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. 2014 Sep 9;111(36):13217-22.
doi: 10.1073/pnas.1409638111. Epub 2014 Aug 25.

Hyperglycemia in rodent models of type 2 diabetes requires insulin-resistant alpha cells

Young Lee  1 , Eric D Berglund  2 , Xinxin Yu  1 , May-Yun Wang  1 , Matthew R Evans  3 , Philipp E Scherer  1 , William L Holland  1 , Maureen J Charron  4 , Michael G Roth  5 , Roger H Unger  1
Affiliations

Hyperglycemia in rodent models of type 2 diabetes requires insulin-resistant alpha cells

Young Lee et al. Proc Natl Acad Sci U S A. .

Abstract

To determine the role of glucagon action in diet-induced and genetic type 2 diabetes (T2D), we studied high-fat-diet-induced obese (DIO) and leptin receptor-defective (LepR(-/-)) rodents with and without glucagon receptors (GcgRs). DIO and LepR(-/-),GcgR(+/+) mice both developed hyperinsulinemia, increased liver sterol response element binding protein 1c, and obesity. DIO GcgR(+/+) mice developed mild T2D, whereas LepR(-/-),GcgR(+/+) mice developed severe T2D. High-fat-fed (HFF) glucagon receptor-null mice did not develop hyperinsulinemia, increased liver sterol response element binding protein 1c mRNA, or obesity. Insulin treatment of HFF GcgR(-/-) to simulate HFF-induced hyperinsulinemia caused obesity and mild T2D. LepR(-/-),GcgR(-/-) did not develop hyperinsulinemia or hyperglycemia. Adenoviral delivery of GcgR to GcgR(-/-),LepR(-/-) mice caused the severe hyperinsulinemia and hyperglycemia of LepR(-/-) mice to appear. Spontaneous disappearance of the GcgR transgene abolished the hyperinsulinemia and hyperglycemia. In conclusion, T2D hyperglycemia requires unsuppressible hyperglucagonemia from insulin-resistant α cells and is prevented by glucagon suppression or blockade.

Keywords: insulin resistance; type two diabetes.

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Conflict of interest statement

Conflict of interest statement: R.H.U. and M.G.R. are founding scientists of SynAlpha Therapeutics, LLC.

Figures

Fig. 1.
Fig. 1.
(A) The effect of glucagon on preproinsulin mRNA in INS-1 cells cultured for 24 h in 0 or 0.4 µg/mL of glucagon (Left). (Right) Mean insulin concentration in the medium after 24 h incubation of INS-1 cells in the absence or presence of 0.4 µg/mL of glucagon. n = 3, and mean values ± SEM are shown. (B) Comparison of SREBP-1c expression in the liver of GcgR+/+ and GcgR−/− mice on a chow diet (striped bar) and a diet of 60% fat with sucrose supplementation in the absence (black bar) and in the presence (white bar) of treatment with exogenous insulin. The gray bar represents values from GcgR−/− mice restricted to 75% of the caloric intake of HFF GcgR+/+ mice. n = 6, and mean values ± SEM are shown. (C) The appearance of GcgR+/+ and mice fed a high-fat diet with sucrose supplementation (Left). (Right) A mouse treated with exogenous insulin. The mean plasma insulin concentration ± SEM for six mice in each group appear under the representative photograph.
Fig. 2.
Fig. 2.
(A) Comparison of plasma glucose and insulin levels in GcgR+/+ (n = 6), GcgR−/− (n = 6), LepR−/−, GcgR+/+ (n = 4), and LepR−/−, GcgR−/− mice (n = 4) treated with adenovirus containing the GcgR cDNA. Blood glucose and insulin levels are significantly lower in LepR−/−,GcgR−/− mice compared with LepR−/−,GcgR+/+ mice, P < 0.05. Treatment of LepR−/−,GcgR−/− mice with Adv-GcgR significantly raised blood glucose and insulin compared with LepR−/−,GcgR−/− mice not treated with Adv, P < 0.05. Treatment with Adv-beta Gal had no effect (Table S2). (B) The time course of mean blood glucose and plasma insulin levels of the LepR−/−,GcgR−/− mice following the injection of adenovirus containing the GcgR cDNA. Errors are SEM.
Fig. 3.
Fig. 3.
Ceramide induces insulin resistance in InR1-G9 alpha cells, and suppression of glucagon corrects the hyperglycemia in T2D. (A) InR1-G9 cells in culture were treated with insulin, ceramide, or insulin plus ceramide for 16 h, and mRNA for glucagon was measured by quantitative PCR. Values are normalized to those of the control sample and are means of triplicate measurements with SEM. The values shown are representative of two independent experiments. (B) A schema for the interaction of insulin and glucagon controlling lipogenesis under situations of caloric balance and excess is shown. (C) Blood glucose concentrations in ZDFfa/fa leptin receptor-deficient rats without (black) and with (white) oral treatment with GABA are shown. n = 6 for each test condition, and errors are SEM. Mean glucagon concentrations without treatment were 103 ± 24.4 pg/mL and with treatment were 58.7 ± 12.9 pg/mL.
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References

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