Mechanisms of insulin resistance in cystic fibrosis

2001 ◽  
Vol 281 (5) ◽  
pp. E1022-E1028 ◽  
Author(s):  
Dana S. Hardin ◽  
Adrian Leblanc ◽  
Gailen Marshall ◽  
Dan K. Seilheimer
Keyword(s):  
Insulin Resistance ◽  
Cystic Fibrosis ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Clinical Status ◽  
Oral Glucose ◽  
Glut 4 ◽  
Tnf Α ◽  
Glut 4 Translocation

Cystic fibrosis (CF) is associated with a high incidence of diabetes. Studies evaluating causes of CF-related diabetes (CFRD) have consistently documented decreased insulin secretion. In patients with CFRD, insulin sensitivity has been documented to be decreased, but controversy exists in patients with normal or impaired glucose tolerance (IGT). We undertook this study 1) to reexplore insulin sensitivity in patients with IGT and 2) to evaluate potential mechanisms of insulin resistance in CF, including GLUT-4 translocation, elevation of serum cytokines, and free fatty acid (FFA) levels. We recruited nine CF subjects with impaired glucose tolerance (IGTCF) and nine age-, gender-, and body mass index-matched control volunteers. Each underwent a hyperinsulinemic euglycemic clamp (200 mU · m−2 · min−1) to measure insulin sensitivity. A muscle biopsy was obtained at maximal insulin stimulation for measure of GLUT-4 translocation with sucrose gradients. An oral glucose tolerance test and National Institutes of Health (NIH) clinical status scores were measured in all volunteers. We also measured tumor necrosis factor (TNF)-α levels and FFA in all subjects. Additionally, we report the results of TNF-α and FFA in 32 CF patients previously studied by our group. Results were that glucose disposal rate (GDR) was significantly lower in the CFIGT subjects than in controls, indicative of impaired insulin action. GLUT-4 translocation was impaired in CF and correlated with GDR. TNF-α levels were higher in all CF subjects than in controls and correlated with GDR. There was no difference in FFA between CF and control subjects. Modified NIH clinical status scores were inversely correlated with GDR and TNF-α levels. We conclude that IGTCF patients have decreased peripheral insulin sensitivity. Mechanisms include elevation of TNF-α and impaired translocation of GLUT-4.

scholarly journals Insulin-secretion abnormalities and clinical deterioration related to impaired glucose tolerance in cystic fibrosis

2005 ◽  
Vol 152 (2) ◽  
pp. 241-247 ◽  
Author(s):  
Santiago Tofé ◽  
José C Moreno ◽  
Luis Máiz ◽  
Milagros Alonso ◽  
Héctor Escobar ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Nutritional Status ◽  
Pulmonary Function ◽  
Impaired Glucose Tolerance ◽  
Clinical Status ◽  
Assessment Model ◽  
Cross Sectional

Objective: To evaluate insulin-secretion kinetics and insulin sensitivity in cystic fibrosis (CF) patients with normal glucose tolerance (CF-NGT), impaired glucose tolerance (CF-IGT) or CF-related diabetes (CFRD), and the potential effects of moderate hyperglycemia on clinical and nutritional status. Design and methods: Cross-sectional study including 50 outpatients with CF. Patients underwent both oral (OGGT) and intravenous (IVGTT) glucose tolerance tests in order to assess insulin secretion and peripheral insulin sensitivity. Homeostasis assessment model and OGGT were used to investigate insulin sensitivity. Forced expiratory volume in the first second (FEV1) and forced vital capacity (FVC) were measured to evaluate pulmonary function. Body mass index (BMI) was determined to assess nutritional status. Results: Insulin secretion was significantly decreased (and delayed at OGTT) in the CFRD group (n = 9) versus the CF-IGT group (n = 10) and the CF-IGT versus the CF-NGT group (n = 31). Insulin sensitivity was significantly different in the CF-IGT and CFRD groups versus the CF-NGT group. FEV1, FVC and BMI presented a significant linear correlation with plasma glucose value at 120 min at OGTT and were significantly lower in both CF-IGT and CFRD versus the CF-NGT group, whereas no differences were found between the CF-IGT and CFRD groups. Conclusions: CF patients with IGT present diminished insulin secretion and increased peripheral insulin resistance, correlating with a worse clinical status, undernutrition and impaired pulmonary function. These findings open the question of whether early treatment of mild alterations of glucose metabolism with insulin secretagogues or short-action insulin may lead to improvement of clinical status in CF patients.

No changes of insulin sensitivity in cystic fibrosis patients with different degrees of glucose tolerance: an epidemiological and longitudinal study

1994 ◽  
Vol 130 (3) ◽  
pp. 253-258 ◽  
Author(s):  
Domenico Cucinotta ◽  
Filippo De Luca ◽  
Alfonso Gigante ◽  
Teresa Arrigo ◽  
Antonino Di Benedetto ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Insulin Secretion ◽  
Longitudinal Study ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Clinical Status ◽  
Fasting Blood Glucose ◽  
Oral Glucose ◽  
Insulin Responses ◽  
Over Time

Cucinotta D, De Luca F, Gigante A, Arrigo T, Di Benedetto A, Tedeschi A, Lombardo F, Romano G, Sferlazzas C. No changes of insulin sensitivity in cystic fibrosis patients with different degrees of glucose tolerance: an epidemiological and longitudinal study. Eur J Endocrinol 1994;130:253–8. ISSN 0804–4643 Plasma glucose and insulin responses to oral glucose and insulin sensitivity by the euglycemic hyperinsulinemic clamp technique were investigated in 30 cystic fibrosis patients with normal fasting blood glucose levels and normal (N = 12), impaired (N = 12) or diabetic (N = 6) glucose tolerance, and in 12 control subjects. In a subgroup of 10 cystic fibrosis patients with non-diabetic glucose tolerance both oral glucose tolerance test and clamp were performed again 48–52 months later. Following oral glucose, glycemic responses were higher in cystic fibrosis patients than in controls, whereas insulin responses were reduced significantly only in the patients with diabetic glucose tolerance. Insulin sensitivity did not differ significantly in the patient subgroups with different degrees of glucose tolerance and in controls. In the 10 patients who underwent a 4-year follow-up, insulin responses to oral glucose decreased significantly, whilst insulin sensitivity did not change substantially. Insulin sensitivity persisted unmodified even in the patients with deteriorating glucose tolerance. No correlations were observed between metabolic data and clinical status of patients. In conclusion, in cystic fibrosis subjects with fasting euglycemia and different degrees of glucose tolerance: (i) insulin sensitivity is not impaired; (ii) eventual changes of glucose tolerance over time are not associated with modifications of insulin sensitivity; (iii) insulin secretion deteriorates over time even in the patients with stable glucose tolerance; (iv) eventual deterioration of both glucose tolerance and insulin secretion is not linked to a worsening of either nutritional or clinical parameters. F De Luca, Istituto di Clinica Pediatrica, Policlinico Universitario, 98100 Messina, Italy

scholarly journals QOL-43. ENDOCRINE AND METABOLIC CHANGES IN CHILDREN TREATED FOR MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii439-iii439
Author(s):  
Alexey Kalinin ◽  
Natalia Strebkova ◽  
Olga Zheludkova
Keyword(s):  
Insulin Resistance ◽  
Body Composition ◽  
Glucose Tolerance ◽  
Oral Glucose Tolerance Test ◽  
Impaired Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Hormone Deficiency ◽  
Oral Glucose ◽  
Oral Glucose Tolerance

Abstract We examined 63 patients (40 males/23 females) after complex treatment of medulloblastoma. Patients had a median age (range) of 11.3 (5.5 ÷ 17.9) years. The median time after the end of treatment was 3.7 (1.5 ÷ 11.6) years. Endocrine disorders were detected with the following frequency: growth hormone deficiency - 98.41% (62 of 63 patients), thyroid hormone deficiency – 69.8% (44/63), adrenal hormone deficiency - 17.4% (11/63). Three cases (4.7%) of premature sexual development were also detected. Lipids levels, beta-cell function and insulin resistance (IR) during 2-h oral glucose tolerance test were evaluated. A mono frequent bioelectrical impedanciometer was used to measure body composition. Overweight (SDS BMI> 1) was observed only in 16 patients (3 girls and 13 boys), obesity (SDS BMI> 2) in 1 boy. Dyslipidemia was found in 34 patients (54%). All patients underwent oral glucose tolerance test. Insulin resistance (ISI Matsuda <2.5 and/or HOMA-IR> 3.2) was detected in 7 patients (11/1%), impaired glucose tolerance (120 min glucose ≥7.8 mmol / l) was observed in 2 patients with IR and in 2 patients without IR. At the same time, IR and impaired glucose tolerance were encountered in only 5 children with overweight and no one with obesity. All patients with impaired glucose tolerance had normal values of fasting glucose (4.3 ÷ 5.04 mmol / l) and HbA1c (4.8 ÷ 5.8%). A bioelectrical impedanciometer was used to measure body composition in 49 cases, the percentage of adipose tissue was increased in 14 patients (28%) with normal BMI.

scholarly journals Elevated Circulating Fetuin-B Levels Are Associated with Insulin Resistance and Reduced by GLP-1RA in Newly Diagnosed PCOS Women

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Mani Mokou ◽  
Shan Yang ◽  
Bin Zhan ◽  
Shan Geng ◽  
Kejia Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Glucose Tolerance ◽  
Metabolic Diseases ◽  
Polycystic Ovary ◽  
Fasting Blood Glucose ◽  
Resistance Index ◽  
Oral Glucose ◽  
Healthy Women ◽  
Tnf Α

Background. Previous studies have suggested that Fetuin-B seems to be a secreted adipokine related to metabolic diseases. However, the results have been inconsistent. Here, our objective is to investigate the changes in circulating Fetuin-B levels in women with polycystic ovary syndrome (PCOS) and analyze the association of Fetuin-B and insulin resistance (IR). Methods. The current study is comprised of a cross-sectional study and a series of interventional studies. Oral glucose tolerance test (OGTT) and euglycemic-hyperinsulinemic clamp (EHC) were engaged to assess glucose tolerance and insulin sensitivity. Serum Fetuin-B levels were determined by ELISA. Results. Serum Fetuin-B and TNF-α levels were markedly increased in women with PCOS compared to healthy women. Circulating Fetuin-B was positively associated with body mass index, waist-to-hip ratio, the percentage of body fat (FAT%), systolic blood pressure, triglyceride, low-density lipoprotein cholesterol, fasting blood glucose, 2 h blood glucose after glucose overload, fasting insulin, 2 h insulin after glucose overload, HOMA-insulin resistance index (HOMA-IR), the area under the curve for insulin (AUCi), AUCg, and TNF-α, while negatively associated with M value and follicular stimulating hormone (FSH). During the EHC, Fetuin-B levels were found to be significantly increased in PCOS women. After a glucose challenge, serum Fetuin-B levels in healthy women were significantly increased. Lipid infusion reduced serum Fetuin-B levels in 30 healthy subjects. After six months of glucagon-like peptide-1 receptor agonist (GLP-1RA) intervention, serum Fetuin-B concentrations in PCOS women markedly decreased following ameliorated IR. Conclusion. Our results indicate that Fetuin-B may be a biomarker of IR in individuals with PCOS. This trial is registered with ChiCTR-IIR-16007901.

Pancreas and gut hormone responses to oral glucose and intravenous glucagon in cystic fibrosis patients with normal, impaired, and diabetic glucose tolerance

1993 ◽  
Vol 128 (3) ◽  
pp. 207-214 ◽  
Author(s):  
Susanne Lanng ◽  
Birger Thorsteinsson ◽  
Michael E Røder ◽  
Cathrine Ørskov ◽  
Jens J Holst ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Pancreatic Polypeptide ◽  
Oral Glucose ◽  
C Peptide ◽  
Control Subjects ◽  
Gut Hormone ◽  
Patient Groups ◽  
Hormone Responses

Pancreatic and gut hormone responses to oral glucose, and insulin sensitivity were studied in cystic fibrosis patients with normal (N= 14), impaired (N=4), and diabetic (N= 12) glucose tolerance, and in 10 control subjects, and beta cell responses to oral glucose and intravenous glucagon were compared. Compared to control subjects, initial insulin and C-peptide responses to oral glucose were lower in all patient groups, and decreased with decreasing glucose tolerance. Insulin sensitivity in patients with impaired and diabetic glucose tolerance was lower than in control subjects. The 6 min post-glucagon C-peptide concentration was positively correlated with the initial insulin response to oral glucose. Fasting levels of pancreatic polypeptide, pancreatic glucagon, total glucagon, glucagon-like peptide-1 7-36 amide, and gastric inhibitory polypeptide were normal in all patient groups. Following oral glucose, pancreatic polypeptide responses were absent in all patients, suppressibility of pancreatic glucagon secretion was increasingly impaired with decreasing glucose tolerance, and gut hormone levels were normal. In conclusion, at cystic fibrosis (a) insulin secretion is impaired even when glucose tolerance and insulin sensitivity are within the normal range, (b) the glucagon test gives valid estimates of residual beta cell function, (c) pancreatic polypeptide response to oral glucose is absent, (d) glucagon suppressibility decreases with decreasing glucose tolerance, and (e) the enteroinsular axis is intact.

Impaired glucose tolerance in first-episode drug-naïve patients with schizophrenia: relationships with clinical phenotypes and cognitive deficits

2016 ◽  
Vol 46 (15) ◽  
pp. 3219-3230 ◽  
Author(s):  
D. C. Chen ◽  
X. D. Du ◽  
G. Z. Yin ◽  
K. B. Yang ◽  
Y. Nie ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cognitive Impairment ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Cognitive Deficits ◽  
First Episode ◽  
Oral Glucose ◽  
Model Assessment ◽  
Clinical Phenotypes ◽  
Drug Naïve

BackgroundSchizophrenia patients have a higher prevalence of type 2 diabetes mellitus with impaired glucose tolerance (IGT) than normals. We examined the relationship between IGT and clinical phenotypes or cognitive deficits in first-episode, drug-naïve (FEDN) Han Chinese patients with schizophrenia.MethodA total of 175 in-patients were compared with 31 healthy controls on anthropometric measures and fasting plasma levels of glucose, insulin and lipids. They were also compared using a 75 g oral glucose tolerance test and the homeostasis model assessment of insulin resistance (HOMA-IR). Neurocognitive functioning was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Patient psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS).ResultsOf the patients, 24.5% had IGT compared with none of the controls, and they also had significantly higher levels of fasting blood glucose and 2-h glucose after an oral glucose load, and were more insulin resistant. Compared with those patients with normal glucose tolerance, the IGT patients were older, had a later age of onset, higher waist or hip circumference and body mass index, higher levels of low-density lipoprotein and triglycerides and higher insulin resistance. Furthermore, IGT patients had higher PANSS total and negative symptom subscale scores, but no greater cognitive impairment except on the emotional intelligence index of the MCCB.ConclusionsIGT occurs with greater frequency in FEDN schizophrenia, and shows association with demographic and anthropometric parameters, as well as with clinical symptoms but minimally with cognitive impairment during the early course of the disorder.

scholarly journals Effect of the rs997509 Polymorphism on the Association between Ectonucleotide Pyrophosphatase Phosphodiesterase 1 and Metabolic Syndrome and Impaired Glucose Tolerance in Childhood Obesity

2009 ◽  
Vol 94 (1) ◽  
pp. 300-305 ◽  
Author(s):  
Nicola Santoro ◽  
Grazia Cirillo ◽  
Maria Grazia Lepore ◽  
Alfonsina Palma ◽  
Alessandra Amato ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Insulin Sensitivity ◽  
Confidence Interval ◽  
Glucose Tolerance ◽  
Impaired Glucose Tolerance ◽  
Odds Ratio ◽  
Rare Allele ◽  
Common Allele ◽  
Obese Children

Abstract Context: Variants on the nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP-1) gene have been associated with obesity and insulin resistance. Because insulin resistance is a pivotal factor in the development of metabolic syndrome (MS) and impaired glucose tolerance (IGT), we aimed to test the association between the K121Q and rs997509 ENPP-1 variants with obesity, MS and IGT in obese children and adolescents. Methods: We screened 809 children, 409 obese and 400 lean controls. Obese subjects underwent a standard oral glucose tolerance test, whole body insulin sensitivity index (WBISI) and homeostasis model assessment (HOMA) were calculated. Results: No difference in prevalence for K121Q and rs997509 polymorphisms between obese and controls (P > 0.05) were observed. Obese children carrying the rs997509 rare allele showed higher insulin (P = 0.001), HOMA (P < .001) and lower WBISI values (P = 0.04) compared with common allele homozygous. A similar observation was done for K121Q variant, with 121Q allele carriers showing higher insulin (P = 0.03) and HOMA (P = 0.04) values than 121K homozygotes. Moreover, subjects carrying the rs997509 rare allele had higher risk of MS (odds ratio 2.4, 95% confidence interval: 1.3–4.3) and IGT (odds ratio 4.7, 95% confidence interval: 1.9–11.4) than common allele homozygotes. Evaluating combined effects of both polymorphisms, which are in strong linkage disequilibrium, we showed that the effect on insulin sensitivity was due to the rs997509 T variant. Conclusion: We conclude that the ENPP1 rs997509T allele can predispose obese children to MS and IGT and that this variant might drive the association between the ENPP1 121Q allele and insulin resistance.

scholarly journals SUN-670 P300 and CBP Are Necessary for Skeletal Muscle Insulin-Stimulated Glucose Uptake

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Vitor Fernandes Martins ◽  
Samuel LaBarge ◽  
Kristoffer Svensson ◽  
Jennifer M Cunliffe ◽  
Dion Banoian ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Uptake ◽  
Ex Vivo ◽  
Binding Protein ◽  
Whole Body ◽  
Oral Glucose ◽  
Skeletal Muscle Insulin Sensitivity

Abstract Introduction: Akt is a critical mediator of insulin-stimulated glucose uptake in skeletal muscle. The acetyltransferases, E1A binding protein p300 (p300) and cAMP response element-binding protein binding protein (CBP) are phosphorylated and activated by Akt, and p300/CBP can acetylate and inactivate Akt, thus giving rise to a possible Akt-p300/CBP axis. Our objective was to determine the importance of p300 and CBP to skeletal muscle insulin sensitivity. Methods: We used Cre-LoxP methodology to generate mice with a tamoxifen-inducible, conditional knock out of Ep300 and/or Crebbp in skeletal muscle. At 13-15 weeks of age, the knockout was induced via oral gavage of tamoxifen and oral glucose tolerance, ex vivo skeletal muscle insulin sensitivity, and microarray and proteomics analysis were done. Results: Loss of both p300 and CBP in adult mouse skeletal muscle rapidly and severely impairs whole body glucose tolerance and skeletal muscle insulin sensitivity. Furthermore, giving back a single allele of either p300 or CBP rescues both phenotypes. Moreover, the severe insulin resistance in the p300/CBP double knockout mice is accompanied by significant changes in both mRNA and protein expression of transcript/protein networks critical for insulin signaling, GLUT4 trafficking, and metabolism. Lastly, in human skeletal muscle samples, p300 and CBP protein levels correlate significantly and negatively with markers of insulin resistance. Conclusions: p300 and CBP are jointly required for maintaining whole body glucose tolerance and insulin sensitivity in skeletal muscle.

Insulin infusion induces endothelin-1-dependent hypertension in rats

2004 ◽  
Vol 287 (5) ◽  
pp. E948-E954 ◽  
Author(s):  
Chi-Chang Juan ◽  
Yi-Wen Shen ◽  
Yueh Chien ◽  
Yen-Jie Lin ◽  
Shau-Feng Chang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Systolic Blood Pressure ◽  
Insulin Infusion ◽  
Experimental Period ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Bq 610

We previously showed that chronic insulin infusion induces insulin resistance, hyperendothelinemia, and hypertension in rats (C. C. Juan, V. S. Fang, C. F. Kwok, J. C. Perng, Y. C. Chou, and L. T. Ho. Metabolism 48: 465–471, 1999). Endothelin-1 (ET-1), a potent vasoconstrictor, is suggested to play an important role in maintaining vascular tone and regulating blood pressure, and insulin increases ET-1 production in vivo and in vitro. In the present study, BQ-610, a selective endothelin A receptor antagonist, was used to examine the role of ET-1 in insulin-induced hypertension in rats. BQ-610 (0.7 mg/ml; 0.5 ml/kg body wt) or normal saline was given intraperitoneally two times daily for 25 days to groups of rats infused with either saline or insulin (2 U/day via sc-implanted osmotic pumps), and changes in plasma levels of insulin, glucose, and ET-1 and the systolic blood pressure were measured over the experimental period, whereas changes in insulin sensitivity were examined at the end of the experimental period. Plasma insulin and ET-1 levels were measured by RIA, plasma glucose levels using a glucose analyzer, systolic blood pressure by the tail-cuff method, and insulin sensitivity by an oral glucose tolerance test. Our studies showed that insulin infusion caused sustained hyperinsulinemia in both saline- and BQ-610-injected rats over the infusion period. After pump implantation (2 wk), the systolic blood pressure was significantly higher in insulin-infused rats than in saline-infused rats in the saline-injected group (133 ± 3.1 vs. 113 ± 1.1 mmHg, P < 0.05) but not in the BQ-610-injected group (117 ± 1.2 vs. 117 ± 1.8 mmHg). Plasma ET-1 levels in both sets of insulin-infused rats were higher than in saline-infused controls (2.5 ± 0.6 and 2.5 ± 0.8 vs. 1.8 ± 0.4 and 1.7 ± 0.3 pmol/l, P < 0.05). Oral glucose tolerance tests showed that BQ-610 treatment did not prevent the insulin resistance caused by chronic insulin infusion. No significant changes were found in insulin sensitivity and blood pressure in saline-infused rats treated with BQ-610. In a separate experiment, insulin infusion induced the increase in arterial ET-1 content, hypertension, and subsequent plasma ET-1 elevation in rats. These results suggest that, in the insulin infusion rat model, ET-1 plays a mediating role in the development of hypertension, but not of insulin resistance.

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