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

2001 ◽  
Vol 86 (3) ◽  
pp. 1235-1239 ◽  
Author(s):  
M. Stumvoll
Keyword(s):  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Cell Dysfunction ◽  
Proinsulin Processing ◽  
Rate Limiting

scholarly journals Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice

2020 ◽  
Author(s):  
Marie-Sophie Nguyen-Tu ◽  
Aida Martinez-Sanchez ◽  
Isabelle Leclerc ◽  
Guy A. Rutter ◽  
Gabriela da Silva Xavier
Keyword(s):  
Insulin Secretion ◽  
Lipid Metabolism ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Glucose Homeostasis ◽  
Knockout Mice ◽  
Male Mice ◽  
Glucose Stimulated Insulin Secretion

AbstractTranscription factor 7-like 2 (TCF7L2) is a downstream effector of the Wnt/beta-catenin signalling pathway and its expression is critical for adipocyte development. The precise role of TCF7L2 in glucose and lipid metabolism in adult adipocytes remains to be defined. Here, we aim to investigate how changes in TCF7L2 expression in mature adipocytes affect glucose homeostasis. Tcf7l2 was selectively ablated from mature adipocytes in C57BL/6J mice using an adiponectin promoter-driven Cre recombinase to recombine alleles floxed at exon 1 of the Tcf7l2 gene. Mice lacking Tcf7l2 in mature adipocytes displayed normal body weight. Male mice exhibited normal glucose homeostasis at eight weeks of age. Male heterozygote knockout mice (aTCF7L2het) exhibited impaired glucose tolerance (AUC increased 1.14 ± 0.04 -fold, p=0.03), as assessed by intraperitoneal glucose tolerance test, and changes in fat mass at 16 weeks (increased by 1.4 ± 0.09-fold, p=0.007). Homozygote knockout mice exhibited impaired oral glucose tolerance at 16 weeks of age (AUC increased 2.15 ± 0.15-fold, p=0.0001). Islets of Langerhans exhibited impaired glucose-stimulated insulin secretion in vitro (decreased 0.54 ± 0.13-fold aTCF7L2KO vs control, p=0.02), but no changes in in vivo glucose-stimulated insulin secretion. Female mice in which one or two alleles of the Tcf7l2 gene was knocked out in adipocytes displayed no changes in glucose tolerance, insulin sensitivity or insulin secretion. Plasma levels of glucagon-like peptide-1 and gastric inhibitory polypeptide were lowered in knockout mice (decreased 0.57 ± 0.03-fold and 0.41 ± 0.12-fold, p=0.04 and p=0.002, respectively), whilst plasma free fatty acids and Fatty Acid Binding Protein 4 circulating levels were increased by 1.27 ± 0.07 and 1.78 ± 0.32-fold, respectively (p=0.05 and p=0.03). Mice with biallelic Tcf7l2 deletion exposed to high fat diet for 9 weeks exhibited impaired glucose tolerance (p=0.003 at 15 min after glucose injection) which was associated with reduced in vivo glucose-stimulated insulin secretion (decreased 0.51 ± 0.03-fold, p=0.02). Thus, our data indicate that loss of Tcf7l2 gene expression in adipocytes leads to impairments on metabolic responses which are dependent on gender, age and nutritional status. Our findings further illuminate the role of TCF7L2 in the maintenance of glucose homeostasis.

scholarly journals Role of the Transcription Factor Sox4 in Insulin Secretion and Impaired Glucose Tolerance

Diabetes ◽  
2008 ◽  
Vol 57 (8) ◽  
pp. 2234-2244 ◽  
Author(s):  
M. Goldsworthy ◽  
A. Hugill ◽  
H. Freeman ◽  
E. Horner ◽  
K. Shimomura ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Insulin Secretion ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance

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.

Increased prevalence of β-cell dysfunction despite normal HbA1c in youth and young adults with Turner Syndrome

2021 ◽  
Author(s):  
Nicole Sheanon ◽  
Deborah Elder ◽  
Jane Khoury ◽  
Lori Casnellie ◽  
Iris Gutmark-Little ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Turner Syndrome ◽  
P Value ◽  
Oral Glucose ◽  
Adult Women ◽  
Β Cell ◽  
Cell Dysfunction ◽  
The Impact

Intro: Adult women with Turner syndrome (TS) have a high prevalence of diabetes and β-cell dysfunction that increases morbidity and mortality, but, it is unknown if there is β-cell dysfunction present in youth with TS. This study aimed to determine the prevalence of β-cell dysfunction in youth with TS and the impact of traditional therapies on insulin sensitivity and insulin secretion. Methods: Cross-sectional, observational study recruited 60 girls with TS and 60 healthy controls (HC) matched on pubertal status. Each subject had a history, physical exam and oral glucose tolerance test (OGTT). Oral glucose and c-peptide minimal modeling was used to determine β-cell function. Results: Twenty-one TS girls (35%) met criteria for pre-diabetes. Impaired fasting glucose (IFG) was present in 18% of girls with TS and 2% HC (p-value = 0.0003). Impaired glucose tolerance (IGT) was present in 23% of TS girls and 0% HC (p-value < 0.001). The HbA1c was not different between TS and HC (median 5%, p= 0.42). Youth with TS had significant reductions in insulin sensitivity (SI), β-cell responsivity (Φ), and disposition index (DI) compared to HC. These differences remained significant when controlling for BMI z-score (p-values: 0.0006, 0.002, <0.0001 for SI, Φtotal, DI, respectively). Conclusions: β-cell dysfunction is present in youth with TS compared to controls. The presence of both reduced insulin secretion and insulin sensitivity suggest a unique TS-related glycemic phenotype. Based on the data from this study, we strongly suggest that providers employ serial OGTT to screen for glucose abnormalities in TS youth.

Abstract 1924: Carriers of Loss-of-Function Mutations in ABCA1 Display Pancreatic Beta Cell Dysfunction

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Menno Vergeer ◽  
Liam R Brunham ◽  
Joris Koetsveld ◽  
Janine K Kruit ◽  
C B Verchere ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Plasma Glucose ◽  
Sensitivity Index ◽  
Loss Of Function ◽  
Β Cell ◽  
C Peptide ◽  
Cell Dysfunction ◽  
Time Interaction

Background The ATP Binding Cassette transporter A1 (ABCA1) transports free cholesterol to nascent high-density lipoproteins (HDL) and maintains plasma HDL levels. In mice, ABCA1 is essential in regulating intracellular cholesterol homeostasis and insulin secretion in the β cell. The role of ABCA1 in human glucose metabolism is unclear. Objective and methods To assess the effects of ABCA1 dysfunction on glucose homeostasis in humans , we matched heterozygous carriers of disruptive mutations in ABCA1 and non-carriers for age, gender and BMI and performed oral glucose tolerance tests (OGTT; 9 vs. 8 respectively) and hyperglycemic clamping experiments (6 vs. 6). Results Carriers had lower HDL-C levels than non-carriers (0.58 ± 0.3 vs. 1.46 ± 0.4 mmol/L, p=0.001) but LDL-C did not differ (3.4 ± 1.0 vs. 2.8 ± 0.8 mmol/L, p=0.21). Fasting plasma glucose was not different (5.2 ± 1.5 vs. 5.0 ± 0.4 mmol/L). Glucose curves after OGTT were significantly higher in carriers than in non-carriers (genotype * time interaction, p=0.005; plasma glucose at t=60 min 9.0 ± 3.0 mmol/L vs. 6.0 ± 1.4 mmol/L respectively, p=0.02). During hyperglycemic clamps, carriers showed a lower first phase insulin and C-peptide response than non-carriers (genotype * time interaction, p<0.05 and p<0.01 respectively; insulin at t=5 min 164±118 vs. 352 ±141 pmol/L, p<0.05; C-peptide at t=5 min 1033 ± 628 vs. 1942 ± 723 pmol/L, p<0.05) but no difference in insulin sensitivity index (0.0216 ± 0.012 mg kg −1 . min −1 . pM −1 for carriers and 0.0197 ± 0.005 mg kg −1 . min −1 . pM −1 for non-carriers; p=0.73). Disposition index - a measure of β cell function, adjusted for insulin sensitivity - was lower in carriers than in non-carriers (1037 ± 610 vs. 2718 ± 1524; p<0.05). Non-carriers responded to an arginine stimulus with an increase in C-peptide levels (from 3558 ± 1240 pM to 6817 ± 1665 pM; p<0.005), whereas in carriers this increase did not reach statistical significance (from 3727 ± 1843 pM to 5480 ± 1757 pM; p=0.12). Conclusion Carriers of loss-of-function mutations in ABCA1 show impaired insulin secretion without insulin resistance, resulting in glucose intolerance. Our data confirm previous studies in mice and provide evidence for a role of ABCA1 in β cell dysfunction and the pathophysiology of diabetes mellitus in man.

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