scholarly journals Evidence against a Rate-Limiting Role of Proinsulin Processing for Maximal Insulin Secretion in Subjects with Impaired Glucose Tolerance and β-Cell Dysfunction1

2001 ◽  
Vol 86 (3) ◽  
pp. 1235-1239 ◽  
Author(s):  
Michael Stumvoll ◽  
Andreas Fritsche ◽  
Norbert Stefan ◽  
Elke Hardt ◽  
Hans Häring
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Β Cell ◽  
Hyperglycemic Clamp ◽  
Maximal Stimulation ◽  
Proinsulin Processing ◽  
Normal Glucose ◽  
Glucagon Like Peptide 1 ◽  
Stimulation Of

In subjects with impaired glucose tolerance (IGT) insulin secretion is impaired. Increased proinsulin/insulin (PI/I) ratios suggest that there is also reduced processing of proinsulin to insulin in this condition. The PI/I ratio in the insulin secretory granule is ideally assessed by plasma measurements in response to acute stimulation of insulin secretion. In the present study we tested the hypothesis that maximal stimulation of insulin secretion results in exhaustion of the proinsulin conversion pathway to insulin. We therefore determined the PI/I ratio in 11 normal glucose-tolerant subjects (NGT) and 11 subjects with IGT in response to glucose (squarewave hyperglycemic clamp, 10 mmol/L), glucagon-like peptide-1 (GLP-1; primed-continuous infusion), and arginine given during the continued GLP-1 infusion. In IGT, insulin levels were significantly lower during the first phase (144 ± 20 vs. 397 ± 119 pmol/L; P = 0.02), at the end of the GLP infusion (2142 ± 350 vs. 5430 ± 1091 pmol/L; P = 0.002), and in response to arginine (3983± 375 vs. 8663 ± 1430 pmol/L; P = 0.005). In response to glucose, the minimum PI/I ratio was significantly higher in IGT (3.4 ± 0.6%) than in NGT (1.4 ± 0.5%; P = 0.02), suggesting defective proinsulin processing in this condition. In subjects with IGT, the PI/I ratio decreased significantly after GLP-1 priming (1.7 ± 0.2%; P = 0.02) and after arginine given during GLP-1 (1.4 ± 0.2%; P = 0.007) and was not significantly different from those values in NGT (1.3 ± 0.2% and 1.3 ± 0.2%, respectively; both P = NS). In conclusion, during maximal stimulation of insulin secretion in subjects with IGT, the PI/I ratio in plasma decreased significantly and was not different from that in normal controls. This strongly argues against the hypothesis that defective processing of proinsulin to insulin represents a major component of the β-cell dysfunction in IGT.

scholarly journals Metabolic Effects of Selective Deletion of Group VIA Phospholipase A2 from Macrophages or Pancreatic Islet Beta-Cells

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1455
Author(s):  
John Turk ◽  
Haowei Song ◽  
Mary Wohltmann ◽  
Cheryl Frankfater ◽  
Xiaoyong Lei ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Phospholipase A2 ◽  
Ex Vivo ◽  
Isolated Islets ◽  
Metabolic Effects ◽  
Β Cell ◽  
Cell Functions ◽  
Normal Glucose

To examine the role of group VIA phospholipase A2 (iPLA2β) in specific cell lineages in insulin secretion and insulin action, we prepared mice with a selective iPLA2β deficiency in cells of myelomonocytic lineage, including macrophages (MØ-iPLA2β-KO), or in insulin-secreting β-cells (β-Cell-iPLA2β-KO), respectively. MØ-iPLA2β-KO mice exhibited normal glucose tolerance when fed standard chow and better glucose tolerance than floxed-iPLA2β control mice after consuming a high-fat diet (HFD). MØ-iPLA2β-KO mice exhibited normal glucose-stimulated insulin secretion (GSIS) in vivo and from isolated islets ex vivo compared to controls. Male MØ-iPLA2β-KO mice exhibited enhanced insulin responsivity vs. controls after a prolonged HFD. In contrast, β-cell-iPLA2β-KO mice exhibited impaired glucose tolerance when fed standard chow, and glucose tolerance deteriorated further when introduced to a HFD. β-Cell-iPLA2β-KO mice exhibited impaired GSIS in vivo and from isolated islets ex vivo vs. controls. β-Cell-iPLA2β-KO mice also exhibited an enhanced insulin responsivity compared to controls. These findings suggest that MØ iPLA2β participates in HFD-induced deterioration in glucose tolerance and that this mainly reflects an effect on insulin responsivity rather than on insulin secretion. In contrast, β-cell iPLA2β plays a role in GSIS and also appears to confer some protection against deterioration in β-cell functions induced by a HFD.

Impact of incretin hormones on β-cell function in subjects with normal or impaired glucose tolerance

2006 ◽  
Vol 291 (6) ◽  
pp. E1144-E1150 ◽  
Author(s):  
Elza Muscelli ◽  
Andrea Mari ◽  
Andrea Natali ◽  
Brenno D. Astiarraga ◽  
Stefania Camastra ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Cell Function ◽  
Oral Glucose ◽  
Incretin Effect ◽  
Β Cell ◽  
Β Cell Function ◽  
Glucose Sensitivity ◽  
Cell Glucose

The mechanisms by which the enteroinsular axis influences β-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolution to calculate insulin secretion rates and mathematical modeling to quantitate β-cell function. The incretin effect was taken to be the ratio of oral to IV responses. In NGT, incretin-mediated insulin release [oral glucose tolerance test (OGTT)/IV ratio = 1.59 ± 0.18, P = 0.004] amounted to 18 ± 2 nmol/m2 (32 ± 4% of oral response), and its time course matched that of total insulin secretion. The β-cell glucose sensitivity (OGTT/IV ratio = 1.52 ± 0.26, P = 0.02), rate sensitivity (response to glucose rate of change, OGTT/IV ratio = 2.22 ± 0.37, P = 0.06), and glucose-independent potentiation were markedly higher with oral than IV glucose. In IGT, β-cell glucose sensitivity (75 ± 14 vs. 156 ± 28 pmol·min−1·m−2·mM−1 of NGT, P = 0.01) and potentiation were impaired on the OGTT. The incretin effect was not significantly different from NGT in terms of plasma glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of β-cell glucose sensitivity (OGTT/IV ratio = 1.73 ± 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered, with a predominance of glucose-induced vs. incretin-mediated stimulation. We conclude that, under physiological circumstances, incretin-mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of β-cell function, particularly β-cell glucose sensitivity. In IGT, β-cell function is inherently impaired, whereas the incretin effect is only partially affected.

scholarly journals Impaired fasting glucose with or without impaired glucose tolerance: progressive or parallel states of prediabetes?

2008 ◽  
Vol 295 (2) ◽  
pp. E428-E435 ◽  
Author(s):  
Leigh Perreault ◽  
Bryan C. Bergman ◽  
Mary C. Playdon ◽  
Chiara Dalla Man ◽  
Claudio Cobelli ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Impaired Fasting Glucose ◽  
Insulin Action ◽  
Low Dose ◽  
Fasting Glucose ◽  
Normal Glucose Tolerance ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Normal Glucose

Our objective was to determine whether defects underlying impaired fasting glucose (IFG) are maintained and additive when combined with impaired glucose tolerance (IGT) (representing a progressive form of prediabetes) or are distinct in IFG/IGT (reflecting a parallel form of prediabetes). Volunteers with IFG ( n = 10), IFG/IGT ( n = 14), or normal glucose tolerance (NGT; n = 15) were matched for demographics and anthropometry. Insulin secretion was assessed using the glucose step-up protocol and insulin action through the use of a two-stage hyperinsulinemic euglycemic clamp with infusion of [6,6-2H2]glucose. Modeling of insulin secretory parameters revealed similar basal (Φb) but diminished dynamic (Φd) components in both IFG and IFG/IGT ( P = 0.05 vs. NGT for both). Basal glucose rate of appearance (Ra) was higher in IFG compared with NGT ( P < 0.01) and also, surprisingly, with IFG/IGT ( P < 0.04). Moreover, glucose Ra suppressed more during the low-dose insulin clamp in IFG ( P < 0.01 vs. NGT, P = 0.08 vs. IFG/IGT). Insulin-stimulated glucose uptake [glucose rate of disappearance (Rd)] was similar in IFG, IFG/IGT, and NGT throughout the clamp. We conclude that nuances of β-cell dysfunction observed in IFG were also noted in IFG/IGT. A trend for additional insulin secretory defects was observed in IFG/IGT, possibly suggesting progression in β-cell failure in this group. In contrast, basal glucose Ra and its suppressability with insulin were higher in IFG, but not IFG/IGT, compared with NGT. Together, these data indicate that IFG/IGT may be a distinct prediabetic syndrome rather than progression from IFG.

scholarly journals Ghrelin Impairs Prandial Glucose Tolerance and Insulin Secretion in Healthy Humans Despite Increasing GLP-1

2016 ◽  
Vol 101 (6) ◽  
pp. 2405-2414 ◽  
Author(s):  
Jenny Tong ◽  
Harold W. Davis ◽  
Amalia Gastaldelli ◽  
David D'Alessio
Keyword(s):  
Insulin Secretion ◽  
Steady State ◽  
Glucose Tolerance ◽  
Healthy Subjects ◽  
Tolerance Test ◽  
Β Cell ◽  
Meal Tolerance Test ◽  
Healthy Humans ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Objectives: Administration of ghrelin inhibits the acute insulin response to glucose and worsens IV glucose tolerance in healthy subjects. Evidence from preclinical studies suggests that ghrelin may have differential effects on glucose metabolism during fasting and feeding. Our objective was to test the effects of ghrelin on glucose and insulin responses during a meal tolerance test. Design: Acyl ghrelin (0.26 and 2.0 μg/kg/h) or saline was infused in 13 healthy subjects on three separate occasions in randomized order. Ghrelin was infused for 45 minutes to achieve steady-state levels and continued for 240 minutes after ingestion of a liquid test meal. Primary outcomes were area under the curve for glucose and insulin secretion. Results: We found that ghrelin infusions of 0.26 and 2.0 μg/kg/h raised steady-state plasma total ghrelin levels to 1.7- and 4.8-fold above fasting concentrations, but did not alter fasting plasma glucose or insulin levels. During the meal tolerance test, ghrelin decreased insulin sensitivity, impaired β-cell function, and induced glucose intolerance. The high-dose ghrelin infusion also raised postprandial glucagon like peptide 1 secretion without affecting glucose dependent insulinotropic polypeptide, glucagon, or peptide YY concentrations. Conclusions: We conclude that both physiologic and pharmacologic doses of ghrelin worsen the glucose and β-cell responses to meal ingestion in healthy humans. The increase in postprandial glucagon like peptide 1 secretion by ghrelin suggests a novel enteroendocrine connection, but does not mitigate the glucose intolerance.

scholarly journals GLP-1 signaling is required for improvement of glucose tolerance by osteocalcin

2020 ◽  
Vol 244 (2) ◽  
pp. 285-296 ◽  
Author(s):  
Akiko Mizokami ◽  
Satoru Mukai ◽  
Jing Gao ◽  
Tomoyo Kawakubo-Yasukochi ◽  
Takahito Otani ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Serum Insulin ◽  
Fasting Blood Glucose ◽  
Metabolic Effects ◽  
Receptor Signaling ◽  
Β Cell ◽  
Putative Receptor ◽  
Adipocyte Hypertrophy ◽  
Glucagon Like Peptide 1

Osteocalcin is a bone-derived hormone that in its uncarboxylated form (GluOC) plays an important role in glucose and energy metabolism by stimulating insulin secretion and pancreatic β-cell proliferation through its putative receptor GPRC6A. We previously showed that the effect of GluOC on insulin secretion is mediated predominantly by glucagon-like peptide-1 (GLP-1) released from intestinal endocrine cells in response to GluOC stimulation. Moreover, oral administration of GluOC was found to reduce the fasting blood glucose level, to improve glucose tolerance, and to increase the fasting serum insulin concentration and β-cell area in the pancreas in wild-type mice. We have now examined the effects of oral GluOC administration for at least 4 weeks in GLP-1 receptor-knockout mice. Such administration of GluOC in the mutant mice triggered glucose intolerance, enhanced gluconeogenesis and promoted both lipid accumulation in the liver as well as adipocyte hypertrophy and inflammation in adipose tissue. Furthermore, inactivation of GLP-1 receptor signaling in association with GluOC administration induced activation of the transcription factor FoxO1 and expression of its transcriptional coactivator PGC1α in the liver, likely accounting for the observed upregulation of gluconeogenic gene expression. Our results thus indicate that the beneficial metabolic effects of GluOC are dependent on GLP-1 receptor signaling.

scholarly journals Determining pancreatic β-cell compensation for changing insulin sensitivity using an oral glucose tolerance test

2014 ◽  
Vol 307 (9) ◽  
pp. E822-E829 ◽  
Author(s):  
Thomas P. J. Solomon ◽  
Steven K. Malin ◽  
Kristian Karstoft ◽  
Sine H. Knudsen ◽  
Jacob M. Haus ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Oral Glucose ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
C Peptide ◽  
Normal Glucose

Plasma glucose, insulin, and C-peptide responses during an OGTT are informative for both research and clinical practice in type 2 diabetes. The aim of this study was to use such information to determine insulin sensitivity and insulin secretion so as to calculate an oral glucose disposition index (DIOGTT) that is a measure of pancreatic β-cell insulin secretory compensation for changing insulin sensitivity. We conducted an observational study of n = 187 subjects, representing the entire glucose tolerance continuum from normal glucose tolerance to type 2 diabetes. OGTT-derived insulin sensitivity (SI OGTT) was calculated using a novel multiple-regression model derived from insulin sensitivity measured by hyperinsulinemic euglycemic clamp as the independent variable. We also validated the novel SI OGTT in n = 40 subjects from an independent data set. Plasma C-peptide responses during OGTT were used to determine oral glucose-stimulated insulin secretion (GSISOGTT), and DIOGTT was calculated as the product of SI OGTT and GSISOGTT. Our novel SI OGTT showed high agreement with clamp-derived insulin sensitivity (typical error = +3.6%; r = 0.69, P < 0.0001) and that insulin sensitivity was lowest in subjects with impaired glucose tolerance and type 2 diabetes. GSISOGTT demonstrated a significant inverse relationship with SI OGTT. GSISOGTT was lowest in normal glucose-tolerant subjects and greatest in those with impaired glucose tolerance. DIOGTT was sequentially lower with advancing glucose intolerance. We hereby derive and validate a novel OGTT-derived measurement of insulin sensitivity across the entire glucose tolerance continuum and demonstrate that β-cell compensation for changing insulin sensitivity can be readily calculated from clinical variables collected during OGTT.

scholarly journals The role of incretins on insulin function and glucose homeostasis

Endocrinology ◽  
2021 ◽  
Author(s):  
Jens Juul Holst ◽  
Lærke Smidt Gasbjerg ◽  
Mette Marie Rosenkilde
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Postprandial Glucose ◽  
Normal Glucose Tolerance ◽  
Incretin Effect ◽  
Normal Glucose ◽  
Individual Contributions ◽  
Glucagon Like Peptide 1 ◽  
The Individual

Abstract The incretin effect – the amplification of insulin secretion after oral versus intravenous administration of glucose as a mean to improve glucose tolerance – was suspected even before insulin was discovered, and today we know that the effect is due to the secretion of two insulinotropic peptides, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). But how important is it? Physiological experiments have shown that, because of the incretin effect, we can ingest increasing amounts of amounts of glucose (carbohydrates) without increasing postprandial glucose excursions, which otherwise might have severe consequences. The mechanism behind this is incretin-stimulated insulin secretion. The availability of antagonists for GLP-1 and most recently also for GIP has made it possible to directly estimate the individual contributions to postprandial insulin secretion of a) glucose itself: 26%; b) GIP: 45%; and c) GLP-1: 29%. Thus, in healthy individuals, GIP is the champion. When the action of both incretins is prevented, glucose tolerance is pathologically impaired. Thus, after 100 years of research, we now know that insulinotropic hormones from the gut are indispensable for normal glucose tolerance. The loss of the incretin effect in type 2 diabetes, therefore, contributes greatly to the impaired postprandial glucose control.

scholarly journals β-Cell-specific ablation of sirtuin 4 does not affect nutrient-stimulated insulin secretion in mice

2020 ◽  
Vol 319 (4) ◽  
pp. E805-E813
Author(s):  
Frank K. Huynh ◽  
Brett S. Peterson ◽  
Kristin A. Anderson ◽  
Zhihong Lin ◽  
Aeowynn J. Coakley ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Whole Body ◽  
Β Cells ◽  
Β Cell ◽  
Direct Role ◽  
Normal Glucose

Sirtuins are a family of proteins that regulate biological processes such as cellular stress and aging by removing posttranslational modifications (PTMs). We recently identified several novel PTMs that can be removed by sirtuin 4 (SIRT4), which is found in mitochondria. We showed that mice with a global loss of SIRT4 [SIRT4-knockout (KO) mice] developed an increase in glucose- and leucine-stimulated insulin secretion, and this was followed by accelerated age-induced glucose intolerance and insulin resistance. Because whole body SIRT4-KO mice had alterations to nutrient-stimulated insulin secretion, we hypothesized that SIRT4 plays a direct role in regulating pancreatic β-cell function. Thus, we tested whether β-cell-specific ablation of SIRT4 would recapitulate the elevated insulin secretion seen in mice with a global loss of SIRT4. Tamoxifen-inducible β-cell-specific SIRT4-KO mice were generated, and their glucose tolerance and glucose- and leucine-stimulated insulin secretion were measured over time. These mice exhibited normal glucose- and leucine-stimulated insulin secretion and maintained normal glucose tolerance even as they aged. Furthermore, 832/13 β-cells with a CRISPR/Cas9n-mediated loss of SIRT4 did not show any alterations in nutrient-stimulated insulin secretion. Despite the fact that whole body SIRT4-KO mice demonstrated an age-induced increase in glucose- and leucine-stimulated insulin secretion, our current data indicate that the loss of SIRT4 specifically in pancreatic β-cells, both in vivo and in vitro, does not have a significant impact on nutrient-stimulated insulin secretion. These data suggest that SIRT4 controls nutrient-stimulated insulin secretion during aging by acting on tissues external to the β-cell, which warrants further study.

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