vol. 147, no. 6, pp. 2619-2630. https://doi.org/10.1210/en.2005-1556
Pennisi, Patricia ; Gavrilova, Oksana ; Setser-Portas, Jennifer ; Jou, William ; Santopietro, Stefania ; Clemmons, David ; Yakar, Shoshana ; LeRoith, Derek. / Recombinant human insulin-like growth factor-I treatment inhibits gluconeogenesis in a transgenic mouse model of type 2 diabetes mellitus. In: Endocrinology. 2006 ; Vol. 147, No. 6. pp. 2619-2630.
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