| 1. |
- Bunck, M. C., et al.
(författare)
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One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial
- 2009
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Ingår i: Diabetes Care. - 1935-5548. ; 32:5, s. 762-8
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Traditional blood glucose-lowering agents do not sustain adequate glycemic control in most type 2 diabetic patients. Preclinical studies with exenatide have suggested sustained improvements in beta-cell function. We investigated the effects of 52 weeks of treatment with exenatide or insulin glargine followed by an off-drug period on hyperglycemic clamp-derived measures of beta-cell function, glycemic control, and body weight. RESEARCH DESIGN AND METHODS: Sixty-nine metformin-treated patients with type 2 diabetes were randomly assigned to exenatide (n = 36) or insulin glargine (n = 33). beta-Cell function was measured during an arginine-stimulated hyperglycemic clamp at week 0, at week 52, and after a 4-week off-drug period. Additional end points included effects on glycemic control, body weight, and safety. RESULTS: Treatment-induced change in combined glucose- and arginine-stimulated C-peptide secretion was 2.46-fold (95% CI 2.09-2.90, P < 0.0001) greater after a 52-week exenatide treatment compared with insulin glargine treatment. Both exenatide and insulin glargine reduced A1C similarly: -0.8 +/- 0.1 and -0.7 +/- 0.2%, respectively (P = 0.55). Exenatide reduced body weight compared with insulin glargine (difference -4.6 kg, P < 0.0001). beta-Cell function measures returned to pretreatment values in both groups after a 4-week off-drug period. A1C and body weight rose to pretreatment values 12 weeks after discontinuation of either exenatide or insulin glargine therapy. CONCLUSIONS: Exenatide significantly improves beta-cell function during 1 year of treatment compared with titrated insulin glargine. After cessation of both exenatide and insulin glargine therapy, beta-cell function and glycemic control returned to pretreatment values, suggesting that ongoing treatment is necessary to maintain the beneficial effects of either therapy.
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| 2. |
- 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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| 3. |
- Auro, K., et al.
(författare)
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USF1 gene variants contribute to metabolic traits in men in a longitudinal 32-year follow-up study
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:3, s. 464-472
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Genetic variants of upstream transcription factor 1 (USF1) have previously been associated with dyslipidaemias in family studies. Our aim was to further address the role of USF1 in metabolic syndrome and cardiovascular traits at the population level in a large Swedish male cohort (n=2,322) with multiple measurements for risk factors during 32 years of follow-up. METHODS: Participants, born in 1920-1924, were examined at 50, 60, 70 and 77 years of age. The follow-up period for cardiovascular events was 1970-2002. We genotyped three haplotype tagging polymorphisms capturing the major allelic variants of USF1. RESULTS: SNP rs2774279 was associated with the metabolic syndrome. The minor allele of rs2774279 was less common among individuals with metabolic syndrome than among healthy controls [p=0.0029 when metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III; p=0.0073 when defined according to the International Diabetes Federation (IDF)]. The minor allele of rs2774279 was also associated with lower BMI, lower fasting glucose values and higher HDL-cholesterol concentrations in longitudinal analyses. With SNP rs2073658, a borderline association with metabolic syndrome was observed (p=0.036, IDF), the minor allele being the risk-increasing allele. The minor allele of rs2073658 also associated with higher total and LDL-cholesterol, apolipoprotein B-100 and lipoprotein(a) concentrations in longitudinal analyses. Importantly, these trends with respect to the allelic variants prevailed throughout the follow-up time of three decades. CONCLUSIONS/INTERPRETATION: Our results suggest that USF1 variants associate with the metabolic syndrome at population level and influence the cardiovascular risk factors throughout adulthood in a consistent, longitudinal manner.
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| 4. |
- Kotronen, A., et al.
(författare)
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Serum saturated fatty acids containing triacylglycerols are better markers of insulin resistance than total serum triacylglycerol concentrations
- 2009
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 52:4, s. 684-690
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The weak relationship between insulin resistance and total serum triacylglycerols (TGs) could be in part due to heterogeneity of TG molecules and their distribution within different lipoproteins. We determined concentrations of individual TGs and the fatty acid composition of serum and major lipoprotein particles and analysed how changes in different TGs and fatty acid composition are related to features of insulin resistance and abdominal obesity.METHODS: We performed lipidomic analyses of all major lipoprotein fractions using two analytical platforms in 16 individuals, who exhibited a broad range of insulin sensitivity.RESULTS: We identified 45 different TGs in serum. Serum TGs containing saturated and monounsaturated fatty acids were positively, while TGs containing essential linoleic acid (18:2 n-6) were negatively correlated with HOMA-IR. Specific serum TGs that correlated positively with HOMA-IR were also significantly positively related to HOMA-IR when measured in very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs) and LDL, but not in HDL subfraction 2 (HDL(2)) or 3 (HDL(3)). Analyses of proportions of esterified fatty acids within lipoproteins revealed that palmitic acid (16:0) was positively related to HOMA-IR when measured in VLDL, IDL and LDL, but not in HDL(2) or HDL(3). Monounsaturated palmitoleic (16:1 n-7) and oleic (18:1 n-9) acids were positively related to HOMA-IR when measured in HDL(2) and HDL(3), but not in VLDL, IDL or LDL. Linoleic acid was negatively related to HOMA-IR in all lipoproteins.CONCLUSIONS/INTERPRETATION: Serum concentrations of specific TGs, such as TG(16:0/16:0/18:1) or TG(16:0/18:1/18:0), may be more precise markers of insulin resistance than total serum TG concentrations.
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| 5. |
- Adiels, Martin, 1976, et al.
(författare)
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A new combined multicompartmental model for apolipoprotein B-100 and triglyceride metabolism in VLDL subfractions
- 2005
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Ingår i: J Lipid Res. - 0022-2275 .- 1539-7262. ; 46:1, s. 58-67
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Tidskriftsartikel (refereegranskat)abstract
- The use of stable isotopes in conjunction with compartmental modeling analysis has greatly facilitated studies of the metabolism of the apolipoprotein B (apoB)-containing lipoproteins in humans. The aim of this study was to develop a multicompartment model that allows us to simultaneously determine the kinetics of apoB and triglyceride (TG) in VLDL(1) and VLDL(2) after a bolus injection of [(2)H(3)]leucine and [(2)H(5)]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Here, we describe the model and present the results of its application in a fasting steady-state situation in 17 subjects with lipid values representative of a Western population. Analysis of the correlations showed that plasma TG was determined by the VLDL(1) and VLDL(2) apoB and TG fractional catabolic rate. Furthermore, the model showed a linear correlation between VLDL(1) TG and apoB production. A novel observation was that VLDL TG entered the circulation within 21 min after its synthesis, whereas VLDL apoB entered the circulation after 33 min. These observations are consistent with a sequential assembly model of VLDL and suggest that the TG is added to a primordial apoB-containing particle in the liver.
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| 6. |
- 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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| 7. |
- Adiels, Martin, 1976, et al.
(författare)
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Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia
- 2005
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Ingår i: Arterioscler Thromb Vasc Biol. - 1524-4636 .- 1079-5642. ; 25:8, s. 1697-703
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We sought to compare the synthesis and metabolism of VLDL1 and VLDL2 in patients with type 2 diabetes mellitus (DM2) and nondiabetic subjects. METHODS AND RESULTS: We used a novel multicompartmental model to simultaneously determine the kinetics of apolipoprotein (apo) B and triglyceride (TG) in VLDL1 and VLDL2 after a bolus injection of [2H3]leucine and [2H5]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Our results show that the overproduction of VLDL particles in DM2 is explained by enhanced secretion of VLDL1 apoB and TG. Direct production of VLDL2 apoB and TG was not influenced by diabetes per se. The production rates of VLDL1 apoB and TG were closely related, as were the corresponding pool sizes. VLDL1 and VLDL2 compositions did not differ in subjects with DM2 and controls, and the TG to apoB ratio of newly synthesized particles was very similar in the 2 groups. Plasma glucose, insulin, and free fatty acids together explained 55% of the variation in VLDL1 TG production rate. CONCLUSIONS: Insulin resistance and DM2 are associated with excess hepatic production of VLDL1 particles similar in size and composition to those in nondiabetic subjects. We propose that hyperglycemia is the driving force that aggravates overproduction of VLDL1 in DM2.
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| 8. |
- Hero, M., et al.
(författare)
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Blockade of oestrogen biosynthesis in peripubertal boys: effects on lipid metabolism, insulin sensitivity, and body composition
- 2006
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Ingår i: Eur J Endocrinol. - : Oxford University Press (OUP). - 0804-4643. ; 155:3, s. 453-60
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: In males, the pubertal increase in sex hormone production has been associated with proatherogenic changes in lipid and carbohydrate metabolism. Aromatase inhibitors, a novel treatment modality for some growth disorders, may significantly influence these risk factors for cardiovascular disease by suppressing oestrogen biosynthesis and stimulating gonadal androgen production. In the current study, we explored the effects of aromatase inhibition on lipid metabolism, insulin sensitivity, body composition and serum adiponectin in peripubertal boys. DESIGN: Prospective, double-blind, randomised, placebo-controlled clinical study. METHODS: Thirty-one boys, aged 9.0-14.5 years, with idiopathic short stature were treated with the aromatase inhibitor letrozole (2.5 mg/day) or placebo for 2 years. During the treatment, the concentrations of sex hormones, IGF-I, lipids, lipoproteins and adiponectin were followed-up. The percentage of fat mass (FM) was assessed by skinfold measurements and insulin resistance by homeostasis model assessment (HOMA) index. RESULTS: In pubertal boys, who received letrozole, high-density lipoprotein cholesterol (HDL-C) decreased by 0.47 mmol/l (P<0.01) during the study. Simultaneously, their percentage of FM decreased from 17.0 to 10.5 (P<0.001), in an inverse relationship with serum testosterone. The concentrations of low-density lipoprotein cholesterol, triglycerides and HOMA index remained at pretreatment level in both groups. Serum adiponectin decreased similarly in letrozole- and placebo-treated pubertal boys (2.9 and 3.3 mg/l respectively). CONCLUSIONS: In males, aromatase inhibition reduces HDL-C and decreases relative FM after the start of puberty. The treatment does not adversely affect insulin sensitivity in lean subjects.
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| 9. |
- Sammalisto, S, et al.
(författare)
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A male-specific quantitative trait locus on 1p21 controlling human stature
- 2005
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 42:12, s. 932-939
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Tidskriftsartikel (refereegranskat)abstract
- Background: Many genome-wide scans aimed at complex traits have been statistically underpowered due to small sample size. Combining data from several genome-wide screens with comparable quantitative phenotype data should improve statistical power for the localisation of genomic regions contributing to these traits. Objective: To perform a genome-wide screen for loci affecting adult stature by combined analysis of four previously performed genome-wide scans. Methods: We developed a web based computer tool, Cartographer, for combining genetic marker maps which positions genetic markers accurately using the July 2003 release of the human genome sequence and the deCODE genetic map. Using Cartographer, we combined the primary genotype data from four genome-wide scans and performed variance components (VC) linkage analyses for human stature on the pooled dataset of 1417 individuals from 277 families and performed VC analyses for males and females separately. Results: We found significant linkage to stature on 1p21 (multipoint LOD score 4.25) and suggestive linkages on 9p24 and 18q21 (multipoint LOD scores 2.57 and 2.39, respectively) in males-only analyses. We also found suggestive linkage to 4q35 and 22q13 (multipoint LOD scores 2.18 and 2.85, respectively) when we analysed both females and males and to 13q12 (multipoint LOD score 2.66) in females-only analyses. Conclusions: We strengthened the evidence for linkage to previously reported quantitative trait loci (QTL) for stature and also found significant evidence of a novel male-specific QTL on 1p21. Further investigation of several interesting candidate genes in this region will help towards characterisation of this first sex-specific locus affecting human stature.
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| 10. |
- Adiels, Martin, 1976, et al.
(författare)
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Diabetic dyslipidaemia
- 2006
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Ingår i: Curr Opin Lipidol. - 0957-9672 .- 1473-6535. ; 17:3, s. 238-46
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE OF REVIEW: Diabetic dyslipidaemia is a cluster of plasma lipid and lipoprotein abnormalities that are metabolically interrelated. The increase of large type 1 very low density lipoprotein particles in type 2 diabetes initiates a sequence of events that generates atherogenic remnants, small dense low-density lipoprotein and small dense high-density lipoprotein particles. Thus, it is of great importance to elucidate the mechanisms behind the overproduction of large very low density lipoprotein particles in diabetic dyslipidaemia. This review discusses the pathophysiology of very low density lipoprotein metabolism in type 2 diabetes and recent concepts of lipid management of diabetic dyslipidaemia. RECENT FINDINGS: Results indicate that triglyceride and apolipoprotein B production in types 1 and 2 very low density lipoprotein are significantly correlated, suggesting a coupling of the two processes governing the metabolism of these lipoprotein subpopulations. Insulin resistance, hyperglycaemia, and liver fat were associated with excess hepatic production of type 1 but not type 2 very low density lipoprotein particles. These data provide support for the independent regulation of types 1 and 2 very low density lipoprotein apolipoprotein B production. SUMMARY: Recent data suggest that the assembly of very low density lipoprotein is fundamentally altered in type 2 diabetes, explaining the overproduction of large type 1 very low density lipoprotein as well as the inability of insulin to suppress production of type 1 very low density lipoprotein in type 2 diabetes. Future discoveries hopefully will delineate the regulatory steps to allow more targeted treatment of diabetic dyslipidaemia.
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