| 11. |
- Galli, J, et al.
(författare)
-
Pathophysiological and genetic characterization of the major diabetes locus in GK rats
- 1999
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 48:12, s. 2463-2470
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of the type 2 diabetes-like GK rat have revealed several susceptibility loci for the compound diabetes phenotype. Congenic strains were established for Niddm1, the major quantitative trait locus (QTL) for postprandial glucose levels, by transfer of GK alleles onto the genome of the normoglycemic F344 rat. Despite the polygenic nature of diabetes in GK, the locus-specific diabetes phenotype was retained in the congenic strain Niddmla, containing a GK-derived genomic fragment of 52 cM from the Niddm1 locus. Furthermore, Niddm1 was divided into two non-overlapping loci, physically separated in the two congenic strains Niddmlb and Niddm1i with distinct metabolic phenotypes. Both strains displayed postprandial hyperglycemia and reduced insulin action in isolated adipose cells. Furthermore, Niddm1i already exhibits a pronounced in vivo insulin secretion defect at 65 days, while Niddm1b develops a relative insulin secretory defect at 95 days. This suggests that Niddm1i impairs mechanisms common to insulin secretion in pancreatic B-cells and insulin action in adipocytes. Niddm1b rats show signs of increasing insulin resistance with age associated with obesity, hyperinsulinemia, and dyslipidemia. Moreover, the data indicated nonallelic interaction (epistasis) between Niddm1b and Niddm1i on the postprandial glucose levels. These data emphasize the pathophysiological complexity of diabetes, even within an apparently single QTL, and demonstrate the potential of the GK model in transforming the multifactorial diabetes phenotype into single traits, suitable for positional cloning.
|
|
| 12. |
- Goodyear, LJ, et al.
(författare)
-
Glucose ingestion causes GLUT4 translocation in human skeletal muscle
- 1996
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 45:8, s. 1051-1056
-
Tidskriftsartikel (refereegranskat)abstract
- In humans, ingestion of carbohydrates causes an increase in blood glucose concentration, pancreatic insulin release, and increased glucose disposal into skeletal muscle. The underlying molecular mechanism for the increase in glucose disposal in human skeletal muscle after carbohydrate ingestion is not known. We determined whether glucose ingestion increases glucose uptake in human skeletal muscle by increasing the number of glucose transporter proteins at the cell surface and/or by increasing the activity of the glucose transporter proteins in the plasma membrane. Under local anesthesia, ∼1 g of vastus lateralis muscle was obtained from six healthy subjects before and 60 min after ingestion of a 75-g glucose load. Plasma membranes were isolated from the skeletal muscle and used to measure GLUT4 and GLUT1 content and glucose transport in plasma membrane vesicles. Glucose ingestion increased the plasma membrane content of GLUT4 per gram muscle (3,524 ± 729 vs. 4,473 ± 952 arbitrary units for basal and 60 min, respectively; P < 0.005). Transporter-mediated glucose transport into plasma membrane vesicles was also significantly increased (130 ± 11 vs. 224 ± 38 pmol · mg−1 · s−1; P < 0.017), whereas the calculated ratio of glucose transport to GLUT4, an indication of transporter functional activity, was not significantly increased 60 min after glucose ingestion (2.3 ± 0.4 vs. 3.0 ± 0.5 pmol · GLUT4 arbitrary units−1 · s−1; P < 0.17). These results demonstrate that oral ingestion of glucose increases the rate of glucose transport across the plasma membrane and causes GLUT4 translocation in human skeletal muscle. These findings suggest that under physiological conditions the translocation of GLUT4 is an important mechanism for the stimulation of glucose uptake in human skeletal muscle.
|
|
| 13. |
- Goodyear, Laurie J.L, et al.
(författare)
-
Glucoseingestion causes GLUT4 translocation in human skeletal muscle
- 1996
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 45:8, s. 1051-1056
-
Tidskriftsartikel (refereegranskat)abstract
- In humans, ingestion of carbohydrates causes an increase in blood glucose concentration, pancreatic insulin release, and increased glucose disposal into skeletal muscle. The underlying molecular mechanism for the increase in glucose disposal in human skeletal muscle after carbohydrate ingestion is not known. We determined whether glucoseingestion increases glucose uptake in human skeletal muscle by increasing the number of glucose transporter proteins at the cell surface and/or by increasing the activity of the glucose transporter proteins in the plasma membrane. Under local anesthesia, approximately 1 g of vastus lateralis muscle was obtained from six healthy subjects before and 60 min after ingestion of a 75-g glucose load. Plasma membranes were isolated from the skeletal muscle and used to measure GLUT4 and GLUT1 content and glucosetransport in plasma membrane vesicles. Glucose ingestion increased the plasma membrane content of GLUT4 per gram muscle (3,524 +/- 729 vs. 4,473 +/- 952 arbitrary units for basal and 60 min, respectively; P < 0.005). Transporter-mediated glucosetransport into plasma membrane vesicles was also significantly increased (130 +/- 11 vs. 224 +/- 38 pmol.mg-1.s-1; P < 0.017), whereas the calculated ratio of glucose transport to GLUT4, an indication of transporter functional activity, was not significantly increased 60 min after glucose ingestion (2.3 +/- 0.4 vs. 3.0 +/- 0.5 pmol.GLUT4 arbitrary units-1.s-1; P < 0.17). These results demonstrate that oral ingestion of glucose increases the rate of glucose transport across the plasma membrane and causes GLUT4 translocation in human skeletal muscle. These findings suggest that under physiological conditions the translocation of GLUT4 is an important mechanism for the stimulation of glucose uptake in human skeletal muscle.
|
|
| 14. |
- Gromada, J, et al.
(författare)
-
Glucagon-like peptide I increases cytoplasmic calcium in insulin-secreting beta TC3-cells by enhancement of intracellular calcium mobilization
- 1995
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 44:7, s. 767-774
-
Tidskriftsartikel (refereegranskat)abstract
- In the insulin-secreting beta-cell line beta TC3, stimulation with 11.2 mmol/l glucose caused a rise in the intracellular free Ca2+ concentration ([Ca2+]i) in only 18% of the tested cells. The number of glucose-responsive cells increased after pretreatment of the cells with glucagon-like peptide I (GLP-I)(7-36)amide and at 10(-11) mol/l; 84% of the cells responded to glucose with a rise in [Ca2+]i. GLP-I(7-36)amide induces a rapid increase in [Ca2+]i only in cells exposed to elevated glucose concentrations (> or = 5.6 mmol/l). The action of GLP-I(7-36)amide and forskolin involved a 10-fold increase in cytoplasmic cAMP concentration and was mediated by activation of protein kinase A. It was not associated with an effect on the membrane potential but required some (small) initial entry of Ca2+ through voltage-dependent L-type Ca2+ channels, which then produced a further increase in [Ca2+]i by mobilization from intracellular stores. The latter effect reflected Ca(2+)-induced Ca2+ release and was blocked by ryanodine. Similar increases in [Ca2+]i were also observed in voltage-clamped cells, although there was neither activation of a background (Ca(2+)-permeable) inward current nor enhancement of the voltage-dependent L-type Ca2+ current. These observations are consistent with GLP-I(7-36) amide inducing glucose sensitivity by promoting mobilization of Ca2+ from intracellular stores. We propose that this novel action of GLP-I(7-36)amide represents an important factor contributing to its insulinotropic action.
|
|
| 15. |
- Hagström-Toft, E, et al.
(författare)
-
Role of phosphodiesterase III in the antilipolytic effect of insulin in vivo
- 1995
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 44:10, s. 1170-5
-
Tidskriftsartikel (refereegranskat)abstract
- The effect of three types of phosphodiesterase (PDE) inhibitors on in vivo antilipolysis was investigated in healthy subjects using a 2-h euglycemic, hyperinsulinemic (40 mU · m-2·min) clamp together with microdialysis of abdominal subcutaneous adipose tissue. During hyperinsulinemia (∼330 pmol/l), the circulating glycerol concentration was reduced to ∼50% of the basal level of 53.2 ± 3.6 μmol/l, indicating an antilipolytic effect. The decrease in adipose tissue dialysate glycerol, which mirrors the change in interstitial glycerol concentration, was about 40% during hyperinsulinemia when Ringer's solution alone was perfused. Local perfusion with a selective PDE IV inhibitor, rolipram (10−4) mol/l), did not influence the insulin-induced decrease in dialysate glycerol (F = 0.8 vs. perfusion with Ringer's solution by two-factor analysis of variance [ANOVA]), although rolipram increased the dialysate glycerol level by 144 ± 7% of the baseline value. However, local perfusion with a selective PDE III inhibitor, amrinone (10−3) mol/l), or a nonselective PDE inhibitor, theophylline (10−2) mol/l), abolished the ability of insulin to lower dialysate glycerol (F = 16.5, P < 0.01 and F = 8.5, P < 0.01, respectively, as compared with perfusion with Ringer's solution). The findings could not be explained by changes in the local blood flow (as measured by a microdialysis–ethanol escape technique), which was not affected by hyperinsulinemia in the presence or the absence of PDE inhibitors in the dialysis solvent. We conclude that PDEs play an important role in mediating the antilipolytic effect of insulin in vivo and that PDE III is the dominant isoenzyme modulating this effect.
|
|
| 16. |
|
|
| 17. |
- Hotamisligil, GS, et al.
(författare)
-
Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance
- 1997
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 46:3, s. 451-455
-
Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that tumor necrosis factor (TNF)-α production from adipose tissue is elevated in rodent and human obesity and plays an important role in insulin resistance in experimental animal models. In this study, we examined the adipose expression of both TNF receptors (TNFR1 and TNFR2) in human obesity and demonstrated that obese female subjects express approximately twofold more TNFR2 mRNA in fat tissue and approximately sixfold more soluble TNFR2 in circulation relative to lean control subjects. In contrast, TNFR1 expression and protein levels were similar in these subjects. TNFR2 expression levels in adipose tissue were strongly correlated with BMI (r = 0.65, P < 0.001) and level of hyperinsulinemia (P < 0.001), an indirect measure of insulin resistance, as well as level of TNF-α mRNA expression in fat tissue (r = 0.56, P < 0.001). These results suggest that TNFR2 might play a role in human obesity by modulating the actions of TNF-α.
|
|
| 18. |
- JensenUrstad, KJ, et al.
(författare)
-
Early atherosclerosis is retarded by improved long-term blood glucose control in patients with IDDM
- 1996
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 45:9, s. 1253-1258
-
Tidskriftsartikel (refereegranskat)abstract
- Microangiopathy is retarded by improved blood glucose control in patients with IDDM. Whether or not this is true for macroangiopathy (atherosclerosis) has remained unclear. A total of 59 patients (44 ± 1.5 years, previous HbA1c 9.4 ± 0.2%, mean ± SE) with IDDM were investigated. Of the 59 patients, 31 had been randomized to long-term intensified conventional insulin treatment (ICT), and the remaining 28 had received standard insulin treatment (ST). Blood glucose control was significantly better in the ICT patients with an HbA1c value (mean of 29 values during 10 years) of 7.1 ± 0.1% compared with the ST patients' 8.2 ± 0.2% (P < 0.0001). With high-frequency ultrasound, endothelial function was measured as flow-mediated dilation of the right brachial artery. The carotid arteries were scanned for plaques, intima-media thickness was measured, and arterial wall stiffness was calculated in the right common carotid artery. These measurements correlate with manifest and/or risk factors for coronary atherosclerosis. The patients in the ST group had stiffer arteries (P = 0.011) and thicker intima-media in the left common carotid artery (P = 0.009) than those in the ICT group. Patients with lower HbA1c generally had better endothelial function (P = 0.028) and less stiff arteries (P = 0.009). Better blood glucose control in patients with IDDM is related not only to less microangiopathy but also to a slower development of atherosclerosis.
|
|
| 19. |
- Krook, A, et al.
(författare)
-
Improved glucose tolerance restores insulin-stimulated Akt kinase activity and glucose transport in skeletal muscle from diabetic Goto-Kakizaki rats
- 1997
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 46:12, s. 2110-2114
-
Tidskriftsartikel (refereegranskat)abstract
- The serine/threonine kinase Akt (protein kinase B [PKB] or related to A and C protein kinase [RAC] has recently been implicated to play a role in the signaling pathway to glucose transport. However, little is known concerning the regulation of Akt activity in insulinsensitive tissues such as skeletal muscle. To explore the role of hyperglycemia on Akt kinase activity in skeletal muscle, normal Wistar rats or Goto-Kakizaki (GK) diabetic rats were treated with phlorizin. Phlorizin treatment normalized fasting blood glucose and significantly improved glucose tolerance (P < 0.001) in GK rats, whereas in Wistar rats, the compound had no effect on glucose homeostasis. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l) Akt kinase activity was reduced by 68% (P < 0.01) and glucose transport was decreased by 39% (P < 0.05), compared with Wistar rats. Importantly, the defects at the level of Akt kinase and glucose transport were completely restored by phlorizin treatment. There was no significant difference in Akt kinase protein expression among the three groups. At a submaximal insulin concentration (2.4 nmol/l), activity of Akt kinase and glucose transport were unaltered. In conclusion, improved glucose tolerance in diabetic GK rats by phlorizin treatment fully restored insulin-stimulated activity of Akt kinase and glucose transport. Thus, hyperglycemia may directly contribute to the development of muscle insulin resistance through alterations in insulin action on Akt kinase and glucose transport.
|
|
| 20. |
- Krook, A, et al.
(författare)
-
Uncoupling protein 3 is reduced in skeletal muscle of NIDDM patients
- 1998
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 47:9, s. 1528-1531
-
Tidskriftsartikel (refereegranskat)abstract
- Two recently described proteins in the mitochondrial uncoupling protein (UCP) family, UCP-2 and UCP-3, have been linked to phenotypes of obesity and NIDDM. We determined the mRNA levels of UCP-2 and UCP-3 in skeletal muscle of NIDDM patients and of healthy control subjects. No difference in the mRNA levels or in the protein expression of UCP-2 was observed between the two groups. In contrast, mRNA levels of UCP-3 were significantly reduced in skeletal muscle of NIDDM patients compared with control subjects. In the NIDDM patients, a positive correlation between UCP-3 expression and whole-body insulin-mediated glucose utilization rate was also noted. These results suggest that UCP-3 regulation may be altered in states of insulin resistance.
|
|
