Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Obesity Surgery
Published in: Obesity Surgery 1/2020

01-01-2020 | Insulins | Original Contributions

Duodenal-Jejunal Bypass Ameliorates Type 2 Diabetes Mellitus by Activating Insulin Signaling and Improving Glucose Utilization in the Brain

Authors: Na Li, Qing-Tao Yan, Qi Jing, Rui-Yan Pan, Huai-Jie Wang, Bin Jiang, Xian-Jun Li, Yi Wang, Jun-Hong Dong, Xue-Jian Wang, Mei-Jia Zhang, Qing-Guo Meng, Xiang-Zhen Li, Zhi-Jun Liu, Zhi-Qin Gao, Mei-Hua Qu

Published in: Obesity Surgery | Issue 1/2020

Login to get access

Abstract

Background

Duodenal-jejunal bypass (DJB) can dramatically improve type 2 diabetes independent of weight loss and food restriction. Increasing evidence has demonstrated that brain insulin signaling plays an important role in the pathophysiology of type 2 diabetes. This study explores whether the antidiabetic effect of DJB is involved in brain insulin signaling activation and brain glucose utilization.

Methods

A diabetic rat model was established by high-fat and high-glucose diet. DJB or sham surgery was performed in diabetic rats. 18F-FDG PET scanning was used to detect glucose uptake in different organs, particularly in the brain. The levels of glucose transporters, glucose utilization-related proteins (HK1 and PFK2), insulin, and insulin signaling pathway-related proteins (InsR, IRS1/2, PI3K, and p-Akt) in the brain tissues were evaluated and analyzed.

Results

The results showed that DJB significantly improved basal glycemic parameters and reversed the decreasing glucose uptake in the brains of type 2 diabetic rats. DJB significantly increased not only the expression levels of brain insulin, IRS1/2, PI3K, and p-Akt but also the levels of the glucose utilization enzymes HK1 and PFK2 in the brain.

Conclusion

These results indicate that enhanced brain insulin signaling transduction and brain glucose utilization play important roles in the antidiabetic effect of DJB.
Appendix
Available only for authorised users
Literature
1.
Cho NH, Shaw JE, Karuranga S, et al. IDF Diabetes Atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271–81.PubMedCrossRef
2.
Guariguata L, Whiting D, Hambleton I, et al. Global estimates of prevalence of diabetes in adults for 2013 and projections to 2035. Diabetes Res Clin Pract. 2014;103(2):137–49.PubMedCrossRef
3.
Pareek M, Schauer PR, Kaplan LM, et al. Metabolic surgery: weight loss, diabetes, and beyond. J Am Coll Cardiol. 2018;71(6):670–87.PubMedCrossRef
4.
Rubino F, Forgione A, Cummings DE, et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg. 2006;244(5):741–9.PubMedPubMedCentralCrossRef
5.
Rubino F, R’Bibo SL, del Genio F, et al. Metabolic surgery: the role of the gastrointestinal tract in diabetes mellitus. Nat Rev Endocrinol. 2010;6(2):102–9.PubMedPubMedCentralCrossRef
6.
7.
Hu C, Zhang G, Sun D, et al. Duodenal-jejunal bypass improves glucose metabolism and adipokine expression independently of weight loss in a diabetic rat model. Obes Surg. 2013;23(9):1436–44.PubMedCrossRef
8.
9.
10.
Chen Z, Zhong C. Decoding Alzheimer’s disease from perturbed cerebral glucose metabolism: implications for diagnostic and therapeutic strategies. Prog Neurobiol. 2013;108:21–43.PubMedCrossRef
11.
Rubino F, Cummings DE. Surgery: the coming of age of metabolic surgery. Nat Rev Endocrinol. 2012;8(12):702–4.PubMedCrossRef
12.
Rubino F, Marescaux J. Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. Ann Surg. 2004;239(1):1–11.PubMedPubMedCentralCrossRef
13.
Kuhre RE, Wewer Albrechtsen NJ, Larsen O, et al. Bile acids are important direct and indirect regulators of the secretion of appetite- and metabolism-regulating hormones from the gut and pancreas. Mol Metab. 2018;11:84–95.PubMedPubMedCentralCrossRef
14.
Li M, Li H, Zhou Z, et al. Duodenal-jejunal bypass surgery ameliorates glucose homeostasis and reduces endoplasmic reticulum stress in the liver tissue in a diabetic rat model. Obes Surg. 2016;26(5):1002–9.CrossRef
15.
Li N, Huo LG, Su H, et al. Duodenum-jejunum bypass surgery (DJB) improved the glucose and lipid metabolism in Zucker diabetic rat. Diabetes. 2017;66:A681–1.
16.
Patriti A, Facchiano E, Donini A. Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease. A Ann Surg. 2004;240(2):388–9.PubMedCrossRef
17.
Hu C, Su Q, Li F, et al. Duodenal-jejunal bypass improves glucose homeostasis in association with decreased proinflammatory response and activation of JNK in the liver and adipose tissue in a T2DM rat model. Obes Surg. 2014;24(9):1453–62.PubMedCrossRef
18.
Filippi BM, Abraham MA, Yue JT, et al. Insulin and glucagon signaling in the central nervous system. Rev Endocr Metab Disord. 2013;14(4):365–75.PubMedCrossRef
19.
Molnar G, Farago N, Kocsis AK, et al. GABAergic neurogliaform cells represent local sources of insulin in the cerebral cortex. J Neurosci. 2014;34(4):1133–7.PubMedCrossRef
20.
Brüning JC, Gautam D, Burks DJ, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289(5487):2122–5.PubMedCrossRef
21.
Diggsandrews KA, Zhang X, Song Z, et al. Brain insulin action regulates hypothalamic glucose sensing and the counterregulatory response to hypoglycemia. Diabetes. 2010;59(9):2271–80.CrossRef
22.
Lam CK, Chari M, Lam TK. CNS regulation of glucose homeostasis. Physiology (Bethesda). 2009;24:159–70.
23.
Arnold SE, Arvanitakis Z, Macauleyrambach SL, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14(3):168–81.PubMedPubMedCentralCrossRef
24.
Pan RY, Li N, Zhao TK, et al. DJB surgery improved the T2DM rats glucose homeostasis, elevated the glucose utilization, and the GLUT3 expression in brain. Diabetes. 2018;67:1794–P.CrossRef
25.
Li N, Wang HJ, Su H, et al. DJB surgery improves glucose homeostasis by affecting glucose transporter expression levels in different intestinal limbs of type 2 diabetic rats and the possible underlying mechanisms. Diabetes Metab Res Rev. 2017;33
26.
Wang H, Li N, Yan Q, et al. Tu1930 - duodenal-Jejunal bypass surgery improved glucose homeostasis through modulating the expression of SGLT1, GLUT2, T1R2 and T1R3 in different intestinal segments of type 2 diabetic rats. Gastroenterology. 2018;154(6):S1057.CrossRef
27.
Hu P, Cheng D, Huang T, et al. Evaluation of novel 64Cu-labeled theranostic gadolinium-based nanoprobes in HepG2 tumor-bearing nude mice. Nanoscale Res Lett. 2017;12(1):523.
28.
Simpson IA, Chundu KR, Davies-Hill T, et al. Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer’s disease. Ann Neurol. 1994;35(5):546–51.PubMedCrossRef
29.
Yu S, Tooyama I, Ding WG, et al. Immunohistochemical localization of glucose transporters (GLUT1 and GLUT3) in the rat hypothalamus. Obes Res. 1995;3(Suppl 5):753S–60S.PubMedCrossRef
30.
Yin X, Xu Z, Zhang Z, et al. Association of PI3K/AKT/mTOR pathway genetic variants with type 2 diabetes mellitus in Chinese. Diabetes Res Clin Pract. 2017;128:127–35.PubMedCrossRef
31.
32.
Rubino F, Schauer PR, Kaplan LM, et al. Metabolic surgery to treat type 2 diabetes: clinical outcomes and mechanisms of action. Annu Rev Med. 2010;61:393–411.PubMedCrossRef
33.
Kullmann S, Heni M, Hallschmid M, et al. Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiol Rev. 2016;96(4):1169–209.PubMedCrossRef
34.
Christian B, Swantje B, Schiöth HB, et al. Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men. Diabetes. 2011;60(1):114–8.CrossRef
35.
Dash S, Xiao C, Morgantini C, et al. Intranasal insulin suppresses endogenous glucose production in humans compared with placebo in the presence of similar venous insulin concentrations. Diabetes. 2015;64(3):766–74.PubMedCrossRef
36.
Heni M, Wagner R, Kullmann S, et al. Central insulin administration improves whole-body insulin sensitivity via hypothalamus and parasympathetic outputs in men. Diabetes. 2014;63(12):4083–8.
37.
Heni M, Kullmann S, Preissl H, et al. Impaired insulin action in the human brain: causes and metabolic consequences. Nat Rev Endocrinol. 2015;11(12):701–11.PubMedCrossRef
38.
Schulingkamp RJ, Pagano TC, Hung D, et al. Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev. 2000;24(8):855–72.CrossRef
39.
Kullmann S, Heni M, Veit R, et al. Selective insulin resistance in homeostatic and cognitive control brain areas in overweight and obese adults. Diabetes Care. 2015;38(6):1044–50.PubMedCrossRef
40.
Frank S, Wilms B, Veit R, et al. Altered brain activity in severely obese women may recover after Roux-en Y gastric bypass surgery. Int J Obes. 2014;38(3):341–8.PubMedCrossRef
41.
Scholtz S, Miras AD, Chhina N, et al. Obese patients after gastric bypass surgery have lower brain-hedonic responses to food than after gastric banding. Gut. 2014;63(6):891–902.PubMedCrossRef
42.
Hunt KF, Dunn JT, Le RC, et al. Differences in regional brain responses to food ingestion after Roux-en-Y gastric bypass and the role of gut peptides: a neuroimaging study. Diabetes Care. 2016;39(10):1787–95.PubMedCrossRef
43.
Tuulari JJ, Karlsson HK, Hirvonen J, et al. Weight loss after bariatric surgery reverses insulin-induced increases in brain glucose metabolism of the morbidly obese. Diabetes. 2013;62(8):2747–51.PubMedPubMedCentralCrossRef
44.
Lam TK, Gutierrezjuarez R, Pocai A, et al. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science. 2005;309(5736):943–7.PubMedCrossRef
45.
Lópezgambero AJ, Martínez F, Salazar K, et al. Brain glucose-sensing mechanism and energy homeostasis. Mol Neurobiol. 2019;56(2):769–96.CrossRef
46.
Hwang JJJL, Rangel ES, Fan X, et al. Glycemic variability and brain glucose 1 levels in T1DM. Diabetes. 2019;68(1):163–71.PubMedCrossRef
47.
Hirvonen J, Virtanen KA, Nummenmaa L, et al. Effects of insulin on brain glucose metabolism in impaired glucose tolerance. Diabetes. 2011;60(2):443–7.PubMedPubMedCentralCrossRef
48.
Minchenko DO, Kharkova AP, Hubenia OV, et al. Insulin receptor, IRS1, IRS2, INSIG1, INSIG2, RRAD, and BAIAP2 gene expressions in glioma U87 cells with ERN1 loss of function: effect of hypoxia and glutamine or glucose deprivation. Endocr Regul. 2013;47(1):15–26.PubMedCrossRef
49.
Bathina S, Das UN. Dysregulation of PI3K-Akt-mTOR pathway in brain of streptozotocin-induced type 2 diabetes mellitus in Wistar rats. Lipids Health Dis. 2018;17(1):168.PubMedPubMedCentralCrossRef
Metadata
Title
Duodenal-Jejunal Bypass Ameliorates Type 2 Diabetes Mellitus by Activating Insulin Signaling and Improving Glucose Utilization in the Brain
Authors
Na Li
Qing-Tao Yan
Qi Jing
Rui-Yan Pan
Huai-Jie Wang
Bin Jiang
Xian-Jun Li
Yi Wang
Jun-Hong Dong
Xue-Jian Wang
Mei-Jia Zhang
Qing-Guo Meng
Xiang-Zhen Li
Zhi-Jun Liu
Zhi-Qin Gao
Mei-Hua Qu
Publication date
01-01-2020
Publisher
Springer US
Published in
Obesity Surgery / Issue 1/2020
Print ISSN: 0960-8923
Electronic ISSN: 1708-0428
DOI
https://doi.org/10.1007/s11695-019-04153-3

Other articles of this Issue 1/2020

Obesity Surgery 1/2020 Go to the issue

Original Contributions

Effects of the Postoepartive Dietetic/Behavioral Counseling on the Weight Loss After Bariatric Surgery

Original Contributions

Changes in Central 24-h Ambulatory Blood Pressure and Hemodynamics 12 Months After Bariatric Surgery: the BARIHTA Study

Brief Communication

Laparoscopic Conversion from Single Anastomosis Duodeno-Jejunal Bypass with Sleeve Gastrectomy (SADJ-S) to Roux-en-Y Gastric Bypass (GBP): Improving Unsatisfactory Outcomes

Original Contributions

Intraoperative Liver Biopsy During Adolescent Bariatric Surgery: Is It Really Necessary?

Original Contributions

Changes in Bone Mineral Density in Patients with Type 2 Diabetes After Different Bariatric Surgery Procedures and the Role of Gastrointestinal Hormones

Original Contributions

An Extended Pouch in a Roux-En-Y Gastric Bypass Reduces Weight Regain: 3-Year Results of a Randomized Controlled Trial