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      Response to Comment on: Turban et al. Optimal Elevation of β-Cell 11β-Hydroxysteroid Dehydrogenase Type 1 Is a Compensatory Mechanism That Prevents High-Fat Diet–Induced β-Cell Failure. Diabetes 2012;61:642–652

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      Diabetes
      American Diabetes Association

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          Abstract

          We thank the editor for allowing us to clarify an aspect of our recent article (1) in response to Liu et al. (2). We and others (3) found that KsJ mice resist excessive weight gain on a high-fat (HF) diet. There are well-known strain differences in this response. Nevertheless, epididymal fat pad mass and fed plasma nonesterified fatty acid levels were increased by HF in both genotypes (Table 1 in ref. 1). We did not claim obesity or diabetes. We agree that β-cell dysfunction was subclinical by basic measures after 12 weeks’ exposure (Table 1 in ref. 1). Importantly, insulin secretion was reduced in HF-fed KsJ mice when they were challenged with glucose in vivo 15–120 min (Fig. 2A vs. 2B in ref. 1). Our original submission showed the control and HF-diet data within each genotype together, but the figure was modified in review. While insulin area under the curve was similar over the whole glucose challenge (Fig. 2C in ref. 1), it was significantly lower in the second phase (15–120 min: KsJ HF diet, 155.4 ± 24.52 vs. KsJ control diet, 239.4 ± 20.60; P < 0.05, n = 6). In vitro insulin secretion from islets of HF-fed KsJ mice showed a trend for suppressed glucose-stimulated insulin secretion (Fig. 3E in ref. 1). There were fewer islets in the HF-fed KsJ mice due to β-cell loss (which follows failure) (Fig. 3A–C in ref. 1), and we chose size-matched islets to better compare the secretory profile with our transgenics. Thus, Fig. 3E in ref. 1 effectively overestimates the secretory capacity of HF-fed KsJ mice by selecting their “healthy” surviving islets. Overall we concluded that there was β-cell failure in HF-fed KsJ mice. The positive message is that β-cell–specific 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) overexpression unexpectedly augments glucose-stimulated insulin secretion against a lipotoxic challenge. Modest β-cell 11β-HSD1 elevation resembled the pattern found in mice that robustly compensate on HF diet. Going over this optimal threshold (homozygotes) compromised β-cell function, as found in genetically diabetic mice. As much as we would prefer simplistic linear answers to our research questions, the data are compatible with a U-shaped response. Liu et al. (2) are incorrect in their assertion that glucocorticoids are purely suppressive of β-cell function—we provided a list of published data that evidenced both positive and negative effects. We offered plausible explanations for the discrepancies.

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          Optimal Elevation of β-Cell 11β-Hydroxysteroid Dehydrogenase Type 1 Is a Compensatory Mechanism That Prevents High-Fat Diet–Induced β-Cell Failure

          Type 2 diabetes ultimately results from pancreatic β-cell failure. Abnormally elevated intracellular regeneration of glucocorticoids by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in fat or liver may underlie pathophysiological aspects of the metabolic syndrome. Elevated 11β-HSD1 is also found in pancreatic islets of obese/diabetic rodents and is hypothesized to suppress insulin secretion and promote diabetes. To define the direct impact of elevated pancreatic β-cell 11β-HSD1 on insulin secretion, we generated β-cell–specific, 11β-HSD1–overexpressing (MIP-HSD1) mice on a strain background prone to β-cell failure. Unexpectedly, MIP-HSD1tg/+ mice exhibited a reversal of high fat–induced β-cell failure through augmentation of the number and intrinsic function of small islets in association with induction of heat shock, protein kinase A, and extracellular signal–related kinase and p21 signaling pathways. 11β-HSD1−/− mice showed mild β-cell impairment that was offset by improved glucose tolerance. The benefit of higher β-cell 11β-HSD1 exhibited a threshold because homozygous MIP-HSD1tg/tg mice and diabetic Lep db/db mice with markedly elevated β-cell 11β-HSD1 levels had impaired basal β-cell function. Optimal elevation of β-cell 11β-HSD1 represents a novel biological mechanism supporting compensatory insulin hypersecretion rather than exacerbating metabolic disease. These findings have immediate significance for current therapeutic strategies for type 2 diabetes.
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            Author and article information

            Journal
            Diabetes
            Diabetes
            diabetes
            diabetes
            Diabetes
            Diabetes
            American Diabetes Association
            0012-1797
            1939-327X
            September 2012
            17 August 2012
            : 61
            : 9
            : e14
            Affiliations
            [1]From the 1Molecular Metabolism Group, University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, U.K.; and the
            [2] 2Endocrinology Unit, University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, U.K
            Author notes
            Corresponding author: Nicholas M. Morton, nik.morton@ 123456ed.ac.uk .
            Article
            0583
            10.2337/db12-0583
            3425415
            8ced6c1b-b3ac-4951-8428-db9ff81d37b5
            © 2012 by the American Diabetes Association.

            Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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            Endocrinology & Diabetes
            Endocrinology & Diabetes

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