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- Adiels, Martin, 1976, et al.
(författare)
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Acute suppression of VLDL(1) secretion rate by insulin is associated with hepatic fat content and insulin resistance
- 2007
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 50:11, s. 2356-2365
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Overproduction of VLDL(1) seems to be the central pathophysiological feature of the dyslipidaemia associated with type 2 diabetes. We explored the relationship between liver fat and suppression of VLDL(1) production by insulin in participants with a broad range of liver fat content. METHODS: A multicompartmental model was used to determine the kinetic parameters of apolipoprotein B and TG in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol during a hyperinsulinaemic-euglycaemic clamp in 20 male participants: eight with type 2 diabetes and 12 control volunteers. The participants were divided into two groups with low or high liver fat. All participants with diabetes were in the high liver-fat group. RESULTS: The results showed a rapid drop in VLDL(1)-apolipoprotein B and -triacylglycerol secretion in participants with low liver fat during the insulin infusion. In contrast, participants with high liver fat showed no significant change in VLDL(1) secretion. The VLDL(1) suppression following insulin infusion correlated with the suppression of NEFA, and the ability of insulin to suppress the plasma NEFA was impaired in participants with high liver fat. A novel finding was an inverse response between VLDL(1) and VLDL(2) secretion in participants with low liver fat: VLDL(1) secretion decreased acutely after insulin infusion whereas VLDL(2) secretion increased. CONCLUSIONS/INTERPRETATION: Insulin downregulates VLDL(1) secretion and increases VLDL(2) secretion in participants with low liver fat but fails to suppress VLDL(1) secretion in participants with high liver fat, resulting in overproduction of VLDL(1). Thus, liver fat is associated with lack of VLDL(1) suppression in response to insulin.
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| 2. |
- Adiels, Martin, 1976, et al.
(författare)
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Overproduction of large VLDL particles is driven by increased liver fat content in man
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 49:4, s. 755-65
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We determined whether hepatic fat content and plasma adiponectin concentration regulate VLDL(1) production. METHODS: A multicompartment model was used to simultaneously determine the kinetic parameters of triglycerides (TGs) and apolipoprotein B (ApoB) in VLDL(1) and VLDL(2) after a bolus of [(2)H(3)]leucine and [(2)H(5)]glycerol in ten men with type 2 diabetes and in 18 non-diabetic men. Liver fat content was determined by proton spectroscopy and intra-abdominal fat content by MRI. RESULTS: Univariate regression analysis showed that liver fat content, intra-abdominal fat volume, plasma glucose, insulin and HOMA-IR (homeostasis model assessment of insulin resistance) correlated with VLDL(1) TG and ApoB production. However, only liver fat and plasma glucose were significant in multiple regression models, emphasising the critical role of substrate fluxes and lipid availability in the liver as the driving force for overproduction of VLDL(1) in subjects with type 2 diabetes. Despite negative correlations with fasting TG levels, liver fat content, and VLDL(1) TG and ApoB pool sizes, adiponectin was not linked to VLDL(1) TG or ApoB production and thus was not a predictor of VLDL(1) production. However, adiponectin correlated negatively with the removal rates of VLDL(1) TG and ApoB. CONCLUSIONS/INTERPRETATION: We propose that the metabolic effect of insulin resistance, partly mediated by depressed plasma adiponectin levels, increases fatty acid flux from adipose tissue to the liver and induces the accumulation of fat in the liver. Elevated plasma glucose can further increase hepatic fat content through multiple pathways, resulting in overproduction of VLDL(1) particles and leading to the characteristic dyslipidaemia associated with type 2 diabetes.
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| 4. |
- Agardh, Carl-David, et al.
(författare)
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GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes.
- 2009
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 52, s. 1363-1368
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The aim of this study was to ascertain whether treatment of GAD65 autoantibody (GADA)-positive diabetic patients with alum-formulated recombinant GAD65 (GAD-alum) is safe and does not compromise beta cell function. METHODS: This Phase 2, placebo-controlled, dose-escalation clinical trial, which was randomized through a central office, was performed in 47 GADA-positive type 2 diabetic patients, who received subcutaneous injections of GAD-alum (4 [n = 9], 20 [n = 8], 100 [n = 9] or 500 [n = 8] mug) or placebo (n = 13) at weeks 1 and 4 of the trial. Participants and caregivers were blinded to group assignments. The primary outcome was safety as assessed by neurological tests, medications and beta cell function evaluated over 5 years, representing the end of the trial. RESULTS: No severe study-related adverse events occurred during the 5 year follow-up. None of the dose groups was associated with an increased risk of starting insulin treatment compared with the placebo group. The use of oral hypoglycaemic agents did not differ between the dose groups. After 5 years, fasting C-peptide levels declined in the placebo group (-0.24; 95% CI -0.41 to -0.07 log(10) nmol/l; p = 0.01) and the 500 microg dose group (-0.37; 95% CI -0.57 to -0.17 log(10) nmol/l; p = 0.003), but not in the 4 microg (-0.10; 95% CI -0.28 to 0.07 log(10) nmol/l; p = 0.20), 20 microg (0.04; 95% CI -0.12 to 0.19 log(10) nmol/l; p = 0.58) and 100 microg (0.00; 95% CI -0.20 to -0.20 log(10) nmol/l; p = 0.98) dose groups. CONCLUSIONS/INTERPRETATION: The primary outcome of safety was achieved, since no severe study-related adverse events occurred. TRIAL REGISTRATION: Because the study was initiated before 1 July 2005, the protocol was not registered in a registry. FUNDING: This trial was funded by the National Institutes of Health (grant numbers DK26190 and DK53004), the Swedish Research Council (grant number 72X-14064) and Diamyd Therapeutics (Stockholm, Sweden).
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| 6. |
- Agardh, Elisabet, et al.
(författare)
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Visual acuity and perimetry as measures of visual function in diabetic macular oedema
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:1, s. 200-206
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We examined to what extent visual acuity and perimetric sensitivity as measures of central and paracentral visual function would be useful for evaluating the presence and severity of diabetic macular oedema.MATERIALS AND METHODS: We evaluated 59 eyes of 59 diabetic patients by identifying the presence (n=20) or absence (n=39) of macular oedema on stereo fundus photographs. The area of oedema and its distance to the centre of the macula were measured. Ischaemic macular damage was quantified by measuring the foveal avascular zone and adjacent perifoveolar intercapillary areas on fluorescein angiograms. Visual function was assessed by visual acuity charts and by short-wavelength perimetry and standard white-on-white perimetry of the central 10 degrees field.RESULTS: Visual acuity did not differ between eyes with and without macular oedema. In eyes with oedema, visual acuity was correlated to the distance of the oedema from the centre of the macula (log of minimum angle of resolution {LogMar} score decreased by 0.15/mm; p=0.006) and to the thickness of the retina when the centre was affected (LogMar score decreased by 0.003/mum of thickness; p=0.0002). Multivariate analyses confirmed the results (R (2)=0.46 and 0.77, respectively). Short-wavelength perimetry sensitivity was more depressed in eyes with oedema (p=0.033) but was not significantly associated with the presence of oedema after correction for macular ischaemic damage. There was no correlation between these field defects and the severity of oedema.CONCLUSIONS/INTERPRETATION: Visual acuity was a useful measure of visual function in diabetic macular oedema involving the centre. Visual field defects were more common in eyes with macular oedema but reflected ischaemic damage of the macula rather than macular oedema itself.
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| 9. |
- Ahrén, Bo
(författare)
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Evidence that autonomic mechanisms contribute to the adaptive increase in insulin secretion during dexamethasone-induced insulin resistance in humans.
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 51:6, s. 1018-1024
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: This study examined whether autonomic mechanisms contribute to adaptively increased insulin secretion in insulin-resistant humans, as has been proposed from studies in animals. METHODS: Insulin secretion was evaluated before and after induction of insulin resistance with or without interruption of neural transmission. Insulin resistance was induced by dexamethasone (15 mg given over 3 days) in nine healthy women (age 67 years, BMI 25.2 +/- 3.4 kg/m(2), fasting glucose 5.1 +/- 0.4 mmol/l, fasting insulin 46 +/- 6 pmol/l). Insulin secretion was evaluated as the insulin response to intravenous arginine (5 g) injected at fasting glucose and after raising glucose to 13 to15 mmol/l or to >28 mmol/l. Neural transmission across the ganglia was interrupted by infusion of trimethaphan (0.3-0.6 mg kg(-1) min(-1)). RESULTS: As an indication of insulin resistance, dexamethasone increased fasting insulin (to 75 +/- 8 pmol/l, p < 0.001) without significantly affecting fasting glucose. Arginine-induced insulin secretion was increased by dexamethasone at all glucose levels (by 64 +/- 12% at fasting glucose, by 80 +/- 19% at 13-15 mmol glucose and by 43 +/- 12% at >28 mmol glucose; p <0.001 for all). During dexamethasone-induced insulin resistance, trimethaphan reduced the insulin response to arginine at all three glucose levels. The augmentation of the arginine-induced insulin responses by dexamethasone-induced insulin resistance was reduced by trimethaphan by 48 +/- 6% at fasting glucose, 61 +/- 8% at 13-15 mmol/l glucose and 62 +/- 8% at >28 mmol/l glucose (p < 0.001 for all). In contrast, trimethaphan did not affect insulin secretion before dexamethasone was given. CONCLUSIONS/INTERPRETATIONS: Autonomic mechanisms contribute to the adaptative increase in insulin secretion in dexamethasone-induced insulin resistance in healthy participants.
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| 10. |
- Ahrén, Bo
(författare)
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Glucagon secretion in relation to insulin sensitivity in healthy subjects.
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:1, s. 117-122
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: The study evaluated whether glucagon secretion is regulated by changes in insulin sensitivity under normal conditions. Materials and methods: A total of 155 healthy women with NGT (aged 53-70 years) underwent a glucose-dependent arginine-stimulation test for evaluation of glucagon secretion. Arginine (5 g) was injected i.v. under fasting conditions (plasma glucose 4.8 +/- 0.1 mmol/l) and after raising blood glucose concentrations to 14.8 +/- 0.1 and 29.8 +/- 0.2 mmol/l. The acute glucagon response (AGR) to arginine during the three glucose levels (AGR(1), AGR(2), AGR(3)) was estimated, as was the suppression of baseline glucagon by the increased glucose. All women also underwent a 2-h euglycaemic-hyperinsulinaemic clamp study for estimation of insulin sensitivity. Results: Insulin sensitivity was normally distributed, with a mean of 73.2 +/- 29.3 (SD) nmol glucose kg(-1) min(-1)/pmol insulin l(-1). When relating the variables obtained from the arginine test to insulin sensitivity, insulin resistance was associated with increased AGR and with increased suppression of glucagon levels by glucose. For example, the regression between insulin sensitivity and AGR(2) was r=-0.38 (p < 0.001) and between insulin sensitivity and suppression of glucagon levels by 14.8 mmol/l glucose r=0.36 (p < 0.001). Insulin sensitivity also correlated negatively with insulin secretion; multivariate analysis revealed that changes in insulin sensitivity and insulin secretion were independently related to changes in glucagon secretion. Conclusions/interpretation: The body adapts to insulin resistance by increasing the glucagon response to arginine and by increasing the suppression of glucagon levels by glucose. Hence, not only the islet beta cells but also the alpha cells seem to undergo compensatory changes during the development of insulin resistance.
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