Volume 7, Issue 5, September 2018, Page: 124-130
View Insulin Resistance from an Interaction Between Pancreatic Islets and Peripheral Tissues
Ming Li, Department of Physiology, Tulane University, New Orleans, USA
You Lu, Department of Physiology, Tulane University, New Orleans, USA
Alun Rongxiang Wang, Department of Pathology, Tulane University, New Orleans, USA
Received: Aug. 20, 2018;       Accepted: Oct. 31, 2018;       Published: Nov. 26, 2018
DOI: 10.11648/j.cmr.20180705.14      View  21      Downloads  2
Curl rent hypotheses of insulin resistance mostly emphasize cellular mechanisms in peripheral tissues. Although received broad recognition, these opinions may have overlooked the interaction between pancreatic endocrine cells and the peripheral tissues in the process of establishment and maintenance of insulin resistance in the whole body. It has been suggested that basal hyperinsulinemia is the root cause of insulin resistance. Basal insulin release does not share the same intracellular mechanism of high glucose stimulated insulin release; instead, it is regulated by local Ca2+ fluctuation and activation of the cAMP-Epac2/Rap1 signaling pathway. Basal insulin release is controlled by the interaction between pancreatic head β-cells and pancreatic tail α-cells, which release insulin and glucagon, respectively. In diabetes, an elevated basal insulin level would mitigate the sensitivity of peripheral tissues to insulin; the decreased insulin sensitivity and elevated plasma glucose concentration could further stimulate more basal insulin release partially by increasing T-type Ca2+ channel expression and activity in β-cells. This interaction forms a positive feedback loop. Therefore, T-type Ca2+ channel antagonists can potentially be employed to break this positive feedback loop, thus reversing insulin resistance.
nsulin Resistance, Hyperinsulinemia, T-type Ca2+ Channel
To cite this article
Ming Li, You Lu, Alun Rongxiang Wang, View Insulin Resistance from an Interaction Between Pancreatic Islets and Peripheral Tissues, Clinical Medicine Research. Vol. 7, No. 5, 2018, pp. 124-130. doi: 10.11648/j.cmr.20180705.14
Copyright © 2018 Authors retain the copyright of this article.
This article is an open access article distributed under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes estimates for the year 2000 and projections for 2030. Diabetes care 2004;27:1047-1053.
Diabetes. World Health Organization. Available at: http://www.who.int/news-room/fact-sheets/detail/diabetes. 2018.
Nations, United. World population prospects: The 2015 revision. United Nations Econ Soc Aff 2015;33:2:1-66.
Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev 1995;75:473-486.
Caspard H, Jabbour S, Hammar N, Fenici P, Sheehan JJ, Kosiborod M. Recent trends in the prevalence of type 2 diabetes and the association with abdominal obesity lead to growing health disparities in the USA: an analysis of the NHANES surveys from 1999 to 2014. Diabetes, Obesity and Metabolism. 2018;20:3:667-671.
Cersosimo E, Triplitt C, Solis-Herrera C, Mandarino LJ, DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. 2018;In Endotext [Internet]. MDText. com, Inc.
Group, U. P. D. S., Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). The Lancet 1998;352:837-853.
Kahn CR. Insulin resistance, insulin insensitivity, and insulin unresponsiveness: a necessary distinction. Metab Clin Exp 1978;27:1893-1902.
Kahn SE, Prigeon RL, McCulloch DK, Boyko EJ, Bergman RN, Schwartz MW, Neifing JL, Ward WK, Beard JC, Palmer JP. Quantification of the relationship between insulin sensitivity and β-cell function in human subjects: evidence for a hyperbolic function. Diabetes 1993;42:1663-1672.
Olefsky JM. Lilly lecture 1980: Insulin resistance and insulin action: an in vitro and in vivo perspective. Diabetes 1981;30:148-162.
Reno, CM, Puente EC, Sheng Z, Daphna-Iken D, Bree AJ, Routh VH, Kahn BB, Fisher SJ. Brain GLUT4 knockout mice have impaired glucose tolerance, decreased insulin sensitivity, and impaired hypoglycemic counterregulation. Diabetes 2017;66(3):587-597.
Bril F, Cusi K. Basic Concepts in Insulin Resistance and Diabetes Treatment. In Dermatology and Diabetes. 2018;19-35. Springer, Cham.
Müller HK, Kellerer M, Ermel B Mühlhöfer A, Obermaier-Kusser B, Vogt B, Häring HU. Prevention by protein kinase C inhibitors of glucose-induced insulin-receptor tyrosine kinase resistance in rat fat cells. Diabetes 1991;40:1440-1448.
Kahn SE. The importance of β-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab 2001;86:4047-4058.
Alberti KGMM. The clinical implications of impaired glucose tolerance. Diabetic Med 1996;13:927-937.
Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest 2000;10: 171-176.
Wellen KE, Hotamisligil GS. Hotamisligil, Inflammation, stress, and diabetes. J Clin Invest 2005;115:1111-1119.
Taubes G. Prosperity's plague. Science 2009;325:256-260.
Colosia AD, Palencia R, Khan S. Prevalence of hypertension and obesity in patients with type 2 diabetes mellitus in observational studies: a systematic literature review. Diabetes Metab Syndr Obes 2013;6:327-38.
Cohen RV, Rubino F, Schiavon C, Cummings DE. Diabetes remission without weight loss following duodenal bypass surgery. Surg Obes Relat Dis 2012;8:e66-e68.
Rubino F, and Gagner M. Potential of surgery for curing type 2 diabetes mellitus. Annals of Surgery 2002;236:554-559.
Corkey BE. Banting lecture 2011 hyperinsulinemia: cause or consequence? Diabetes, 2012;61:4-13.
Reed MA, Pories WJ, Chapman W, Pender J, Bowden R, Barakat H, Gavin TP, Green T, Tapscott ED, Zheng DH, Shankley N, Yieh L, Polidori D, Piccoli SP, Brenner-Gati L, Dohm GL. Roux-en-Y gastric bypass corrects hyperinsulinemia implications for the remission of type 2 diabetes. J Clin Endocrinol Metab 2011; 96:2525-2531.
Destefano Mb, Stern JS, Castonguay TW. Effect of chronic insulin administration on food intake and body weight in rats. Physiol Behav 1991;50:801-806. 

Poggi-Travert F, Martin D, de Villemeur TB, Bonnefont JP, Vassault A, Rabier D, Charpentier C, Kamoun P, Munnich A, Saudubray JM. Metabolic intermediates in lactic acidosis: compounds, samples and interpretation. J Inherit Metab Dis 1996;19:478-488.
Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes/Metab Res Rev 1999;15:412-426.
Rorsman R, Eliasson L, Renström E, Gromada J, Barg S, Göpel S. The cell physiology of biphasic insulin secretion. Physiol 2000;15:72-77.
Straub SG, Sharp GWG. Glucose-stimulated signaling pathways in biphasic insulin secretion. Diabetes/Metab Res Rev 2002;18:451-463.
Ward WK, Beard JC, Halter JB, Pfeifer MA, Porte D. Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus. Diabetes Care 1984;7:491-502. 

Hosker JP, Rudenski AS, Burnett MA, Matthews DR, Turner RC. Similar reduction of first-and second-phase B-cell responses at three different glucose levels in type II diabetes and the effect of gliclazide therapy. Metab 1989;38:767-772.
Hou JCQ, Min L, Pessin JE. Insulin granule biogenesis, trafficking and exocytosis. Vitam Horm 2009;80:473-506.
Li M. Role of T-type Ca2+ channels in basal insulin release. In T-type Calcium Channels in Basic and Clinical Science. Schaffer SW & Li M (Eds.) 2015, Springer. pp. 137-150.
Ivanov AI, Calabrese RL. Intracellular Ca2+ dynamics during spontaneous and evoked activity of leech heart interneurons: low-threshold Ca currents and graded synaptic transmission. J Neurosci 2000;20:4930-4943.
Pan ZH, Hu HJ, Perring P, Andrade R. T-type Ca2+ channels mediate neurotransmitter release in retinal bipolar cells. Neuron 2001;32:89-98.
Carabelli V, Marcantoni A, Comunanza V, Luca AD, Diaz J, Borges R, Carbone E. Chronic hypoxia up-regulates α1H T-type channels and low-threshold catecholamine secretion in rat chromaffin cells. J Physiol 2007;584:149-165.
Tang AH, Karson MA, Nagode DA, McIntosh JM, Uebele VN, Renger JJ, Klugmann M, Milner TA, Alger BE. Nerve terminal nicotinic acetylcholine receptors initiate quantal gaba release from perisomatic interneurons by activating axonal T-type (Cav3) Ca2+ channels and Ca2+ release from stores. J Neurosci 2011; 31:13546–13561.
Keyser BM, Taylor JT, Choi SK, Lu Y, Bhattacharjee A, Huang L, Pottle J, Matrougui K, Xu Z, Li M. Role of T-type Ca2+ channels in basal [Ca2+]i regulation and basal insulin secretion in rat islet cells. Curr Trend Endocrinol 2014;7:35-44.
Bhattacharjee A, Whitehurst Jr RM, Zhang M, Wang L, Li M. T-type calcium channels facilitate insulin secretion by enhancing general excitability in the insulin-secreting β-cell line, INS-1. Endocrinol 1997;138:3735-3740.
Wang L, Bhattacharjee A, Fu J, Li M. Abnormally expressed low-voltage-activated calcium channels in β-cells from NOD mice and a related clonal cell line. Diabetes 1996;45:1678-1683.
Huang L, Bhattacharjee A, Taylor JT, Zhang M, Keyser BM, Marrero L, Li M. [Ca2+]i regulates trafficking of Cav1.3 (α1D Ca2+ channel) in insulin-secreting cells. Am J Physiol Cell Physiol 2004;286:213-221.
Vestergaard ET, Jessen N, Møller N, Jørgensen JOL. Acyl ghrelin induces insulin resistance independently of GH, cortisol, and free fatty acids. Sci Rep 2017;7:42706.
Unger RH. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM: genetic and clinical implications. Diabetes 1995;44:863-870.
Polonsky KS, Sturis J, Bell GI. Non-insulin-dependent diabetes mellitus—a genetically programmed failure of the beta cell to compensate for insulin resistance. New Eng J Med 1996;334:777-783.
Holz GG, Leech CA, Chepurny OG. New insights concerning the molecular basis for defective glucoregulation in soluble adenylyl cyclase knockout mice. Biochim Biophys Acta-Mol Basis of Dis 2014;1842:2593-2600.

Lee YS, Hee SJ. Glucagon-like peptide-1 receptor agonist and glucagon increase glucose-stimulated insulin secretion in beta cells via distinct adenylyl cyclases. Inter J Med Sci 2018 15;6-603.
Wiggins SV, Steegborn C, Levin RL, Buck J. Pharmacological modulation of the CO 2/HCO 3−/pH-, calcium-, and ATP-sensing soluble adenylyl. Pharm Therap 2018.
Robichaux III WG, Cheng XD. Intracellular cAMP sensor EPAC: physiology, pathophysiology, and therapeutics. Physiol Rev 2018;98:919-1053.
Mei FC, Cheng XD. Interplay between exchange protein directly activated by cAMP (Epac) and microtubule cytoskeleton. Mol Biosyst 2005;1:325-331.
Shibasaki T, Takahashi H, Miki T, Sunaga Y, Matsumura K, Yamanaka M, Zhang CL, Tamamoto A, Satoh T, Miyazaki J, Seino S. Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP. Proc Nat Acad Sci 2007;104:19333-19338.
Zhu D, Xie L, Karimian N, Liang T, Kang Y, Huang YC, Gaisano HY. Munc18c mediates exocytosis of pre-docked and newcomer insulin granules underlying biphasic glucose stimulated insulin secretion in human pancreatic beta-cells. Mol Meta 2015;4:418-426.
Novara M, Baldelli P, Cavallari D, Carabelli V, Giancippoli A, Carbone E. Exposure to cAMP andβadrenergic stimulation recruits CaV3 T-type channels in rat chromaffin cells through Epac cAMP-receptor proteins. J Physiol 2004;558:433-449.

Lu YJ, Long M, Zhou SW, Xu ZH, Hu FQ, Li M. Mibefradil reduces blood glucose concentration in db/db mice. Clinics 2014;69:61-67.
Browse journals by subject