Loss of tetraspanin‐7 expression reduces pancreatic β‐cell exocytosis Ca²⁺ sensitivity but has limited effect on systemic metabolism

Abstract

Background Tetraspanin‐7 (Tspan7) is an islet autoantigen involved in autoimmune type 1 diabetes and known to regulate β‐cell L‐type Ca2+ channel activity. However, the role of Tspan7 in pancreatic β‐cell function is not yet fully understood. Methods Histological analyses were conducted using immunostaining. Whole‐body metabolism was tested using glucose tolerance test. Islet hormone secretion was quantified using static batch incubation or dynamic perifusion. β‐cell transmembrane currents, electrical activity and exocytosis were measured using whole‐cell patch‐clamping and capacitance measurements. Gene expression was studied using mRNA‐sequencing and quantitative PCR. Results Tspan7 is expressed in insulin‐containing granules of pancreatic β‐cells and glucagon‐producing α‐cells. Tspan7 knockout mice (Tspan7y/− mouse) exhibit reduced body weight and ad libitum plasma glucose but normal glucose tolerance. Tspan7y/− islets have normal insulin content and glucose‐ or tolbutamide‐stimulated insulin secretion. Depolarisation‐triggered Ca2+ current was enhanced in Tspan7y/− β‐cells, but β‐cell electrical activity and depolarisation‐evoked exocytosis were unchanged suggesting that exocytosis was less sensitive to Ca2+. TSPAN7 knockdown (KD) in human pseudo‐islets led to a significant reduction in insulin secretion stimulated by 20 mM K+. Transcriptomic analyses show that TSPAN7 KD in human pseudo‐islets correlated with changes in genes involved in hormone secretion, apoptosis and ER stress. Consistent with rodent β‐cells, exocytotic Ca2+ sensitivity was reduced in a human β‐cell line (EndoC‐βH1) following Tspan7 KD. Conclusion Tspan7 is involved in the regulation of Ca2+‐dependent exocytosis in β‐cells. Its function is more significant in human β‐cells than their rodent counterparts.

Characterization of metabolic phenotypes and distinctive genes in mice with low‐weight gain

“…37 Thus, the role of Tspan7 has been reported primarily in relation to its function in the brain, however, its function in metabolism has also been suggested recently. [38][39][40][41][42] TSPAN7 regulates insulin secretion levels by defining a set-point for glucose-stimulated insulin secretion, 39 and TSPAN7 is a target of autoantibodies in type 1 diabetes. [40][41][42] Thus, Tspan7 is involved in metabolic disorders such and diabetes.…”

“…Mutations in Tspan7 have been associated with X‐linked intellectual disability, 36 and Tspan7 has been implicated in the development of the nervous system and synaptic function 37 . Thus, the role of Tspan7 has been reported primarily in relation to its function in the brain, however, its function in metabolism has also been suggested recently 38–42 . TSPAN7 regulates insulin secretion levels by defining a set‐point for glucose‐stimulated insulin secretion, 39 and TSPAN7 is a target of autoantibodies in type 1 diabetes 40–42 .…”

New insights into the role of tetraspanin 6, 7, and 8 in physiology and pathology

“…Tetraspanin 8 (also known as CO-029/TM4SF3) is mainly found in the gastrointestinal tract, particularly in the epithelium of the colon and stomach. 36 It has been shown to be overexpressed in human glioma cells. In addition, tetraspanin 8 is present in vascular smooth muscle cells and tubular cells in normal kidney.…”

Stellar science: Basic science has lift off!

“…Rory McCrimmon, 9 this year's Dorothy Hodgkin Lecture recipient, has written an engaging overview of his prize lecture in which he has provided mechanistic insights into recurrent hypoglycaemia in diabetes. We are confident that the articles in this special issue, which are a mixture of primary research, 1–5,7 and state of the art reviews, 6,8,9 are accessible to non‐specialists and will be enjoyed by a wide readership.…”

“…The most outstanding basic science diabetes researchers in the UK are awarded five‐year RD Lawrence Fellowships after competitive interview. Three of the current RD Lawrence Fellows (Benoit Hastoy and Quan Zhang 7 and Hanieh Yaghootkar 8 ) contributed articles that emphasise their expertise in the regulation of beta‐cell exocytosis 7 and genetic studies of vascular complications of diabetes 8 . The Diabetes UK Dorothy Hodgkin Lecture is awarded annually to internationally recognised basic science researchers in recognition of Hodgkin's achievement in determining the crystal structure of insulin.…”