| 1. |
- Bunck, M. C., et al.
(author)
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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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In: Diabetes Care. - 1935-5548. ; 32:5, s. 762-8
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Journal article (peer-reviewed)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. |
- Bunck, M. C., et al.
(author)
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Exenatide treatment did not affect bone mineral density despite body weight reduction in patients with type 2 diabetes
- 2011
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In: Diabetes, obesity & metabolism. - : Wiley. - 1463-1326 .- 1462-8902. ; 13:4, s. 374-377
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Journal article (peer-reviewed)abstract
- Preclinical studies suggest that incretin-based therapies may be beneficial for the bone; however, clinical data are largely lacking. We assessed whether the differential effects of these therapies on body weight differed with respect to their effect on bone mineral density (BMD) and markers of calcium homeostasis in patients with type 2 diabetes (T2D). Sixty-nine metformin-treated patients with T2D were randomized to exenatide twice daily (n = 36) or insulin glargine once daily (n = 33). Total body BMD, measured by dual-energy X-ray absorptiometry, and serum markers of calcium homeostasis were assessed before and after 44-week treatment. Exenatide or insulin glargine treatment decreased body weight by 6%. Endpoint BMD was similar in both groups after 44-week therapy (LSmean +/- s.e.m. between-group difference -0.002 +/- 0.007 g/cm(2) ; p = 0.782). Fasting serum alkaline phosphatase, calcium and phosphate remained unaffected. Forty-four-week treatment with exenatide or insulin glargine had no adverse effects on bone density in patients with T2D, despite differential effects on body weight.
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| 3. |
- Mardinoglu, Adil, 1982, et al.
(author)
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Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD
- 2017
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In: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 13:3
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Journal article (peer-reviewed)abstract
- To elucidate the molecular mechanisms underlying non-alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome-scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD(+) and glutathione (GSH) in subjects with high HS. Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD(+) repletion on the development of NAFLD, we added precursors for GSH and NAD(+) biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof-of-concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.
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| 4. |
- Bunck, M. C., et al.
(author)
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Exenatide affected circulating cardiovascular risk biomarkers independently of changes in body composition
- 2010
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In: Diabetes Care. - 0149-5992. ; 33:8, s. 1734-1737
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Journal article (peer-reviewed)abstract
- OBJECTIVE To study the effect of exenatide on body composition and circulating cardiovascular risk biomarkers. RESEARCH DESIGN AND METHODS Metformin-treated patients with type 2 diabetes (N = 69) were randomized to exenatide or insulin glargine and treated for 1 year. Body composition was evaluated by dual-energy X-ray absorptiometry. Additionally, body weight, waist circumference, and cardiovascular biomarkers were measured. RESULTS Treatment with exenatide for 1 year significantly reduced body weight, waist circumference, and total body and trunkal fat mass by 6, 5, 11, and 13%, respectively. In addition, exenatide increased total adiponectin by 12% and reduced high-sensitivity C-reactive protein by 61%. Insulin glargine significantly reduced endothelin-1 by 7%. These changes were statistically independent of the change in total body fat mass and body weight. CONCLUSIONS Exenatide treatment for 1 year reduced body fat mass and improved the profile of circulating biomarkers of cardiovascular risk. No significant changes were seen with insulin glargine except a trend for reduced endothelin-1 levels.
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| 5. |
- Eliasson, Björn, 1959, et al.
(author)
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Lowering of postprandial lipids in individuals with type 2 diabetes treated with alogliptin and/or pioglitazone: a randomised double-blind placebo-controlled study.
- 2012
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In: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 55:4, s. 915-925
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Journal article (peer-reviewed)abstract
- AIMS/HYPOTHESIS: Pharmacological augmentation of glucagon-like peptide 1 receptor signalling by dipeptidyl peptidase 4 (DPP-4) inhibition reduced intestinal lipoprotein secretion in experimental studies, suggesting that DPP-4 inhibitors may ameliorate dyslipidaemia and thus reduce cardiovascular risk in patients with type 2 diabetes. We assessed the effects of alogliptin (Alo) and Alo co-administered with pioglitazone (Pio) vs placebo (Pbo) on triacylglycerol (TG)-rich lipoproteins in type 2 diabetes before and following a high-fat meal. METHODS: Seventy-one patients (age 18-70years), who did not reach HbA(1c) 6.5% (48mmol/mol) with lifestyle and/or metformin, sulfonylurea or glinide therapy, participated in this 16week, double-centre (university hospitals) Pbo-controlled parallel-group study. All participants, people doing measurements or examinations, and people assessing the outcomes were blinded to group assignment. Fasting TG 1.7-5.0mmol/l was among the entry criteria. Patients received a high-fat mixed meal before and 4 and 16weeks after randomisation (allocation by central office) to Alo (n=25), Alo/Pio (n=22) or Pbo (n=24). Blood was sampled at pre-specified intervals, starting at 15min before and ending 8h after meal ingestion. RESULTS: At week 16, Alo (n=25) and Alo/Pio (n=21) vs Pbo (n=24) produced similar significant reductions in total postprandial TG response (incremental AUC [iAUC]; p<0.001), as well as in chylomicron TG (p<0.001) and VLDL1 TG iAUCs (p<0.001 and p=0.012, respectively). Postprandial chylomicron apolipoprotein B-48 iAUC showed a significant decrease after Alo treatment (p=0.028), and a non-significant trend towards a decrease with Alo/Pio (p=0.213). The incidence of adverse events was low and consistent with previous studies. CONCLUSIONS/INTERPRETATION: Treatment with Alo and Alo/Pio produced significant reductions in postprandial TG and TG-rich lipoproteins, contributing to an improved overall cardiometabolic risk profile in type 2 diabetes. The data support the concept that incretins not only modulate glucose metabolism but also influence chylomicron metabolism in intestinal cells. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00655863. FUNDING: The study was funded by Takeda Global Research & Development.
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| 6. |
- Mero, N., et al.
(author)
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Postprandial elevation of ApoB-48-containing triglyceride-rich particles and retinyl esters in normolipemic males who smoke
- 1997
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In: Arterioscler Thromb Vasc Biol. - 1079-5642. ; 17:10, s. 2096-102
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Journal article (peer-reviewed)abstract
- Smokers have an increased risk for coronary artery disease (CAD), which can only partly be explained by fasting lipoprotein changes. Recent studies have indicated that smokers express metabolic abnormalities characteristic of insulin resistance syndrome. A preliminary study reported an increased postprandial triglyceride (TG) response in smokers compared with nonsmokers. To investigate the effect of smoking on postprandial lipemia, a fat-rich mixed meal (837 kcal, 63 g of fat) was served to 12 healthy smokers and 12 controls with similar fasting lipoprotein profiles, body composition, and lifestyles. Blood was drawn before and 3, 4, 6, and 8 hours postprandially, and triglyceride-rich lipoprotein (TRL) fractions (chylomicrons, VLDL1, VLDL2, and IDL) were separated with density gradient ultracentrifugation. Pre- and postprandial TG, retinyl esters (RE), apolipoprotein B-48 (apoB-48) and B-100 (apoB-100) were measured in each fraction. Smokers showed a significantly increased postprandial TG response in chylomicrons, VLDL1, and VLDL2. The areas under the incremental curve (AUIC) of apoB-48 in chylomicrons (2.83 +/- 0.84 versus 0.56 +/- 0.17; P < .05) and VLDL1 (10.17 +/- 1.96 versus 2.95 +/- 2.44; P = < .01) were markedly higher in smokers than in controls. Changes of RE responses of all TRL fractions were consistent with those of apoB-48. Postprandial apoB-100 concentrations and lipolytic enzymes were similar between the two groups. In conclusion, smokers have the syndrome of impaired TG tolerance because of defective clearance of chylomicrons and their remnants. Prolonged residence time of atherogenic remnant particles may constitute a significant risk factor for CAD in smokers.
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| 7. |
- Axelsen, Mette, 1965, et al.
(author)
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Lipid intolerance in smokers
- 1995
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In: J Intern Med. - 0954-6820. ; 237:5, s. 449-55
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Journal article (peer-reviewed)abstract
- OBJECTIVES. Smokers have recently been shown to be insulin resistant and to exhibit several characteristics of the insulin resistance syndrome (IRS). In this study, we assessed fasting and postprandial lipid levels in healthy, normolipidaemic, chronic smokers and a matched group of non-smoking individuals. DESIGN. A standardized mixed meal (containing 3.78 MJ and 51 g of fat) was given in the morning after an overnight fast. The smokers were either abstinent from tobacco for 48 h or were allowed to smoke freely, including being allowed to smoke six cigarettes during the study. SUBJECTS. Twenty-two middle-aged, healthy male subjects, nine habitual smokers and 13 non-smoking control subjects, were recruited to the study. The smokers had all been smoking at least 10 cigarettes per day for at least 10 years. RESULTS. The smokers exhibited a lipid intolerance in that their postprandial increase in triglyceride levels was more than 50% higher than in the non-smokers' group. This lipid intolerance could not be discerned in the postabsorptive state because the fasting triglyceride levels were the same in both groups, while the smokers had significantly lower high-density lipoprotein (HDL) cholesterol. The peak postprandial triglyceride level correlated closely and negatively with fasting HDL cholesterol, indicating an impaired lipolytic removal capacity in smokers. CONCLUSIONS. Healthy, normotriglyceridaemic smokers exhibit an abnormal postprandial lipid metabolism consistent with lipid intolerance. It is suggested that postprandial hyperlipidaemia is a characteristic trait of the insulin resistance syndrome and that the defect in lipid removal is related to the low HDL cholesterol in this syndrome. The insulin resistance syndrome is likely to be an important reason for the increased propensity for cardiovascular disease in smokers.
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| 8. |
- Axelsen, Mette, 1965, et al.
(author)
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Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with type 2 diabetes.
- 1999
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In: Annals of internal medicine. - 0003-4819 .- 1539-3704. ; 131:1, s. 27-31
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Journal article (peer-reviewed)abstract
- BACKGROUND: Impaired ability to eliminate lipids in the postprandial state is an atherogenic trait associated with insulin resistance. OBJECTIVE: To assess insulin sensitivity and postprandial triglyceride metabolism in prediabetic persons. DESIGN: Cross-sectional study. SETTING: Sahlgrenska University Hospital, Göteborg, Sweden. PARTICIPANTS: 13 healthy, normotriglyceridemic men with two first-degree relatives with type 2 diabetes and 13 carefully matched controls without known diabetes heredity. MEASUREMENTS: Oral glucose tolerance test, insulin sensitivity (euglycemic clamp technique), and fasting and postprandial triglyceride levels after a mixed meal. RESULTS: Relatives of persons with type 2 diabetes were insulin resistant but had normal glucose tolerance. They exhibited postprandial hypertriglyceridemia; the 6-hour triglyceride incremental area under the curve was 50% higher than that of the control group (P = 0.037). CONCLUSIONS: These healthy male first-degree relatives of patients with type 2 diabetes are insulin resistant and exhibit postprandial lipid intolerance despite having normal fasting triglyceride levels. These characteristics, which occur in the absence of glucose intolerance, are associated with an increased risk for macroangiopathy.
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| 9. |
- Axelsen, Mette, 1965, et al.
(author)
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Suppression of nocturnal fatty acid concentrations by bedtime carbohydrate supplement in type 2 diabetes: effects on insulin sensitivity, lipids, and glycemic control.
- 2000
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In: The American journal of clinical nutrition. - 0002-9165. ; 71:5, s. 1108-14
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Journal article (peer-reviewed)abstract
- BACKGROUND: Bedtime ingestion of slow-release carbohydrates leads to sustained nocturnal fatty acid suppression and improved glucose tolerance in type 2 diabetic patients. OBJECTIVE: This study assessed the effects of 2 different doses of bedtime carbohydrate supplement (BCS) on morning glycemic control and glycated hemoglobin (Hb A(1c)) in type 2 diabetic patients. In addition, the effects of the high-dose BCS on insulin sensitivity and postprandial glucose and triacylglycerol concentrations were assessed. DESIGN: Two BCS doses were studied separately in 7-wk randomized, placebo-controlled, double-blind studies with either a parallel (low-dose BCS; n = 24 patients) or crossover (high-dose BCS; n = 14 patients) design. The effects of the low and high doses (0.30 and 0.55 g uncooked cornstarch/kg body wt, respectively) were compared with those of a starch-free placebo. RESULTS: Compared with the starch-free placebo, the high-dose BCS ( approximately 45 g) produced enhanced nocturnal glucose (P < 0.01) and insulin (P < 0.01) concentrations as well as a 32% suppression of fatty acid concentrations (P < 0.01). Moreover, glucose tolerance (P < 0.05) and C-peptide response (P < 0.05) improved after breakfast the next morning. The low-dose BCS ( approximately 25 g) improved fasting blood glucose concentrations (P < 0.05). However, there were no improvements in insulin sensitivity, postprandial triacylglycerol concentrations, or Hb A(1c) after 7 wk. CONCLUSION: Nocturnal fatty acid suppression by BCS improved fasting and postprandial blood glucose concentrations in type 2 diabetic patients the next morning. In contrast, no improvements in insulin sensitivity, postprandial triacylglycerol concentrations, or long-term glycemic control assessed by Hb A(1c) were seen after BCS supplementation.
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| 10. |
- Eliasson, Björn, 1959, et al.
(author)
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Long-term use of nicotine gum is associated with hyperinsulinemia and insulin resistance
- 1996
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In: Circulation. - 0009-7322. ; 94:5, s. 878-81
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Journal article (peer-reviewed)abstract
- BACKGROUND: Insulin sensitivity and cardiovascular risk profile were examined in 20 healthy, nonobese, middle-aged men who were long-term users of nicotine-containing chewing gum and in 20 matched control subjects who did not use nicotine. METHODS AND RESULTS: Long-term use of nicotine-containing chewing gum was associated with insulin resistance and hyperinsulinemia. The degree of insulin sensitivity correlated negatively to the extent of nicotine use measured as plasma cotinine levels. CONCLUSIONS: These findings suggest that nicotine is the major constituent in cigarette smoke that leads to insulin resistance, metabolic abnormalities associated with the insulin resistance syndrome, and increased cardiovascular morbidity. Thus, the use of nicotine replacement therapy during smoking cessation should be transient and limited.
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