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. 2011 Jul 4;1(7):e10.
doi: 10.1038/nutd.2011.6.

Insulin detemir attenuates food intake, body weight gain and fat mass gain in diet-induced obese Sprague-Dawley rats

J M Rojas  1 , R L Printz, K D Niswender
Affiliations

Insulin detemir attenuates food intake, body weight gain and fat mass gain in diet-induced obese Sprague-Dawley rats

J M Rojas et al. Nutr Diabetes. .

Abstract

Objective: Initiation and intensification of insulin therapy commonly causes weight gain, a barrier to therapy. A contrasting body of evidence indicates that insulin functions as an adiposity negative feedback signal and reduces food intake, weight gain and adiposity via action in the central nervous system. Basal insulin analogs, detemir (Det) and glargine (Glar), have been associated with less hypoglycemia compared with neutral protamine hagedorn insulin, and Det with less weight gain, especially in patients with higher body mass index (BMI). We sought to determine whether insulin therapy per se causes body weight and fat mass gain when delivered via a clinically relevant subcutaneous (SC) route in the absence of hypoglycemia and glycosuria in non-diabetic lean and diet-induced obese rats.

Materials and methods: Rats were exposed to either a low-fat diet (LFD; 13.5% fat) or high-fat diet (HFD; 60% fat), and received Det (0.5 U kg(-1)), Glar (0.2 U kg(-1)) or vehicle (Veh) SC once daily for 4 weeks. These dosages of insulin were equipotent in rats with respect to blood-glucose concentration and did not induce hypoglycemia.

Results: As predicted by current models of energy homeostasis, neither insulin Det nor Glar therapy affected food intake and weight gain in LFD rats. Det treatment significantly attenuated food intake, body weight gain and fat mass gain relative to the Glar and Veh in high-fat fed animals, mirroring observations in humans.

Conclusions: That neither insulin group gained excess weight, suggests weight gain with SC basal insulin therapy may not be inevitable. Our data further suggest that Det possesses a unique property to attenuate the development of obesity associated with a HFD.

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Figures

Figure 1
Figure 1
Glycemic effects of Det and Glar in rats. (a, b) Blood glucose was determined at indicated time points after SC insulin administration of Det 0.5 U kg−1 (triangle) or Glar 0.2 U kg−1 (diamond) in LF-fed rats (a; n=11–13 per group) or HF-fed rats (b; n=6–8 per group). Data are presented as the mean±s.e.m. and were analyzed by Student's two-tailed, unpaired t-test; P=NS, Glar vs Det.
Figure 2
Figure 2
Effects of Det and Glar on food intake in LFD and HFD rats. Food intake was measured daily for each treatment group, Veh (circle), Det (triangle) and Glar (diamond); and presented as cumulative food intake in rats fed either LFD (a; n=5 per group) or HFD (b; n=6–8 per group). Total cumulative food intake for each treatment and diet group is shown (c). Data are presented as the mean±s.e.m. and were analyzed by two-way repeated measures ANOVA. Bonferroni's post-test shows that Det reduced cumulative food intake in HF-fed rats relative to Glar from 10 to 27 days and relative to Veh from 24 to 27 days. For all panels: *P<0.05 for Veh vs Det; #P<0.05, αP<0.01 and βP<0.001 for Glar vs Det comparisons as analyzed by Bonferroni's post-test.
Figure 3
Figure 3
Insulin Det attenuates weight and adipose gain in HFD, but not LFD rats. Body weight was measured daily in rats fed either LFD (a; n=5 per group) or HFD (b; n=6–8 per group) for each treatment group; Veh (circle), Det (triangle) and Glar (diamond). Body weight gain was determined for the 4-week study period for all groups (c). Fat mass was measured three times weekly by NMR in rats fed either LFD (d; n=5 per group) or HFD (e; n=6–8 per group) for each treatment group; Veh (circle), Det (triangle) and Glar (diamond). Fat mass gain was determined for the 4-week study period for all groups (f). Data are presented as the mean±s.e.m. and were analyzed by either two-way repeated measures ANOVA (for body weight and fat mass) or two-way ANOVA (for body weight and fat mass gain). Bonferroni's post-test shows that daily fat mass (e) was reduced by Det relative to Veh from 13 to 26 days and relative to Glar from 10 to 26 days. For all panels: *P<0.05, **P<0.01, and ***P<0.001 for Veh vs Det; #P<0.05, αP<0.01 and βP<0.001 for Glar vs Det comparisons as analyzed by Bonferroni's post-test.
Figure 4
Figure 4
Effects of Det and Glar on RNA levels of white adipose tissue markers of lipogenesis. RNA isolated from epididymal fat of rats of all treatment groups (Veh, Det and Glar) after 4 weeks of diet consisting of either LFD (n=5 per group) or HFD (n=6–8 per group) was assessed by real-time PCR for changes in RNA levels of WAT lipogenic markers, fatty acid synthase (FAS) (a) and lipoprotein lipase (LPL) (b). RNAs of interest were normalized to RPL13α and for comparative analysis, RNA ratios were normalized to the Veh LF control. Data are presented as the mean±s.e.m. and were analyzed by two-way ANOVA. For all panels, analysis with Bonferroni's post-test shows: *P<0.05 and ***P<0.001 for Veh vs Det; #P<0.05, βP<0.001 for Glar vs Det comparisons.
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