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Cited by 105Pancreatic function and diabetesDiabetes Treatment and ManagementDiabetes and associated disorders

Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

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Omar-Hmeadi, Muhmmad, Lund, Per-Eric, Gandasi, Nikhil R., Tengholm, Anders, Barg, Sebastian·2020·Nature Communications
DOI 10.1038/s41467-020-15717-8PMC PMC7171169

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Abstract

Glucagon is released from pancreatic α-cells to activate pathways that raise blood glucose. Its secretion is regulated by α-cell-intrinsic glucose sensing and paracrine control through insulin and somatostatin. To understand the inadequately high glucagon levels that contribute to hyperglycemia in type-2 diabetes (T2D), we analyzed granule behavior, exocytosis and membrane excitability in α-cells of 68 non-diabetic and 21 T2D human donors. We report that exocytosis is moderately reduced in α-cells of T2D donors, without changes in voltage-dependent ion currents or granule trafficking. Dispersed α-cells have a non-physiological V-shaped dose response to glucose, with maximal exocytosis at hyperglycemia. Within intact islets, hyperglycemia instead inhibits α-cell exocytosis, but not in T2D or when paracrine inhibition by insulin or somatostatin is blocked. Surface expression of somatostatin-receptor-2 is reduced in T2D, suggesting a mechanism for the observed somatostatin resistance. Thus, elevated glucagon in human T2D may reflect α-cell insensitivity to paracrine inhibition at hyperglycemia.

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  • Elevated plasma glucagon levels in T2DM reflect an altered insulin inhibition of alpha-cell glucagon exocytosis.

    “which have been shown to reflect an altered insulin inhibition of alpha-cell glucagon exocytosis (8)”

    From Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test (2021) · cites this paper as [8]

    The Results ('Rapid paracrine inhibition by insulin and somatostatin') show that insulin’s inhibition of α-cell exocytosis is lost in cells from T2D donors. The Abstract says elevated glucagon in human T2D *may* reflect impaired paracrine inhibition, and the Discussion implicates resistance to both insulin and somatostatin. The claim overstates this proposed explanation as established and attributes it to altered insulin inhibition alone. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Omar-Hmeadi, M., Lund, P.-E., Gandasi, N. R., Tengholm, A., & Barg, S.
Affiliations
Uppsala University (SE)
Corresponding author
Barg, Sebastian
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-04-20
Volume
11
Issue
1
Pages
1896-1896
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-15717-8
PMC
PMC7171169
OpenAlex
W3016802199
Cited by
105
References
11
Citations by year
2026: 13 · 2025: 21 · 2024: 12 · 2023: 26 · 2022: 10 · 2021: 17 · 2020: 6
FWCI
13.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • University of Alberta
  • European Foundation for the Study of Diabetes
  • Uppsala Universitet
  • Novo Nordisk Fonden (NNF17OC0027038, NNF14OC0010363, NNF15OC0016260, NNF20OC0064000, NNF18OC0034450, NNF14OC0010001, NNF17OC0027344)
  • East China Institute of Technology
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
glucagon, alpha cells, type 2 diabetes, exocytosis, paracrine regulation, insulin, somatostatin, somatostatin receptor 2, hyperglycemia, islets, membrane excitability, glucose detection, glucagon resistance
MeSH terms
Diabetes Mellitus, Type 2, Exocytosis, Glucagon, Glucose, Humans, Hyperglycemia, Insulin, Somatostatin, Receptors, Somatostatin, Glucagon-Secreting Cells, Optical Imaging

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