Dynamics of glucose-induced insulin secretion in normal human islets

2015 ◽  
Vol 309 (7) ◽  
pp. E640-E650 ◽  
Author(s):  
Jean-Claude Henquin ◽  
Denis Dufrane ◽  
Julie Kerr-Conte ◽  
Myriam Nenquin
Keyword(s):  
Insulin Secretion ◽  
Stimulation Index ◽  
Human Islets ◽  
Diabetic Patients ◽  
Second Phase ◽  
Biphasic Insulin ◽  
Biphasic Insulin Secretion ◽  
Normal Human ◽  
Second Phases

The biphasic pattern of glucose-induced insulin secretion is altered in type 2 diabetes. Impairment of the first phase is an early sign of β-cell dysfunction, but the underlying mechanisms are still unknown. Their identification through in vitro comparisons of islets from diabetic and control subjects requires characterization and quantification of the dynamics of insulin secretion by normal islets. When perifused normal human islets were stimulated with 15 mmol/l glucose (G15), the proinsulin/insulin ratio in secretory products rapidly and reversibly decreased (∼50%) and did not reaugment with time. Switching from prestimulatory G3 to G6–G30 induced biphasic insulin secretion with flat but sustained (2 h) second phases. Stimulation index reached 6.7- and 3.6-fold for the first and second phases induced by G10. Concentration dependency was similar for both phases, with half-maximal and maximal responses at G6.5 and G15, respectively. First-phase response to G15–G30 was diminished by short (30–60 min) prestimulation in G6 (vs. G3) and abolished by prestimulation in G8, whereas the second phase was unaffected. After 1–2 days of culture in G8 (instead of G5), islets were virtually unresponsive to G15. In both settings, a brief return to G3–G5 or transient omission of CaCl2 restored biphasic insulin secretion. Strikingly, tolbutamide and arginine evoked immediate insulin secretion in islets refractory to glucose. In conclusion, we quantitatively characterized the dynamics of glucose-induced insulin secretion in normal human islets and showed that slight elevation of prestimulatory glucose reversibly impairs the first phase, which supports the view that the similar impairment in type 2 diabetic patients might partially be a secondary phenomenon.

scholarly journals Assessment of the Metabolic Pathways Associated With Glucose-Stimulated Biphasic Insulin Secretion

Endocrinology ◽  
2014 ◽  
Vol 155 (5) ◽  
pp. 1653-1666 ◽  
Author(s):  
Mei Huang ◽  
Jamie W. Joseph
Keyword(s):  
Insulin Secretion ◽  
Time Course ◽  
Tricarboxylic Acid Cycle ◽  
Global Analysis ◽  
Tricarboxylic Acid ◽  
Second Phase ◽  
Data Set ◽  
Negatively Associated ◽  
Biphasic Insulin ◽  
Biphasic Insulin Secretion

Biphasic glucose-stimulated insulin secretion involves a rapid first phase followed by a prolonged second phase of insulin secretion. The biochemical pathways that control these 2 phases of insulin secretion are poorly defined. In this study, we used a gas chromatography mass spectroscopy-based metabolomics approach to perform a global analysis of cellular metabolism during biphasic insulin secretion. A time course metabolomic analysis of the clonal β-cell line 832/13 cells showed that glycolytic, tricarboxylic acid, pentose phosphate pathway, and several amino acids were strongly correlated to biphasic insulin secretion. Interestingly, first-phase insulin secretion was negatively associated with l-valine, trans-4-hydroxy-l-proline, trans-3-hydroxy-l-proline, dl-3-aminoisobutyric acid, l-glutamine, sarcosine, l-lysine, and thymine and positively with l-glutamic acid, flavin adenine dinucleotide, caprylic acid, uridine 5′-monophosphate, phosphoglycerate, myristic acid, capric acid, oleic acid, linoleic acid, and palmitoleic acid. Tricarboxylic acid cycle intermediates pyruvate, α-ketoglutarate, and succinate were positively associated with second-phase insulin secretion. Other metabolites such as myo-inositol, cholesterol, dl-3-aminobutyric acid, and l-norleucine were negatively associated metabolites with the second-phase of insulin secretion. These studies provide a detailed analysis of key metabolites that are either negatively or positively associated with biphasic insulin secretion. The insights provided by these data set create a framework for planning future studies in the assessment of the metabolic regulation of biphasic insulin secretion.

scholarly journals Calcium signaling and secretory granule pool dynamics underlie biphasic insulin secretion and its amplification by glucose: experiments and modeling

2019 ◽  
Vol 316 (3) ◽  
pp. E475-E486 ◽  
Author(s):  
Morten Gram Pedersen ◽  
Alessia Tagliavini ◽  
Jean-Claude Henquin
Keyword(s):  
Insulin Secretion ◽  
Glucose Concentration ◽  
Calcium Influx ◽  
Secretory Granules ◽  
Cytosolic Calcium ◽  
Second Phase ◽  
Calcium Dynamics ◽  
Β Cells ◽  
Biphasic Insulin ◽  
Biphasic Insulin Secretion

Glucose-stimulated insulin secretion from pancreatic β-cells is controlled by a triggering pathway that culminates in calcium influx and regulated exocytosis of secretory granules, and by a less understood amplifying pathway that augments calcium-induced exocytosis. In response to an abrupt increase in glucose concentration, insulin secretion exhibits a first peak followed by a lower sustained second phase. This biphasic secretion pattern is disturbed in diabetes. It has been attributed to depletion and subsequent refilling of a readily releasable pool of granules or to the phasic cytosolic calcium dynamics induced by glucose. Here, we apply mathematical modeling to experimental data from mouse islets to investigate how calcium and granule pool dynamics interact to control dynamic insulin secretion. Experimental calcium traces are used as inputs in three increasingly complex models of pool dynamics, which are fitted to insulin secretory patterns obtained using a set of protocols of glucose and tolbutamide stimulation. New calcium and secretion data for so-called staircase protocols, in which the glucose concentration is progressively increased, are presented. These data can be reproduced without assuming any heterogeneity in the model, in contrast to previous modeling, because of nontrivial calcium dynamics. We find that amplification by glucose can be explained by increased mobilization and priming of granules. Overall, our results indicate that calcium dynamics contribute substantially to shaping insulin secretion kinetics, which implies that better insight into the events creating phasic calcium changes in human β-cells is needed to understand the cellular mechanisms that disturb biphasic insulin secretion in diabetes.

The Cell Physiology of Biphasic Insulin Secretion

Physiology ◽  
2000 ◽  
Vol 15 (2) ◽  
pp. 72-77 ◽  
Author(s):  
Patrik Rorsman ◽  
Lena Eliasson ◽  
Erik Renström ◽  
Jesper Gromada ◽  
Sebastian Barg ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Secretory Granules ◽  
Diabetes Type ◽  
Cell Physiology ◽  
Second Phase ◽  
Type Ii ◽  
Diabetes Type Ii ◽  
Biphasic Insulin ◽  
Biphasic Insulin Secretion ◽  
Glucose Stimulated Insulin Secretion

Glucose-stimulated insulin secretion consists of a transient first phase followed by a sustained second phase. Diabetes (type II) is associated with abnormalities in this release pattern. Here we review the evidence that biphasic insulin secretion reflects exocytosis of two functional subsets of secretory granules and the implications for diabetes.

Use of diphenylhydantoin and diazoxide to investigate insulin secretory mechanisms

1975 ◽  
Vol 229 (1) ◽  
pp. 49-54 ◽  
Author(s):  
SR Levin ◽  
MA Charles ◽  
M O'connor ◽  
GM Grodsky
Keyword(s):  
Insulin Secretion ◽  
Computer Analysis ◽  
Early Response ◽  
Proximal Portion ◽  
Second Phase ◽  
Perfused Rat Pancreas ◽  
Rat Pancreas ◽  
Early Release ◽  
Biphasic Insulin ◽  
Biphasic Insulin Secretion

In the isolated, perfused rat pancreas, we contrasted effects of diphenylhydantoin (DPH) and diazoxide on glucose-induced biphasic insulin secretion. Either drug partially inhibited the first phase. However, DPH completely inhibited the second phase, whereas diazoxide produced inhibition, then escape and post-inhibitory overshoot. Exposure to DPH prior to glucose further inhibited the first phase, and increasing the dose had no additional effects, whereas only raising the diazoxide dose intensified inhibition of early release. DPH sequentially suppressed early response to a series of two, short, glucose pulses. In contrast, no additional effects of diazoxide were noted after its initial inhibition of the first pulse. A computer analysis was programmed from hypotheses based on these experiments. It suggests that DPH inhibits release from a labile compartment and provision of insulin to that compartment, whereas diazoxide divides the labile compartment into two sequential subcompartments. Further, the computer analysis indicates that, with diazoxide, insulin (or substances on which secretion depends) accumulates not at the final release step but at a proximal portion of the labile compartment.

Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes

2007 ◽  
Vol 292 (6) ◽  
pp. E1775-E1781 ◽  
Author(s):  
Kenneth Cusi ◽  
Sangeeta Kashyap ◽  
Amalia Gastaldelli ◽  
Mandeep Bajaj ◽  
Eugenio Cersosimo
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Family History ◽  
Second Phase ◽  
Β Cell ◽  
C Peptide ◽  
Hyperglycemic Clamp ◽  
History Of ◽  
Plasma Ffa

Elevated plasma FFA cause β-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% ( P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or ΔC-peptide/Δglucose AUC (+177%, P = 0.02), an index of improved β-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 ± 5% ( P < 0.04). First- (+19 ± 6%, P = 0.1) and second-phase (+31 ± 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 ± 7 ( P < 0.05) and 41 ± 8% ( P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR ( r2 = 0.31, P < 0.02) and acute (2–4 min) glucose-induced insulin release after acipimox ( r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.

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