| 21. |
- Andersson, DP, et al.
(författare)
-
Relationship Between a Sedentary Lifestyle and Adipose Insulin Resistance
- 2023
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 72:3, s. 316-325
-
Tidskriftsartikel (refereegranskat)abstract
- Sedentary people have insulin resistance in their skeletal muscle, but whether this also occurs in fat cells was unknown. Insulin inhibition of hydrolysis of triglycerides (antilipolysis) and stimulation of triglyceride formation (lipogenesis) were investigated in subcutaneous fat cells from 204 sedentary and 336 physically active subjects. Insulin responsiveness (maximum hormone effect) and sensitivity (half-maximal effective concentration) were determined. In 69 women, hyperinsulinemia-induced circulating fatty acid levels were measured. In 128 women, adipose gene expression was analyzed. Responsiveness of insulin for antilipolysis (60% inhibition) and lipogenesis (twofold stimulation) were similar between sedentary and active subjects. Sensitivity for both measures decreased ˜10-fold in sedentary subjects (P < 0.01). However, upon multiple regression analysis, only the association between antilipolysis sensitivity and physical activity remained significant when adjusting for BMI, age, sex, waist-to-hip ratio, fat-cell size, and cardiometabolic disorders. Fatty acid levels decreased following hyperinsulinemia but remained higher in sedentary compared with active women (P = 0.01). mRNA expression of insulin receptor and its substrates 1 and 2 was decreased in sedentary subjects. In conclusion, while the maximum effect is preserved, sensitivity to insulin’s antilipolytic effect in subcutaneous fat cells is selectively lower in sedentary subjects.
|
|
| 22. |
- Andersson, Lotta E., et al.
(författare)
-
Glutamine-elicited secretion of glucagon-like peptide 1 is governed by an activated glutamate dehydrogenase
- 2018
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 67:3, s. 372-384
-
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.
|
|
| 23. |
- Andrew, R, et al.
(författare)
-
The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans
- 2005
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 54:5, s. 1364-1370
-
Tidskriftsartikel (refereegranskat)abstract
- Cortisol is regenerated from cortisone by 11β-hydroxysteroid dehydrogenase type 1 (11HSD1), amplifying glucocorticoid action in adipose tissue and liver. 11HSD1 inhibitors are being developed for type 2 diabetes and may be most effective in obesity, where adipose 11HSD1 is increased. However, the magnitude of regeneration of cortisol in different tissues in humans is unknown, hindering understanding of the pathophysiological and therapeutic importance of 11HSD1. In eight healthy men, we infused 9,11,12,12-2H4-cortisol and measured tracer enrichment in the hepatic vein as an indicator of total splanchnic cortisol generation. Oral cortisone (25 mg) was then given to measure first-pass hepatic cortisol generation. In steady state, splanchnic cortisol production was 45 ± 11 nmol/min when arterialized plasma cortisone concentration was 92 ± 7 nmol/l. Extrapolation from hepatic cortisol generation after oral corti-sone suggested that, at steady state, the liver contributes 15.2 nmol/min and extrahepatic splanchnic tissue contributes 29.8 nmol/min to the total splanchnic cortisol production. We conclude that tissues draining into the portal vein, including visceral adipose tissue, contribute substantially to the regeneration of cortisol. Thus, in addition to free fatty acids and adipokines, the portal vein delivers cortisol to the liver, and inhibition of 11HSD1 in visceral adipose tissue may indeed be valuable in ameliorating insulin resistance in obesity.
|
|
| 24. |
- Armour, Sarah L., et al.
(författare)
-
Glucose Controls Glucagon Secretion by Regulating Fatty Acid Oxidation in Pancreatic α-Cells
- 2023
-
Ingår i: DIABETES. - 0012-1797 .- 1939-327X. ; 72:10, s. 1446-1459
-
Tidskriftsartikel (refereegranskat)abstract
- Whole-body glucose homeostasis is coordinated through secretion of glucagon and insulin from pancreatic islets. When glucose is low, glucagon is released from alpha-cells to stimulate hepatic glucose production. However, the mechanisms that regulate glucagon secretion from pancreatic alpha-cells remain unclear. Here we show that in alpha-cells, the interaction between fatty acid oxidation and glucose metabolism controls glucagon secretion. The glucose-dependent inhibition of glucagon secretion relies on pyruvate dehydrogenase and carnitine palmitoyl transferase 1a activity and lowering of mitochondrial fatty acid oxidation by increases in glucose. This results in reduced intracellular ATP and leads to membrane repolarization and inhibition of glucagon secretion. These findings provide a new framework for the metabolic regulation of the alpha-cell, where regulation of fatty acid oxidation by glucose accounts for the stimulation and inhibition of glucagon secretion.Article Highlights It has become clear that dysregulation of glucagon secretion and alpha-cell function plays an important role in the development of diabetes, but we do not know how glucagon secretion is regulated. Here we asked whether glucose inhibits fatty acid oxidation in alpha-cells to regulate glucagon secretion. We found that fatty acid oxidation is required for the inhibitory effects of glucose on glucagon secretion through reductions in ATP. These findings provide a new framework for the regulation of glucagon secretion by glucose.
|
|
| 25. |
- Arner, Erik, et al.
(författare)
-
Adipocyte Turnover : Relevance to Human Adipose Tissue Morphology
- 2010
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 59:1, s. 105-109
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Adipose tissue may contain few large adipocytes (hypertrophy) or many small adipocytes (hyperplasia). We investigated factors of putative importance for adipose tissue morphology. RESEARCH DESIGN AND METHODS-Subcutaneous adipocyte size and total fat mass were compared in 764 subjects with BMI 18-60 kg/m(2). A morphology value was defined as tire difference between the measured adipocyte volume and the expected volume given by a curved-line fit for a given body fat mass and was related to insulin values. In 35 subjects, in vivo adipocyte turnover was measured by exploiting incorporation of atmospheric C-14 into DNA. RESULTS-Occurrence of hyperplasia (negative morphology value) or hypertrophy (positive morphology value) was independent of sex and body weight but con-elated with fasting plasma insulin levels and insulin sensitivity, independent of adipocyte volume (beta-coefficient = 0.3, P < 0.0001). Total adipocyte number and morphology were negatively related (r = -0.66); i.e., the total adipocyte number was greatest in pronounced hyperplasia and smallest in pronounced hypertrophy. The absolute number of new adipocytes generated each year was 70% lower (P < 0.001) in hypertrophy than in hyperplasia, and individual values for adipocyte generation and morphology were strongly related (r = 0.7, P < 0.001). The relative death rate (similar to 10% per year) or mean age of adipocytes (similar to 10 years) was not correlated with morphology. CONCLUSIONS-Adipose tissue morphology correlates with insulin measures and is linked to the total adipocyte number independently of sex and body fat level. Low generation rates of adipocytes associate with adipose tissue hypertrophy, whereas high generation rates associate with adipose hyperplasia. Diabetes 59:105-109, 2010
|
|
| 26. |
- Artner, Isabella, et al.
(författare)
-
MafA and MafB Regulate Genes Critical to beta-Cells in a Unique Temporal Manner
- 2010
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 59:10, s. 2530-2539
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Several transcription factors are essential to pancreatic islet beta-cell development, proliferation, and activity, including MafA and MafB. However, MafA and MafB are distinct from others in regard to temporal and islet cell expression pattern, with beta-cells affected by MafB only during development and exclusively by MafA in the adult. Our aim was to define the functional relationship between these closely related activators to the beta-cell. RESEARCH DESIGN AND METHODS-The distribution of MafA and MafB in the beta-cell population was determined immunohistochemically at various developmental and perinatal stages in mice. To identify genes regulated by MafB, microarray profiling was performed on wild-type and MafB(-/-) pancreata at embryonic day 18.5, with candidates evaluated by quantitative RT-PCR and in situ hybridization. The potential role of MafA in the expression of verified targets was next analyzed in adult islets of a pancreas-wide MafA mutant (termed MafA(Delta Panc)). RESULTS-MafB was produced in a larger fraction of beta-cells than MafA during development and found to regulate potential effectors of glucose sensing, hormone processing, vesicle formation, and insulin secretion. Notably, expression from many of these genes was compromised in MafA(Delta Panc) islets, suggesting that MafA is required to sustain expression in adults. CONCLUSIONS-Our results provide insight into the sequential manner by which MafA and MafB regulate islet beta-cell formation and maturation. Diabetes 59:2530-2539, 2010
|
|
| 27. |
- Arvidsson, E, et al.
(författare)
-
Effects of different hypocaloric diets on protein secretion from adipose tissue of obese women
- 2004
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 53:8, s. 1966-1971
-
Tidskriftsartikel (refereegranskat)abstract
- Little is known about common factors (e.g., macronutrients and energy supply) regulating the protein secretory function of adipose tissue. We therefore compared the effects of randomly assigned 10-week hypoenergetic (−600 kcal/day) diets with moderate-fat/moderate-carbohydrate or low-fat/high-carbohydrate content on circulating levels and production of proteins (using radioimmunoassays and enzyme-linked immunosorbent assays) from subcutaneous adipose tissue in 40 obese but otherwise healthy women. Similar results were obtained by the two diets. Body weight decreased by ∼7.5%. The secretion rate of leptin decreased by ∼40%, as did that of tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 and -8 decreased by 25–30%, whereas the secretion of plasminogen activator inhibitor 1 (PAI-1) and adiponectin did not show any changes. Regarding mRNA expression (by real-time PCR), only that of leptin and IL-6 decreased significantly. Circulating levels of leptin and PAI-1 decreased by 30 and 40%, respectively, but there were only minor changes in circulating TNF-α, IL-6, or adiponectin. In conclusion, moderate caloric restriction but not macronutrient composition influences the production and secretion of adipose tissue–derived proteins during weight reduction, leptin being the most sensitive and adiponectin and PAI-1 the least sensitive.
|
|
| 28. |
- Augestad, IL, et al.
(författare)
-
Regulation of Glycemia in the Recovery Phase After Stroke Counteracts the Detrimental Effect of Obesity-Induced Type 2 Diabetes on Neurological Recovery
- 2020
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 69:9, s. 1961-1973
-
Tidskriftsartikel (refereegranskat)abstract
- The interplay between obesity and type 2 diabetes (T2D) in poststroke recovery is unclear. Moreover, the impact of glucose control during the chronic phase after stroke is undetermined. We investigated whether obesity-induced T2D impairs neurological recovery after stroke by using a clinically relevant experimental design. We also investigated the potential efficacy of two clinically used T2D drugs: the dipeptidyl peptidase 4 inhibitor linagliptin and the sulfonylurea glimepiride. We induced transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (after 7 months of high-fat diet [HFD]) and age-matched controls. After stroke, we replaced HFD with standard diet for 8 weeks to mimic the poststroke clinical situation. Linagliptin or glimepiride were administered daily from 3 days after tMCAO for 8 weeks. We assessed neurological recovery weekly by upper-limb grip strength. Brain damage, neuroinflammation, stroke-induced neurogenesis, and atrophy of parvalbumin-positive (PV+) interneurons were quantified by immunohistochemistry. T2D/obesity impaired poststroke neurological recovery in association with hyperglycemia, neuroinflammation, and atrophy of PV+ interneurons. Both drugs counteracted these effects. In nondiabetic mice, only linagliptin accelerated recovery. These findings shed light on the interplay between obesity and T2D in stroke recovery. Moreover, they promote the use of rehabilitative strategies that are based on efficacious glycemia regulation, even if initiated days after stroke.
|
|
| 29. |
- Aydemir, O, et al.
(författare)
-
Genetic Variation Within the HLA-DRA1 Gene Modulates Susceptibility to Type 1 Diabetes in HLA-DR3 Homozygotes
- 2019
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 68:7, s. 1523-1527
-
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.
|
|
| 30. |
- Baboota, Ritesh, et al.
(författare)
-
Emerging Role of Bone Morphogenetic Protein 4 in Metabolic Disorders
- 2021
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 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.
|
|
