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Article ; Online: Glucose-induced insulin secretion in isolated human islets: Does it truly reflect β-cell function in vivo?

Henquin, Jean-Claude

2021 Volume 48, Page(s) 101212

Abstract: Background: Diabetes always involves variable degrees of β-cell demise and malfunction leading to insufficient insulin secretion. Besides clinical investigations, many research projects used rodent islets to study various facets of β-cell ... ...

Abstract	Background: Diabetes always involves variable degrees of β-cell demise and malfunction leading to insufficient insulin secretion. Besides clinical investigations, many research projects used rodent islets to study various facets of β-cell pathophysiology. Their important contributions laid the foundations of steadily increasing numbers of experimental studies resorting to isolated human islets. Scope of review: This review, based on an analysis of data published over 60 years of clinical investigations and results of more recent studies in isolated islets, addresses a question of translational nature. Does the information obtained in vitro with human islets fit with our knowledge of insulin secretion in man? The aims are not to discuss specificities of pathways controlling secretion but to compare qualitative and quantitative features of glucose-induced insulin secretion in isolated human islets and in living human subjects. Major conclusions: Much of the information gathered in vitro can reliably be translated to the in vivo situation. There is a fairly good, though not complete, qualitative and quantitative coherence between insulin secretion rates measured in vivo and in vitro during stimulation with physiological glucose concentrations, but the concordance fades out under extreme conditions. Perplexing discrepancies also exist between insulin secretion in subjects with Type 2 diabetes and their islets studied in vitro, in particular concerning the kinetics. Future projects should ascertain that the experimental conditions are close to physiological and do not alter the function of normal and diabetic islets.
MeSH term(s)	Adolescent ; Adult ; Age Factors ; Aged ; Aged, 80 and over ; Animals ; Body Mass Index ; Child ; Child, Preschool ; Diabetes Mellitus, Type 2/metabolism ; Female ; Glucose/metabolism ; Homeostasis ; Humans ; Infant ; Infant, Newborn ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/metabolism ; Male ; Middle Aged ; Sex Factors ; Young Adult
Chemical Substances	Insulin ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2021-03-15
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	2708735-9
ISSN	2212-8778 ; 2212-8778
ISSN (online)	2212-8778
ISSN	2212-8778
DOI	10.1016/j.molmet.2021.101212
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Article ; Online: Non-glucose modulators of insulin secretion in healthy humans: (dis)similarities between islet and in vivo studies.

Henquin, Jean-Claude

Metabolism: clinical and experimental

2021 Volume 122, Page(s) 154821

Abstract: Optimal metabolic homeostasis requires precise temporal and quantitative control of insulin secretion. Both in vivo and in vitro studies have often focused on the regulation by glucose although many additional factors including other nutrients, ... ...

Abstract	Optimal metabolic homeostasis requires precise temporal and quantitative control of insulin secretion. Both in vivo and in vitro studies have often focused on the regulation by glucose although many additional factors including other nutrients, neurotransmitters, hormones and drugs, modulate the secretory function of pancreatic β-cells. This review is based on the analysis of clinical investigations characterizing the effects of non-glucose modulators of insulin secretion in healthy subjects, and of experimental studies testing the same modulators in islets isolated from normal human donors. The aim was to determine whether the information gathered in vitro can reliably be translated to the in vivo situation. The comparison evidenced both convincing similarities and areas of discordance. The lack of coherence generally stems from the use of exceedingly high concentrations of test agents at too high or too low glucose concentrations in vitro, which casts doubts on the physiological relevance of a number of observations made in isolated islets. Future projects resorting to human islets should avoid extreme experimental conditions, such as oversized stimulations or inhibitions of β-cells, which are unlikely to throw light on normal insulin secretion and contribute to the elucidation of its defects.
MeSH term(s)	Glucagon/metabolism ; Glucose/metabolism ; Homeostasis/physiology ; Humans ; Insulin/metabolism ; Insulin Secretion/physiology ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/physiology
Chemical Substances	Insulin ; Glucagon (9007-92-5) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2021-06-24
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	80230-x
ISSN	1532-8600 ; 0026-0495
ISSN (online)	1532-8600
ISSN	0026-0495
DOI	10.1016/j.metabol.2021.154821
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Article ; Online: Paracrine and autocrine control of insulin secretion in human islets: evidence and pending questions.

Henquin, Jean-Claude

American journal of physiology. Endocrinology and metabolism

2020 Volume 320, Issue 1, Page(s) E78–E86

Abstract: Insulin secretion by β-cells is largely controlled by circulating nutrients, hormones, and neurotransmitters. However, recent years have witnessed the multiplication of studies investigating whether local regulation also takes place within pancreatic ... ...

Abstract	Insulin secretion by β-cells is largely controlled by circulating nutrients, hormones, and neurotransmitters. However, recent years have witnessed the multiplication of studies investigating whether local regulation also takes place within pancreatic islets, in which β-cells cohabit with several other cell types. The cell composition and architectural organization of human islets differ from those of rodent islets and are particularly favorable to cellular interactions. An impressive number of hormonal (glucagon, glucagon-like peptide-1, somatostatin, etc.) and nonhormonal products (ATP, acetylcholine, γ-aminobutyric acid, dopamine, etc.) are released by islet cells and have been implicated in a local control of insulin secretion. This review analyzes reports directly testing paracrine and autocrine control of insulin secretion in isolated human islets. Many of these studies were designed on background information collected in rodent islets. However, the perspective of the review is not to highlight species similarities or specificities but to contrast established and speculative mechanisms in human islets. It will be shown that the current evidence is convincing only for a minority of candidates for a paracrine function whereas arguments supporting a physiological role of others do not stand up to scrutiny. Several pending questions await further investigation.
MeSH term(s)	Autocrine Communication/drug effects ; Autocrine Communication/physiology ; Hormones/pharmacology ; Humans ; Insulin Secretion/drug effects ; Insulin Secretion/physiology ; Islets of Langerhans/drug effects ; Islets of Langerhans/metabolism ; Paracrine Communication/drug effects ; Paracrine Communication/physiology
Chemical Substances	Hormones
Language	English
Publishing date	2020-10-26
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	603841-4
ISSN	1522-1555 ; 0193-1849
ISSN (online)	1522-1555
ISSN	0193-1849
DOI	10.1152/ajpendo.00485.2020
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Article ; Online: Glucose-induced insulin secretion in isolated human islets

Jean-Claude Henquin

Molecular Metabolism, Vol 48, Iss , Pp 101212- (2021)

Does it truly reflect β-cell function in vivo?

2021

Abstract	Background: Diabetes always involves variable degrees of β-cell demise and malfunction leading to insufficient insulin secretion. Besides clinical investigations, many research projects used rodent islets to study various facets of β-cell pathophysiology. Their important contributions laid the foundations of steadily increasing numbers of experimental studies resorting to isolated human islets. Scope of review: This review, based on an analysis of data published over 60 years of clinical investigations and results of more recent studies in isolated islets, addresses a question of translational nature. Does the information obtained in vitro with human islets fit with our knowledge of insulin secretion in man? The aims are not to discuss specificities of pathways controlling secretion but to compare qualitative and quantitative features of glucose-induced insulin secretion in isolated human islets and in living human subjects. Major conclusions: Much of the information gathered in vitro can reliably be translated to the in vivo situation. There is a fairly good, though not complete, qualitative and quantitative coherence between insulin secretion rates measured in vivo and in vitro during stimulation with physiological glucose concentrations, but the concordance fades out under extreme conditions. Perplexing discrepancies also exist between insulin secretion in subjects with Type 2 diabetes and their islets studied in vitro, in particular concerning the kinetics. Future projects should ascertain that the experimental conditions are close to physiological and do not alter the function of normal and diabetic islets.
Keywords	Insulin secretion ; Human islets ; Diabetes ; β-cells ; Plasma insulin ; Glucose homeostasis ; Internal medicine ; RC31-1245
Subject code	571
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The challenge of correctly reporting hormones content and secretion in isolated human islets.

Henquin, Jean-Claude

Molecular metabolism

2019 Volume 30, Page(s) 230–239

Abstract: Background: An increased access of research laboratories to isolated human islets has improved our understanding of the biology of the endocrine pancreas and hence the mechanisms causing diabetes. However, in vitro studies of human islets remain ... ...

Abstract	Background: An increased access of research laboratories to isolated human islets has improved our understanding of the biology of the endocrine pancreas and hence the mechanisms causing diabetes. However, in vitro studies of human islets remain technically challenging, and optimal use of such precious material requires a minimum of rigor and coordination to optimize the reliability and share of the information. A detailed report of the demographics of pancreas donors and of the procedures of islet handling after isolation is important but insufficient. Correct characterization of islet basic functions (a token of quality) at the time of experimentation is also crucial. Scope of review: I have analyzed the literature reporting measurements of insulin and glucagon in the human pancreas or isolated human islets. The published information is often fragmentary. Elementary features such as islet size, insulin content, or rate of hormone secretion are either unreported or incorrectly reported in many papers. Although internal comparisons between control and test groups may remain valid, comparisons with data from other laboratories are problematic. The drawbacks, pitfalls and errors of common ways of expressing hormone content or secretion rates are discussed and alternatives to harmonize data presentation are proposed. Major conclusions: Greater coherence and rigor in the report of in vitro studies using human islets are necessary to ensure optimal progress in our understanding of the pathogenesis of diabetes.
MeSH term(s)	Diabetes Mellitus/metabolism ; Glucagon/analysis ; Glucagon/metabolism ; Glucose/metabolism ; Humans ; Insulin/analysis ; Insulin/metabolism ; Insulin Secretion ; Islets of Langerhans/metabolism ; Islets of Langerhans/physiology ; Pancreas/metabolism ; Reproducibility of Results ; Specimen Handling/methods
Chemical Substances	Insulin ; Glucagon (9007-92-5) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2019-10-16
Publishing country	Germany
Document type	Journal Article ; Review
ISSN	2212-8778
ISSN (online)	2212-8778
DOI	10.1016/j.molmet.2019.10.003
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Article ; Online: Influence of organ donor attributes and preparation characteristics on the dynamics of insulin secretion in isolated human islets.

Henquin, Jean-Claude

Physiological reports

2018 Volume 6, Issue 5

Abstract: In vitro studies of human pancreatic islets are critical for understanding normal insulin secretion and its perturbations in diabetic β-cells, but the influence of islet preparation characteristics and organ donor attributes in such experiments is poorly ...

Abstract	In vitro studies of human pancreatic islets are critical for understanding normal insulin secretion and its perturbations in diabetic β-cells, but the influence of islet preparation characteristics and organ donor attributes in such experiments is poorly documented. Preparations from normal donors were tested with a standardized protocol evaluating dynamic insulin secretion induced by glucose, tolbutamide, and cAMP (forskolin). Secretion rates, normalized to insulin content (fractional insulin secretion), were analyzed as a function of preparation and donor characteristics. Low purity (25-45%) of the preparation (n = 8) blunted the first phase of insulin secretion induced by glucose or tolbutamide and increased basal secretion, resulting in threefold lower stimulation index than in more pure (55-95%) preparations (n = 43). In these more pure preparations, cold ischemia time (1-13 h) before pancreas digestion did not impact insulin secretion. Islet size (estimated by the islet size index) did not influence the dynamics of secretion, but fractional insulin secretion rates were greater in large than small islets, and positively correlated with islet size. Age of the donors (20-68 years) had no influence on islet size and insulin content or on dynamics and amplitude of insulin secretion, which were also similar in islets from male and female donors. In contrast, islet size and islet insulin content (normalized for size), and basal or stimulated insulin secretion positively correlated with Body-Mass Index (19-33). These results contradict previous reports on the impact of donor age and islet size and point to possible confounding effects of donor BMI in insulin secretion studies with isolated human islets.
MeSH term(s)	Adult ; Age Factors ; Aged ; Cells, Cultured ; Colforsin/pharmacology ; Glucose/pharmacology ; Humans ; Insulin Secretion ; Insulin-Secreting Cells/cytology ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Middle Aged ; Tissue Donors ; Tissue and Organ Harvesting/standards ; Tolbutamide/pharmacology
Chemical Substances	Colforsin (1F7A44V6OU) ; Tolbutamide (982XCM1FOI) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2018-03-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2724325-4
ISSN	2051-817X ; 2051-817X
ISSN (online)	2051-817X
ISSN	2051-817X
DOI	10.14814/phy2.13646
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Article ; Online: Misunderstandings and controversies about the insulin-secreting properties of antidiabetic sulfonylureas.

Henquin, Jean-Claude

Biochimie

2017 Volume 143, Page(s) 3–9

Abstract: After 60 years of use in the treatment of type 2 diabetes, hypoglycemic sulfonylureas remain a recommended option in current therapeutic charts. Their binding to sulfonylurea receptor-1, the regulatory subunit of ATP-sensitive potassium channels in the ... ...

Abstract	After 60 years of use in the treatment of type 2 diabetes, hypoglycemic sulfonylureas remain a recommended option in current therapeutic charts. Their binding to sulfonylurea receptor-1, the regulatory subunit of ATP-sensitive potassium channels in the plasma membrane of pancreatic β-cells, leads to closure of the channels, membrane depolarization and influx of Ca
MeSH term(s)	Animals ; Calcium/metabolism ; Exocytosis/drug effects ; Glucose/metabolism ; Humans ; Hypoglycemic Agents/pharmacology ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Potassium Channel Blockers/pharmacology ; Sulfonylurea Compounds/pharmacology
Chemical Substances	Hypoglycemic Agents ; Insulin ; Potassium Channel Blockers ; Sulfonylurea Compounds ; Glucose (IY9XDZ35W2) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2017-07-12
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	120345-9
ISSN	1638-6183 ; 0300-9084
ISSN (online)	1638-6183
ISSN	0300-9084
DOI	10.1016/j.biochi.2017.07.002
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Article ; Online: The challenge of correctly reporting hormones content and secretion in isolated human islets

Jean-Claude Henquin

Molecular Metabolism, Vol 30, Iss , Pp 230-

2019 Volume 239

Abstract	Background: An increased access of research laboratories to isolated human islets has improved our understanding of the biology of the endocrine pancreas and hence the mechanisms causing diabetes. However, in vitro studies of human islets remain technically challenging, and optimal use of such precious material requires a minimum of rigor and coordination to optimize the reliability and share of the information. A detailed report of the demographics of pancreas donors and of the procedures of islet handling after isolation is important but insufficient. Correct characterization of islet basic functions (a token of quality) at the time of experimentation is also crucial. Scope of review: I have analyzed the literature reporting measurements of insulin and glucagon in the human pancreas or isolated human islets. The published information is often fragmentary. Elementary features such as islet size, insulin content, or rate of hormone secretion are either unreported or incorrectly reported in many papers. Although internal comparisons between control and test groups may remain valid, comparisons with data from other laboratories are problematic. The drawbacks, pitfalls and errors of common ways of expressing hormone content or secretion rates are discussed and alternatives to harmonize data presentation are proposed. Major Conclusions: Greater coherence and rigor in the report of in vitro studies using human islets are necessary to ensure optimal progress in our understanding of the pathogenesis of diabetes. Keywords: Isolated human islets, Insulin, Glucagon, Hormone content, Secretion, Diabetes
Keywords	Internal medicine ; RC31-1245
Subject code	306
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article: Misunderstandings and controversies about the insulin-secreting properties of antidiabetic sulfonylureas

Henquin, Jean-Claude

Biochimie. 2017,

2017

Abstract	After 60 years of use in the treatment of type 2 diabetes, hypoglycemic sulfonylureas remain a recommended option in current therapeutic charts. Their binding to sulfonylurea receptor-1, the regulatory subunit of ATP-sensitive potassium channels in the plasma membrane of pancreatic Î²-cells, leads to closure of the channels, membrane depolarization and influx of Ca2+ through voltage-gated calcium channels. The resulting increase in cytosolic Ca2+ triggers exocytosis of insulin granules. Sulfonylureas and glucose thus produce the same triggering signal but, unlike sulfonylureas, glucose does so via acceleration of Î²-cell metabolism. Glucose metabolism also produces amplifying signals that approximately double the secretory response to triggering Ca2+. One persistent misunderstanding about sulfonylureas is the alleged glucose-independence of their effects. It is correct that high concentrations of these drugs can induce insulin secretion in low glucose and cause hypoglycemic episodes in treated patients. Conversely, that untoward effect is erroneously considered as evidence that their therapeutic action is independent of glucose. Another evolving controversy about the action of sulfonylureas in Î²-cells is whether, like glucose, they also produce intracellular amplifying signals able to augment the efficacy of Ca2+ on exocytosis. The aims of this review are to dissipate the misunderstanding and discuss the controversy. Reasons why proposed amplifying effects of sulfonylureas are unlikely to be relevant for their action in vivo will be presented. Possible interactions of sulfonylureas and glucagon-like peptide-1 in Î²-cells will be discussed. Mechanisms whereby the ambient glucose concentration modulates the insulin-secreting action of therapeutic concentrations of sulfonylureas will be explained.
Keywords	calcium ; calcium channels ; drugs ; exocytosis ; glucagon-like peptide 1 ; glucose ; granules ; insulin ; insulin secretion ; islets of Langerhans ; metabolism ; noninsulin-dependent diabetes mellitus ; patients ; plasma membrane ; potassium channels ; sulfonylureas
Language	English
Size	p. .
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	120345-9
ISSN	0300-9084
ISSN	0300-9084
DOI	10.1016/j.biochi.2017.07.002
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Immaturity of insulin secretion by pancreatic islets isolated from one human neonate.

Henquin, Jean-Claude / Nenquin, Myriam

Journal of diabetes investigation

2017 Volume 9, Issue 2, Page(s) 270–273

Abstract: Human β-cells are functionally mature by the age of 1 year. The timeline and mechanisms of this maturation are unknown owing to the exceptional availability of testable tissue. Here, we report the first in vitro study of insulin secretion by islets from ... ...

Abstract	Human β-cells are functionally mature by the age of 1 year. The timeline and mechanisms of this maturation are unknown owing to the exceptional availability of testable tissue. Here, we report the first in vitro study of insulin secretion by islets from a 5-day-old newborn. Glucose was inefficient alone, but induced insulin secretion, which was concentration-dependent, showed a biphasic time-course and was of similar magnitude as in infant islets when β-cell cyclic adenosine monophosphate was raised by forskolin. Tolbutamide alone was effective in low glucose, but its effect was not augmented by high glucose. Metabolic amplification by glucose was thus inoperative, in contrast to amplification by cyclic adenosine monophosphate. Newborn islets showed high basal insulin secretion that could be inhibited by diazoxide or omission of CaCl
MeSH term(s)	Cell Separation ; Cells, Cultured ; Colforsin/pharmacology ; Female ; Glucose/pharmacology ; Humans ; In Vitro Techniques ; Infant, Newborn ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Islets of Langerhans/drug effects ; Islets of Langerhans/growth & development ; Islets of Langerhans/metabolism
Chemical Substances	Insulin ; Colforsin (1F7A44V6OU) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2017-07-17
Publishing country	Japan
Document type	Journal Article
ZDB-ID	2625840-7
ISSN	2040-1124 ; 2040-1116
ISSN (online)	2040-1124
ISSN	2040-1116
DOI	10.1111/jdi.12701
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