| 1. |
- Abrahamsson, Niclas, 1976-, et al.
(författare)
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Gastric bypass reduces symptoms and hormonal responses to hypoglycemia
- 2016
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:9, s. 2667-2675
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Tidskriftsartikel (refereegranskat)abstract
- Gastric bypass (GBP) surgery, one of the most common bariatric procedures, induces weight loss and metabolic effects. The mechanisms are not fully understood, but reduced food intake and effects on gastrointestinal hormones are thought to contribute. We recently observed that GBP patients have lowered glucose levels and frequent asymptomatic hypoglycemic episodes. Here, we subjected patients before and after undergoing GBP surgery to hypoglycemia and examined symptoms and hormonal and autonomic nerve responses. Twelve obese patients without diabetes (8 women, mean age 43.1 years [SD 10.8] and BMI 40.6 kg/m(2) [SD 3.1]) were examined before and 23 weeks (range 19-25) after GBP surgery with hyperinsulinemic-hypoglycemic clamp (stepwise to plasma glucose 2.7 mmol/L). The mean change in Edinburgh Hypoglycemia Score during clamp was attenuated from 10.7 (6.4) before surgery to 5.2 (4.9) after surgery. There were also marked postsurgery reductions in levels of glucagon, cortisol, and catecholamine and the sympathetic nerve responses to hypoglycemia. In addition, growth hormone displayed a delayed response but to a higher peak level. Levels of glucagon-like peptide 1 and gastric inhibitory polypeptide rose during hypoglycemia but rose less postsurgery compared with presurgery. Thus, GBP surgery causes a resetting of glucose homeostasis, which reduces symptoms and neurohormonal responses to hypoglycemia. Further studies should address the underlying mechanisms as well as their impact on the overall metabolic effects of GBP surgery.
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| 2. |
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| 3. |
- Al-Majdoub, Mahmoud, et al.
(författare)
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Metabolite profiling of LADA challenges the view of a metabolically distinct subtype
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:4, s. 806-814
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Tidskriftsartikel (refereegranskat)abstract
- Latent autoimmune diabetes in adults (LADA) usually refers to GAD65 autoantibodies (GADAb)-positive diabetes with onset after 35 years of age and no insulin treatment within the first 6 months after diagnosis. However, it is not always easy to distinguish LADA fromtype 1 or type 2 diabetes. In this study, we examined whether metabolite profiling could help to distinguish LADA (n = 50) from type 1 diabetes (n = 50) and type 2 diabetes (n = 50). Of 123 identified metabolites, 99 differed between the diabetes types. However, no unique metabolite profile could be identified for any of the types. Instead, the metabolome varied along a C-peptide-driven continuum from type 1 diabetes via LADA to type 2 diabetes. LADA was more similar to type 2 diabetes than to type 1 diabetes. In a principal component analysis, LADA patients overlapping with type 1 diabetes progressed faster to insulin therapy than those overlapping with type 2 diabetes. In conclusion, we could not find any unique metabolite profile distinguishing LADA from type 1 and type 2 diabetes. Rather, LADA was metabolically an intermediate of type 1 and type 2 diabetes, with those patients closer to the former showing a faster progression to insulin therapy than those closer to the latter.
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| 4. |
- Alenkvist, Ida, et al.
(författare)
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Recruitment of Epac2A to Insulin Granule Docking Sites Regulates Priming for Exocytosis
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:10, s. 2610-2622
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Tidskriftsartikel (refereegranskat)abstract
- Epac is a cAMP-activated guanine nucleotide exchange factor that mediates cAMP signaling in various types of cells, including -cells, where it is involved in the control of insulin secretion. Upon activation, the protein redistributes to the plasma membrane, but the underlying molecular mechanisms and functional consequences are unclear. Using quantitative high-resolution microscopy, we found that cAMP elevation caused rapid binding of Epac2A to the -cell plasma membrane, where it accumulated specifically at secretory granules and rendered them more prone to undergo exocytosis. cAMP-dependent membrane binding required the high-affinity cyclic nucleotide-binding (CNB) and Ras association domains, but not the disheveled-Egl-10-pleckstrin domain. Although the N-terminal low-affinity CNB domain (CNB-A) was dispensable for the translocation to the membrane, it was critical for directing Epac2A to the granule sites. Epac1, which lacks the CNB-A domain, was recruited to the plasma membrane but did not accumulate at granules. We conclude that Epac2A controls secretory granule release by binding to the exocytosis machinery, an effect that is enhanced by prior cAMP-dependent accumulation of the protein at the plasma membrane.
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| 5. |
- Amrutkar, Manoj, et al.
(författare)
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Genetic Disruption of Protein Kinase STK25 Ameliorates Metabolic Defects in a Diet-Induced Type 2 Diabetes Model
- 2015
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 64:8, s. 2791-2804
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the molecular networks controlling ectopic lipid deposition, glucose tolerance, and insulin sensitivity is essential to identifying new pharmacological approaches to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a negative regulator of glucose and insulin homeostasis based on observations in myoblasts with acute depletion of STK25 and in STK25-overexpressing transgenic mice. Here, we challenged Stk25 knockout mice and wild-type littermates with a high-fat diet and showed that STK25 deficiency suppressed development of hyperglycemia and hyperinsulinemia, improved systemic glucose tolerance, reduced hepatic gluconeogenesis, and increased insulin sensitivity. Stk25(-/-) mice were protected from diet-induced liver steatosis accompanied by decreased protein levels of acetyl-CoA carboxylase, a key regulator of both lipid oxidation and synthesis. Lipid accumulation in Stk25(-/-) skeletal muscle was reduced, and expression of enzymes controlling the muscle oxidative capacity (Cpt1, Acox1, Cs, Cycs, Ucp3) and glucose metabolism (Glut1, Glut4, Hk2) was increased. These data are consistent with our previous study of STK25 knockdown in myoblasts and reciprocal to the metabolic phenotype of Stk25 transgenic mice, reinforcing the validity of the results. The findings suggest that STK25 deficiency protects against the metabolic consequences of chronic exposure to dietary lipids and highlight the potential of STK25 antagonists for the treatment of type 2 diabetes.
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| 6. |
- Anderberg, Rozita H, et al.
(författare)
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Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight
- 2017
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:4, s. 1062-1073
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT2A) and 5-HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT2A, but surprisingly not the 5-HT2C, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin-producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase the electrical activity of the DR serotonin neurons. Finally, our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as a new critical neural substrate for GLP-1 impact on energy homeostasis and expands the current map of brain areas impacted by GLP-1R activation.
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| 7. |
- Andersson, Lotta E., et al.
(författare)
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Glutamine-elicited secretion of glucagon-like peptide 1 is governed by an activated glutamate dehydrogenase
- 2018
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 67:3, s. 372-384
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Tidskriftsartikel (refereegranskat)abstract
- Glucagon-like peptide 1 (GLP-1), secreted from intestinal L cells, glucose dependently stimulates insulin secretion from β-cells. This glucose dependence prevents hypoglycemia, rendering GLP-1 analogs a useful and safe treatment modality in type 2 diabetes. Although the amino acid glutamine is a potent elicitor of GLP-1 secretion, the responsible mechanism remains unclear. We investigated how GLP-1 secretion is metabolically coupled in L cells (GLUTag) and in vivo inmice using the insulin-secreting cell line INS-1 832/13 as reference. A membrane-permeable glutamate analog (dimethylglutamate [DMG]), acting downstream of electrogenic transporters, elicited similar alterations in metabolism as glutamine in both cell lines. Both DMG and glutamine alone elicited GLP-1 secretion in GLUTag cells and in vivo, whereas activation of glutamate dehydrogenase (GDH) was required to stimulate insulin secretion from INS-1 832/13 cells. Pharmacological inhibition in vivo of GDH blocked secretion of GLP-1 in response to DMG. In conclusion, our results suggest that nonelectrogenic nutrient uptake and metabolism play an important role in L cell stimulus-secretion coupling. Metabolism of glutamine and related analogs by GDH in the L cell may explain why GLP-1 secretion, but not that of insulin, is activated by these secretagogues in vivo.
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| 8. |
- Aydemir, O, et al.
(författare)
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Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes
- 2019
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 68:7, s. 1523-1527
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes (T1D) involves the interaction of multiple gene variants, environmental factors, and immunoregulatory dysfunction. Major T1D genetic risk loci encode HLA-DR and -DQ. Genetic heterogeneity and linkage disequilibrium in the highly polymorphic HLA region confound attempts to identify additional T1D susceptibility loci. To minimize HLA heterogeneity, T1D patients (N = 365) and control subjects (N = 668) homozygous for the HLA-DR3 high-risk haplotype were selected from multiple large T1D studies and examined to identify new T1D susceptibility loci using molecular inversion probe sequencing technology. We report that risk for T1D in HLA-DR3 homozygotes is increased significantly by a previously unreported haplotype of three single nucleotide polymorphisms (SNPs) within the first intron of HLA-DRA1. The homozygous risk haplotype has an odds ratio of 4.65 relative to the protective homozygous haplotype in our sample. Individually, these SNPs reportedly function as “expression quantitative trait loci,” modulating HLA-DR and -DQ expression. From our analysis of available data, we conclude that the tri-SNP haplotype within HLA-DRA1 may modulate class II expression, suggesting that increased T1D risk could be attributable to regulated expression of class II genes. These findings could help clarify the role of HLA in T1D susceptibility and improve diabetes risk assessment, particularly in high-risk HLA-DR3 homozygous individuals.
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| 9. |
- Barbarroja, Nuria, et al.
(författare)
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Increased dihydroceramide/ceramide ratio mediated by defective expression of degs1 impairs adipocyte differentiation and function
- 2015
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 64:4, s. 1180-1192
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Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue dysfunction is an important determinant of obesity-associated, lipid-induced metabolic complications. Ceramides are well-known mediators of lipid-induced insulin resistance in peripheral organs such as muscle. DEGS1 is the desaturase catalyzing the last step in the main ceramide biosynthetic pathway. Functional suppression of DEGS1 activity results in substantial changes in ceramide species likely to affect fundamental biological functions such as oxidative stress, cell survival, and proliferation. Here, we show that degs1 expression is specifically decreased in the adipose tissue of obese patients and murine models of genetic and nutritional obesity. Moreover, loss-of-function experiments using pharmacological or genetic ablation of DEGS1 in preadipocytes prevented adipogenesis and decreased lipid accumulation. This was associated with elevated oxidative stress, cellular death, and blockage of the cell cycle. These effects were coupled with increased dihydroceramide content. Finally, we validated in vivo that pharmacological inhibition of DEGS1 impairs adipocyte differentiation. These data identify DEGS1 as a new potential target to restore adipose tissue function and prevent obesity-associated metabolic disturbances.
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