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Animal Models

Effects of insulin therapy on weight gain and fat distribution in the HF/HS-STZ rat model of type 2 diabetes

Abstract

Background/Objectives:

Insulin therapy is required for many patients with the obesity-related disorder type 2 diabetes, but is also associated with weight gain. The specific location of adipose tissue location matters to cardiovascular disease (CVD) risk. We investigated effects of exogenous insulin on fat distribution in the high-fat/high-sucrose fed rat treated with streptozotocin (HF/HS-STZ) rat model of type 2 diabetes. We also examined effects of insulin therapy on circulating CVD markers, including adiponectin, triglycerides (TGs), total cholesterol and high-density lipoprotein.

Subjects/Methods:

Male SD rats were HF/HS fed for 5 weeks followed by STZ treatment to mimic the hallmarks of human obesity-associated insulin resistance followed by hyperglycemia. Magnetic resonance imaging and computed tomography were used to determine total fat, abdominal fat distribution and liver fat before and after insulin therapy in HF/HS-STZ rats. HbA1c%, TGs, cholesterol, high-density lipoprotein and adiponectin were analyzed by conventional methods adapted for rats.

Results:

Insulin therapy lowered HbA1c (P<0.001), increased body weight (P<0.001), increased lean mass (P<0.001) and led to a near doubling of total fat mass (P<0.001), with the highest increase in subcutaneous adipose tissue as compared with visceral adipose tissue (P<0.001). No changes in liver fat were observed after insulin therapy, whereas plasma TG and cholesterol levels were decreased (P<0.001, P<0.01), while high-density lipoprotein (HDL) and adiponectin levels were elevated (P<0.01, P<0.001).

Conclusions:

Using the HF/HS-STZ rat as an animal model for type 2 diabetes, we find that insulin therapy modulates fat distribution. Specifically, our data show that insulin has a relatively positive effect on CVD-associated parameters, including abdominal fat distribution, lean body mass, adiponectin, TGs and HDL in HF/HS-STZ rats, despite a modest gain in weight.

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Acknowledgements

Professor Jim Johnson, University of British Columbia (Vancouver, Canada), is thanked for discussing the data and for providing advice throughout the writing of this manuscript. Moreover, senior scientist Ulla Ribel, Novo Nordisk A/S (Måløv, Denmark), is thanked for her discussions and guidance given in the early phase of the writing phase of this manuscript. Helle Nygaard and Helle Hebo, Novo Nordisk A/S (Måløv, Denmark), are thanked for their impressive technical support throughout the conduction of this study. Marianne Schiødt is thanked for her kind and technical support of the adiponectin analyses. Finally, Gitte Ronald Andersen and Stine Drent Larsen are thanked for their unique caretaking of the rats in the animal facility at Novo Nordisk A/S (Måløv, Denmark). This work was supported by the Department of Insulin Pharmacology, Novo Nordisk A/S, Måløv, Denmark, the Danish In vivo Pharmacology Graduate program and the LIFEPHARM Centre, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.

Author Contributions

SS and JD designed the study and performed all the experiments. SS analyzed as well as interpreted the data, made the figures and wrote the manuscript. XAW, BR and JJH performed additional interpretation of the data and they contributed significantly to the writing of the manuscript. JJF and GSO contributed with data acquisition of C-peptide and adiponectin data, respectively.

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Correspondence to S Skovsø.

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JD, JJF, GSO, XAW and BR are all employees at Novo Nordisk A/S and hold stocks in the company. JJH is a consultant for Novo Nordisk A/S. NPH, used for insulin therapy in this study, is a product of Novo Nordisk A/S.

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Skovsø, S., Damgaard, J., Fels, J. et al. Effects of insulin therapy on weight gain and fat distribution in the HF/HS-STZ rat model of type 2 diabetes. Int J Obes 39, 1531–1538 (2015). https://doi.org/10.1038/ijo.2015.92

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