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Sökning: L773:0012 1797 OR L773:1939 327X > (2020-2021) > (2021)

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1.
  • Almby, Kristina E, et al. (författare)
  • Effects of Gastric Bypass Surgery on the Brain; Simultaneous Assessment of Glucose Uptake, Blood Flow, Neural Activity and Cognitive Function during Normo- and Hypoglycemia.
  • 2021
  • Ingår i: Diabetes. - 0012-1797 .- 1939-327X.
  • Tidskriftsartikel (refereegranskat)abstract
    • While Roux-en-Y Gastric Bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes hypoglycemia. Previous work showed attenuated counter-regulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear.In this study, 11 non-diabetic subjects with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by FDG PET and activation of brain networks by functional MRI. Post- vs pre-surgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake and this was similar for post- and pre-surgery, whereas hypothalamic FDG uptake was reduced. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen post-surgery. In early hypoglycemia, there was increased activation post- vs pre-surgery of neural networks in CNS regions implicated in glucose regulation such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.
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2.
  • Eriksson, Olof, et al. (författare)
  • Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography
  • 2021
  • Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 70:4, s. 842-853
  • Tidskriftsartikel (refereegranskat)abstract
    • Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic drug development. The aim of this study was to develop a positron emission tomography (PET) radioligand for the GIPR to enable the assessment of target distribution and drug target engagement in vivo. The GIPR-selective peptide S02-GIP was radiolabeled with Ga-68. The resulting PET tracer [Ga-68]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [Ga-68]S02-GIP-T4 as well as the occupancy of a drug candidate with GIPR activity were assessed in nonhuman primates (NHPs) by PET. [Ga-68]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [Ga-68]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [Ga-68]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [Ga-68]S02-GIP-T4 is a novel PET biomarker for safe, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.
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3.
  • Espes, Daniel, 1985-, et al. (författare)
  • Longitudinal Assessment of 11C-5-Hydroxytryptophan Uptake in Pancreas After Debut of Type 1 Diabetes
  • 2021
  • Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 70:4, s. 966-975
  • Tidskriftsartikel (refereegranskat)abstract
    • The longitudinal alterations of the pancreatic β-cell and islet mass in the progression of type 1 diabetes (T1D) are still poorly understood. The objective of this study was to repeatedly assess the endocrine volume and the morphology of the pancreas for up to 24 months after T1D diagnosis (n = 16), by 11C-5-hydroxytryptophan (11C-5-HTP) positron emission tomography (PET) and MRI. Study participants were examined four times by PET/MRI: at recruitment and then after 6, 12, and 24 months. Clinical examinations and assessment of β-cell function by a mixed-meal tolerance test and fasting blood samples were performed in connection with the imaging examination. Pancreas volume has a tendency to decrease from 50.2 ± 10.3 mL at T1D debut to 42.2 ± 14.6 mL after 24 months (P < 0.098). Pancreas uptake of 11C-5-HTP (e.g., the volume of the endocrine pancreas) did not decrease from T1D diagnosis (0.23 ± 0.10 % of injected dose) to 24-month follow-up, 0.21 ± 0.14% of injected dose, and exhibited low interindividual changes. Pancreas perfusion was unchanged from diagnosis to 24-month follow-up. The pancreas uptake of 11C-5-HTP correlated with the long-term metabolic control as estimated by HbA1c (P < 0.05). Our findings argue against a major destruction of β-cell or islet mass in the 2-year period after diagnosis of T1D.
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4.
  • Jersin, R. A., et al. (författare)
  • Role of the Neutral Amino Acid Transporter SLC7A10 in Adipocyte Lipid Storage, Obesity, and Insulin Resistance
  • 2021
  • Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 70:3, s. 680-695
  • Tidskriftsartikel (refereegranskat)abstract
    • Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.
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5.
  • Baboota, Ritesh, et al. (författare)
  • Emerging Role of Bone Morphogenetic Protein 4 in Metabolic Disorders
  • 2021
  • Ingår i: Diabetes. - 0012-1797. ; 70:2, s. 303-312
  • Tidskriftsartikel (refereegranskat)abstract
    • Bone morphogenetic proteins (BMPs) are a group of signaling molecules that belong to the TGF-beta superfamily. Initially discovered for their ability to induce bone formation, BMPs are known to play a diverse and critical array of biological roles. We here focus on recent evidence showing that BMP4 is an important regulator of white/beige adipogenic differentiation with important consequences for thermogenesis, energy homeostasis, and development of obesity in vivo. BMP4 is highly expressed in, and released by, human adipose tissue, and serum levels are increased in obesity. Recent studies have now shown BMP4 to play an important role not only for white/beige/brown adipocyte differentiation and thermogenesis but also in regulating systemic glucose homeostasis and insulin sensitivity. It also has important suppressive effects on hepatic glucose production and lipid metabolism. Cellular BMP4 signaling/action is regulated by both ambient cell/systemic levels and several endogenous and systemic BMP antagonists. Reduced BMP4 signaling/action can contribute to the development of obesity, insulin resistance, and associated metabolic disorders. In this article, we summarize the pleiotropic functions of BMP4 in the pathophysiology of these diseases and also consider the therapeutic implications of targeting BMP4 in the prevention/treatment of obesity and its associated complications.
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7.
  • Jönsson, Josefine, et al. (författare)
  • Lifestyle Intervention in Pregnant Women With Obesity Impacts Cord Blood DNA Methylation, Which Associates With Body Composition in the Offspring
  • 2021
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 1939-327X. ; 70:4, s. 854-866
  • Tidskriftsartikel (refereegranskat)abstract
    • Maternal obesity may lead to epigenetic alterations in the offspring and might thereby contribute to disease later in life. We investigated whether a lifestyle intervention in pregnant women with obesity is associated with epigenetic variation in cord blood and body composition in the offspring. Genome-wide DNA methylation was analyzed in cord blood from 208 offspring from the Treatment of Obese Pregnant women (TOP)-study, which includes pregnant women with obesity randomized to lifestyle interventions comprised of physical activity with or without dietary advice versus control subjects (standard of care). DNA methylation was altered at 379 sites, annotated to 370 genes, in cord blood from offspring of mothers following a lifestyle intervention versus control subjects (false discovery rate [FDR] <5%) when using the Houseman reference-free method to correct for cell composition, and three of these sites were significant based on Bonferroni correction. These 370 genes are overrepresented in gene ontology terms, including response to fatty acids and adipose tissue development. Offspring of mothers included in a lifestyle intervention were born with more lean mass compared with control subjects. Methylation at 17 sites, annotated to, for example, DISC1, GBX2, HERC2, and HUWE1, partially mediates the effect of the lifestyle intervention on lean mass in the offspring (FDR <5%). Moreover, 22 methylation sites were associated with offspring BMI z scores during the first 3 years of life (P < 0.05). Overall, lifestyle interventions in pregnant women with obesity are associated with epigenetic changes in offspring, potentially influencing the offspring's lean mass and early growth.
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8.
  • Li, Qian, et al. (författare)
  • Plasma Metabolome and Circulating Vitamins Stratified Onset Age of an Initial Islet Autoantibody and Progression to Type 1 Diabetes : the TEDDY Study
  • 2021
  • Ingår i: Diabetes. - : American Diabetes Association Inc.. - 1939-327X. ; 70:1, s. 282-292
  • Tidskriftsartikel (refereegranskat)abstract
    • Children's plasma metabolome, especially lipidome reflects gene regulation and dietary exposures, heralding the development of islet autoantibodies (IA) and type 1 diabetes (T1D). The TEDDY study enrolled 8676 newborns by screening HLA-DR-DQ genotypes at six clinical centers in four countries; profiled metabolome and measured concentrations of ascorbic acid, 25-hydroxyvitamin D (25(OH)D), erythrocyte membrane fatty acids following birth until IA seroconversion under nested case-control design. We grouped children having an initial autoantibody only against insulin (IAA-first) or glutamic acid decarboxylase (GADA-first) by unsupervised clustering of temporal lipidome, identifying a subgroup of children having early onset of each initial autoantibody, i.e., IAA-first by 12 months and GADA-first by 21 months, consistent with population-wide early seroconversion age. Differential analysis showed that infants having reduced plasma ascorbic acid and cholesterol experienced IAA-first earlier, while early onset of GADA-first was preceded by reduced sphingomyelins at infancy. Plasma 25(OH)D prior to either autoantibody was lower in T1D progressors compared to non-progressors, with simultaneous lower diglycerides, lysophosphatidylcholines, triglycerides, alanine before GADA-first. Plasma ascorbic acid and 25(OH)D at infancy were lower in HLA-DR3/DR4 children among IA cases but not in matched controls, implying gene expression dysregulation of circulating vitamins as latent signals for IA or T1D progression.
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