scholarly journals FOXN3 hyperglycemic risk allele and insulin sensitivity in humans

2019 ◽  
Vol 7 (1) ◽  
pp. e000688 ◽  
Author(s):  
Melissa L Erickson ◽  
Santhosh Karanth ◽  
Eric Ravussin ◽  
Amnon Schlegel
Keyword(s):  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Allele Frequency ◽  
Risk Allele ◽  
Fasting Blood Glucose ◽  
Fat Free Mass ◽  
Glucose Disposal ◽  
Oral Glucose ◽  
Allele Carrier ◽  
Euglycemic Hyperinsulinemic Clamp

ObjectiveThe rs8004664 variation within the FOXN3 gene is significantly and independently associated with fasting blood glucose in humans. We have previously shown that the hyperglycemia risk allele (A) increases FOXN3 expression in primary human hepatocytes; over-expression of human FOXN3 in zebrafish liver increases fasting blood glucose; and heterozygous deletion of the zebrafish orthologfoxn3decreases fasting blood glucose. Paralleling these model organism findings, we found that rs8004664 A|A homozygotes had blunted glucagon suppression during an oral glucose tolerance test. Here, we test associations between insulin sensitivity and the rs8004664 variation.Research design and methods92 participants (49±13 years, body mass index: 32±6 kg/m2, 28 with and 64 without type 2 diabetes mellitus) were genotyped at rs8004664. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp technique.ResultsThe “A” allele frequency was 59%; the protective (G) allele frequency was 41% (A|A: n=29; G|G: n=12; A|G: n=50). Clamp-measured glucose disposal rate (GDR) was not different by genotype (F=0.046, p=0.96) or by “A” allele carrier (p=0.36). Female G|G homozygotes had better insulin sensitivity compared to female “A” allele carriers (GDR; G|G: 9.9±3.0 vs A|A+A|G: 7.1±3.0 mg/kg fat-free mass+17.7/min; p=0.04). Insulin sensitivity was not different by genotype or by “A” allele carriers.ConclusionThe rs8004664 variation within the FOXN3 gene may modulate insulin sensitivity in women.

scholarly journals A dose titration model for recombinant GH substitution aiming at normal plasma concentrations of IGF-I in hypopituitary adults

2002 ◽  
pp. 49-57 ◽  
Author(s):  
B Ekman ◽  
T Lindstrom ◽  
F Nystrom ◽  
AG Olsson ◽  
G Toss ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Insulin Sensitivity ◽  
Fasting Blood Glucose ◽  
Dose Titration ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Fasting Insulin ◽  
Control Subjects ◽  
Normal Plasma ◽  
Igf I

OBJECTIVE: To evaluate a dose titration model for recombinant human GH substitution in adult patients with GH deficiency, aiming at normal plasma levels of IGF-I. DESIGN AND METHODS: Eighteen patients participated and a start dose of 0.17 mg GH/day was used except by two men who started with 0.33 mg/day. To demonstrate a clear GH effect the patients were first titrated, with steps of 0.17 mg GH/day every 6-8 weeks, to IGF-I levels in the upper range of age-adjusted reference values. The GH dose was then reduced 1 dose step and kept for a further 6 months. For comparison we investigated 17 healthy control subjects. RESULTS: Plasma IGF-I was increased after 2 weeks on the start dose and did not increase further for up to 8 weeks. Women had significantly lower GH sensitivity than men measured as net increment of IGF-I on the start dose of GH. GH sensitivity was not changed by age. The plasma IGF-I levels increased from 76.3+/-47.0 (s.d.) to 237+/-97 microg/l at the end of the study (P<0.001), and similar IGF-I levels were obtained in both sexes. The maintenance median GH dose was 0.33 mg/day in males and 0.83 mg/day in females (P=0.017). The GH dose correlated negatively with age in both sexes. Body weight, very low density triglycerides, lipoprotein(a) (Lp(a)), and fasting insulin increased, whereas insulin sensitivity index (QUICKI) decreased significantly. In comparison with the controls, the patients had lower fasting blood glucose, fasting insulin and Lp(a) levels at baseline, but these differences disappeared after GH substitution. The two groups had equal insulin sensitivity (QUICKI), but 2 h oral glucose tolerance test values of blood glucose and insulin were significantly higher in the patients at the end of the study. CONCLUSIONS: In conclusion our data suggest that the starting dose of GH substitution and the dose titration steps should be individualised according to GH sensitivity (gender) and the IGF-I level aimed for (age). The reduced insulin sensitivity induced by GH substitution could be viewed as a normalisation if compared with control subjects.

scholarly journals Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

2013 ◽  
Vol 305 (10) ◽  
pp. E1292-E1298 ◽  
Author(s):  
Steven K. Malin ◽  
Jacob M. Haus ◽  
Thomas P. J. Solomon ◽  
Alecia Blaszczak ◽  
Sangeeta R. Kashyap ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Exercise Training ◽  
Glucose Tolerance ◽  
Glucose Disposal ◽  
Oral Glucose ◽  
Metabolic Flexibility ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Hepatic Insulin Sensitivity ◽  
Peripheral Insulin Sensitivity ◽  
Chronic Hyperglycemia

Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization in adults with IFG, IGT, or IFG + IGT is unknown. Twenty-four older (66.7 ± 0.8 yr) obese (34.2 ± 0.9 kg/m2) adults were categorized as IFG ( n = 8), IGT ( n = 8), or IFG + IGT ( n = 8) according to a 75-g oral glucose tolerance test (OGTT). Subjects underwent 12-wk of exercise (60 min/day for 5 days/wk at ∼85% HRmax) and were instructed to maintain a eucaloric diet. A euglycemic hyperinsulinemic clamp (40 mU·m2·min−1) with [6,6-2H]glucose was used to determine peripheral and hepatic insulin sensitivity. Nonoxidative glucose disposal and metabolic flexibility [insulin-stimulated respiratory quotient (RQ) minus fasting RQ] were also assessed. Glucose incremental area under the curve (iAUCOGTT) was calculated from the OGTT. Exercise increased clamp-derived peripheral and hepatic insulin sensitivity more in adults with IFG or IGT alone than with IFG + IGT ( P < 0.05). Exercise reduced glucose iAUCOGTT in IGT only ( P < 0.05), and the decrease in glucose iAUCOGTT was inversely correlated with the increase in peripheral but not hepatic insulin sensitivity ( P < 0.01). Increased clamp-derived peripheral insulin sensitivity was also correlated with enhanced metabolic flexibility, reduced fasting RQ, and higher nonoxidative glucose disposal ( P < 0.05). Adults with IFG + IGT had smaller gains in clamp-derived peripheral insulin sensitivity and metabolic flexibility, which was related to blunted improvements in postprandial glucose. Additional work is required to assess the molecular mechanism(s) by which chronic hyperglycemia modifies insulin sensitivity following exercise training.

Insulin sensitivity by oral glucose minimal models: validation against clamp

2005 ◽  
Vol 289 (6) ◽  
pp. E954-E959 ◽  
Author(s):  
Chiara Dalla Man ◽  
Kevin E. Yarasheski ◽  
Andrea Caumo ◽  
Heather Robertson ◽  
Gianna Toffolo ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Minimal Model ◽  
Large Scale ◽  
Glucose Disposal ◽  
Oral Glucose ◽  
Minimal Models ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Metabolic Conditions ◽  
Oral Minimal Model ◽  
Models Validation

Measuring insulin sensitivity in the presence of physiological changes in glucose and insulin concentrations, e.g., during a meal or OGTT, is important to better understand insulin resistance in a variety of metabolic conditions. Recently, two oral minimal models have been proposed to measure overall insulin sensitivity (SI) and its selective effect on glucose disposal (SI*) from oral tests. SI and SI* have been successfully validated against multiple tracer meal estimates, but validation against euglycemic hyperinsulinemic clamp estimates is lacking. Here, we do so in 21 subjects who underwent both a multiple-tracer OGTT and a labeled euglycemic hyperinsulinemic clamp. Correlation between minimal-model SI, SI and corresponding clamp estimates SI*clamp, SI*clamp was satisfactory, respectively r = 0.81, P < 0.001, and r = 0.71, P < 0.001. SI was significantly lower than SIclamp (8.08 ± 0.89 vs. 13.66 ± 1.69 10−4 dl·kg−1·min−1 per μU/ml, P = 0.0002), whereas SI and SI*clamp were very similar (8.17 ± 1.59 vs. 8.84 ± 1.39 10−4 dl·kg−1·min−1 per μU/ml, P = 0.52). These results add credibility to the oral minimal-model method as a simple and reliable physiological tool to estimate SI and SI*, also in large-scale clinical trials.

Effect of antioxidant supplementation on insulin sensitivity in response to endurance exercise training

2011 ◽  
Vol 300 (5) ◽  
pp. E761-E770 ◽  
Author(s):  
Christina Yfanti ◽  
Anders R. Nielsen ◽  
Thorbjörn Åkerström ◽  
Søren Nielsen ◽  
Adam J. Rose ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Vitamin C ◽  
Glucose Uptake ◽  
Endurance Training ◽  
Time Effect ◽  
Fat Free Mass ◽  
Antioxidant Supplementation ◽  
Hexokinase Ii ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Maximal Power Output

While production of reactive oxygen and nitrogen species (RONS) is associated with some of the beneficial adaptations to regular physical exercise, it is not established whether RONS play a role in the improved insulin-stimulated glucose uptake in skeletal muscle obtained by endurance training. To assess the effect of antioxidant supplementation during endurance training on insulin-stimulated glucose uptake, 21 young healthy (age 29 ± 1 y, BMI 25 ± 3 kg/m2) men were randomly assigned to either an antioxidant [AO; 500 mg vitamin C and 400 IU vitamin E (α-tocopherol) daily] or a placebo (PL) group that both underwent a supervised intense endurance-training program 5 times/wk for 12 wk. A 3-h euglycemic-hyperinsulinemic clamp, a maximal oxygen consumption (V̇o2max) and maximal power output (Pmax) test, and body composition measurements (fat mass, fat-free mass) were performed before and after the training. Muscle biopsies were obtained for determination of the concentration and activity of proteins regulating glucose metabolism. Although plasma levels of vitamin C ( P < 0.05) and α-tocopherol ( P < 0.05) increased markedly in the AO group, insulin-stimulated glucose uptake increased similarly in both the AO (17.2%, P < 0.05) and the PL (18.9%, P < 0.05) group in response to training. V̇o2max and Pmax also increased similarly in both groups (time effect, P < 0.0001 for both) as well as protein content of GLUT4, hexokinase II, and total Akt (time effect, P ≤ 0.05 for all). Our results indicate that administration of antioxidants during strenuous endurance training has no effect on the training-induced increase in insulin sensitivity in healthy individuals.

HDL Containing Apolipoprotein C-III is Associated with Insulin Sensitivity: a Multi-Center Cohort Study

2021 ◽  
Author(s):  
Rain Yamamoto ◽  
Majken K Jensen ◽  
Sarah Aroner ◽  
Jeremy D Furtado ◽  
Bernard Rosner ◽  
...  
Keyword(s):  
Cohort Study ◽  
Insulin Sensitivity ◽  
Clinical Investigation ◽  
Biological Effects ◽  
Sandwich Elisa ◽  
Insulin Response ◽  
Protein Composition ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Euglycemic Hyperinsulinemic Clamp

Abstract Context HDL in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects. Objective We investigated the prospective associations between HDL subspecies containing and lacking apoC-III at baseline and insulin sensitivity at year 3. Design, Setting, and Participants A prospective cohort study of 864 healthy volunteers drawn from the RISC study, a multi-center European clinical investigation, whose recruitment initiated in 2002 with a follow-up of 3 years. Main Measures Insulin sensitivity was estimated from an oral glucose tolerance test (OGTT) at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The apolipoprotein concentrations were measured at baseline by a sandwich ELISA-based method. Results The two HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (p-heterogeneity=0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (p-trend=0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (p-trend=0.01), compared to the lowest quintile. No significant association was observed for total HDL, and VLDL and LDL containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III. Conclusion Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment.

Glucose tolerance and insulin action in healthy centenarians

1996 ◽  
Vol 270 (5) ◽  
pp. E890-E894 ◽  
Author(s):  
G. Paolisso ◽  
A. Gambardella ◽  
S. Ammendola ◽  
A. D'Amore ◽  
V. Balbi ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Plasma Glucose ◽  
Insulin Action ◽  
Glucose Tolerance Test ◽  
Tolerance Test ◽  
Fat Free Mass ◽  
Whole Body ◽  
Glucose Disposal ◽  
Oral Glucose ◽  
Aged Subjects

Advancing age has been found to be associated with a decline in insulin action. Nevertheless, no study has been conducted in healthy centenarians. Our study investigates glucose tolerance and insulin action in centenarians. Fifty-two subjects were enrolled. The subjects were divided in three groups as follows: 1) adults (< 50 yr; n = 20);2) aged subjects (> 75 yr; n = 22); and 3) centenarians (> 100 yr; n = 14). Body composition was studied by bioimpedance analysis. In all subjects, an oral glucose tolerance test and euglycemic glucose clamp were performed. Centenarians have a lower fat-free mass (FFM) than aged subjects and adults, whereas fasting plasma glucose, triglycerides, free fatty acids, urea, and creatinine were not different in the groups studies. Centenarians had a 2-h plasma glucose concentration (6.0 +/- 0.2 mmol/l) that was lower than that in aged subjects (6.6 +/- 0.5 mmol/l, P < 0.05) but not different from adults [6.4 +/- 0.4 mmol/l, P = not significant (NS)]. During the clamp, plasma glucose and insulin concentrations were similar in the three groups. In these conditions, centenarians had a whole body glucose disposal (34.1 +/- 0.6 mumol.kg FFM-1.min 1) that was greater than that in aged subjects (23.3 +/- 0.5 mumol.kg FFM-1.min-1 P < 0.01) but not different from adults (34.6 +/- 0.5 mumol/kg x min, P = NS). In conclusion, our study demonstrates that centenarians compared with aged subjects had a preserved glucose tolerance and insulin action.

scholarly journals GESTATIONAL DIABETES MELLITUS

2012 ◽  
Vol 19 (04) ◽  
pp. 462-468
Author(s):  
M. IKRAM ◽  
SYED HAIDER HASAN ALAM ◽  
SHAFQAT MUKHTAR ◽  
M. Saeed
Keyword(s):  
Diabetes Mellitus ◽  
Blood Glucose ◽  
Gestational Diabetes ◽  
Glucose Tolerance ◽  
Gestational Diabetes Mellitus ◽  
Glucose Tolerance Test ◽  
Fasting Blood Glucose ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Oral Glucose Tolerance

Introduction: Gestational diabetes mellitus is common disorder in pregnancy. It is associated with adverse pregnancy outcome. There is no consensus regarding the optimal approach to screening of gestational diabetes mellitus. The present study has tried toobserve the value of fasting blood glucose in screening of gestational diabetes. Objective: To determine the frequency of patients in whomfasting blood glucose and 100gm glucose tolerance show agreement for screening of gestational diabetes mellitus at 24 -28 wks. Studydesign: Comparative cross sectional study. Settings: The study was conducted at Gynecology and Obstetrics department Shaikh ZayedFederal Post Graduate Institute Lahore. Duration of study with dates: 6 months from 12Nov 2010 to 11 May 2011. Material and method: Thestudy included 135 booked patients with positive family history of diabetes mellitus. All patients underwent fasting blood glucose at 24-28 weeksof gestation, regardless of results of fasting blood glucose on next visit they underwent 100g oral glucose tolerance test (OGTT). The agreementbetween fasting blood glucose and 100g oral glucose tolerance test was calculated in frequency and percentages. Results: The mean age ofwomen in studied population was 27.15±3.70.Out of 135 patients 86.7 %( 117) showed agreement between results of fasting blood glucose and100g OGTT while 13.31 %( 18) showed no agreement between both of the tests. Conclusions: Fasting blood glucose is a good screeningoption for gestational diabetes mellitus along with positive history. It provides a simple, cheap and more practical test for screening of gestationaldiabetes mellitus. However diagnostic confirmation with 100g OGTT should be done.

scholarly journals An evolving spectrum of diabetes in a woman with GCK-MODY

2019 ◽  
Vol 2019 ◽  
Author(s):  
Aoife Garrahy ◽  
Matilde Bettina Mijares Zamuner ◽  
Maria M Byrne
Keyword(s):  
Blood Glucose ◽  
Fasting Glucose ◽  
Autoimmune Diabetes ◽  
Post Partum ◽  
Fasting Blood Glucose ◽  
Oral Glucose ◽  
List Type ◽  
Latent Autoimmune Diabetes ◽  
Frequent Episodes ◽  
First Case

Summary Coexistence of autoimmune diabetes and maturity-onset diabetes of the young (MODY) is rare. We report the first case of coexisting latent autoimmune diabetes of adulthood (LADA) and glucokinase (GCK) MODY. A 32-year-old woman was treated with insulin for gestational diabetes at age 32 years; post-partum, her fasting blood glucose was 6.0 mmol/L and 2-h glucose was 11.8 mmol/L following an oral glucose tolerance test, and she was maintained on diet alone. Five years later, a diagnosis of LADA was made when she presented with fasting blood glucose of 20.3 mmol/L and HbA1C 125 mmol/mol (13.6%). GCK-MODY was identified 14 years later when genetic testing was prompted by identification of a mutation in her cousin. Despite multiple daily insulin injections her glycaemic control remained above target and her clinical course has been complicated by multiple episodes of hypoglycaemia with unawareness. Although rare, coexistence of latent autoimmune diabetes of adulthood and monogenic diabetes should be considered if there is a strong clinical suspicion, for example, family history. Hypoglycaemic unawareness developed secondary to frequent episodes of hypoglycaemia using standard glycaemic targets for LADA. This case highlights the importance of setting fasting glucose targets within the expected range for GCK-MODY in subjects with coexisting LADA. Learning points: We report the first case of coexisting latent autoimmune diabetes of adulthood (LADA) and GCK-MODY. It has been suggested that mutations in GCK may lead to altered counter-regulation and recognition of hypoglycaemia at higher blood glucose levels than patients without such mutation. However, in our case, hypoglycaemic unawareness developed secondary to frequent episodes of hypoglycaemia using standard glycaemic targets for LADA. This case highlights the importance of setting fasting glucose targets within the expected range for GCK-MODY in subjects with coexisting LADA to avoid hypoglycaemia.

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.

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