Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes

Abstract

Gastrointestinal bypass surgeries restore metabolic homeostasis in patients with type 2 diabetes and obesity1, but the underlying mechanisms remain elusive. Duodenal-jejunal bypass surgery (DJB), an experimental surgical technique that excludes the duodenum and proximal jejunum from nutrient transit1,2, lowers glucose concentrations in nonobese type 2 diabetic rats2,3,4,5. Given that DJB redirects and enhances nutrient flow into the jejunum and that jejunal nutrient sensing affects feeding6,7, the repositioned jejunum after DJB represents a junction at which nutrients could regulate glucose homeostasis. Here we found that intrajejunal nutrient administration lowered endogenous glucose production in normal rats through a gut-brain-liver network in the presence of basal plasma insulin concentrations. Inhibition of jejunal glucose uptake or formation of long chain fatty acyl-coA negated the metabolic effects of glucose or lipid, respectively, in normal rats, and altered the rapid (2 d) glucose-lowering effect induced by DJB in streptozotocin (STZ)-induced uncontrolled diabetic rats during refeeding. Lastly, in insulin-deficient autoimmune type 1 diabetic rats and STZ-induced diabetic rats, DJB lowered glucose concentrations in 2 d independently of changes in plasma insulin concentrations, food intake and body weight. These data unveil a glucoregulatory role of jejunal nutrient sensing and its relevance in the early improvement of glycemic control after DJB in rat models of uncontrolled diabetes.

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Figure 1: Jejunal nutrient-sensing mechanisms lower glucose production via a neuronal network.
Figure 2: DJB surgery lowers glucose concentrations in uncontrolled diabetic rats.
Figure 3: Jejunal nutrient sensing is required for DJB to rapidly lower glucose concentrations in uncontrolled diabetic rats.
Figure 4: DJB lowers glucose concentrations in nonobese type 1 diabetes.

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Acknowledgements

We are extremely grateful to P.Y.T. Wang for excellent technical assistance. This work was supported by a research grant to T.K.T.L. from the Canadian Institutes of Health Research (MOP-82701). D.M.B. is supported by a post-doctoral fellowship from the University Health Network and the Banting and Best Diabetes Centre (BBDC), University of Toronto. B.A.R. is supported by a BBDC graduate scholarship. A.K. and G.W.C.C. were supported by Canadian Institutes of Health Research and BBDC graduate scholarships. T.K.T.L. holds the John Kitson McIvor (1915–1942) Endowed Chair in Diabetes Research and the Canada Research Chair in Obesity at the Toronto General Research Institute and the University of Toronto.

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D.M.B. conducted and designed experiments, performed data analyses and wrote the manuscript; B.A.R., A.K. and G.W.C.C. assisted in experiments; R.W. assisted in setting up the DJB surgical procedure; and T.K.T.L. supervised the project, designed experiments and edited the manuscript.

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Correspondence to Tony K T Lam.

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The authors declare no competing financial interests.

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Supplementary Figures 1–6, Supplementary Tables 1–3 and Supplementary Methods (PDF 2324 kb)

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Breen, D., Rasmussen, B., Kokorovic, A. et al. Jejunal nutrient sensing is required for duodenal-jejunal bypass surgery to rapidly lower glucose concentrations in uncontrolled diabetes. Nat Med 18, 950–955 (2012). https://doi.org/10.1038/nm.2745

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