| 1. |
- Stenlid, Rasmus, et al.
(författare)
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Adolescents with obesity treated with exenatide maintain endogenous GLP-1, reduce DPP-4, and improve glycemic control
- 2023
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media S.A.. - 1664-2392. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: GLP-1 receptor agonists (GLP-1RA) are increasingly used to treat adolescent obesity. However, the effect on endogenous GLP-1 secretory patterns following treatment in adolescents is unknown. The GLP-1RA exenatide was shown to significantly lower BMI and 2-hour glucose in adolescents with obesity, in the placebo-controlled, randomized controlled trial Combat-JUDO. The aim of this study was to evaluate effects of weekly injections of 2 mg exenatide extended release on secretory patterns of endogenous hormones during OGTT.Subjects and Measurements: This study was a pre-planned sub-study of the Combat-JUDO trial, set at the Pediatric clinic at Uppsala University Hospital, Sweden and Paracelsus Medical University, Austria. 44 adolescents with obesity were included and randomized 1:1 to treatment:placebo. 19 patients in the treatment group and 18 in the placebo group completed the trial. Before and after treatment, GLP-1, glucose, insulin, glucagon and glicentin levels were measured during OGTT; DPP-4 and proinsulin were measured at fasting. A per-protocol approach was used in the analyses.Results: Exenatide treatment did not affect GLP-1 levels during OGTT. Treatment significantly lowered DPP-4, proinsulin and the proinsulin-to-insulin ratio at fasting, increased glicentin levels but did not affect insulin, C-peptide or glucagon levels during OGTT.Conclusion: Weekly s.c. injections with 2 mg of exenatide maintains endogenous total GLP-1 levels and lowers circulating DPP-4 levels. This adds an argument in favor of using exenatide in the treatment of pediatric obesity.
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| 2. |
- Stenlid, Rasmus, et al.
(författare)
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Low Fasting Concentrations of Glucagon in Patients with Very Long-Chain Acyl-CoA Dehydrogenase Deficiency
- 2023
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Ingår i: Metabolites. - : MDPI AG. - 2218-1989 .- 2218-1989. ; 13:7
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Tidskriftsartikel (refereegranskat)abstract
- (1) Background: Deficiencies of mitochondrial fatty acid oxidation (FAO) define a subgroup of inborn errors of metabolism, with medium-chain acyl-CoA dehydrogenase deficiency (MCAD) and very long-chain acyl-CoA dehydrogenase deficiency (VLCAD) being two of the most common. Hypoketotic hypoglycemia is a feared clinical complication and the treatment focuses on avoiding hypoglycemia. In contrast, carnitine uptake deficiency (CUD) is treated as a mild disease without significant effects on FAO. Impaired FAO has experimentally been shown to impair glucagon secretion. Glucagon is an important glucose-mobilizing hormone. If and how glucagon is affected in patients with VLCAD or MCAD remains unknown. (2)Methods: A cross-sectional study was performed with plasma hormone concentrations quantified after four hours of fasting. Patients with VLCAD (n = 10), MCAD (n = 7) and CUD (n = 6) were included. (3)Results: The groups were similar in age, sex, weight, and height. The glucagon and insulin levels were significantly lower in the VLCAD group compared to the CUD group (p < 0.05, respectively). The patients with CUD had glucagon concentrations similar to the normative data. No significant differences were seen in GLP-1, glicentin, glucose, amino acids, or NEFAs. (4)Conclusions: Low fasting concentrations of glucagon are present in patients with VLCAD and cannot be explained by altered stimuli in plasma.
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| 3. |
- Stenlid, Rasmus, et al.
(författare)
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Screening for inflammatory markers identifies IL18-Rα as a potential link between exenatide and its anti-inflammatory effect : New results from the Combat-JUDO randomized controlled trial
- 2023
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Ingår i: Annals of Nutrition and Metabolism. - : S. Karger. - 0250-6807 .- 1421-9697. ; 79:6, s. 522-527
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Obesity is associated with chronic inflammation. Chronic inflammation has also been linked to insulin resistance and type 2 diabetes, non-alcoholic fatty liver disease and cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor analogs (GLP-1RA) are clinically used to treat obesity, with known anti-inflammatory properties. How the GLP-1RA exenatide effects inflammation in adolescents with obesity is not fully investigated.Methods: 44 patients were randomized to receive weekly subcutaneous injections with either 2 mg exenatide or placebo for 6 months. Plasma samples were collected at baseline and at the end of the study, and 90 inflammatory proteins were measured.Results: Following treatment with exenatide, 15 out of the 90 proteins were decreased, and one was increased. However, after adjustment for multiple testing, only IL18-R alpha was significantly lowered following treatment.Conclusions: Weekly injections with 2 mg of exenatide lowers circulating IL18-R alpha in adolescents with obesity, which may be a potential link between exenatide and its anti-inflammatory effect in vivo. This contributes to exenatide's pharmaceutical potential as a treatment for obesity beyond weight control and glucose tolerance, and should be further studied mechanistically.
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| 4. |
- Wen, Quan
(författare)
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Islet hormonal hypersecretion and metformin’s effect on islet hormonal secretion studied in vitro and in vivo
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Childhood obesity has surged globally. Elevated levels of free fatty acids contribute to hyperinsulinemia, hyperproinsulinemia, and hyperglucagonemia connected with both obesity and type 2 diabetes mellitus (T2DM). Metformin has beneficial effects on islets by influencing metabolism and reducing stress-induced cell death. The aim of the study was to define underlying mechanisms of free fatty acids induced islet hormone hypersecretion, especially in insulin, proinsulin and glucagon and how metformin influenced hormone levels in vitro and in vivo.Glucose stimulated insulin secretion (GSIS) from isolated human islets increased after culture in palmitate for up to 1 day, but declined with continued palmitate exposure. Whereas addition of metformin increased GSIS from islets exposed to palmitate for 1 day, metformin reduced GSIS from islets exposed to palmitate for 0.5 day. In some children with obesity insulin levels were accentuated after metformin treatment for at least 6 months, whereas insulin levels were attenuated in other children. The reduction of insulin levels was accompanied by lowering in 2-h glucose and triglycerides levels.In islets, palmitate treatment also increased proinsulin secretion, which was connected with decreasing prohormone convertase 1/3 (PC1/3) and carboxypeptidase E (CPE). Metformin normalized expression of PC1/3 and CPE, and proinsulin and insulin secretion. In children with obesity, metformin treatment reduced the proinsulin to insulin ratio (PI:I) in subjects with T2DM as well as in subjects with prediabetes, coupled with reduced 2-hour glucose and HbA1c.To address the role of palmitate on glucagon secretion we cultured αTC1 cells with palmitate. Palmitate exposure increased glucagon secretion, which was accompanied by increased ATP production, maximal respiratory capacity and protein levels of fission protein DRP-1. Knockdown or inhibition of DRP-1 decreased ATP production and glucagon secretion. Long-term palmitate treatment also changed transcripts levels of genes related to glycolysis and TCA cycle metabolism.In conclusion, metformin has beneficial effects on hyperinsulinemia and insulin processing, if introduced when insulin secretory levels are high and stable and not declining. Additionally, palmitate-induced glucagon hypersecretion was connected with increased mitochondrial fission protein DRP-1 and metabolism. Thereby, the thesis could contribute to understanding T2DM development and delineate ways to prevent its development.
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| 5. |
- Wen, Quan, et al.
(författare)
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Metformin Can Attenuate Beta-Cell Hypersecretion-Implications for Treatment of Children with Obesity
- 2023
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Ingår i: Metabolites. - : MDPI. - 2218-1989 .- 2218-1989. ; 13:8
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Tidskriftsartikel (refereegranskat)abstract
- In children with obesity, insulin hypersecretion is proposed to precede insulin resistance. We investigated if metformin could be used to attenuate insulin secretion from palmitate-treated isolated islets and its implication for children with obesity. Human islets were exposed to palmitate for 0.5 or 1 day, when metformin was introduced. After culture, glucose-stimulated insulin secretion (GSIS) was measured. Children with obesity, who had received metformin for over six months (n = 21, age 13.9 +/- 1.8), were retrospectively evaluated. Children were classified as either "reducing" or "increasing" based on the difference between AUC(0-120) of insulin during OGTT before and after metformin treatment. In human islets, GSIS increased after culture in palmitate for up to 1 day but declined with continued palmitate exposure. Whereas adding metformin after 1 day of palmitate exposure increased GSIS, adding metformin after 0.5 days reduced GSIS. In children with "reducing" insulin AUC(0-120) (n = 9), 2 h glucose and triglycerides decreased after metformin treatment, which was not observed in patients with "increasing" insulin AUC(0-120) (n = 12). In isolated islets, metformin attenuated insulin hypersecretion if introduced when islet secretory capacity was maintained. In children with obesity, improved glycemic and lipid levels were accompanied by reduced insulin levels during OGTT after metformin treatment.
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