Glucose-Dependent Granule Docking Limits Insulin Secretion and Is Decreased in Human Type 2 Diabetes

Gandasi, Nikhil RUppsala University,Uppsala universitet,Institutionen för medicinsk cellbiologi (author)

Glucose-stimulated insulin secretion is biphasic, with a rapid first phase and a slowly developing sustained second phase; both are disturbed in type 2 diabetes (T2D). Biphasic secretion results from vastly different release probabilities of individual insulin granules, but the morphological and molecular basis for this is unclear. Here, we show that human insulin secretion and exocytosis critically depend on the availability of membrane-docked granules and that T2D is associated with a strong reduction in granule docking. Glucose accelerated granule docking, and this effect was absent in T2D. Newly docked granules only slowly acquired release competence; this was regulated by major signaling pathways, but not glucose. Gene expression analysis indicated that key proteins involved in granule docking are downregulated in T2D, and overexpression of these proteins increased granule docking. The findings establish granule docking as an important glucose-dependent step in human insulin secretion that is dysregulated in T2D.

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Endokrinologi och diabetes hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Endocrinology and Diabetes hsv//eng
GLP-1
biphasic secretion
dense core vesicle
docking
exocytosis
genome-wide association
insulin secretion
priming
somatostatin
type 2 diabetes
biphasic secretion
dense core vesicle
docking
exocytosis
genome-wide association
GLP-1
insulin secretion
priming
somatostatin
type 2 diabetes

Yin, Peng,1982-Uppsala University,Uppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)yinyi639 (author)
Omar-Hmeadi, MuhmmadUppsala University,Uppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:uu)muhhm810 (author)
Ottosson Laakso, EmiliaLund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups(Swepub:lu)med-eo_ (author)
Vikman, PetterLund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups(Swepub:lu)wbl-pwi (author)
Barg, Sebastian,1969-Uppsala University,Uppsala universitet,Institutionen för medicinsk cellbiologi(Swepub:lu)mphy-sba (author)
Uppsala universitetInstitutionen för medicinsk cellbiologi (creator_code:org_t)

By the author/editor: Gandasi, Nikhil ...; Yin, Peng, 1982-; Omar-Hmeadi, Muh ...; Ottosson Laakso, ...; Vikman, Petter; Barg, Sebastian, ...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Endocrinology an ...

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