| 61. |
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| 62. |
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| 63. |
- Bjursell, Mikael, 1977, et al.
(författare)
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Opposing effects of adiponectin receptors 1 and 2 on energy metabolism
- 2007
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Ingår i: DIABETES. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 56:3, s. 583-593
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Tidskriftsartikel (refereegranskat)abstract
- The adipocyte-derived hormone adiponectin regulates glucose and lipid metabolism and influences the risk for developing obesity, type 2 diabetes, and cardiovascular disease. Adiponectin binds to two different seven-transmembrane domain receptors termed AdipoR1 and AdipoR2. To study the physiological importance of these receptors, AdipoR1 gene knockout mice (AdipoR1−/−) and AdipoR2 gene knockout mice (AdipoR2−/−) were generated. AdipoR1−/− mice showed increased adiposity associated with decreased glucose tolerance, spontaneous locomotor activity, and energy expenditure. However, AdipoR2−/− mice were lean and resistant to high-fat diet–induced obesity associated with improved glucose tolerance and higher spontaneous locomotor activity and energy expenditure and reduced plasma cholesterol levels. Thus, AdipoR1 and AdipoR2 are clearly involved in energy metabolism but have opposing effects.
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| 64. |
- Bohlooly-Yeganeh, Mohammad, 1966, et al.
(författare)
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Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia.
- 2005
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Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 54:1, s. 51-62
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Tidskriftsartikel (refereegranskat)abstract
- It is well known that peripherally administered growth hormone (GH) results in decreased body fat mass. However, GH-deficient patients increase their food intake when substituted with GH, suggesting that GH also has an appetite stimulating effect. Transgenic mice with an overexpression of bovine GH in the central nervous system (CNS) were created to investigate the role of GH in CNS. This study shows that overexpression of GH in the CNS differentiates the effect of GH on body fat mass from that on appetite. The transgenic mice were not GH-deficient but were obese and showed increased food intake as well as increased hypothalamic expression of agouti-related protein and neuropeptide Y. GH also had an acute effect on food intake following intracerebroventricular injection of C57BL/6 mice. The transgenic mice were severely hyperinsulinemic and showed a marked hyperplasia of the islets of Langerhans. In addition, the transgenic mice displayed alterations in serum lipid and lipoprotein levels and hepatic gene expression. In conclusion, GH overexpression in the CNS results in hyperphagia-induced obesity indicating a dual effect of GH with a central stimulation of appetite and a peripheral lipolytic effect.
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| 65. |
- Bolinder, J, et al.
(författare)
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Rates of skeletal muscle and adipose tissue glycerol release in nonobese and obese subjects
- 2000
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 49:5, s. 797-802
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Tidskriftsartikel (refereegranskat)abstract
- Skeletal muscle and adipose tissue lipolysis rates were quantitatively compared in 12 healthy nonobese and 14 insulin-resistant obese subjects for 3.5 h after an oral glucose load using microdialysis measurements of interstitial glycerol concentrations and determinations of local blood flow with 133Xe clearance in the gastrocnemius muscle and in abdominal subcutaneous adipose tissue. Together with measurements of arterialized venous plasma glycerol, the absolute rates of glycerol mobilization were estimated. In the basal state, skeletal muscle and adipose tissue glycerol levels were 50% higher (P < 0.05-0.01) and adipose tissue blood flow (ATBF) and muscle blood flow (MBF) rates were 30-40% lower (P < 0.02-0.05) in obese versus nonobese subjects. After glucose ingestion, adipose tissue glycerol levels were rapidly and transiently reduced, whereas in muscle, a progressive and less pronounced fall in glycerol levels was evident. MBF remained unchanged in both study groups, whereas ATBF increased more markedly (P < 0.01) in the nonobese versus obese subjects after the oral glucose load. The fasting rates of glycerol release per unit of tissue weight from skeletal muscle were between 20 and 25% of that from adipose tissue in both groups. After glucose ingestion, the rates of glycerol release from skeletal muscle and from adipose tissue were almost identical in nonobese and obese subjects. However, the kinetic patterns differed markedly between tissues; in adipose tissue, the rate of glycerol mobilization was suppressed by 25-30% (P < 0.05) after glucose ingestion, whereas no significant reduction was registered in skeletal muscle. We conclude that significant amounts of glycerol are released from skeletal muscle, which suggests that muscle lipolysis provides an important endogenous energy source in humans. In response to glucose ingestion, the regulation of skeletal muscle glycerol release differs from that in adipose tissue; although the rate of glycerol release from adipose tissue is clearly suppressed, the rate of glycerol mobilization from skeletal muscle remains unaltered. In quantitative terms, the rate of glycerol release per unit of tissue weight in adipose tissue and in skeletal muscle is similar in nonobese and obese subjects in both the postabsorptive state and after glucose ingestion.
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| 66. |
- Borg, Henrik, et al.
(författare)
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A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes.
- 2002
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 51:6, s. 1754-1762
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Tidskriftsartikel (refereegranskat)abstract
- To clarify the relationships between islet antibodies (islet cell antibody [ICA], GAD antibody [GADA], and IA-2 antibody [IA-2A]) versus the progression of beta-cell dysfunction, we have followed a group of diabetic patients from their diagnosis at 21-73 years of age. Patients with ICA had high levels of GADA and/or IA-2A at diagnosis and a more severe beta-cell dysfunction 5 years after diagnosis than those with only GADA in low concentrations. The aim of the current 12-year follow-up study was to examine the further progression of beta-cell dysfunction in relation to islet antibodies at and after diagnosis. Among 107 patients, complete beta-cell failure 12 years after diagnosis was restricted to those with islet antibodies at diagnosis (16 of 21 [77%] with multiple antibodies and 4 of 5 [80%] with only GADA). In contrast, among antibody-negative patients, fasting P-C-peptide levels were unchanged. Most GADA-positive patients (22 of 27 [81%]) remained GADA positive after 12 years. Associated with decreasing fasting P-C-peptide levels (0.85 nmol/l [0.84] at diagnosis vs. 0.51 nmol/l [0.21] 12 years after diagnosis, P < 0.05), ICA developed after diagnosis in 6 of 105 originally antibody negative mostly overweight patients. In conclusion, multiple islet antibodies or GADA alone at diagnosis of diabetes predict future complete beta-cell failure. After diagnosis, GADA persisted in most patients, whereas ICA development in patients who were antibody negative at diagnosis indicated decreasing beta-cell function.
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| 67. |
- Borg, ML, et al.
(författare)
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Modified UCN2 Peptide Acts as an Insulin Sensitizer in Skeletal Muscle of Obese Mice
- 2019
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 68:7, s. 1403-1414
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Tidskriftsartikel (refereegranskat)abstract
- The neuropeptide urocortin 2 (UCN2) and its receptor corticotropin-releasing hormone receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance and glucose metabolism. We investigated a modified UCN2 peptide as a potential therapeutic agent for the treatment of obesity and insulin resistance, with a specific focus on skeletal muscle. High-fat–fed mice (C57BL/6J) were injected daily with a PEGylated UCN2 peptide (compound A) at 0.3 mg/kg subcutaneously for 14 days. Compound A reduced body weight, food intake, whole-body fat mass, and intramuscular triglycerides compared with vehicle-treated controls. Furthermore, whole-body glucose tolerance was improved by compound A treatment, with increased insulin-stimulated Akt phosphorylation at Ser473 and Thr308 in skeletal muscle, concomitant with increased glucose transport into extensor digitorum longus and gastrocnemius muscle. Mechanistically, this is linked to a direct effect on skeletal muscle because ex vivo exposure of soleus muscle from chow-fed lean mice to compound A increased glucose transport and insulin signaling. Moreover, exposure of GLUT4-Myc–labeled L6 myoblasts to compound A increased GLUT4 trafficking. Our results demonstrate that modified UCN2 peptides may be efficacious in the treatment of type 2 diabetes by acting as an insulin sensitizer in skeletal muscle.
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| 68. |
- Boström, Pontus, 1982, et al.
(författare)
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The SNARE protein SNAP23 and the SNARE-interacting protein Munc18c in human skeletal muscle are implicated in insulin resistance/type 2 diabetes.
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 59:8, s. 1870-8
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Our previous studies suggest that the SNARE protein synaptosomal-associated protein of 23 kDa (SNAP23) is involved in the link between increased lipid levels and insulin resistance in cardiomyocytes. The objective was to determine whether SNAP23 may also be involved in the known association between lipid accumulation in skeletal muscle and insulin resistance/type 2 diabetes in humans, as well as to identify a potential regulator of SNAP23. RESEARCH DESIGN AND METHODS: We analyzed skeletal muscle biopsies from patients with type 2 diabetes and healthy, insulin-sensitive control subjects for expression (mRNA and protein) and intracellular localization (subcellular fractionation and immunohistochemistry) of SNAP23, and for expression of proteins known to interact with SNARE proteins. Insulin resistance was determined by a euglycemic hyperinsulinemic clamp. Potential mechanisms for regulation of SNAP23 were also investigated in the skeletal muscle cell line L6. RESULTS: We showed increased SNAP23 levels in skeletal muscle from patients with type 2 diabetes compared with that from lean control subjects. Moreover, SNAP23 was redistributed from the plasma membrane to the microsomal/cytosolic compartment in the patients with the type 2 diabetes. Expression of the SNARE-interacting protein Munc18c was higher in skeletal muscle from patients with type 2 diabetes. Studies in L6 cells showed that Munc18c promoted the expression of SNAP23. CONCLUSIONS: We have translated our previous in vitro results into humans by showing that there is a change in the distribution of SNAP23 to the interior of the cell in skeletal muscle from patients with type 2 diabetes. We also showed that Munc18c is a potential regulator of SNAP23.
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| 69. |
- Bouzakri, K, et al.
(författare)
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IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:3, s. 785-791
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-dependent diabetic recipients of successful pancreas allografts achieve self-regulatory insulin secretion and discontinue exogenous insulin therapy; however, chronic hyperinsulinemia and impaired insulin sensitivity generally develop. To determine whether insulin resistance is accompanied by altered signal transduction, skeletal muscle biopsies were obtained from pancreas-kidney transplant recipients (n = 4), nondiabetic kidney transplant recipients (receiving the same immunosuppressive drugs; n = 5), and healthy subjects (n = 6) before and during a euglycemic-hyperinsulinemic clamp. Basal insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1–associated phosphatidylinositol 3-kinase activity, and extracellular signal–regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. Basal IRS-1 Ser (312) and Ser (616) phosphorylation was also increased in nondiabetic kidney transplant recipients. Insulin increased phosphorylation of IRS-1 at Ser (312) but not Ser (616) in healthy subjects, with impairments noted in nondiabetic kidney and pancreas-kidney transplant recipients. Insulin action on ERK-1/2 and Akt phosphorylation was impaired in pancreas-kidney transplant recipients and was preserved in nondiabetic kidney transplant recipients. Importantly, insulin stimulation of the Akt substrate AS160 was impaired in nondiabetic kidney and pancreas-kidney transplant recipients. In conclusion, peripheral insulin resistance in pancreas-kidney transplant recipients may arise from a negative feedback regulation of the canonical insulin-signaling cascade from excessive serine phosphorylation of IRS-1, possibly as a consequence of immunosuppressive therapy and hyperinsulinemia.
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| 70. |
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