Effect of Iron Chelation Therapy on Glucose Metabolism in Non-Transfusion-Dependent Thalassaemia

Although a hyperbolic relationship between insulin secretion and insulin sensitivity has been shown, the relationship has been often questioned. We examined the relationship using oral glucose tolerance test (OGTT)-derived indexes. A total of 374 Japanese subjects who had never been given a diagnosis of diabetes underwent a 75-g OGTT. In subjects with normal glucose tolerance (NGT), the ln [insulinogenic index (IGI)] was described by a linear function of ln ( x) ( x, insulin sensitivity index) in regression analysis when the reciprocal of the insulin resistance index in homeostasis model assessment, Matsuda's index, and oral glucose insulin sensitivity index were used as x. Because the 95% confidence interval of the slope of the regression line did not necessarily include −1, the relationships between IGI and x were not always hyperbolic, but power functions IGI × xα = a constant. We thought that IGI × xα was an appropriate β-cell function estimate adjusted by insulin sensitivity and referred to it as β-cell function index (BI). When Matsuda's index was employed as x, the BI values were decreased in subjects without NGT. Log BI had a better correlation with fasting plasma glucose (PG; FPG) and 2-h PG in non-NGT subjects than in NGT subjects. In subjects with any glucose tolerance, log BI was linearly correlated with 1-h PG and glucose spike (the difference between maximum PG and FPG). In conclusion, the relationship between insulin secretion and insulin sensitivity was not always hyperbolic. The BI is a useful tool in the estimation of β-cell function with a mathematical basis.

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Agreement and Reliability of Fasted and Oral Glucose Tolerance Test-Derived Indices of Insulin Sensitivity and Beta Cell Function in Boys

International Journal of Sports Medicine ◽

10.1055/s-0043-104932 ◽

2017 ◽

Vol 38 (06) ◽

pp. 411-417 ◽

Cited By ~ 3

Author(s):

Emma Cockcroft ◽

Craig Williams ◽

Sarah Jackman ◽

Neil Armstrong ◽

Alan Barker

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Tolerance Test ◽

Cell Function ◽

Tolerance Test ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Β Cell ◽

Β Cell Function ◽

Method Agreement

AbstractAssessment of plasma insulin and glucose outcomes is important in paediatric studies aimed at reducing future risk of type 2 diabetes and cardiovascular disease. The aims of this study are to determine the between-method agreement and the day-to-day reliability of fasting and oral glucose tolerance test (OGTT)-derived estimates of insulin sensitivity and β-cell function in healthy boys. Fasting and OGTT assesments of insulin resistance and β-cell function were performed on 28 boys (12.3±2.9 years). Measurements were repeated after 1 week (fasting, n=28) and 1 day (OGTT, n=8). Agreement between estimates of insulin resistance and β-cell function was examined using Pearson’s correlation coefficient. Reliability was assessed using change in the mean, Pearson’s correlation coefficient, and typical error expressed as a coefficient of variation (CV). The Matsuda index was positively related with QUICKI (r=0.88, P<0.001) and negatively related to HOMA-IR (r=−0.76, P<0.001). The Cederholm index was not significantly related with fasting estimates of insulin resistance (all r<0.40, P>0.05). For reliability, QUICKI had the lowest CV% for the fasting (4.7%) and the Cederholm index for the OGTT (6.4%) estimates. The largest CV% was observed in fasting insulin (30.8%) and insulinogenic index 30’ (62.5%). This study highlights differences in between-method agreement and day-to-day reliability for estimates of insulin resistance in youth. The low CV supports the use of the FGIR (fasting) and Cederholm (OGTT) indices in this population.

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Early Detection of Insulin Sensitivity and β-Cell Function with Simple Tests Indicates Future Derangements in Late Pregnancy

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2007-1363 ◽

2008 ◽

Vol 93 (3) ◽

pp. 876-880 ◽

Cited By ~ 31

Author(s):

A. Lapolla ◽

M. G. Dalfrà ◽

G. Mello ◽

E. Parretti ◽

R. Cioni ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Early Pregnancy ◽

Cell Function ◽

Late Pregnancy ◽

Tolerance Test ◽

Oral Glucose ◽

Β Cell ◽

Β Cell Function

Abstract Objective: Insulin sensitivity and secretion during early and late pregnancy were assessed in women with normal glucose tolerance and gestational diabetes mellitus (GDM). Research Design and Methods: The oral glucose tolerance test (OGTT) was performed in 903 women at 16–20th gestational week, of whom 37 had GDM (GDM1 group), and 859 repeated the OGTT at wk 26–30. At the second test, 55 had GDM (GDM2 group); the others remained normotolerant (ND group). Insulin sensitivity from OGTT (as quantitative insulin sensitivity check index and OGTT insulin sensitivity) and β-cell function (as the ratio of the areas under the insulin and glucose concentration curves, adjusted for insulin sensitivity) were assessed in both tests. Results: In early pregnancy the quantitative insulin sensitivity check index was not different in the three groups, whereas OGTT insulin sensitivity was lowest in GDM2, intermediate in GDM1, and highest in ND. In late pregnancy both indices were reduced in GDM compared with ND and lower than in early pregnancy. In early pregnancy GDM1, but not GDM2, had lower β-cell function than ND. During the late visit, GDM2 also showed impaired β-cell function compared with ND; furthermore, the adaptation to the increase to insulin resistance from early to late pregnancy was defective in GDM2. Conclusions: In early pregnancy insulin sensitivity, as assessed from the OGTT but not from fasting measurements, is impaired in women who developed GDM. β-Cell function impairment is evident only when GDM is manifest and is characterized by inappropriate adaptation to the pregnancy induced increase in insulin resistance.

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Assessment of β-cell function in humans, simultaneously with insulin sensitivity and hepatic extraction, from intravenous and oral glucose tests

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00421.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. E1-E15 ◽

Cited By ~ 207

Author(s):

Claudio Cobelli ◽

Gianna Maria Toffolo ◽

Chiara Dalla Man ◽

Marco Campioni ◽

Paolo Denti ◽

...

Keyword(s):

Insulin Sensitivity ◽

Minimal Model ◽

Glucose Tolerance Test ◽

Cell Function ◽

Tolerance Test ◽

Oral Glucose ◽

Β Cell ◽

Physiological Conditions ◽

Β Cell Function ◽

Hepatic Insulin Extraction

Assessment of insulin secretion in humans under physiological conditions has been a challenge because of its complex interplay with insulin action and hepatic insulin extraction. The possibility of simultaneously assessing β-cell function, insulin sensitivity, and hepatic insulin extraction under physiological conditions using a simple protocol is appealing, since it has the potential to provide novel insights regarding the regulation of fasting and postprandial glucose metabolism in diabetic and nondiabetic humans. In this Perspective, we review data indicating that an oral glucose tolerance test (OGTT) or a meal test is able to accomplish this goal when interpreted with the oral β-cell minimal model. We begin by using the well-established intravenous minimal model to highlight how the oral minimal model was developed and how the oral assessment parallels that of an intravenous glucose tolerance test (IVGTT). We also point out the unique aspects of both approaches in relation to their ability to assess different aspects of the β-cell secretory cascade. We review the ability of the oral model to concurrently measure insulin sensitivity and hepatic insulin extraction, thereby enabling it to quantitatively portray the complex relationship among β-cell function, hepatic insulin extraction, and insulin action. In addition, data from 204 individuals (54 young and 159 elderly) who underwent both IVGTT and meal tolerance tests are used to illustrate how these different approaches provide complementary but differing insights regarding the regulation of β-cell function in humans.

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Evaluation of different methods for assessment of insulin sensitivity in Göttingen minipigs: introduction of a new, simpler method

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90851.2008 ◽

2009 ◽

Vol 297 (4) ◽

pp. R1195-R1201 ◽

Cited By ~ 35

Author(s):

Berit Christoffersen ◽

Ulla Ribel ◽

Kirsten Raun ◽

Valeria Golozoubova ◽

Giovanni Pacini

Keyword(s):

Insulin Sensitivity ◽

Cell Function ◽

High Energy ◽

Tolerance Test ◽

Insulin Tolerance Test ◽

Oral Glucose ◽

Β Cell ◽

Simple Index ◽

Insulin Tolerance ◽

Β Cell Function

The use of animal models in diabetes research requires reliable tests for evaluation of insulin sensitivity and β-cell function. Minipigs are being increasingly used in metabolic research, and the aim of this study was to compare different tests and indexes for evaluation of insulin sensitivity and β-cell function in Göttingen minipigs. Hyperinsulinemic, isoglycemic clamp, intravenous (IVGTT) and oral glucose tolerance tests (OGTT), and a modified insulin tolerance test were performed in minipigs fed either low- or high-energy diet. Furthermore, the reproducibility of IVGTT-derived parameters was assessed. Previously described insulin sensitivity indexes [steady-state glucose infusion rate/glucose concentration/insulin concentration from clamp (M/G/I); oral glucose insulin sensitivity (OGIS) and ISIcomp from OGTT; SI from minimal model analysis of IVGTT; and quantitative insulin sensitivity check index from fasting values] were calculated together with an insulin sensitivity index from the modified insulin tolerance test (ISIITT) and a new simple index (S2) derived from the first 30 min of the IVGTT. β-Cell function was assessed from the IVGTT and the OGTT. Reproducibility of the IVGTT-derived parameters was calculated as median intraindividual coefficient of variation (CV%).M/G/I correlated significantly only with S2 ( P < 0.05, r = 0.54). S2 furthermore correlated with SI ( P < 0.001, r = 0.81), ISIITT ( P < 0.001, r = 0.57), and the two indexes from OGTT, ISIcomp ( P < 0.001, r = 0.78) and OGIS ( p < 0.05, r = 0.48). No correlation was found between β-cell function indexes from OGTT and IVGTT. The median CV% of the new S2 index was 13. In conclusion, the new simple index of insulin sensitivity, S2, was revealed to be useful for evaluation of insulin sensitivity in pigs.

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OGTT Glucose Response Curves, Insulin Sensitivity, and β-Cell Function in RISE: Comparison Between Youth and Adults at Randomization and in Response to Interventions to Preserve β-Cell Function

10.2337/figshare.13373708.v1 ◽

2021 ◽

Author(s):

Silva Arslanian ◽

Laure El ghormli ◽

Joon Young Kim ◽

Ashley H. Tjaden ◽

Elena Barengolts ◽

...

Keyword(s):

Insulin Sensitivity ◽

B Cell ◽

Cell Function ◽

Tolerance Test ◽

Oral Glucose ◽

Β Cell ◽

Response Curves ◽

Glucose Response ◽

Cross Sectional ◽

Β Cell Function

Objective: We examined the glucose-response-curves [Biphasic (BPh), Monophasic (MPh), Incessant-Increase (IIn)], during an oral glucose tolerance test (OGTT), and their relationship to insulin sensitivity (IS) and b-cell function (bCF) in youth vs. adults with IGT or recently diagnosed type 2 diabetes. Research Design and Methods: This was both a cross-sectional and longitudinal evaluation of participants in the RISE study randomized to metformin alone for 12 months or glargine for 3 months followed by metformin for 9 months. At baseline/randomization, OGTTs (85 youth, 353 adults) were categorized as BPh, MPh, or IIn. The relationship of the glucose-response-curves to hyperglycemic-clamp-measured IS and bCF at baseline, and the change in glucose-response-curves 12 months after randomization were assessed. Results: At randomization, the prevalence of the BPh-curve was significantly higher in youth than adults (18.8% vs. 8.2%), with no differences in MPh or IIn. IS did not differ across glucose-response-curves in youth or adults. However, irrespective of curve type, youth had lower IS than adults (p<0.05). bCF was lowest in IIn vs. MPh and BPh in youth and adults (p <0.05). Yet, compared with adults, youth had higher bCF in BPh and MPh (p<0.005), but not IIn curves. At month 12, the change in glucose-response-curves did not differ between youth and adults, and there was no treatment effect. Conclusions: Despite a 2-fold higher prevalence of the more-favorable BPh curve in youth at randomization, RISE interventions did not result in beneficial changes in glucose-response-curves in youth compared with adults. Moreover, the typical b-cell hypersecretion in youth was not present in the IIn curve, emphasizing the severity of b-cell dysfunction in youth with this least- favorable glucose-response-curve.

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Effect of Iron Chelation Therapy on Glucose Metabolism in Non-Transfusion-Dependent Thalassemia

Blood ◽

10.1182/blood.v126.23.4568.4568 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4568-4568

Author(s):

Ampaiwan Chuansumrit ◽

Pimprae Pengpis ◽

Pat Mahachoklertwattana ◽

Nongnuch Sirachainan ◽

Preamrudee Poomthavorn ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Serum Ferritin ◽

Chelation Therapy ◽

Cell Function ◽

Iron Chelation ◽

Iron Chelation Therapy ◽

Β Cell ◽

Β Cell Function

Abstract Background: Increased intestinal iron absorption has been shown in non-transfusion-dependent thalassemia (NTDT) and thus results in mild to moderate iron excess. Therefore, these patients should theoretically have increased risks of pre-diabetes and diabetes. However, there have been no studies addressing insulin and glucose metabolism in these patients. We, therefore, hypothesize that NTDT with iron excess may have impaired β-cell function and reduced insulin sensitivity and their improvements may occur following iron chelation therapy. Objective: To assess insulin sensitivity and β-cell function in NTDT with iron excess pre- and post-iron chelation therapy. Study design: non-randomized open-labelled prospective cohort study Patients: Inclusion criteria: NTDT patients, aged older than 10 years who have had serum ferritin >300 ng/mL and/or transferrin saturation ≥70% and/or liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight. Exclusion criteria: Known case of type I or type II DM and taking medications affecting glucose metabolism or iron chelation therapy within one month prior to study. Methods: The complete patient histories were obtained and physical examinations were performed initially and at 3- and 6-month follow-up. Deferasirox at the dose of 10 mg/kg was prescribed daily to the studied patients for 6 months. Iron status indicators including serum ferritin, serum iron, total iron biding capacity (TIBC), transferrin saturation, non-transferrin-binding iron (NTBI) and hepcidin were determined pre- and 6-month post-chelation. For assessment of glucose metabolism, an oral glucose tolerance test (OGTT) and serum adiponectin were determined pre- and 6-month post-chelation. During an OGTT, serum insulin and plasma glucose at 0, 30, 60, 90 and 120 min were obtained. Insulin resistance, insulin sensitivity and β-cell function indices including homeostatic model assessment-insulin resistance (HOMA-IR), whole body insulin sensitivity index (WBISI) and disposition index (WBISI x insulinogenic index), were calculated. Also, MRI of the heart, liver and pancreas were monitored pre- and 6-month post-chelation. Results: Ten patients (7 males) with a median age of 17.4 years enrolled in the study. Seven patients were b-thalassemia /Hb E disease of either b0 or b+ thalassemia genes and three patients were non-deletion type of Hb H disease with Hb Constant Spring or Hb Pakse. One of these three patients had additional Hb E resulting in AE Bart's disease. The severity of the thalassemia diseases was classified using a scoring system for b-thal/HbE revealing severe (n=1), moderate (n=6) and mild (n=3) degrees. For iron status indicators, the median pre-chelation serum ferritin was significantly higher than that of post-chelation (551.4 vs. 486.1 ng/mL, p=0.049). Also, the median pre-chelation TIBC was significantly lower than that of post-chelation (211.5 vs. 233.5 µg/dL, p=0.006). The median pre-chelation NTBI was higher than that of post-chelation (6.2 vs 4.0 µM, p =0.068) but no statistical significance. Also, the median pre-chelation hepcidin was lower than that of post-chelation but no statistical significance. For glucose metabolism, the median pre-chelation serum adiponectin was not different from that of post-chelation (46.41 vs. 48.77 ng/mL, p=0.508). All patients had normal glucose tolerance both pre- and post-chelation with no significant changes of body mass index during the 6-month period. However, there was a significant reduction of fasting plasma glucose after iron chelation (85.0 vs.79.5 mg/dL, p =0.045). In comparison between pre- and post-chelation, there were trends towards decreasing insulin resistance index expressed as HOMA-IR (0.8 vs. 0.2, p =0.219) and increasing insulin sensitivity indices expressed as WBISI (11.5 vs. 19.8, p =0.105). Also, there was a trend towards improving β-cell function expressed as disposition index (5.1 vs. 6.2, p=0.064). MRI revealed no significant changes of iron accumulation in liver, pancreas and myocardium following 6-month iron chelation therapy. No adverse effects following oral iron chelation therapy were detected. Conclusions: There was a trend towards improving insulin sensitivity and β-cell function following 6-month iron chelation therapy. Longer term of iron chelating agent treatment may demonstrate a significant beneficial effect on glucose metabolism. Disclosures No relevant conflicts of interest to declare.

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OGTT Glucose Response Curves, Insulin Sensitivity, and β-Cell Function in RISE: Comparison Between Youth and Adults at Randomization and in Response to Interventions to Preserve β-Cell Function

10.2337/figshare.13373708 ◽

2021 ◽

Author(s):

Silva Arslanian ◽

Laure El ghormli ◽

Joon Young Kim ◽

Ashley H. Tjaden ◽

Elena Barengolts ◽

...

Keyword(s):

Insulin Sensitivity ◽

B Cell ◽

Cell Function ◽

Tolerance Test ◽

Oral Glucose ◽

Β Cell ◽

Response Curves ◽

Glucose Response ◽

Cross Sectional ◽

Β Cell Function

Objective: We examined the glucose-response-curves [Biphasic (BPh), Monophasic (MPh), Incessant-Increase (IIn)], during an oral glucose tolerance test (OGTT), and their relationship to insulin sensitivity (IS) and b-cell function (bCF) in youth vs. adults with IGT or recently diagnosed type 2 diabetes. Research Design and Methods: This was both a cross-sectional and longitudinal evaluation of participants in the RISE study randomized to metformin alone for 12 months or glargine for 3 months followed by metformin for 9 months. At baseline/randomization, OGTTs (85 youth, 353 adults) were categorized as BPh, MPh, or IIn. The relationship of the glucose-response-curves to hyperglycemic-clamp-measured IS and bCF at baseline, and the change in glucose-response-curves 12 months after randomization were assessed. Results: At randomization, the prevalence of the BPh-curve was significantly higher in youth than adults (18.8% vs. 8.2%), with no differences in MPh or IIn. IS did not differ across glucose-response-curves in youth or adults. However, irrespective of curve type, youth had lower IS than adults (p<0.05). bCF was lowest in IIn vs. MPh and BPh in youth and adults (p <0.05). Yet, compared with adults, youth had higher bCF in BPh and MPh (p<0.005), but not IIn curves. At month 12, the change in glucose-response-curves did not differ between youth and adults, and there was no treatment effect. Conclusions: Despite a 2-fold higher prevalence of the more-favorable BPh curve in youth at randomization, RISE interventions did not result in beneficial changes in glucose-response-curves in youth compared with adults. Moreover, the typical b-cell hypersecretion in youth was not present in the IIn curve, emphasizing the severity of b-cell dysfunction in youth with this least- favorable glucose-response-curve.

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Identification of insulin secretory defects and insulin resistance during oral glucose tolerance test in a cohort of cystic fibrosis patients

Acta Endocrinologica ◽

10.1530/eje-10-1003 ◽

2011 ◽

Vol 165 (1) ◽

pp. 69-76 ◽

Cited By ~ 21

Author(s):

A Battezzati ◽

A Mari ◽

L Zazzeron ◽

G Alicandro ◽

L Claut ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Glucose Tolerance Test ◽

Cell Function ◽

Tolerance Test ◽

Oral Glucose ◽

Oral Glucose Tolerance ◽

Β Cell ◽

Β Cell Function

BackgroundCystic fibrosis (CF)-related diabetes is a leading complication of CF and is associated with pulmonary and nutritional deterioration, years before an evident hyperglycemia, possibly because of insulin deficiency and resistance.AimTo evaluate glucose tolerance, insulin secretion, and insulin sensitivity by a widely applicable method suitable for accurate and prospective measurements in a CF population.MethodsA total of 165 CF subjects (80 females) aged 17±5 years and 18 age- and sex-matched healthy controls (CON) received an oral glucose tolerance test with glucose, insulin and C-peptide determinations. Insulin sensitivity was defined on the basis of glucose and insulin concentrations using the oral glucose insulin sensitivity index, whereas β-cell function was determined on the basis of a model relating insulin secretion (C-peptide profile) to glucose concentration.ResultsFifteen percent of CF patients had glucose intolerance and 6% had diabetes without fasting hyperglycemia and 3% had diabetes with fasting hyperglycemia. β-cell function was reduced in CF patients compared with CON (70.0±4.1 vs 117.9±11.6 pmol/min per m2 per mM, P<0.001) and decreased significantly with age by −2.7 pmol/min per m2 per mM per year (confidence interval (CI) −4.5 to −0.82), i.e. almost 4% yearly. The early insulin secretion index was also reduced. Insulin sensitivity was similar to CON. CF patients who attained glucose tolerance comparable to CON had lower β-cell function and higher insulin sensitivity.ConclusionThe major alteration in insulin secretion and insulin sensitivity of CF patients is slowly declining β-cell function, consisting of delayed and reduced responsiveness to hyperglycemia, that in CF patients with normal glucose tolerance may be compensated by an increased insulin sensitivity.

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