| 1. |
- Bergthorsdottir, Ragnhildur, 1971, et al.
(author)
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Visceral Fat and Novel Biomarkers of Cardiovascular Disease in Patients With Addison's Disease: A Case-Control Study
- 2017
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In: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 102:11, s. 4264-4272
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Journal article (peer-reviewed)abstract
- Context: Patients with Addison's disease (AD) have increased cardiovascular mortality. Objective: To study visceral fat and conventional and exploratory cardiovascular risk factors in patients with AD. Subjects: Patients (n = 76; n = 51 women) with AD and 76 healthy control subjects were matched for sex, age, body mass index (BMI), and smoking habits. Main outcome measures: The primary outcome variable was visceral abdominal adipose tissue (VAT) measured using computed tomography. Secondary outcome variables were prevalence of metabolic syndrome (MetS) and 92 biomarkers of cardiovascular disease. Results: The mean 6 standard deviation age of all subjects was 53 6 14 years; mean BMI, 25 6 4 kg/ m2; and mean duration of AD, 17 6 12 years. The median (range) daily hydrocortisone dose was 30 mg (10 to 50 mg). Median (interquartile range) 24-hour urinary free cortisol excretion was increased in patients vs controls [359 nmol (193 to 601 nmol) vs 175 nmol (140 to 244 nmol); P, 0.001]. VAT did not differ between groups. After correction for multiple testing, 17 of the 92 studied biomarkers differed significantly between patients and control subjects. Inflammatory, proinflammatory, and proatherogenic risk biomarkers were increased in patients [fold change (FC),.1] and vasodilatory protective marker was decreased (FC, < 1). Twenty-six patients (34%) vs 12 control subjects (16%) fulfilled the criteria for MetS (P = 0.01). Conclusion: Despite higher cortisol exposure, VAT was not increased in patients with AD. The prevalence of MetS was increased and several biomarkers of cardiovascular disease were adversely affected in patients with AD.
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| 2. |
- Boersma, Greta J., et al.
(author)
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Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study
- 2018
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In: Hormone and Metabolic Research. - : Georg Thieme Verlag KG. - 0018-5043 .- 1439-4286. ; 50:8
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Journal article (peer-reviewed)abstract
- We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body 18F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r = 0.884, r = 0.574, r = 0.707 and r = 0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r = -0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r2 = 0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r = 0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.
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| 3. |
- Cavalli, Marco, et al.
(author)
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Studies of liver tissue identify functional gene regulatory elements associated to gene expression, type 2 diabetes, and other metabolic diseases
- 2019
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In: Human Genomics. - : Springer Science and Business Media LLC. - 1473-9542 .- 1479-7364. ; 13
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Journal article (peer-reviewed)abstract
- Background:Genome-wide association studies (GWAS) of diseases and traits have found associations to gene regions but not the functional SNP or the gene mediating the effect. Difference in gene regulatory signals can be detected using chromatin immunoprecipitation and next-gen sequencing (ChIP-seq) of transcription factors or histone modifications by aligning reads to known polymorphisms in individual genomes. The aim was to identify such regulatory elements in the human liver to understand the genetics behind type 2 diabetes and metabolic diseases.Methods: The genome of liver tissue was sequenced using 10X Genomics technology to call polymorphic positions. Using ChIP-seq for two histone modifications, H3K4me3 and H3K27ac, and the transcription factor CTCF, and our established bioinformatics pipeline, we detected sites with significant difference in signal between the alleles.Results:We detected 2329 allele-specific SNPs (AS-SNPs) including 25 associated to GWAS SNPs linked to liver biology, e.g., 4 AS-SNPs at two type 2 diabetes loci. Two hundred ninety-two AS-SNPs were associated to liver gene expression in GTEx, and 134 AS-SNPs were located on 166 candidate functional motifs and most of them in EGR1-binding sites.Conclusions:This study provides a valuable collection of candidate liver regulatory elements for further experimental validation.
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| 4. |
- Eriksson, Olof, et al.
(author)
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In Vivo Visualization of beta-Cells by Targeting of GPR44
- 2018
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 67:2, s. 182-192
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Journal article (peer-reviewed)abstract
- GPR44 expression has recently been described as highly beta-cell selective in the human pancreas and constitutes a tentative surrogate imaging biomarker in diabetes. A radiolabeled small-molecule GPR44 antagonist, [C-11]AZ12204657, was evaluated for visualization of beta-cells in pigs and non-human primates by positron emission tomography as well as in immunodeficient mice transplanted with human islets under the kidney capsule. In vitro autoradiography of human and animal pancreatic sections from subjects without and with diabetes, in combination with insulin staining, was performed to assess beta-cell selectivity of the radiotracer. Proof of principle of in vivo targeting of human islets by [C-11]AZ12204657 was shown in the immunodeficient mouse transplantation model. Furthermore, [C-11]AZ12204657 bound by a GPR44-mediated mechanism in pancreatic sections from humans and pigs without diabetes, but not those with diabetes. In vivo [C-11]AZ12204657 bound specifically to GPR44 in pancreas and spleen and could be competed away dose-dependently in nondiabetic pigs and nonhuman primates. [C-11]AZ12204657 is a first-in-class surrogate imaging biomarker for pancreatic beta-cells by targeting the protein GPR44.
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| 5. |
- Hellstrom-Lindahl, E., et al.
(author)
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Toward molecular imaging of the free fatty acid receptor 1
- 2017
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In: Acta Diabetologica. - : Springer Science and Business Media LLC. - 0940-5429 .- 1432-5233. ; 54:7, s. 663-668
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Journal article (peer-reviewed)abstract
- Molecular imaging of the free fatty acid receptor 1 (FFAR1) would be a valuable tool for drug development by enabling in vivo target engagement studies in human. It has also been suggested as a putative target for beta cell imaging, but the inherent lipophilicity of most FFAR1 binders produces high off-target binding, which has hampered progress in this area. The aim of this study was to generate a suitable lead compound for further PET labeling. In order to identify a lead compound for future PET labeling for quantitative imaging of FFAR1 in human, we evaluated tritiated small molecule FFAR1 binding probes ([H-3]AZ1, [H-3]AZ2 and [H-3]TAK-875) for their off-target binding, receptor density and affinity in human pancreatic tissue (islets and exocrine) and rodent insulinoma. [H-3]AZ1 showed improved specificity to FFAR1, with decreased off-target binding compared to [H-3]AZ2 and [H-3]TAK-875, while retaining high affinity in the nanomolar range. FFAR1 density in human islets was approximately 50% higher than in exocrine tissue. AZ1 is a suitable lead compound for PET labeling for molecular imaging of FFAR1 in humans, due to high affinity and reduced off-target binding.
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| 6. |
- Jahan, Mahabuba, et al.
(author)
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The development of a GPR44 targeting radioligand [11C]AZ12204657 for in vivo assessment of beta cell mass.
- 2018
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In: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 8
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Journal article (peer-reviewed)abstract
- BACKGROUND: The G-protein-coupled receptor 44 (GPR44) is a beta cell-restricted target that may serve as a marker for beta cell mass (BCM) given the development of a suitable PET ligand.METHODS: The binding characteristics of the selected candidate, AZ12204657, at human GPR44 were determined using in vitro ligand binding assays. AZ12204657 was radiolabeled using 11C- or 3H-labeled methyl iodide ([11C/3H]CH3I) in one step, and the conversion of [11C/3H]CH3I to the radiolabeled product [11C/3H]AZ12204657 was quantitative. The specificity of radioligand binding to GPR44 and the selectivity for beta cells were evaluated by in vitro binding studies on pancreatic sections from human and non-human primates as well as on homogenates from endocrine and exocrine pancreatic compartments.RESULTS: The radiochemical purity of the resulting radioligand [11C]AZ12204657 was > 98%, with high molar activity (MA), 1351 ± 575 GBq/μmol (n = 18). The radiochemical purity of [3H]AZ12204657 was > 99% with MA of 2 GBq/μmol. Pancreatic binding of [11C/3H]AZ12204657 was co-localized with insulin-positive islets of Langerhans in non-diabetic individuals and individuals with type 2 diabetes (T2D). The binding of [11C]AZ12204657 to GPR44 was > 10 times higher in islet homogenates compared to exocrine homogenates. In human islets of Langerhans GPR44 was co-expressed with insulin, but not glucagon as assessed by co-staining and confocal microscopy.CONCLUSION: We radiolabeled [11C]AZ12204657, a potential PET radioligand for the beta cell-restricted protein GPR44. In vitro evaluation demonstrated that [3H]AZ12204657 and [11C]AZ12204657 selectively target pancreatic beta cells. [11C]AZ12204657 has promising properties as a marker for human BCM.
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| 7. |
- Johannsson, Gudmundur, et al.
(author)
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Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone : a pharmacokinetic study
- 2016
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In: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 175:1, s. 85-93
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Journal article (peer-reviewed)abstract
- Objective: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure-time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5-20 mg and assess intrasubject variability. Methods: Thirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20-55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3 x 5), and 20 mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24 h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography-tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration-time profiles. Results: DR-HC 20 mg provided higher than endogenous cortisol plasma concentrations 0-4 h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (C-max) was 82.0 and 178.1 ng/mL, while mean area under the concentration-time curve (AUC)(0-infinity) was 562.8 and 1180.8 h x ng/mL with DR-HC 5 and 20 mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20 mg. All exposure PK parameters were less than dose proportional (slope < 1). PK differences between ethnicities were explained by body weight differences. Conclusions: DR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional - an important consideration when managing intercurrent illness in patients with adrenal insufficiency.
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| 8. |
- Johannsson, Gudmundur, 1960, et al.
(author)
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Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study
- 2016
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In: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 175:1, s. 85-93
-
Journal article (peer-reviewed)abstract
- Objective: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure-time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5-20 mg and assess intrasubject variability. Methods: Thirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20-55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3 x 5), and 20 mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24 h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography-tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration-time profiles. Results: DR-HC 20 mg provided higher than endogenous cortisol plasma concentrations 0-4 h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (C-max) was 82.0 and 178.1 ng/mL, while mean area under the concentration-time curve (AUC)(0-infinity) was 562.8 and 1180.8 h x ng/mL with DR-HC 5 and 20 mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20 mg. All exposure PK parameters were less than dose proportional (slope < 1). PK differences between ethnicities were explained by body weight differences. Conclusions: DR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional - an important consideration when managing intercurrent illness in patients with adrenal insufficiency.
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| 9. |
- Johannsson, Gudmundur, 1960, et al.
(author)
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Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy.
- 2015
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In: Clinical endocrinology. - : Wiley. - 1365-2265 .- 0300-0664. ; 82:1, s. 2-11
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Journal article (peer-reviewed)abstract
- Glucocorticoid replacement therapy in patients with adrenal insufficiency (AI), whether primary (Addison's disease) or secondary (due to hypopituitarism), has been established for some 50years. The current standard treatment regimen involves twice- or thrice-daily dosing with a glucocorticoid, most commonly oral hydrocortisone. Based on previous small-scale studies and clinical perception, life expectancy with conventional glucocorticoid replacement therapy has been considered normal, with a low incidence of adverse events. Data from the past 10-15years, however, have shown that morbidity remains high and life expectancy is reduced. The increased morbidity and decreased life expectancy appear to be due to both increased exposure to cortisol and insufficient cortisol coverage during infections and other stress-related events. This is thought to reflect a failure of treatment to replicate the natural circadian rhythm of cortisol release, together with a failure to identify and deliver individualized cortisol exposure and to manage patients adequately when increased doses are required. The resulting over- or under-treatment may result in Cushing-like symptoms or adrenal crisis, respectively. This review summarizes the morbidity and mortality seen in patients receiving the current standard of care for AI and suggests areas for improvement in glucocorticoid replacement therapy.
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| 10. |
- Johansson, Emil, et al.
(author)
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Whole-Body Imaging of Tissue-specific Insulin Sensitivity and Body Composition by Using an Integrated PET/MR System: A Feasibility Study
- 2018
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In: Radiology. - : Radiological Society of North America (RSNA). - 0033-8419 .- 1527-1315. ; 286:1, s. 271-278
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Journal article (peer-reviewed)abstract
- Purpose: To develop, evaluate, and demonstrate the feasibility of a whole-body protocol for simultaneous assessment of tissue-specific insulin-mediated fluorine 18 (F-18) fluorodeoxyglucose (FDG) influx rates, tissue depots, and whole-body insulin sensitivity (referred to as the M value). Materials and Methods: An integrated positron emission tomography (PET)/magnetic resonance (MR) imaging system combined with hyperinsulinemic euglycemic clamp (HEC) was used. Dynamic whole-body PET imaging was used to determine the insulin-mediated F-18-FDG tissue influx rate (K-i) in the whole-body region by using the Patlak method. M value was determined with the HEC method at PET imaging. Tissue depots were quantified by using water-fat separated MR imaging and manual segmentations. Feasibility of the imaging protocol was demonstrated by using five healthy control participants and five patients with type 2 diabetes. Associations between M value and K-i were studied in multiple tissues by using the Pearson correlation. Results: Positive correlations were found between M value and K-i in multiple tissues: the gluteus muscle (r = 0.875; P = .001), thigh muscle (r = 0.903; P < .001), calf muscle (r = 0.825; P = .003), and abdominal visceral adipose tissue (r = 0.820; P = .004). A negative correlation was found in the brain (r = 0.798; P = .006). The MR imaging-based method for quantification of tissue depots was feasible for determining adipose tissue volumes and fat fractions. Conclusion: This PET/MR imaging protocol may be feasible for simultaneous assessment of tissue-specific insulin-mediated F-18-FDG influx rates, tissue depots, and M value. (C) RSNA, 2017
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| 11. |
- Nilsson, Anna G., et al.
(author)
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Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency : a phase 3b, open-label, extension study
- 2017
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In: European Journal of Endocrinology. - : Bioscientifica. - 0804-4643 .- 1479-683X. ; 176:6, s. 715-725
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Journal article (peer-reviewed)abstract
- Objective: To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI).Design: Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden.Methods: Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires.Results: Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6-5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P < 0.0001) and HDL cholesterol (0.2 mmol/L; P < 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008).Conclusions: In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.
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| 12. |
- Nilsson, Anna G, 1968, et al.
(author)
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Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study.
- 2017
-
In: European journal of endocrinology. - : BIOSCIENTIFICA LTD. - 1479-683X .- 0804-4643. ; 176:6, s. 715-725
-
Journal article (peer-reviewed)abstract
- To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI).Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden.Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires.Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n=2), gastritis (n=1) and syncope (n=1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6-5.4 episodes per patient per year), fasting plasma glucose (0.7mmol/L; P<0.0001) and HDL cholesterol (0.2mmol/L; P<0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P=0.008).In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.
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| 13. |
- Olafsdottir, Arndis, 1978, et al.
(author)
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A Clinical Trial of the Accuracy and Treatment Experience of the Flash Glucose Monitor FreeStyle Libre in Adults with Type 1 Diabetes
- 2017
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In: Diabetes Technology & Therapeutics. - : Mary Ann Liebert Inc. - 1520-9156 .- 1557-8593. ; 19:3, s. 164-172
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Journal article (peer-reviewed)abstract
- Background: In Sweden, FreeStyle Libre a flash glucose monitoring system came onto the market in 2014 as a complement to self-monitoring of blood glucose. The aim of this study was to evaluate the accuracy and treatment experience of the FreeStyle Libre system. Methods: Fifty-eight adults with type 1 diabetes used FreeStyle Libre for 10-14 days and measured capillary blood glucose levels with the HemoCue blood glucose measurement system at least six times a day simultaneously. Results: For the entire study period, the mean absolute relative difference (MARD) was 13.2% (95% confidence interval [CI] 12.0%-14.4%). MARD was 13.6% (95% CI 12.1%-15.4%) during week 1 and 12.7% (95% CI 11.5%-13.9%) during week 2. The mean absolute difference (MAD) for the whole study period was 19.8mg/dL (1.1mmol/L) (95% CI 17.8-21.8 mg/dL), including 20.5 mg/dL (1.14 mmol/L) during week 1 and 19.0 mg/dL (1.05 mmol/L) during week 2. The overall correlation coefficient was 0.96. For glucose values < 72, 72-180, and > 180mg/dL (< 4, 4-10, and > 10 mmol/L), the MARD was 20.3% (95% CI 17.7%-23.1%), 14.7% (95% CI 13.4%-16%), and 9.6% (95% CI 8.5%-10.8%), respectively, and respective MAD values were 12.3, 17.8, and 23.6 mg/dL (0.69, 0.99, and 1.31mmol/L). Using the 10-item visual analog scale, patients rated their experience with FreeStyle Libre as generally positive, with mean values ranging from 8.22 to 9.8. Conclusions: FreeStyle Libre had a similar overall MARD as continuous blood glucose monitoring systems in earlier studies when studied in similar at-home conditions. The overall patient satisfaction was high.
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| 14. |
- Olsson, Marita, 1965, et al.
(author)
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Contemporary Risk Estimates of Three HbA(1c) Variables for Myocardial Infarction in 101,799 Patients Following Diagnosis of Type 2 Diabetes
- 2015
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In: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 38:8, s. 1481-1486
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Journal article (peer-reviewed)abstract
- OBJECTIVE This study evaluated the risk of myocardial infarction (MI) by impaired glycemic control in a contemporary large cohort of patients with type 2 diabetes followed from diagnosis. Patients with type 2 diabetes diagnosed between 1995 and 2011 were retrieved from the Clinical Practice Research Datalink in the U.K., and followed from diagnosis until event of MI or end of study in 2013. Two subcohorts were defined: an early cohort with those diagnosed from 1997 to 2004 and a recent cohort with those diagnosed from 2004 to 2011. Association between each of three HbA(1c) metrics and MI was estimated using adjusted proportional hazards models. In the overall cohort (n = 101,799), the risk increase for MI per 1% (10 mmol/mol) increase in HbA(1c) was higher for updated latest and updated mean HbA(1c) of 1.11 (95% CI 1.09-1.13) and 1.15 (1.13-1.18) than for baseline HbA(1c) of 1.05 (1.03-1.06). In the early subcohort, the corresponding risk estimates were greater than those in the recent subcohort. When categorized, the updated latest variable showed an increased risk for HbA(1c) <6% (42 mmol/mol), relative category 6-7%, in the recent but not in the early subcohort, with hazard ratios of 1.23 (1.08-1.40) and 1.01 (0.84-1.22), respectively. The two time-updated HbA(1c) variables show a stronger relation with MI than baseline HbA(1c). The risk association between HbA(1c) and MI has decreased over time. In recently diagnosed patients with type 2 diabetes, an increased risk of MI exists at a current HbA(1c) of <6.0% (42 mmol/mol).
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| 15. |
- Parkinson, Joanna, et al.
(author)
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Application of the integrated glucose–insulin model for cross-study characterization of T2DM patients on metformin background treatment
- 2016
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In: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 82, s. 1613-1624
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Journal article (peer-reviewed)abstract
- © 2016 The British Pharmacological Society Aim: The integrated glucose–insulin (IGI) model is a semi-mechanistic physiological model which can describe the glucose–insulin homeostasis system following various glucose challenge settings. The aim of the present work was to apply the model to a large and diverse population of metformin-only-treated type 2 diabetes mellitus (T2DM) patients and identify patient-specific covariates. Methods: Data from four clinical studies were pooled, including glucose and insulin concentration–time profiles from T2DM patients on stable treatment with metformin alone following mixed-meal tolerance tests. The data were collected from a wide range of patients with respect to the duration of diabetes and level of glycaemic control. Results: The IGI model was expanded by four patient-specific covariates. The level of glycaemic control, represented by baseline glycosylated haemoglobin was identified as a significant covariate for steady-state glucose, insulin-dependent glucose clearance and the magnitude of the incretin effect, while baseline body mass index was a significant covariate for steady-state insulin levels. In addition, glucose dose was found to have an impact on glucose absorption rate. The developed model was used to simulate glucose and insulin profiles in different groups of T2DM patients, across a range of glycaemic control, and it was found accurately to characterize their response to the standard oral glucose challenge. Conclusions: The IGI model was successfully applied to characterize differences between T2DM patients across a wide range of glycaemic control. The addition of patient-specific covariates in the IGI model might be valuable for the future development of antidiabetic treatment and for the design and simulation of clinical studies.
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| 16. |
- Pereira, Maria J., et al.
(author)
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Impaired adipose tissue lipid storage, but not altered lipolysis, contributes to elevated levels of NEFA in type 2 diabetes. Degree of hyperglycemia and adiposity are important factors
- 2016
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In: Metabolism: Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 65:12, s. 1768-1780
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Journal article (peer-reviewed)abstract
- Background Elevated levels of circulating non-esterified fatty acids (NEFA) mediate many adverse metabolic effects. In this work we aim to determine the impact of type 2 diabetes (T2D), glycemic control and obesity on lipolysis regulation. Design and Participants 20 control and 20 metformin-treated T2D subjects were matched for sex (10M/10 F), age (58±11 vs 58±9 y) and BMI (30.8±4.6 vs 30.7±4.9kg/m2). In vivo lipolysis was assessed during a 3h-OGTT with plasma glycerol and NEFA levels. Subcutaneous adipose tissue (SAT) biopsies were obtained to measure mRNA and metabolite levels of factors related to lipolysis and lipid storage and to assess in vitro lipolysis in isolated subcutaneous adipocytes. Results Plasma NEFA AUC during the OGTT where higher 30% (P=0.005) in T2D than in control subjects, but plasma glycerol AUC and subcutaneous adipocyte lipolysis in vitro were similar, suggesting that adipose tissue lipolysis is not altered. Expression in SAT of genes involved in lipid storage (FABP4, DGAT1, FASN) were reduced in T2D subjects compared with controls, but no differences were seen for genes involved in lipolysis. T2D subjects had elevated markers of beta-oxidation, α-hydroxybutyrate (1.4-fold, P<0.01) and β-hydroxybutyrate (1.7-fold, P<0.05) in plasma. In multivariate analysis, HbA1c, visceral adipose tissue volume and sex (male) were significantly associated with NEFA AUC in T2D subjects. Conclusions In T2D subjects, NEFA turnover is impaired, but not due to defects in lipolysis or lipid beta-oxidation. Impaired adipose NEFA re-esterification or de novo lipogenesis is likely to contribute to higher NEFA plasma levels in T2D. The data suggest that hyperglycemia and adiposity are important contributing factors for the regulation of plasma NEFA concentrations. © 2016 Elsevier Inc.
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| 17. |
- Sahraoui, Afaf, et al.
(author)
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The Effects of Exendin-4 Treatment on Graft Failure : An Animal Study Using a Novel Re-Vascularized Minimal Human Islet Transplant Model
- 2015
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Journal article (peer-reviewed)abstract
- Islet transplantation has become a viable clinical treatment, but is still compromised by long-term graft failure. Exendin-4, a glucagon-like peptide 1 receptor agonist, has in clinical studies been shown to improve insulin secretion in islet transplanted patients. However, little is known about the effect of exendin-4 on other metabolic parameters. We therefore aimed to determine what influence exendin-4 would have on revascularized minimal human islet grafts in a state of graft failure in terms of glucose metabolism, body weight, lipid levels and graft survival. Introducing the bilateral, subcapsular islet transplantation model, we first transplanted diabetic mice with a murine graft under the left kidney capsule sufficient to restore normoglycemia. After a convalescent period, we performed a second transplantation under the right kidney capsule with a minimal human islet graft and allowed for a second recovery. We then performed a left-sided nephrectomy, and immediately started treatment with exendin-4 with a low (20 mu g/kg/day) or high (200 mu g/kg/day) dose, or saline subcutaneously twice daily for 15 days. Blood was sampled, blood glucose and body weight monitored. The transplanted human islet grafts were collected at study end point and analyzed. We found that exendin-4 exerts its effect on failing human islet grafts in a bell-shaped dose-response curve. Both doses of exendin-4 equally and significantly reduced blood glucose. Glucagon-like peptide 1 (GLP-1), C-peptide and pro-insulin were conversely increased. In the course of the treatment, body weight and cholesterol levels were not affected. However, immunohistochemistry revealed an increase in beta cell nuclei count and reduced TUNEL staining only in the group treated with a low dose of exendin-4 compared to the high dose and control. Collectively, these results suggest that exendin-4 has a potential rescue effect on failing, revascularized human islets in terms of lowering blood glucose, maintaining beta cell numbers, and improving metabolic parameters during hyperglycemic stress.
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| 18. |
- Sidibeh, Cherno O, 1987-, et al.
(author)
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FKBP5 expression in human adipose tissue: potential role in glucose and lipid metabolism, adipogenesis and type 2 diabetes
- 2018
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In: Endocrine. - : Springer Science and Business Media LLC. - 1355-008X .- 1559-0100. ; 62:1, s. 116-128
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Journal article (peer-reviewed)abstract
- Purpose Here, we explore the involvement of FKBP51 in glucocorticoid-induced insulin resistance (IR) in human subcutaneous adipose tissue (SAT), including its potential role in type 2 diabetes (T2D). Moreover, we assess the metabolic effects of reducing the activity of FKBP51 using the specific inhibitor SAFit1. Methods Human SAT was obtained by needle biopsies of the lower abdominal region. FKBP5 gene expression was assessed in fresh SAT explants from a cohort of 20 T2D subjects group-wise matched by gender, age and BMI to 20 nondiabetic subjects. In addition, human SAT was obtained from non-diabetic volunteers (20F/9M). SAT was incubated for 24 h with or without the synthetic glucocorticoid dexamethasone and SAFit1. Incubated SAT was used to measure the glucose uptake rate in isolated adipocytes. Results FKBP5 gene expression levels in SAT positively correlated with several indices of IR as well as glucose area under the curve during oral glucose tolerance test (r = 0.33, p < 0.05). FKBP5 gene expression levels tended to be higher in T2D subjects compared to non-diabetic subjects (p = 0.088). Moreover, FKBP5 gene expression levels were found to inversely correlate with lipolytic, lipogenic and adipogenic genes. SAFit1 partly prevented the inhibitory effects of dexamethasone on glucose uptake. Conclusions FKBP5 gene expression in human SAT tends to be increased in T2D subjects and is related to elevated glucose levels. Moreover, FKBP5 gene expression is inversely associated with the expression of lipolytic, lipogenic and adipogenic genes. SAFit1 can partly prevent glucose uptake impairment by glucocorticoids, suggesting that FKBP51 might be a key factor in glucocorticoid-induced IR.
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| 19. |
- Sidibeh, Cherno O., et al.
(author)
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Role of cannabinoid receptor 1 in human adipose tissue for lipolysis regulation and insulin resistance
- 2017
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In: Endocrine. - : Springer Science and Business Media LLC. - 1355-008X .- 1559-0100. ; 55:3, s. 839-852
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Journal article (peer-reviewed)abstract
- We recently showed that the peripheral cannabinoid receptor type 1 (CNR1) gene is upregulated by the synthetic glucocorticoid dexamethasone. CNR1 is highly expressed in the central nervous system and has been a drug target for the treatment of obesity. Here we explore the role of peripheral CNR1 in states of insulin resistance in human adipose tissue. Subcutaneous adipose tissue was obtained from well-controlled type 2 diabetes subjects and controls. Subcutaneous adipose tissue gene expression levels of CNR1 and endocannabinoid synthesizing and degrading enzymes were assessed. Furthermore, paired human subcutaneous adipose tissue and omental adipose tissue from non-diabetic volunteers undergoing kidney donation or bariatric surgery, was incubated with or without dexamethasone. Subcutaneous adipose tissue obtained from volunteers through needle biopsy was incubated with or without dexamethasone and in the presence or absence of the CNR1-specific antagonist AM281. CNR1 gene and protein expression, lipolysis and glucose uptake were evaluated. Subcutaneous adipose tissue CNR1 gene expression levels were 2-fold elevated in type 2 diabetes subjects compared with control subjects. Additionally, gene expression levels of CNR1 and endocannabinoid-regulating enzymes from both groups correlated with markers of insulin resistance. Dexamethasone increased CNR1 expression dose-dependently in subcutaneous adipose tissue and omental adipose tissue by up to 25-fold. Dexamethasone pre-treatment of subcutaneous adipose tissue increased lipolysis rate and reduced glucose uptake. Co-incubation with the CNR1 antagonist AM281 prevented the stimulatory effect on lipolysis, but had no effect on glucose uptake. CNR1 is upregulated in states of type 2 diabetes and insulin resistance. Furthermore, CNR1 is involved in glucocorticoid-regulated lipolysis. Peripheral CNR1 could be an interesting drug target in type 2 diabetes and dyslipidemia.
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| 20. |
- Skrtic, Stanko, 1970, et al.
(author)
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Contemporary risk estimates of three HbA(1c) variables in relation to heart failure following diagnosis of type 2 diabetes
- 2017
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In: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 103:5, s. 355-360
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Journal article (peer-reviewed)abstract
- Background We evaluated the association between glycaemic control and the risk of heart failure (HF) in a contemporary cohort of persons followed after diagnosis of type 2 diabetes (T2D). Methods and results Persons with T2D diagnosed between 1998 and 2012 were retrieved from the Clinical Practice Research Data Link in the UK and followed from diagnosis until the event of HF, mortality, drop out from the database due to any other reason, or the end of the study on 1 July 2015. The association between each of three different haemoglobin A(1C) (HbA1c) metrics and HF was estimated using adjusted proportional hazard models. In the overall cohort (n= 94 332), the increased risk for HF per 1% (10 mmol/mol) increase in HbA(1c) was 1.15 (95% CI 1.13 to 1.18) for updated mean HbA(1c), and 1.06 (1.04 to 1.07) and 1.06 (1.04 to 1.08) for baseline HbA(1c) and updated latest HbA(1c), respectively. When categorised, the hazard risk (HR) for the updated mean HbA(1c) in relation to HF became higher than for baseline and updated latest HbA(1c) above HbA(1c) levels of 9%, but did not differ at lower HbA(1c) levels. The updated latest variable showed an increased risk for HbA(1c)
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| 21. |
- Skrtic, Stanko, 1970, et al.
(author)
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Exploring the insulin secretory properties of the PGD(2)-GPR44/DP2 axis in vitro and in a randomized phase-1 trial of type 2 diabetes patients
- 2018
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:12
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Journal article (peer-reviewed)abstract
- Aims/Hypothesis GPR44 (DP2, PTGDR2, CRTh2) is the receptor for the pro-inflammatory mediator prosta-glandin D-2 (PGD(2)) and it is enriched in human islets. In rodent islets, PGD(2) is produced in response to glucose, suggesting that the PGD(2)-GPR44/DP2 axis may play a role in human islet function during hyperglycemia. Consequently, the aim of this work was to elucidate the insulinotropic role of GPR44 antagonism in vitro in human beta-cells and in type 2 diabetes (T2DM) patients. We determined the drive on PGD(2) secretion by glucose and IL-1 beta, as well as, the impact on insulin secretion by pharmacological GPR44/DP2 antagonism (AZD1981) in human islets and beta-cells in vitro. To test if metabolic control would be improved by antagonizing a hyperglycemia-driven increased PGD(2) tone, we performed a proof-of-mechanism study in 20 T2DM patients (average 54 years, HbA1c 9.4%, BMI 31.6 kg/m(2)). The randomized, double-blind, placebo-controlled cross-over study consisted of two three-day treatment periods (AZD1981 or placebo) separated by a three-day wash-out period. Mixed meal tolerance test (MMTT) and intravenous graded glucose infusion (GGI) was performed at start and end of each treatment period. Assessment of AZD1981 pharmacokinetics, glucose, insulin, C-peptide, glucagon, GLP-1, and PGD(2) pathway biomarkers were performed. We found (1) that PGD(2) is produced in human islet in response to high glucose or IL-1 beta, but likely by stellate cells rather than endocrine cells; (2) that PGD(2) suppresses both glucose and GLP-1 induced insulin secretion in vitro; and (3) that the GPR44/DP2 antagonist (AZD1981) in human beta-cells normalizes insulin secretion. However, AZD1981 had no impact on neither glucose nor incretin dependent insulin secretion in humans (GGI AUC (C-peptide 1-2h) and MMTT AUC (Glucose 0-4h) LS mean ratios vs placebo of 0.94 (80% CI of 0.90-0.98, p = 0.12) and 0.99 (90% CI of 0.94-1.05, p = 0.45), despite reaching the expected antagonist exposure. Pharmacological inhibition of the PGD(2)-GPR44/DP2 axis has no major impact on the modulation of acute insulin secretion in T2DM patients.
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| 22. |
- Skrtic, Stanko, 1970, et al.
(author)
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Secretagogin is increased in plasma from type 2 diabetes patients and potentially reflects stress and islet dysfunction
- 2018
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 13:4
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Journal article (peer-reviewed)abstract
- Beta cell dysfunction accompanies and drives the progression of type 2 diabetes mellitus (T2D), but there are few clinical biomarkers available to assess islet cell stress in humans. Secretagogin, a protein enriched in pancreatic islets, demonstrates protective effects on beta cell function in animals. However, its potential as a circulating biomarker released from human beta cells and islets has not been studied. In this study primary human islets, beta cells and plasma samples were used to explore secretion and expression of secretagogin in relation to the T2D pathology. Secretagogin was abundantly and specifically expressed and secreted from human islets. Furthermore, T2D patients had an elevated plasma level of secretagogin compared with matched healthy controls, which was confirmed in plasma of diabetic mice transplanted with human islets. Additionally, the plasma secretagogin level of the human cohort had an inverse correlation to clinical assessments of beta cell function. To explore the mechanism of secretagogin release in vitro, human beta cells (EndoC-[beta H1) were exposed to elevated glucose or cellular stress-inducing agents. Secretagogin was not released in parallel with glucose stimulated insulin release, but was markedly elevated in response to endoplasmic reticulum stressors and cytokines. These findings indicate that secretagogin is a potential novel biomarker, reflecting stress and islet cell dysfunction in T2D patients.
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| 23. |
- Sokolov, V., et al.
(author)
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Comparative quantitative systems pharmacology modeling of anti-PCSK9 therapeutic modalities in hypercholesterolemia S
- 2019
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In: Journal of Lipid Research. - 0022-2275. ; 60:9, s. 1610-1621
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Journal article (peer-reviewed)abstract
- Since the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as an attractive target in the treatment of hypercholesterolemia, multiple anti-PCSK9 therapeutic modalities have been pursued in drug development. The objective of this research is to set the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies (mAbs) and small interfering RNA (siRNA). To this end, we developed an integrative mathematical model of lipoprotein homeostasis describing the dynamic interplay between PCSK9, LDL-cholesterol (LDL-C), VLDL-cholesterol, HDL-cholesterol (HDL-C), apoB, lipoprotein a [Lp(a)], and triglycerides (TGs). We demonstrate that LDL-C decreased proportionally to PCSK9 reduction for both mAb and siRNA modalities. At marketed doses, however, treatment with mAbs resulted in an additional similar to 20% LDL-C reduction compared with siRNA. We further used the model as an evaluation tool and determined that no quantitative differences were observed in HDL-C, Lp(a), TG, or apoB responses, suggesting that the disruption of PCSK9 synthesis would provide no additional effects on lipoprotein-related biomarkers in the patient segment investigated. Predictive model simulations further indicate that siRNA therapies may reach reductions in LDL-C levels comparable to those achieved with mAbs if the current threshold of 80% PCSK9 inhibition via siRNA could be overcome.
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