Increased Insulin Secretion and Glucose Tolerance in Mice Lacking Islet Amyloid Polypeptide (Amylin)
Abstract
Islet amyloid polypeptide (IAPP or amylin) is costored and cosecreted with insulin and may regulate insulin secretion and blood glucose handling. However, the role and importance of endogenous IAPP in the regulation of insulin release and glucose homeostasis have been controversial. Here we report on the generation and phenotypic analysis of IAPP-deficient mice. These mice have normal, or near to normal, basal levels of circulating insulin and glucose. However, following glucose administration, IAPP-deficient males presented increased insulin responses paralleled with a more rapid blood glucose elimination compared to wild-type controls. Blood glucose elimination was also found to be enhanced in IAPP-deficient females, but the insulin response in this gender did not differ from controls. In a transgenic rescue experiment, using an insulin-promoter human-IAPP fusion gene, insulin responses and blood glucose elimination were reversed in IAPP-deficient males, whereas the female phenotype appeared unaffected. Our results provide the first firm evidence of a physiological role for endogenous IAPP and indicate that IAPP, apparently in a gender-dependent manner, limits the degree of glucose-induced insulin secretion and the rate of blood glucose elimination.
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IAPP-deficient male mice exhibit increased GIIS and improved glucose tolerance.
“IAPP-deficient male mice exhibit increased GIIS and improved glucose tolerance (201), suggesting that IAPP may be involved in feedback control of insulin secretion.”
From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [201]
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“logical roles have been attributed to IAPP since its identification in 1987 [34, 35], it remains a peptide without a clearly identified function in vivo [36]; moderately improved glucose intolerance was detected in the IAPP knock-out mouse [37, 38] and Type 1 diabetic subjects do not have pathophysiological features w…”
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“These modest findings with respect to energy balance are perhaps not surprising given that deletion of the amylin gene in mice had either very modest and transient [17] to no effect on body weight [18].”
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“Nevertheless, an inhibitoryactionof endogenous IAPPon insulin secretion is supported by the observation that insulin secretion is increased in IAPP-deficient mice (26) and after acute treatments with IAPP antagonists in vitro (27) and in vivo (28).”
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“mice display a similar enhancement of glucose disposal to that in male IAPP2/2 mice (9) but lack the exaggerated glucose-stimulated insulin response; this suggests that the lack of IAPP in these mice confers an enhanced sensitivity to insulin.”
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“While average food consumption does not differ compared to wild-type controls, IAPP−/− mice develop significantly increased body weight from the age of 18 weeks (13).”
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“Conversely, the reverse is observed in IAPP knockout mice [142], suggesting that, in addition to exerting an anti-amyloidogenic effect, inhibiting the production of IAPP may improve glycaemic control through the inhibition of the potentially diabetogenic metabolic effects of the polypeptide.”
BackgroundHigh Plasma Levels of Islet Amyloid Polypeptide in Young with New-Onset of Type 1 Diabetes Mellitus
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“Increased insulin secretion in IAPP deficient mice in response to an oral glucose load supports an intra-islet function [10].”
Self-citationFamily with sequence similarity 3 gene family and nonalcoholic fatty liver disease
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“In addition, female –/– mice showed up to a 10% increase in body weight by 15 weeks of age (174,175).”
BackgroundDisentangling the Amyloid Pathways: A Mechanistic Approach to Etiology
Malmberg, M., Malm, T., Gustafsson, O., Sturchio, A., Graff, C., Espay, A. J., Wright, A. P. H., Andaloussi, S. E., Lindén, A., & Ezzat, K. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00256 · Cited by 30 · see citing works
Lutz, T. A., Tschudy, S., Rushing, P. A., & Scharrer, E. (2000) · Physiology and Behavior · doi:10.1016/s0031-9384(00)00302-4 · Cited by 26 · see citing works
Effects of Amylin Deficiency on Trabecular Bone in Young Mice Are Sex-Dependent
Davey, R. A., Moore, A. J., Chiu, M. W. S., Notini, A. J., Morris, H. A., & Zajac, J. D. (2006) · Calcified Tissue International · doi:10.1007/s00223-005-0286-2 · Cited by 25 · see citing works
“This study demonstrates that the effects of amylin deficiency on bone in this genetically modified animal model [13] are sex-dependent.”
BackgroundMethodInfluentialZhu, H.-H., Tao, Q.-S., Ang, T. F. A., Massaro, J., Gan, Q., Salim, S., Zhu, R., Kolachalama, V. B., Zhang, X., Devine, S., et al. (2019) · JAMA Network Open · doi:10.1001/jamanetworkopen.2019.9826 · Cited by 24 · see citing works
Is Glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer’s disease?
Li, L. (2007) · Neuroscience Bulletin · doi:10.1007/s12264-007-0009-y · Cited by 24 · see citing works
“[59] Gebre-Medhin S, Mulder H, Pekny M, Westermark G, Tornell J, Westermark P, et al.”
BackgroundInhibition of insulin secretion.
Young, A. (2005) · Advances in Pharmacology · doi:10.1016/s1054-3589(05)52009-x · Cited by 24 · see citing works
Christoffersson, G., Waldén, T. B., Sandberg, M., Opdenakker, G., Carlsson, P., & Phillipson, M. (2015) · American Journal of Pathology · doi:10.1016/j.ajpath.2014.12.009 · Cited by 23 · see citing works
Mulder, H., Mårtensson, H., Sundler, F., & Åhrén, B. (2000) · Metabolism · doi:10.1053/meta.2000.18511 · Cited by 22 · see citing works
Self-citationQiu, W. Q. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.05.024 · Cited by 25 · see citing works
“Amylin receptor (AmR) is one type of GPCR and is composed of the calcitonin receptor (CTR) complexed with different receptor-activity-modifying proteins (RAMPs) (Gebre-Medhin et al., 1998; Hay et al., 2015).”
How and Why Do Gastrointestinal Peptides Influence Food Intake?
Woods, S. C., May-Zhang, A. A., & Begg, D. (2018) · Physiology and Behavior · doi:10.1016/j.physbeh.2018.02.048 · Cited by 21 · see citing works
Jeha, G. S., & Heptulla, R. A. (2006) · Pediatric Diabetes · doi:10.1111/j.1399-543x.2006.00159.x · Cited by 22 · see citing works
“to glucose as well as increased insulin sensitivity (192).”
BackgroundConsidering our methods: Methodological issues with rodent models of appetite and obesity research
Lutz, T. A. (2018) · Physiology & Behavior · doi:10.1016/j.physbeh.2018.02.026 · Cited by 19 · see citing works
Mulder, H., Jongsma, H., Zhang, Y.-Z., Gebre-Medhin, S., Sundler, F., & Danielsen, N. (1999) · Molecular Neurobiology · doi:10.1007/bf02821715 · Cited by 16 · see citing works
Self-citationGong, G.-H., Du, W., Xu, J.-F., Huang, X.-Y., & Yin, G.-W. (2018) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2018.08.012 · Cited by 15
Wookey, P., Xuereb, L., Tikellis, C., & Cooper, M. (2003) · TheScientificWorldJournal · doi:10.1100/tsw.2003.17 · Cited by 14 · see citing works
“The physiological consequences of this anatomical abnormality are as yet unclear but it should be noted that these AGD mice clear glucose at a faster rate compared to WT[84,87], which may be related to renal functions in these mice.”
BackgroundHiddinga, H., Sakagashira, S., Ishigame, M., Madde, P., Sanke, T., Nanjo, K., Kudva, Y., Lee, J., van Deursen, J., & Eberhardt, N. (2011) · Journal of Diabetes Investigation · doi:10.1111/j.2040-1124.2011.00166.x · Cited by 13 · see citing works
“insulinostatic actions relative to wild-type hIAPP.(37,38) All mice compensated equally to the high fat diet by increasing their b cell mass approximately 3-fold.”
BackgroundCommonality Between Diabetes and Alzheimer’s Disease and A New Strategy for the Therapy
Li, L. (2008) · Clinical medicine Pathology · doi:10.4137/cpath.s667 · Cited by 13 · see citing works
“Conversely, targeted disruption of IAPP leads to enhanced insulin secretion and improved glucose tolerance[23].”
Onodera, T., Kim, D.-S., Ye, R., Wang, M.-Y., Chen, S., Field, B. C., Straub, L. G., Sun, X., Li, C., Lee, C., et al. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2023.101821 · Cited by 14 · see citing works
“Nonetheless, given that IAPP de fi cient mice show increased insulin responses [47], an increase of IAPP in adiponectin KO mice can un-questionably exert a negative effect on insulin secretion.”
BackgroundLiu, M., Hoskins, A., Verma, N., Bers, D. M., Despa, S. I., & Despa, F. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.10.024 · Cited by 15 · see citing works
“Conversely, amylin gene deletion improved glucose tolerance in mice [17] suggesting that amylin plays a role in energy homeostasis.”
InfluentialDifferential effects of Calca-derived peptides in male mice with diet-induced obesity
Bartelt, A., Jeschke, A., Müller, B., Gaziano, I., Morales, M., Yorgan, T. A., Heckt, T., Heine, M., Gagel, R. F., Emeson, R. B., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0180547 · Cited by 14 · see citing works
Gut-Brain Endocrine Axes in Weight Regulation and Obesity Pharmacotherapy
Merlino, D. J., Blomain, E. S., Aing, A., & Waldman, S. A. (2014) · Journal of Clinical Medicine · doi:10.3390/jcm3030763 · Cited by 11 · see citing works
“attributed to other mechanisms in the regulation of food intake that compensate for the absence of amylin [151].”
Food intake and meal pattern in IAPP knockout mice with and without infusion of exogenous IAPP
Olsson, M., Herrington, M., Reidelberger, R., Permert, J., Gebre-Medhin, S., & Arnelo, U. (2012) · Scandinavian Journal of Gastroenterology · doi:10.3109/00365521.2011.638392 · Cited by 12 · see citing works
“The IAPP KO mouse strain used in this study was generated by homologous recombination as previously described [25].”
BackgroundMethodSelf-citationMapping of a hybrid insulin peptide in the inflamed islet β-cells from NOD mice
Wenzlau, J. M., Peterson, O. J., Vomund, A. N., DiLisio, J. E., Hohenstein, A. C., Haskins, K., & Wan, X.-X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1348131 · Cited by 10
- Authors
- Gebre-Medhin, S., Mulder, H., Pekny, M., Westermark, G., Törnell, J., Westermark, P., Sundler, F., Ahrén, B., & Betsholtz, C.
- Affiliations
- Lund University (SE)
- University of Gothenburg (SE)
- Linköping University (SE)
- Venue
- Biochemical and Biophysical Research Communications
- Publisher
- Elsevier BV
- Published
- 1998-09
- Volume
- 250
- Issue
- 2
- Pages
- 271-277
- ISSN
- 0006-291X (ISSN-L)
- OpenAlex
- W1986688294
- Cited by
- 157
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 10 · 2015: 6 · 2014: 7 · 2013: 9 · 2012: 5
- FWCI
- 7.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical and Biophysical Research Communications (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Göteborgs Läkaresällskap
- Medicinska Forskningsrådet (14x-6834, 5941)
- Trygg-Hansas Forskningsstiftelse
- Novo Nordisk Fonden
- Göran Gustafssons Stiftelse för Naturvetenskaplig och Medicinsk Forskning
- Crafoordska Stiftelsen
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- amylin, insulin secretion, glucose tolerance, glucose homeostasis, sex differences, transgenic rescue
- MeSH terms
- Insulin Secretion, Amyloid, Animals, Blood Glucose, Female, Glucose Tolerance Test, Humans, Insulin, Male, Sex Factors, Gene Deletion, Mice, Rats, Islet Amyloid Polypeptide
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