A Mari

Publications (41)234.86 Total impact

• Source

  Available from: M Paula Macedo

  Article: Systemic inhibition of nitric oxide synthesis in non-diabetic individuals produces a significant deterioration in glucose tolerance by increasing insulin clearance and inhibiting insulin secretion.

  A Natali, R Ribeiro, S Baldi, A Tulipani, M Rossi, E Venturi, A Mari, M P Macedo, E Ferrannini
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  ABSTRACT: AIMS/HYPOTHESIS: Endogenous NO inhibits insulin release in isolated beta cells and insulin-degrading enzyme activity in hepatocytes, while NO release from endothelial cells has been suggested to enhance insulin action. We assessed the overall effect of systemic inhibition of endogenous NO synthesis on glucose homeostasis in humans. METHODS: Twenty-four non-diabetic volunteers underwent two hyperglycaemic (+7 mmol/l) clamps with either saline or L-NG-nitroarginine methyl ester (L-NAME, at rates of 2.5, 5, 10 and 20 μg min(-1) kg(-1)) infusion. Another five volunteers underwent an OGTT with either saline or L-NAME (20 μg min(-1) kg(-1)) infusion. Blood pressure and heart rate were measured to monitor NO blockade; during the OGTT, endothelial function was assessed by peripheral arterial tonometry and insulin secretion by C-peptide deconvolution and insulin secretion modelling. RESULTS: Compared with saline, L-NAME at the highest dose raised mean blood pressure (+20 ± 2 mmHg), depressed heart rate (-12 ± 2 bpm) and increased insulin clearance (+50%). First-phase insulin secretion was impaired, but insulin sensitivity (M/I index) was unchanged. During the OGTT, L-NAME raised 2 h plasma glucose by 1.8 mmol/l (p < 0.01), doubled insulin clearance and impaired beta cell glucose sensitivity while depressing endothelial function. CONCLUSIONS/INTERPRETATION: In humans, systemic NO blockade titrated to increase blood pressure and induce endothelial dysfunction does not affect insulin action but significantly impairs glucose tolerance by increasing plasma insulin clearance and depressing insulin secretion, namely first-phase and beta cell glucose sensitivity.
  Diabetologia 01/2013; · 6.81 Impact Factor
• Source

  Available from: Peter de Jonge

  Article: Depressive symptoms, insulin sensitivity and insulin secretion in the RISC cohort study.

  M Bot, F Pouwer, P De Jonge, J J Nolan, A Mari, K Højlund, A Golay, B Balkau, J M Dekker
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  ABSTRACT: AIM: This study explored the association of depressive symptoms with indices of insulin sensitivity and insulin secretion in a cohort of non-diabetic men and women aged 30 to 64 years. METHODS: The study population was derived from the 3-year follow-up of the Relationship between Insulin Sensitivity and Cardiovascular Disease Risk (RISC) study. Presence of significant depressive symptoms was defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score ≥ 16. Standard oral glucose tolerance tests were performed. Insulin sensitivity was assessed with the oral glucose insulin sensitivity (OGIS) index. Insulin secretion was estimated using three model-based parameters of insulin secretion (beta-cell glucose sensitivity, the potentiation factor ratio, and beta-cell rate sensitivity). RESULTS: A total of 162 out of 1027 participants (16%) had significant depressive symptoms. Having significant depressive symptoms was not related to either OGIS [standardized beta (β) -0.033; P=0.24] or beta-cell glucose sensitivity (β -0.007; P=0.82). Significant depressive symptoms were related to decreased beta-cell rate sensitivity (odds ratio for significant depressive symptoms of the lowest vs. highest quartile of beta-cell rate sensitivity was 2.04; P=0.01). Also, significant depressive symptoms were associated with a statistically significant decrease in the potentiation factor ratio in unadjusted models, but not in the fully adjusted model. CONCLUSION: Depressive symptoms were not related to insulin sensitivity and tended to be weakly associated to some parameters of insulin secretion in non-diabetic individuals. Prospective studies are needed to study the temporal association between depression and insulin secretion.
  Diabetes & Metabolism 11/2012; · 2.41 Impact Factor
• Article: Moderate alcohol consumption is associated with improved insulin sensitivity, reduced basal insulin secretion rate and lower fasting glucagon concentration in healthy women.

  F Bonnet, E Disse, M Laville, A Mari, K Hojlund, C H Anderwald, P Piatti, B Balkau
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  ABSTRACT: AIMS/HYPOTHESIS: Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes with a stronger effect in women. As the underlying mechanisms remain poorly characterised, we investigated its relationship with insulin resistance, insulin secretion, clearance of insulin and glucagon concentration. METHODS: One-thousand two-hundred and seventy-six non-diabetic individuals from the RISC (relationship between insulin sensitivity and cardiovascular disease) study without high alcohol consumption were studied; all had a euglycaemic-hyperinsulinaemic clamp and an OGTT with assessment of insulin sensitivity, secretion and clearance. RESULTS: Alcohol consumption was positively associated with insulin sensitivity in women (β = 0.15, p ( trend ) = 0.005) and in men (β = 0.07, p ( trend ) = 0.07) after controlling for age, centre, waist, smoking and physical activity. In women, this association persisted after adjustment for adiponectin but was attenuated after controlling for HDL-cholesterol, suggesting that part of the protection is related to a higher HDL-cholesterol concentration. Higher alcohol consumption was associated with lower basal insulin secretion in women only (β = -0.10, p ( trend ) = 0.004) and this association persisted after adjustment for insulin sensitivity. In men, increasing alcohol consumption was associated with enhanced insulin clearance and increased fasting NEFA concentrations, independently of insulin sensitivity. Fasting glucagon decreased with increasing alcohol in women only (abstainers 9.2 ± 4.4; <28 g/week 8.6 ± 4.0; 28-64 g/week 8.1 ± 3.7; >64 g/week 7.5 ± 3.1 pmol/l; p ( trend ) = 0.01). CONCLUSIONS/INTERPRETATION: Light-to-moderate alcohol consumption was associated in healthy women with enhanced insulin sensitivity, reduced basal insulin secretion rate and lower fasting plasma glucagon concentration, providing consistent mechanisms for the reduced risk of diabetes.
  Diabetologia 08/2012; · 6.81 Impact Factor
• Article: Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance

  A. Mari, A. Tura, A. Natali, M. Laville, M. Laakso, R. Gabriel, H. Beck-Nielsen, E. Ferrannini, The RISC Investigators
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  ABSTRACT: Aims/hypothesisIt 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. MethodsIn men and women with NGT (n = 1,123) or IGR (n = 156) (age 44 ± 8years, BMI 25 ± 4kg/m2, 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. ResultsAfter 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] vs 133 [86] μmolmin−1 [kg fat-free mass]−1 [nmol/l]−1, median [interquartile range], p < 0.0001) as was beta cell glucose sensitivity (69 [46] vs 119 [83] pmolmin−1m−2 [nmol/l]−1, 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/interpretationInsulin 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. KeywordsBeta cell compensation-Beta cell function-Glucose tolerance-Hyperglycaemia-Insulin sensitivity-Pre-diabetes
  Diabetologia 04/2012; 53(4):749-756. · 6.81 Impact Factor
• Article: Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response

  C. Langenberg, L. Pascoe, A. Mari, A. Tura, M. Laakso, T. M. Frayling, I. Barroso, R. J. F. Loos, N. J. Wareham, M. Walker, The RISC Consortium
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  ABSTRACT: Aims/hypothesisWe investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals, is associated with measures of beta cell function and whole-body insulin sensitivity. MethodsWe studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic–hyperinsulinaemic clamp and indices of beta cell function were derived from a 75g oral glucose tolerance test (including 30min insulin response and glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre. ResultsThe minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d’Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU]; 0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085, 0.25] per G allele, p = 5.8 × 10−5), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response (−0.19 [−0.28, −0.10], p = 1.7 × 10−5), as well as with decreased beta cell glucose sensitivity (−0.11 [−0.20, −0.027], p = 0.010). No associations were observed with clamp-assessed insulin sensitivity (p = 0.15) or different measures of body size (p > 0.7 for all). Conclusions/interpretationGenetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B.
  Diabetologia 04/2012; 52(8):1537-1542. · 6.81 Impact Factor
• Article: Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

  L. Pascoe, T. M. Frayling, M. N. Weedon, A. Mari, A. Tura, E. Ferrannini, M. Walker, on behalf of the RISC Consortium
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  ABSTRACT: Aims/hypothesisNovel 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. MethodsA 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. ResultsThe 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 30min insulin response (p = 4.17 × 10−7). The relationship remained after adding in the other four susceptibility loci (30min insulin response and beta cell glucose sensitivity, p < 0.001 and p = 0.003, respectively). Conclusions/interpretationThis study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in non-diabetic individuals.
  Diabetologia 04/2012; 51(11):1989-1992. · 6.81 Impact Factor
• Article: The Finnish Diabetes Risk Score is associated with insulin resistance but not reduced β-cell function, by classical and model-based estimates.

  K G Brodovicz, J M Dekker, J M Rijkelijkhuizen, T Rhodes, A Mari, M Alssema, G Nijpels, D E Williams-Herman, C J Girman
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  ABSTRACT: The Finnish Diabetes Risk Score (FINDRISC) is widely used for risk stratification in Type 2 diabetes prevention programmes. Estimates of β-cell function vary widely in people without diabetes and reduced insulin secretion has been described in people at risk for diabetes. The aim of this analysis was to evaluate FINDRISC as a tool to characterize reduced β-cell function in individuals without known diabetes. In this population-based cohort from the Hoorn municipal registry, subjects received an oral glucose tolerance test and a meal tolerance test on separate days, in random order, within 2 weeks. One hundred and eighty-six subjects, age 41-66 years, with no known Type 2 diabetes were included. Of those, 163 (87.6%) had normal glucose metabolism and 23 (12.4%) had abnormal glucose metabolism (19 with impaired glucose metabolism; four with newly diagnosed Type 2 diabetes based on study results). Insulin sensitivity and β-cell function (classical: insulinogenic index; ratio of areas under insulin/glucose curves; model-based: glucose sensitivity; rate sensitivity; potentiation) estimates were calculated from oral glucose tolerance test and meal tolerance test data. FINDRISC was associated with insulin sensitivity (r = -0.41, P < 0.0001), insulin/glucose areas under the curve (meal tolerance test: r = 0.29, P < 0.0001; oral glucose tolerance test: r = 0.21, P = 0.01) and potentiation factor (meal tolerance test: r = 0.21, P = 0.01). After adjusting for insulin sensitivity, these associations with β-cell function were no longer significant. After adjustment for insulin sensitivity, FINDRISC was not associated with reduced β-cell function in subjects without known Type 2 diabetes. While insulin secretion and insulin sensitivity are both components in Type 2 diabetes development, insulin sensitivity appears to be the dominant component behind the association between FINDRISC and diabetes risk.
  Diabetic Medicine 09/2011; 28(9):1078-81. · 2.90 Impact Factor
• Source

  Available from: Marco Anselmino

  Article: The role of beta-cell function and insulin sensitivity in the remission of type 2 diabetes after gastric bypass surgery.

  M Nannipieri, A Mari, M Anselmino, S Baldi, E Barsotti, D Guarino, S Camastra, R Bellini, R D Berta, E Ferrannini
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  ABSTRACT: Bariatric surgery can induce remission in a high proportion of severely obese patients with type 2 diabetes mellitus (T2DM). Our objective was to investigate predictors and mechanisms of surgery-induced diabetes remission. Forty-three morbidly obese subjects (body mass index = 45.6 ± 5.0 kg/m(2)), 32 with T2DM and 11 nondiabetic [normal glucose tolerance (NGT)], participated at a clinical research center. Patients underwent Roux-en-Y gastric bypass. Diabetes remission and β-cell function were evaluated. Subjects were tested before and 45 d and 1 yr after surgery. Weight decreased similarly in T2DM and NGT (-39 kg at 1 yr, P < 0.0001). Insulin sensitivity improved in both groups in proportion to the changes in body mass index but remained lower in T2DM than NGT (386 ± 91 vs. 479 ± 89 ml/min · m(2), P < 0.01). Based on glycosylated hemoglobin and oral glucose testing, diabetes had remitted in nine patients at 45 d and in an additional 16 at 1 yr. In T2DM, β-cell glucose sensitivity increased early after surgery but was no further improved and still abnormal at 1 yr [median, 48 (coefficient interval, 53) pmol/min · m(2) · mm vs. median, 100 (coefficient interval, 68) of NGT, P < 0.001]. Baseline β-cell glucose sensitivity was progressively worse in early remitters, late remitters, and nonremitters (median, 54[coefficient interval, 50] vs. median, 22[coefficient interval, 26] vs. median, 4[coefficient interval, 10] pmol/min · m(2) · mm) and, by logistic regression, was the only predictor of failure [odds ratio for bottom tertile = 7.9 (95% confidence interval = 1.2-51.9); P = 0.03]. In morbid obesity, Roux-en-Y gastric bypass causes rapid and profound metabolic adaptations; insulin sensitivity improves in proportion to the weight loss, and β-cell glucose sensitivity increases independently of weight loss. Over a period of 1 yr after surgery, diabetes remission depends on the starting degree of β-cell dysfunction.
  The Journal of clinical endocrinology and metabolism 07/2011; 96(9):E1372-9. · 6.50 Impact Factor
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  Available from: Marco Anselmino

  Article: Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes.

  S Camastra, A Gastaldelli, A Mari, S Bonuccelli, G Scartabelli, S Frascerra, S Baldi, M Nannipieri, E Rebelos, M Anselmino, E Muscelli, E Ferrannini
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  ABSTRACT: Bariatric surgery consistently induces remission of type 2 diabetes. We tested whether there are diabetes-specific mechanisms in addition to weight loss. We studied 25 morbidly obese patients (BMI 51.7 ± 1.5 kg/m(2) [mean ± SEM]), 13 with non-insulin-treated type 2 diabetes (HbA(1c) 7.1 ± 0.5% [54 ± 5 mmol/mol]), before and at 2 weeks and 1 year after Roux-en-Y gastric bypass (RYGB). Lean (n = 8, BMI 23.0 ± 0.5 kg/m(2)) and obese (n = 14) volunteers who were BMI-matched (36.0 ± 1.2) to RYGB patients at 1 year after surgery served as controls. We measured insulin-stimulated glucose disposal (M) and substrate utilisation (euglycaemic clamp/indirect calorimetry), endogenous glucose production (EGP) by 6,6-[(2)H(2)]glucose, lipolysis (rate of appearance of [(2)H(5)]glycerol) and beta cell function (acute insulin response to i.v. glucose [AIR] as determined by C-peptide deconvolution). At baseline, all obese groups showed typical metabolic abnormalities, with M, glucose oxidation and non-oxidative disposal impaired, and EGP, lipolysis, lipid oxidation and energy expenditure increased. Early after RYGB plasma glucose and insulin levels, and energy expenditure had decreased, while lipid oxidation increased, with M, EGP and AIR unchanged. At 1 year post-RYGB (BMI 34.4 ± 1.1 kg/m(2)), all diabetic patients were off glucose-lowering treatment and mean HbA(1c) was 5.4 ± 0.14% (36 ± 2 mmol/mol) (p = 0.03 vs baseline); AIR also improved significantly. In all RYGB patients, M, substrate oxidation, EGP, energy expenditure and lipolysis improved in proportion to weight loss, and were therefore similar to values in obese controls, but still different from those in lean controls. In morbidly obese patients, RYGB has metabolic effects on liver, adipose tissue, muscle insulin sensitivity and pattern of substrate utilisation; these effects can be explained by energy intake restriction and weight loss, the former prevailing early after surgery, the latter being dominant in the longer term.
  Diabetologia 05/2011; 54(8):2093-102. · 6.81 Impact Factor
• Article: Natural history and physiological determinants of changes in glucose tolerance in a non-diabetic population: the RISC Study.

  E Ferrannini, A Natali, E Muscelli, P M Nilsson, A Golay, M Laakso, H Beck-Nielsen, A Mari
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  ABSTRACT: The natural history and physiological determinants of glucose intolerance in subjects living in Europe have not been investigated. The aim of this study was to increase our understanding of this area. We analysed the data from a population-based cohort of 1,048 non-diabetic, normotensive men and women (aged 30-60 years) in whom insulin sensitivity was measured by the glucose clamp technique (M/I index; average glucose infusion rate/steady-state insulin concentration) and beta cell function was estimated by mathematical modelling of the oral glucose tolerance test at baseline and 3 years later. Seventy-seven per cent of the participants had normal glucose tolerance (NGT) and 5% were glucose intolerant both at baseline and follow up; glucose tolerance worsened in 13% (progressors) and improved in 6% (regressors). The metabolic phenotype of the latter three groups was similar (higher prevalence of familial diabetes, older age, higher waist-to-hip ratio, higher fasting and 2 h plasma glucose, higher fasting and 2 h plasma insulin, lower insulin sensitivity and reduced beta cell glucose sensitivity with increased absolute insulin secretion). Adjusting for these factors in a logistic model, progression was predicted by insulin resistance (bottom M/I quartile, OR 2.52 [95% CI 1.51-4.21]) and beta cell glucose insensitivity (bottom quartile, OR 2.39 [95% CI 1.6-3.93]) independently of waist-to-hip ratio (OR 1.44 [95% CI 1.13-1.84] for one SD). At follow up, insulin sensitivity and beta cell glucose sensitivity were unchanged in the stable NGT and stable non-NGT groups, worsened in progressors and improved in regressors. Glucose tolerance deteriorates over time in young, healthy Europids. Progressors, regressors and glucose-intolerant participants share a common baseline phenotype. Insulin sensitivity and beta cell glucose sensitivity predict and track changes in glucose tolerance independently of sex, age and obesity.
  Diabetologia 03/2011; 54(6):1507-16. · 6.81 Impact Factor
• Source

  Available from: PubMed Central

  Article: The heritability of beta cell function parameters in a mixed meal test design.

  A M C Simonis-Bik, D I Boomsma, J M Dekker, M Diamant, E J C de Geus, L M 't Hart, R J Heine, M H H Kramer, J A Maassen, A Mari, A Tura, G Willemsen, E M W Eekhoff
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  ABSTRACT: We estimated the heritability of individual differences in beta cell function after a mixed meal test designed to assess a wide range of classical and model-derived beta cell function parameters. A total of 183 healthy participants (77 men), recruited from the Netherlands Twin Register, took part in a 4 h protocol, which included a mixed meal test. Participants were Dutch twin pairs and their siblings, aged 20 to 49 years. All members within a family were of the same sex. Insulin sensitivity, insulinogenic index, insulin response and postprandial glycaemia were assessed, as well as model-derived parameters of beta cell function, in particular beta cell glucose sensitivity and insulin secretion rates. Genetic modelling provided the heritability of all traits. Multivariate genetic analyses were performed to test for overlap in the genetic factors influencing beta cell function, waist circumference and insulin sensitivity. Significant heritabilities were found for insulinogenic index (63%), beta cell glucose sensitivity (50%), insulin secretion during the first 2 h postprandial (42-47%) and postprandial glycaemia (43-52%). Genetic factors influencing beta cell glucose sensitivity and insulin secretion during the first 30 postprandial min showed only negligible overlap with the genetic factors that influence waist circumference and insulin sensitivity. The highest heritability for postprandial beta cell function was found for the insulinogenic index, but the most specific indices of heritability of beta cell function appeared to be beta cell glucose sensitivity and the insulin secretion rate during the first 30 min after a mixed meal.
  Diabetologia 02/2011; 54(5):1043-51. · 6.81 Impact Factor
• Article: Insulin secretion and impaired glucose tolerance. Reply to Jenkins AB, Campbell LV [letter].

  A Mari, E Ferrannini
  Diabetologia 06/2010; · 6.81 Impact Factor
• Article: Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance.

  A Mari, A Tura, A Natali, M Laville, M Laakso, R Gabriel, H Beck-Nielsen, E Ferrannini
  [show abstract] [hide abstract]
  ABSTRACT: 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. In men and women with NGT (n=1,123) or IGR(n=156) (age 44 +/- 8 years, BMI 25+/-4 kg/m2, 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. 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. InIGR vs NGT, IS was impaired (92 [75] vs 133 [86] micromol min(-1)[kg fat-free mass](-1) [nmol/l](-1), median [interquartile range],p<0.0001) as was beta cell glucose sensitivity (69 [46] vs 119[83] pmol min(-1) m(-2) [nmol/l](-1), 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. 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.
  Diabetologia 04/2010; 53(4):749-56. · 6.81 Impact Factor
• Source

  Available from: Markku Laakso

  Article: Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response.

  C Langenberg, L Pascoe, A Mari, A Tura, M Laakso, T M Frayling, I Barroso, R J F Loos, N J Wareham, M Walker
  [show abstract] [hide abstract]
  ABSTRACT: We investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals, is associated with measures of beta cell function and whole-body insulin sensitivity. We studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic-hyperinsulinaemic clamp and indices of beta cell function were derived from a 75 g oral glucose tolerance test (including 30 min insulin response and glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre. The minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d'Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU]; 0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085, 0.25] per G allele, p = 5.8 x 10(-5)), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response (-0.19 [-0.28, -0.10], p = 1.7 x 10(-5)), as well as with decreased beta cell glucose sensitivity (-0.11 [-0.20, -0.027], p = 0.010). No associations were observed with clamp-assessed insulin sensitivity (p = 0.15) or different measures of body size (p > 0.7 for all). Genetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B.
  Diabetologia 06/2009; 52(8):1537-42. · 6.81 Impact Factor
• Article: Beta-cell function assessment from modelling of oral tests: an effective approach.

  A Mari, E Ferrannini
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  ABSTRACT: The quantitative study of beta-cell function has relied on mathematical models for almost 40 years. During the last decades, the initial elaborate models have been simplified with the aim of obtaining mathematical methods suitable for the assessment of beta-cell function in an individual from an intravenous test. In more recent times, modelling methods have been proposed for analysing oral glucose tolerance tests or meal tests. In this review, we describe these methods with particular emphasis on an approach we have developed. We discuss the relevance of potentiation of insulin secretion in an oral glucose test, which our model has reintroduced after the historical models. We provide evidence on the validity of the method and illustrate significant applications. We emphasize the importance of quantifying beta-cell function through multiple indices and highlight how our approach has provided new insight on the relationships between beta-cell function and insulin sensitivity and on the role of beta-cell function in glucose intolerance and diabetes.
  Diabetes Obesity and Metabolism 11/2008; 10 Suppl 4:77-87. · 3.38 Impact Factor
• Source

  Available from: Claire L Fyfe

  Article: Effects of conjugated linoleic acid plus n-3 polyunsaturated fatty acids on insulin secretion and estimated insulin sensitivity in men.

  B Ahrén, A Mari, C L Fyfe, F Tsofliou, A A Sneddon, K W Wahle, M S Winzell, G Pacini, L M Williams
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  ABSTRACT: Dietary addition of either conjugated linoleic acid (CLA) or n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) has been shown to alter adiposity and circulating lipids, risk markers of cardiovascular diseases. However, CLA may decrease insulin sensitivity, an effect that may be reversed by n-3 LC-PUFA. Thus, the potential of CLA plus n-3 LC-PUFA to affect insulin secretion and sensitivity in non-diabetic young and old, lean and obese subjects was tested. CLA (3 g daily) plus n-3 LC-PUFA (3 g daily) or control oil (6 g daily) was given to lean (n=12; BMI 20-26 kg/m(2)) or obese (n=10; BMI 29-35 kg/m(2)) young (20-37 years old) or lean (n=16) or obese (n=11) older men (50-65 years) for 12 weeks. The study had a double-blind, placebo-controlled randomized crossover design, and primary end points were insulin secretion and sensitivity during a standardized meal test, evaluated by modeling glucose, insulin and C-peptide data. The combination was well tolerated. There was no significant difference in fasting levels of glucose, insulin or C-peptide after CLA/n-3 LC-PUFA treatment compared with control oil. Neither insulin secretion nor estimated sensitivity was affected by CLA/n-3 LC-PUFA in lean or obese young subjects or in older lean subjects. However, in older obese subjects, estimated insulin sensitivity was reduced with CLA/n-3 LC-PUFA compared with control (P=0.024). The results do not support beneficial effects of CLA/n-3 LC-PUFA for beta-cell dysfunction or insulin resistance in humans but suggest that insulin sensitivity in older obese subjects is reduced.
  European journal of clinical nutrition 10/2008; 63(6):778-86. · 3.07 Impact Factor
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  Available from: egir.org

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

  L Pascoe, T M Frayling, M N Weedon, A Mari, A Tura, E Ferrannini, M Walker
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  ABSTRACT: 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. 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. 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 x 10(-6)). The same was seen for the 30 min insulin response (p = 4.17 x 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). This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in non-diabetic individuals.
  Diabetologia 09/2008; 51(11):1989-92. · 6.81 Impact Factor
• Article: Relationships between insulin secretion after intravenous and oral glucose administration in subjects with glucose tolerance ranging from normal to overt diabetes.

  A Mari, A Tura, G Pacini, A Kautzky-Willer, E Ferrannini
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  ABSTRACT: Acute insulin release (AIR) in response to intravenous glucose injection (IVGTT) can be abolished in diabetic subjects when their response to oral glucose is maintained. To elucidate this phenomenon, we examined the relationships between fasting plasma glucose (FPG) and the secretory responses to an IVGTT and an oral glucose test (OGTT). We measured AIR and secretion after a 75-g OGTT in 221 subjects [age 37 +/- 11 years, body mass index (BMI) 28 +/- 5 kg/m(2); mean +/- SD] with normal glucose tolerance (NGT, n = 147), impaired FPG/impaired glucose tolerance (IFG/IGT, n = 28) and Type 2 diabetes (n = 46). Insulin secretion was calculated by C-peptide deconvolution; pancreatic B-cell glucose sensitivity was obtained by OGTT modelling. Both AIR [186 (185), 142 (164) and 10 (16) pmol/l, median (interquartile range)] and B-cell glucose sensitivity [98 (64), 66 (53) and 16 (20) pmol min(-1) m(-2) l mmol(-1)] decreased across glucose tolerance category (P < 0.0001). However, AIR became approximately 0 at approximately 7 mmol/l FPG, whereas B-cell glucose sensitivity declined gradually throughout the FPG range. In addition, for FPG > 7 mmol/l, AIR was no longer related to FPG, whereas a strong relationship between FPG and B-cell glucose sensitivity was preserved (rho = -0.71, P < 0.0001). In a multivariate regression model, adjusting for sex, age and BMI, glucose sensitivity [standardized regression coefficient (std.r.) = -0.67, P < 0.0001], but not AIR (std.r. = 0.03, P = 0.55), was an independent predictor of FPG. AIR vanishes at fasting or 2-h glucose levels, at which levels some B-cell glucose sensitivity is retained; therefore, AIR has a limited ability to quantify B-cell function in hyperglycaemic states.
  Diabetic Medicine 06/2008; 25(6):671-7. · 2.90 Impact Factor
• Article: Early detection of insulin sensitivity and beta-cell function with simple tests indicates future derangements in late pregnancy.

  A Lapolla, M G Dalfrà, G Mello, E Parretti, R Cioni, C Marzari, M Masin, A Ognibene, G Messeri, D Fedele, A Mari, G Pacini
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  ABSTRACT: Insulin sensitivity and secretion during early and late pregnancy were assessed in women with normal glucose tolerance and gestational diabetes mellitus (GDM). 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 beta-cell function (as the ratio of the areas under the insulin and glucose concentration curves, adjusted for insulin sensitivity) were assessed in both tests. 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 beta-cell function than ND. During the late visit, GDM2 also showed impaired beta-cell function compared with ND; furthermore, the adaptation to the increase to insulin resistance from early to late pregnancy was defective in GDM2. In early pregnancy insulin sensitivity, as assessed from the OGTT but not from fasting measurements, is impaired in women who developed GDM. beta-Cell function impairment is evident only when GDM is manifest and is characterized by inappropriate adaptation to the pregnancy induced increase in insulin resistance.
  Journal of Clinical Endocrinology &amp Metabolism 04/2008; 93(3):876-80. · 6.50 Impact Factor
• Article: Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia.

  W A Scherbaum, A Schweizer, A Mari, P M Nilsson, G Lalanne, Y Wang, B E Dunning, J E Foley
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  ABSTRACT: To assess the 2-year efficacy and tolerability of vildagliptin (50 mg once daily) in patients with type 2 diabetes (T2DM) and mild hyperglycaemia. This was a multicentre, randomized, double-blind, placebo-controlled trial comprising a 52-week core study with a 4-week, active treatment-free washout followed by a 52-week extension study with another washout period conducted in 131 drug-naïve patients with T2DM and mild hyperglycaemia [glycosylated haemoglobin (HbA(1c)) 6.2-7.2%]. All patients received lifestyle counselling at each study visit. Efficacy and tolerability were assessed during visits at weeks 0 (core study baseline), 4, 8, 12, 16, 24, 32, 40 and 52 of active treatment; at week 56 (i.e. after the first washout period); at weeks 68, 80, 96 and 108 and at week 112 (i.e. after the second washout period). Standard meal tests were also performed at weeks 0, 24, 52, 56, 80, 108 and 112 to assess postprandial glycaemia and beta-cell function, which was quantified by glucose area under the curve (AUC(0-2) (h))/insulin secretory rate (ISR) AUC(0-2) (h) (ISR/G). Changes from baseline and between-treatment differences (placebo-adjusted changes from baseline during vildagliptin treatment) were analysed by ancova. The placebo-adjusted change from week 0 in HbA(1c) was -0.3 +/- 0.1% after 1 year of vildagliptin treatment (p < 0.001) and -0.5 +/- 0.2% after 2 years (p = 0.008). The placebo-adjusted change from core study baseline in fasting plasma glucose, in glucose AUC(0-2) (h) and in the beta-cell function parameter, ISR/G, tended to be greater after 2 years than after 1 year of treatment with vildagliptin. Even after a 4-week washout, the placebo-adjusted change from week 0 to week 112 in ISR/G was 3.2 +/- 1.6 pmol/min/m(2)/mM (p = 0.058) and the placebo-adjusted difference in the change from week 0 to week 112 in HbA(1c) was -0.3 +/- 0.1% (p = 0.051). The incidences of adverse events (AEs), serious AEs and discontinuations because of AEs were similar in the two treatment groups, and hypoglycaemic episodes were reported by no patient receiving vildagliptin and by two patients receiving placebo. In drug-naïve patients with mild hyperglycaemia, 2-year treatment with vildagliptin 50 mg once daily attenuated the progressive loss of glycaemic control seen in patients receiving only lifestyle counselling (and placebo). This appears to be because of a corresponding attenuation of the deterioration of beta-cell function as assessed by ISR/G.
  Diabetes Obesity and Metabolism 03/2008; 10(11):1114-24. · 3.38 Impact Factor