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Key Event Title
Impaired, insulin secretion
|Level of Biological Organization|
|pancreatic endocrine cell|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|All life stages||High|
Key Event Description
Impaired insulin secretion refers to the inability to robustly secrete insulin in response to a nutrient or insulin secretagogue. In mammals, this can occur due to damage and/or dysfunction of the endocrine pancreas, specifically, β-cells (6). For example, streptozotocin-induced pancreatic β-cell death, used to model type 1 diabetes in rodents, results in the absence of nutrient-stimulated insulin secretion (7).
The mammalian endocrine pancreas is composed of clusters of cells known as islets of Langerhans that contain α-, β-, δ-, ε-, and pancreatic polypeptide-cells (11). Many non-mammal vertebrates have pancreatic islet equivalents and invertebrates cell clusters in other tissues that functionally act as equivalents (15). β-cells, which constitute the bulk of the mammalian islet, have intracellular granules (vesicles) that contain insulin. Insulin is translated from the insulin gene that encodes for preproinsulin. The immature preproinsulin undergoes cleavage and folding in the lumen of the endoplasmic reticulum to afford proinsulin that is stored in vesicles known as granules (18). Inside the granule, proinsulin is cleaved into mature insulin and C-peptide that go on to adopt a hexameric form in coordination with zinc ions (16).
In response to changes to blood nutrient levels, including glucose, lipids, and some amino acids, pancreatic β-cells secrete insulin into circulating blood by triggering exocytosis of insulin granules (6). Glucose, the primary insulin secretagogue, is absorbed via glucose transporters in β-cells, phosphorylated by glucokinase, and undergoes metabolism resulting in increased intracellular ATP (14). The increase in ATP:ADP results in closure of ATP-sensitive potassium channels leading to depolarization (2) and subsequent opening of voltage-gated calcium channels (20). The latter triggers the activation of exocytotic proteins syntaxin 1A (21), SNAP-26 (19), and synaptotagmin (19), that facilitate insulin granule exocytosis.
Insulin is an anabolic peptide hormone that works at target tissues, namely muscle and hepatic tissue, via the insulin receptor to have mitogenic and glycogenic effects, respectively (4). The insulin receptor is a tyrosine kinase that phosphorylates insulin responsive substrates (IRS). IRS proteins are kinases that phosphorylate enzymes including phosphatidylinositol 3-kase to mediate much of the downstream biochemical cascade associated with insulin signaling.
How It Is Measured or Detected
There is no strict definition of hypoinsulinemia. For example, a serum measurement of <1.0 μU/mL has been reported as hypoinsulinemia (1). Adult human fasting serum insulin is typically in the range of 2 - 15 μIU/mL (13, 17).
Insulin can be sampled from blood, typically under fasting conditions, and measured in humans and research animals. More often, a dynamic measure of insulin secretion is more informative of pancreatic β-cell health with the most common being the glucose-stimulated insulin secretion test. Briefly, following the administration of a bolus of glucose, blood is collected in sequential intervals, typically 15-minutes, and insulin is measured.
In vivo: Insulin can be collected from blood plasma and measured via a commercially available enzyme-linked immunosorbent reaction (ELISA) kit. For example, blood is collected from the saphenous vein of mice via a capillary tube. Following centrifugation, plasma is collected and assayed via an ELISA as per manufacturer’s instructions. Briefly, the insulin protein binds to an antibody that is associated with a reporter enzyme. The concentration of insulin is estimated by calculating the activity of the reporter enzyme.
Ex Vivo/In vitro: Insulin can be collected from media and measured via a commercially available ELISA kit. For example, media from plates containing primary murine pancreatic islets exposed to a high concentration of glucose for 1 hour is collected and assayed via an ELISA as per manufacturer’s instructions.
Alternative measure: C-peptide, that is co-secreted with insulin, can also be collected and measured in vivo/vitro as outlined above (i.e., commercially available ELISA kit) as a surrogate measure of insulin secretion. This is a common method of assessing insulin secretion in humans and is often measured as part of a glucose tolerance test (12). Briefly, following the administration of a bolus of glucose, blood is collected in sequential intervals, typically every 30-minutes, and C-peptide is measured.
Domain of Applicability
Taxonomy: Insulin-secreting cells are found in vertebrates including mammals, fish, amphibians, reptiles, and birds (10). Functional insulin equivalent-secreting cells are found in invertebrates including insects, worms, snails, and molluscs (5, 10). Models of type 1 diabetes featuring impaired insulin secretion have been utilized in invertebrates (for example, see 8).
Life Stages: Insulin secretion is observed neonatally (3) and continues throughout life.
Sex Applicability: Insulin secretion occurs in both males and females (8).
Evidence for Perturbation by Stressor
1. Anno T, Kaneto H, Shigemoto R, Kawasaki F, Kawai Y, Urata N, Kawamoto H, Kaku K, Okimoto N. Hypoinsulinemic hypoglycemia triggered by liver injury in elderly subjects with low body weight: case reports. Endocrinol diabetes Metab case reports 2018: 17–155, 2018. doi: 10.1530/EDM-17-0155.
2. Ashcroft FM, Harrison DE, Ashcroft SJH. Glucose induces closure of single potassium channels in isolated rat pancreatic β-cells. Nature 312: 446–448, 1984. doi: 10.1038/312446a0.
3. Aynsley-Green A, Hawdon JM, Deshpande S, Platt MW, Lindley K, Lucas A. Neonatal insulin secretion: implications for the programming of metabolic homeostasis. Acta Paediatr Jpn Overseas Ed 39 Suppl 1: S21-5, 1997.
4. Coops K, White M. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2 [Online]. Diabetologia 55: 2565–2582, 2012. https://pubmed.ncbi.nlm.nih.gov/22869320/.
5. Falkmer S. Insulin production in vertebrates and invertebrates. Gen Comp Endocrinol 3: 184–191, 1972. doi: https://doi.org/10.1016/0016-6480(72)90147-5.
6. Fu Z, R. Gilbert E, Liu D. Regulation of Insulin Synthesis and Secretion and Pancreatic Beta-Cell Dysfunction in Diabetes. Curr Diabetes Rev 9: 25–53, 2012. doi: 10.2174/15733998130104.
7. Furman BL. Streptozotocin-Induced Diabetic Models in Mice and Rats. Curr Protoc 1: 1–21, 2021. doi: 10.1002/cpz1.78.
8. Gannon M, Kulkarni RN, Tse HM, Mauvais-Jarvis F. Sex differences underlying pancreatic islet biology and its dysfunction. Mol Metab 15: 82–91, 2018. doi: 10.1016/j.molmet.2018.05.017.
9. Graham P, Pick L. Drosophila as a Model for Diabetes and Diseases of Insulin Resistance. Curr Top Dev Biol 121: 397–419, 2017. doi: 10.1016/bs.ctdb.2016.07.011.
10. Heller SR. The Comparative Anatomy of Islets. Uppsala, Sweden: Springer, 2010.
11. In’t Veld P, Marichal M. Microscopic Anatomy of the Human Islet of Langerhans. In: The Islets of Langerhans. Uppsala, Sweden: Springer, 2010.
12. Leighton E, Sainsbury CA, Jones GC. A Practical Review of C-Peptide Testing in Diabetes. Diabetes Ther 8: 475–487, 2017. doi: 10.1007/s13300-017-0265-4.
13. Li S, Huang S, Mo Z-N, Gao Y, Yang X-B, Chen X-J, Zhao J-M, Qin X. Generating a reference interval for fasting serum insulin in healthy nondiabetic adult Chinese men. Singapore Med J 53: 821–825, 2012.
14. Meglasson M, Matschinsky F. Pancreatic Islet Glucose Metabolism and Regulation of Insulin Secretion. Diabetes Metab Res Rev 2: 163–214, 1986.
15. Slack JM. Developmental biology of the pancreas. Development 121: 1569–1580, 1995. doi: 10.1242/dev.121.6.1569.
16. Smith GD, Pangborn WA, Blessing RH. The structure of T6 human insulin at 1.0 A resolution. Acta Crystallogr D Biol Crystallogr 59: 474–482, 2003. doi: 10.1107/s0907444902023685.
17. Tohidi M, Ghasemi A, Hadaegh F, Derakhshan A, Chary A, Azizi F. Age- and sex-specific reference values for fasting serum insulin levels and insulin resistance/sensitivity indices in healthy Iranian adults: Tehran Lipid and Glucose Study. Clin Biochem 47: 432–438, 2014. doi: 10.1016/j.clinbiochem.2014.02.007.
18. Tokarz VL, MacDonald PE, Klip A. The cell biology of systemic insulin function. J Cell Biol 217: 2273–2289, 2018. doi: 10.1083/jcb.201802095.
19. Wiser O, Trus M, Hernández A, Renström E, Barg S, Rorsman P, Atlas D. The voltage sensitive Lc-type Ca2+ channel is functionally coupled to the exocytotic machinery. Proc Natl Acad Sci U S A 96: 248–253, 1999. doi: 10.1073/pnas.96.1.248.
20. Yang SN, Berggren PO. The role of voltage-gated calcium channels in pancreatic β-cell physiology and pathophysiology. Endocr Rev 27: 621–676, 2006. doi: 10.1210/er.2005-0888.
21. Yang SN, Larsson O, Bränström R, Bertorello AM, Leibiger B, Leibiger IB, Moede T, Köhler M, Meister B, Berggren PO. Syntaxin 1 interacts with the LD subtype of voltage-gated Ca2+ channels in pancreatic β cells. Proc Natl Acad Sci U S A 96: 10164–10169, 1999. doi: 10.1073/pnas.96.18.10164.