Impaired beta cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects

Walker, Mark; Mari, Andrea; Jayapaul, MK; Bennett, S. M. A.; Ferrannini, Eleuterio

doi:10.1007/s00125-005-0004-7

Cited by 50 publications

(34 citation statements)

References 29 publications

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“…Control subjects, who remained NGT over the entire observational period, also gained weight, but their AIR increased with decreasing insulin sensitivity (3). These findings in a relatively small high-diabetes risk population (n ϭ 17 Pima Indians who transitioned and n ϭ 31 control subjects), based on clamp studies, are in line with results of the present study, as well as findings in 156 nondiabetic subjects from the U.K., based on an OGTT (15). In this latter study, impaired pancreatic ␤-cell glucose sensitivity as well as whole-body insulin sensitivity predicted deteriorating glucose tolerance over 5 years.…”

Section: Discussionsupporting

confidence: 92%

The Natural Course of β-Cell Function in Nondiabetic and Diabetic Individuals

et al. 2006

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Data from the UKPDS (U.K. Prospective Diabetes Study) indicate a continuous decline in ␤-cell function in patients with type 2 diabetes. We studied longitudinal changes in ␤-cell function (follow-up of 5.2 years) in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes, using acute insulin response (AIR) and insulin sensitivity index (S i ) from a frequently sampled intravenous glucose tolerance test among African-American, Hispanic, and non-Hispanic white subjects aged 40 -69 years. At baseline, decreasing levels of both S i and AIR (either unadjusted or adjusted for S i ) mirrored deteriorating glucose tolerance status at baseline and at follow-up. A different pattern was found with respect to longitudinal changes; S i declined in each glucose tolerance category, ranging from ؊0.81 ؋10 ؊4 min ؊1 ⅐ U ؊1⅐ ml ؊1 in NGT at baseline and NGT at follow-up (NGT/NGT) to ؊1.06 ؋10 ؊4 in NGT/diabetes, whereas the directional change in AIR principally determined the glucose tolerance status at follow-up. In NGT/NGT S i decreased by 35% and AIR increased by 34%. Results were similar in each of the three ethnic groups. These data shed light on the natural course of ␤-cell function; over 5.2 years, mean insulin sensitivity declined in each glucose tolerance category. The change in AIR, however, principally determined glucose tolerance status at follow-up; NGT was maintained by a compensatory increase in insulin secretion. Failure to increase insulin secretion led to IGT, and a decrease in insulin secretion led to overt diabetes. This data may have important implications for the prevention and treatment of type 2 diabetes. Diabetes 55:1114 -1120, 2006 I mpaired insulin secretion and impaired insulin action (increased insulin resistance) are the two major components contributing to the pathophysiology of type 2 diabetes (1-3); their complex relationship has been mathematically described as a curvilinear relationship (4 -6). Longitudinal studies indicate that compromised ␤-cell function is detectable in pre-diabetic individuals long before the onset of actual type 2 diabetes (1,7). The natural course of ␤-cell function over time, however, is poorly understood, and published data are scarce. A longitudinal study in Pima Indians highlighted the importance of declining ␤-cell function in individuals transitioning from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) and IGT to diabetes, respectively (3). In the U.K. Prospective Diabetes Study (UKPDS), a continuous decline in ␤-cell function in patients with type 2 diabetes, irrespective of glucose-lowering treatment, was demonstrated (8). No data on the natural course of ␤-cell function is currently available in a large population, across different ethnic groups, and using a direct measure of insulin secretion. Therefore, we studied longitudinal changes in ␤-cell function over 5.2 years by acute insulin response (AIR) relative to insulin sensitivity index (S i ), as assessed from a frequently sampled intravenous gluco...

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Section: Discussionsupporting

confidence: 92%

The Natural Course of β-Cell Function in Nondiabetic and Diabetic Individuals

et al. 2006

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“…This is the first study to show that risk alleles individually associated with impaired pancreatic beta cell function combine in the same additive manner to markedly decrease beta cell function in individuals carrying multiple susceptibility alleles. The additive impact upon beta cell glucose sensitivity is of particular interest, as decreased beta cell glucose sensitivity in non-diabetic individuals has been shown to be a powerful, independent predictor for progression to type 2 diabetes [18]. Importantly, the decrease in the indices of beta cell function with increasing number of risk alleles was not a function of changes in whole-body insulin sensitivity (M/I), which essentially remained unchanged, as shown in Table 1.…”

Section: Resultsmentioning

confidence: 99%

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

et al. 2008

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Aims/hypothesis Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk alleles on measures of beta cell function in non-diabetic individuals. Methods A total of 1,211 non-diabetic individuals underwent metabolic assessment including an OGTT, from which measures of beta cell function were derived. Individuals were genotyped at each of the risk loci and then classified according to the total number of risk alleles that they carried. Initial analysis focused on CDKAL1, HHEX/IDE and TCF7L2 loci, which were individually associated with a decrease in beta cell function in our cohort. Risk alleles for CDKN2A/B, SLC30A8, IGF2BP2 and KCNJ11 loci were subsequently included into the analysis. Results The diabetes-risk alleles for CDKAL1, HHEX/IDE and TCF7L2 showed an additive model of association with measures of beta cell function. Beta cell glucose sensitivity was decreased by 39% in those individuals with five or more risk alleles compared with those individuals with no risk alleles (geometric mean [SEM]: 84 [1.07] vs 137 [1.11] pmol min −1 m −2 (mmol/l) −1 , p=1.51×10 −6 ). The same was seen for the 30 min insulin response (p=4.17×10 −7 ). The relationship remained after adding in the other four susceptibility loci (30 min insulin response and beta cell glucose sensitivity, p<0.001 and p=0.003, respectively).Conclusions/interpretation This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in nondiabetic individuals.

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“…This results from the coexistence of insulin resistance with an intrinsic defect in beta cell glucose sensing on a background of normal coupling between IS and the fasting secretory tone [23]. Clearly, deterioration of the glucose sensing defect over time is likely to be a further contributor to hyperglycaemia [10], possibly sustained by glucotoxicity. For this reason, longitudinal studies showing progressive loss of beta cell function in relation to IS in participants who develop hyperglycaemia [24] do not necessarily indicate defective compensation, as progressive beta cell dysfunction alone is a sufficient explanation.…”

Section: Discussionmentioning

confidence: 99%

“…Our data and analyses were compatible with the idea that beta cell adaptation to insulin resistance does not involve all modes of the secretory response to glucose stimulation. To improve our understanding of how beta cell function is modulated by insulin resistance in persons with normal and impaired glucose tolerance, we extended our previous analysis [9,10] to a much larger group of ∼1,300 healthy non-diabetic participants from the European Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study [11], who underwent a euglycaemichyperinsulinaemic clamp as a direct measure of IS, an OGTT for assessment of beta cell function by mathematical modelling and a glucose bolus to estimate AIR.…”

Section: Introductionmentioning

confidence: 99%

Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance

Mari¹,

Tura²,

Natali

et al. 2010

Diabetologia

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Aims/hypothesis It is commonly thought that hyperglycaemia results from insufficient compensation of insulin secretion for insulin resistance. To verify this hypothesis, we assessed beta cell function and insulin sensitivity (IS) in a large cohort of volunteers with normal glucose tolerance (NGT) or impaired glucose regulation (IGR), i.e. impaired glucose tolerance or impaired fasting glucose. Methods In men and women with NGT (n=1,123) or IGR (n=156) (age 44±8 years, BMI 25±4 kg/m 2 , mean ± SD) we measured: (1) IS by clamp; (2) insulin secretion rates (ISR) and beta cell glucose sensitivity (=slope of the insulin secretion/plasma glucose dose-response) by C-peptide deconvolution and OGTT modelling; and (3) acute insulin response to intravenous glucose. Results After controlling for centre, sex, age and BMI, fasting and total ISR were inversely related to IS in both groups, whereas beta cell glucose sensitivity was not. Acute insulin response was reciprocally related to IS in both groups, but the relationships were incompatible with inadequate compensation and significance was lost after controlling for fasting ISR. In IGR vs NGT, IS was impaired (92 [75] , p<0.0001), whereas fasting and total ISR were increased (35% and 25%, respectively, p< 0.0001). In fully adjusted models, beta cell glucose sensitivity was the strongest determinant of OGTT glucose levels. Conclusions/interpretation Insulin resistance normally upregulates the secretory tone, with no evidence of defective compensation in IGR. In contrast, beta cell glucose sensitivity is independent of insulin resistance, but a key determinant of glucose tolerance. This suggests that hyperglycaemia results from an intrinsic beta cell defect rather than from inadequate compensation for insulin resistance.

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Impaired beta cell glucose sensitivity and whole-body insulin sensitivity as predictors of hyperglycaemia in non-diabetic subjects

Cited by 50 publications

References 29 publications

The Natural Course of β-Cell Function in Nondiabetic and Diabetic Individuals

The Natural Course of β-Cell Function in Nondiabetic and Diabetic Individuals

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance

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