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

Cobelli, Claudio; Toffolo, Gianna; Man, Chiara Dalla; Campioni, Marco; Denti, Paolo; Caumo, Andrea; Butler, Peter C.; Rizza, Robert A.

doi:10.1152/ajpendo.00421.2006

Cited by 294 publications

(330 citation statements)

References 62 publications

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“…Over time this additional demand on pancreatic β-cell function may contribute to early failure of the β-cells to compensate for insulin resistance, which will in turn lead to reduced peripheral glucose uptake and insufficient postprandial suppression of glucose production from gluconeogenesis and glycogenolysis and subsequent hyperglycemia. These findings confirm the importance of assessing β-cell function in relation to the prevailing level of insulin action, from a single test (8). The intravenous injection of a glucose bolus is a relatively easy-to-perform test, but results in a rapid glucose and insulin perturbation, which does not reflect the smoother patterns observed following a meal.…”

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confidence: 52%

β‐Cell Function and Insulin Sensitivity in Adolescents From an OGTT

Sunehag

Man

Toffolo

et al. 2009

Obesity

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Given the increase in the incidence of insulin resistance, obesity, and type 2 diabetes in children and adolescents, it would be of paramount importance to assess quantitative indices of insulin secretion and action during a physiological perturbation, such as a meal or an oral glucose-tolerance test (OGTT). A minimal model method is proposed to measure quantitative indices of insulin secretion and action in adolescents from an oral test. A 7 h, 21-sample OGTT was performed in 11 adolescents. The C-peptide minimal model was identified on C-peptide and glucose data to quantify indices of β-cell function: static Φ s and dynamic Φ d responsivity to glucose from which total responsivity Φ was also measured. The glucose minimal model was identified on glucose and insulin data to estimate insulin sensitivity, S I , which was compared to a reference measure, S I ref , provided by a tracer method. Disposition indices, which adjust insulin secretion for insulin action, were then calculated. Indices of β-cell function were Φ s = 51.35 ± 8.89 × 10 -9 min -1 , Φ d = 1,392 ± 258 × 10 -9 , and Φ = 82.09 ± 17.70 × 10 -9 min -1 . Insulin sensitivity was S I = 14.19 ± 2.73 × 10 -4 , not significantly different from S I ref = 14.96 ± 3.04 × 10 -4 dl/kg . min per μU/ml, and well correlated: r = 0.98, P < 0.0001, thus indicating that S I can be accurately measured from an oral test. Disposition indices were DI s = 1,040 ± 201 × 10 -14 dl/kg/min 2 per pmol/l, DI d = 33,178 ± 10,720 × 10 -14 dl/kg/min per pmol/l, DI = 1,844 ± 522 × 10 -14 dl/kg/min 2 per pmol/l. Virtually the same minimal model assessment was obtained with a reduced 3 h, 9-sample protocol. OGTT interpreted with C-peptide and glucose minimal model has the potential to provide novel insight regarding the regulation of glucose metabolism in adolescents, and to evaluate the effect of obesity and interventions such as diet and exercise.

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confidence: 52%

β‐Cell Function and Insulin Sensitivity in Adolescents From an OGTT

Sunehag

Man

Toffolo

et al. 2009

Obesity

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“…In our study of largescale genetic physiology, we applied OGTT to estimate the glucose-stimulated insulin response, a method that is superior to the HOMA-B model in providing a reliable surrogate measure of first-phase insulin release [19,27]. Yet the correlation between different OGTT-based estimates of insulin release was not complete, as shown by results in ESM Table 2.…”

Section: Discussionmentioning

confidence: 99%

“…While fasting levels of glucose and the derived HOMA-B index may depict important processes in the regulation of basal glycaemia, they are not informative with regard to complex dynamic postprandial glucose regulation [19,20]. We therefore evaluated possible associations with estimates of insulin release and insulin sensitivity based on outcomes of OGTT, with a view to further describing the relationship between these variants and elements of glucose homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Variants at DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci are associated with reduced glucose-stimulated beta cell function in middle-aged Danish people

et al. 2010

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Aims/hypothesis A meta-analysis of 21 genome-wide association studies identified 11 novel genetic loci implicated in fasting glucose homeostasis. We aimed to evaluate the impact of these variants on insulin release and insulin sensitivity estimated from OGTTs. Methods Eleven variants in or near DGKB/TMEM195, ADCY5, MADD, ADRA2A, FADS1, CRY2, SLC2A2, GLIS3, PROX1, C2CD4B and IGF1 were genotyped in 6,784 middle-aged participants of the population-based Inter99 cohort. Association studies of quantitative estimates of insulin release and insulin sensitivity were performed in 5,722 non-diabetic Danish participants on whom an OGTT was performed.Results Assuming an additive genetic model, carriers of the alleles increasing fasting glucose in DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B showed decreased glucosestimulated insulin release as assessed by the BIGTT-acute insulin response index (2.7-3.5%; p<0.005 for all) and by corrected insulin response (2.8-5.9%; p<0.03 for all). In addition, the PROX1 glucose-raising allele showed a 2.9% decreased corrected insulin response (p=0.03), while the hyperglycaemic allele of variants in or near ADRA2A, FADS1, CRY2 and C2CD4B were associated with a 2.6% to T. W. Boesgaard and N. Grarup contributed equally to this work. Diabetologia (2010) 53:1647-1655 DOI 10.1007/s00125-010-1753 9.3% decrease in one or both of two different OGTT-based disposition indices (p<0.02 for all). After correction for multiple testing, variants in the DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci were associated with estimates of beta cell function. Conclusions/interpretation We found that the lead variants at the DGKB/TMEM195, ADRA2A, GLIS3 and C2CD4B loci were associated with decreased glucose-stimulated insulin response. This association underlines the importance of pancreatic beta cell dysfunction in the genetic predisposition to hyperglycaemia and type 2 diabetes.

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“…Using C-peptide instead of insulin, the effectiveness of 1 st phase (ϕ 1 ), 2 nd phase (ϕ 2 ) and basal state (ϕ b ) can be calculated during the modified FSIGT by the C-peptide minimal model analysis. 15,16 Minimal model analysis is simpler and easier than the hyperglycemic glucose clamp method that is a direct method for determination of β-cell function because it is less labor intensive, steady-state conditions are not required, and there is no intravenous infusion that requires constant adjustment. Furthermore, information about insulin sensitivity and glucose effectiveness representing insulin-independent action of glucose per se to normalize glucose concentration, in addition to β-cell function can be derived from a single dynamic test.…”

Section: Homa β-Cellmentioning

confidence: 99%