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1.
Peptides identify the critical hotspots involved in the biological activation of the insulin receptor 总被引:7,自引:0,他引:7
Pillutla RC Hsiao KC Beasley JR Brandt J Østergaard S Hansen PH Spetzler JC Danielsen GM Andersen AS Brissette RE Lennick M Fletcher PW Blume AJ Schäffer L Goldstein NI 《The Journal of biological chemistry》2002,277(25):22590-22594
We used phage display to generate surrogate peptides that define the hotspots involved in protein-protein interaction between insulin and the insulin receptor. All of the peptides competed for insulin binding and had affinity constants in the high nanomolar to low micromolar range. Based on competition studies, peptides were grouped into non-overlapping Sites 1, 2, or 3. Some Site 1 peptides were able to activate the tyrosine kinase activity of the insulin receptor and act as agonists in the insulin-dependent fat cell assay, suggesting that Site 1 marks the hotspot involved in insulin-induced activation of the insulin receptor. On the other hand, Site 2 and 3 peptides were found to act as antagonists in the phosphorylation and fat cell assays. These data show that a peptide display can be used to define the molecular architecture of a receptor and to identify the critical regions required for biological activity in a site-directed manner. 相似文献
2.
Very small fat cells. II. Initial observations on basal and hormone-stimulated metabolism 总被引:1,自引:0,他引:1
Very small fat cells (less than 35 micron diameter) and normal large fat cells (greater than 40 micron diameter) were isolated from adult Fischer 344 rat epididymal adipose depots. These very small fat cell preparations were free from normal, large fat cells (40-130 micron diameter) and stromal-vascular elements. Examination by electron microscopy and lipid analysis showed a similarity in overall organization and composition to normal, large fat cells. Incubations with [U-14C]glucose showed that the very small fat cell preparations oxidized glucose in proportion to both cell number and time. These preparations also responded to insulin, increasing [U-14C]glucose oxidation in a manner similar to normal large fat cell preparations (i.e., 2- to 4-fold increases in CO2 production with insulin stimulation). The very small fat cells also incorporated radiolabeled glucose into lipids; but, unlike normal large fat cells, insulin failed to stimulate this process. Glycerol release from very small fat cells was stimulated by lipolytic hormones in a manner similar to these responses in co-isolated large fat cells. 相似文献
3.
Kotronen A Vehkavaara S Seppälä-Lindroos A Bergholm R Yki-Järvinen H 《American journal of physiology. Endocrinology and metabolism》2007,293(6):E1709-E1715
A fatty liver is associated with fasting hyperinsulinemia, which could reflect either impaired insulin clearance or hepatic insulin action. We determined the effect of liver fat on insulin clearance and hepatic insulin sensitivity in 80 nondiabetic subjects [age 43 +/- 1 yr, body mass index (BMI) 26.3 +/- 0.5 kg/m(2)]. Insulin clearance and hepatic insulin resistance were measured by the euglycemic hyperinsulinemic (insulin infusion rate 0.3 mU.kg(-1).min(-1) for 240 min) clamp technique combined with the infusion of [3-(3)H]glucose and liver fat by proton magnetic resonance spectroscopy. During hyperinsulinemia, both serum insulin concentrations and increments above basal remained approximately 40% higher (P < 0.0001) in the high (15.0 +/- 1.5%) compared with the low (1.8 +/- 0.2%) liver fat group, independent of age, sex, and BMI. Insulin clearance (ml.kg fat free mass(-1).min(-1)) was inversely related to liver fat content (r = -0.52, P < 0.0001), independent of age, sex, and BMI (r = -0.37, P = 0.001). The variation in insulin clearance due to that in liver fat (range 0-41%) explained on the average 27% of the variation in fasting serum (fS)-insulin concentrations. The contribution of impaired insulin clearance to fS-insulin concentrations increased as a function of liver fat. This implies that indirect indexes of insulin sensitivity, such as homeostatic model assessment, overestimate insulin resistance in subjects with high liver fat content. Liver fat content correlated significantly with fS-insulin concentrations adjusted for insulin clearance (r = 0.43, P < 0.0001) and with directly measured hepatic insulin sensitivity (r = -0.40, P = 0.0002). We conclude that increased liver fat is associated with both impaired insulin clearance and hepatic insulin resistance. Hepatic insulin sensitivity associates with liver fat content, independent of insulin clearance. 相似文献
4.
In fat cells isolated from the parametrial adipose tissue of rats, the addition of purified adenosine deaminase increased lipolysis and cyclic adenosine 3':5'-monophosphate (cyclic AMP) accumulation. Adenosine deaminase markedly potentiated cyclic AMP accumulation due to norepinephrine. The increase in cyclic AMP due to adenosine deaminase was as rapid as that of theophylline with near maximal effects seen after only a 20-sec incubation. The increases in cyclic AMP due to crystalline adenosine deaminase from intestinal mucosa were seen at concentrations as low as 0.05 mug per ml. Further purification of the crystalline enzyme preparation by Sephadex G-100 chromatography increased both adenosine deaminase activity and cyclic AMP accumulation by fat cells. The effects of adenosine deaminase on fat cell metabolism were reversed by the addition of low concentrations of N6-(phenylisopropyl)adenosine, an analog of adenosine which is not deaminated. The effects of adenosine deaminase on cyclic AMP accumulation were blocked by coformycin which is a potent inhibitor of the enzyme. These findings suggest that deamination of adenosine is responsible for the observed effects of adenosine deaminase preparations. Protein kinase activity of fat cell homogenates was unaffected by adenosine or N6-(phenylisopropyl)adenosine. Norepinephrine-activated adenylate cyclase activity of fat cell ghosts was not inhibited by N6-(phenylisopropyl)adenosine. Adenosine deaminase did not alter basal or norepinephrine-activated adenylate cyclase activity. Cyclic AMP phosphodiesterase activity of fat cell ghosts was also unaffected by adenosine deaminase. Basal and insulin-stimulated glucose oxidation were little affected by adenosine deaminase. However, the addition of adenosine deaminase to fat cells incubated with 1.5 muM norepinephrine abolished the antilipolytic action of insulin and markedly reduced the increase in glucose oxidation due to insulin. These effects were reversed by N6-(phenylisopropyl)adenosine. Phenylisopropyl adenosine did not affect insulin action during a 1-hour incubation. If fat cells were incubated for 2 hours with phenylisopropyl adenosine prior to the addition of insulin for 1 hour there was a marked potentiation of insulin action. The potentiation of insulin action by prior incubation with phenylisopropyl adenosine was not unique as prostaglandin E1, and nicotinic acid had similar effects. 相似文献
5.
Role of insulin and IGF1 receptors in proliferation of cultured renal proximal tubule cells. 总被引:3,自引:0,他引:3
B L Blazer-Yost M Watanabe T P Haverty F N Ziyadeh 《Biochimica et biophysica acta》1992,1133(3):329-335
We have used a murine proximal tubule cell line (MCT cells) to determine the presence and binding characteristics of insulin and IGF1 receptors and to correlate these parameters with the concentration-response relationships for ligand-induced cellular proliferation. Separate insulin and IGF1 receptors were identified by equilibrium binding assays. Half-maximal displacement of either peptide occurred at 3-10 nM; crossover binding to the alternate receptor occurred with a 10- to 100-fold lower affinity. Peptide effects on cellular proliferation were determined by measuring [3H]thymidine incorporation. Both insulin and IGF1 stimulate thymidine incorporation in a dose-dependent manner with similar increases above the basal level. The estimated half-maximal stimulation (EC50) occurred at 4 nM for IGF1 and 8 nM for insulin. A comparison of the receptor binding affinities with the dose-response relationships for [3H]thymidine incorporation reveals that each growth factor appears to be exerting its effect via binding to its own receptor. Therefore, in this cell line, physiologic concentrations of either insulin or IGF1 can modulate cellular growth. To our knowledge this is the first demonstration of a mitogenic effect which may be modulated by ligand binding to the insulin receptor in proximal tubule epithelia. 相似文献
6.
Reduced glucose transport and increased binding of insulin in adipocytes from diabetic and fasted rats 总被引:3,自引:0,他引:3
1. Animals made diabetic by injection of streptozotocin or animals after 3 days of fasting show decreased insulin levels and a decrease in mean cell diameter of adipocytes from epidydymal fat pads in comparison with cells from normal animals. 2. 14CO2 production from D-[U-14C]glucose is impaired in diabetic and fasted animals both in presence or in absence of a concentration of insulin stimulating 14CO2 production maximally. 3. Insulin binding is increased in adipocytes from diabetic and fasted animals due to changes in affinity. 4. Transport studies show that basal and insulin stimulated 2-deoxy[1-14C]-glucose transport is decreased in absolute terms due to a decrease in V and an increase in Km. 5. The relative stimulatory effect of insulin is impaired in adipocytes of diabetic and fasted animals. 6. A shift of the maximal effect of insulin to lower insulin levels is seen in these cells. 相似文献
7.
Maris M Ferreira GB D'Hertog W Cnop M Waelkens E Overbergh L Mathieu C 《Journal of proteome research》2010,9(12):6274-6287
Chronic hyperglycemia is a hallmark of type 2 diabetes and can contribute to progressive beta cell dysfunction and death. The aim of the present study was to identify pathways mediating high glucose-induced beta cell demise by a proteomic approach. INS-1E cells were exposed to 25 mM glucose for a sustained period of 24 h. Protein profiling of INS-1E cells was done by two-dimensional difference gel electrophoresis, covering the pH ranges 4-7 and 6-9 (n = 4). Differentially expressed proteins (P < 0.05) were identified by MALDI-TOF/TOF and proteomic results were confirmed by functional assays. High glucose levels impaired glucose-stimulated insulin secretion and decreased insulin content. 2D-DIGE analysis revealed 100 differentially expressed proteins that were involved in different pathways. Chaperone proteins were down-regulated, protein biosynthesis and ubiquitin-related proteasomal degradation were attenuated and perturbations in intracellular trafficking and vesicle transport and secretion could be observed. Moreover, several pathways were confirmed by functional assays and a direct role for eEF2 in insulin biosynthesis was demonstrated. The present findings provide new insights in glucotoxicity and identify key target proteins for the prevention and treatment of beta cell dysfunction in type 2 diabetes. 相似文献
8.
Ying-Chi Chu G. Thompson Burke J. B. Alexander Ross Panayotis G. Katsoyannis 《Journal of Protein Chemistry》1993,12(4):499-505
In continuation of our efforts to study the solution structure and conformational dynamics of insulin by time-resolved fluorescence spectroscopy, we have synthesized and examined the biological activity of five insulin analogues in which selected naturally occurring residues in the A-chain have been replaced with the strongly fluorescent tryptophan residue. The potency of these analogues was evaluated in lipogenesis assays in isolated rat adipocytes, in receptor binding assays using rat liver plasma membranes, and in two cases, in receptor binding assays using adipocytes. [A3 Trp]insulin displays a potency of 3% in receptor binding assays in both liver membranes and in adipocytes, but only 0.06% in lipogenesis assays as compared to porcine insulin. [A10 Trp] insulin displays a potency ofca. 40% andca. 25% in rat liver receptor binding and lipogenesis assays, respectively. [A13 Trp]insulin displays a potency ofca. 39% in rat liver receptor binding assays, but onlyca. 9% in receptor binding in adipocytes; in lipogenesis assays, [A13 Trp] insulin displays a potency ofca. 12%, comparable to its potency in adipocyte receptor binding assays. [A15 Trp]insulin exhibits a potency of 18% and 9% in rat liver receptor binding and lipogenesis assays, respectively. The doubly substituted analogue, [A14 Trp, A19 Trp] insulin, displays a potency ofca. 0.7% in both rat liver receptor binding assays and lipogenesis assays. These data suggest two major conclusions: (1) the A3 and A15 residues lie in sensitive regions in the insulin molecule, and structural modifications at these positions have deleterious effects on biological activity of the hormone; and (2) [A13 Trp]insulin appears to be a unique case in which an insulin analogue exhibits a higher potency when assayed in liver tissue than when assayed in fat cells. 相似文献
9.
H Ogawa G T Burke J D Chanley P G Katsoyannis 《International journal of peptide and protein research》1987,30(4):460-473
Hydrogen bonding involving peptide bonds of the backbone of the insulin molecule may play an important role in insulin-receptor interaction. Our previous work suggested that the A2-A8 helical segment of the hormone molecule participates in this interaction. To investigate the possible involvement of peptide bonds of this segment in insulin-receptor interaction the [2-N-methylisoleucine-A]insulin and [3-N-methylvaline-A]insulin ([MeIle2-A]- and [MeVal3-A]insulins) were synthesized. The circular dichroic spectra of the analogues were obtained and their properties were examined in several biological assays. The circular dichroic spectra suggested that the analogues remained monomeric at concentrations at which insulin is predominantly dimeric, and that their A2-A8 helical segments are distorted. The in vitro biological activity and the receptor binding affinity of these analogues were compared with that of natural insulin. Both analogues are weak full agonists. [MeIle2-A]insulin displayed a potency of 5.4 +/- 0.3% in stimulating lipogenesis and 4.6 +/- 2.3% in receptor binding affinity in rat fat cells and rat liver plasma membranes respectively. [MeVal3-A]insulin displayed a potency of 2.1 +/- 0.2% in lipogenesis and 1.0 +/- 0.3% in receptor binding assays. In radioimmunoassays [MeIle2-A]- and [MeVal3-A]insulins exhibited potencies of 13% and 11% respectively relative to the natural hormone. The substantially decreased biological activity and receptor binding affinity of these analogues may be attributed partly to the change of conformation and partly to the loss of hydrogen bonding capacity of the A2-A8 segment brought about by N-methylation of the A1-A2 or A2-A3 peptide bonds. 相似文献
10.
A Taniguchi T Kono H Okuda F Oseko I Nagata K Kataoka H Imura 《Journal of lipid research》1986,27(9):925-929
Basal and insulin-stimulated neutral glyceride syntheses from glucose were studied in fat cells of different size (fat cell volume, 0.07-0.20, 0.20-0.60, 0.60-1.00, 1.00-1.50 micron3 X 10(6)) obtained from subcutaneous adipose tissues in 20 subjects aged 3 months to 67 years. In 0.07-0.20 or 0.20-0.60 micron3 X 10(6) fat cells, the basal rate of glucose conversion to neutral glyceride was significantly lower in mature (36 to 67 years old) than in growing (0 to 12 years old) subjects. In 0.60-1.00 or 1.00-1.50 micron3 X 10(6) fat cells, however, basal rate was not significantly different between the two groups. The stimulating effect of insulin on conversion of glucose to neutral glyceride was not significantly different from the basal rate in fat cells of each size taken from the mature subjects, whereas in fat cells from growing subjects, it was significantly different from the basal rate in each fat cell size category. These results indicate that when fat cell size is taken into account, not only is the rate of basal glucose conversion to neutral glyceride higher in growing subjects but also its responsiveness to exogenous insulin, and that insulin insensitivity of large fat cells, reported previously, may be influenced by age. 相似文献
11.
Insulin receptor regulation was studied in the rat erythroblastic leukemic (EBL) cell in primary culture. After 1-2-hr incubations in medium containing 12 essential amino acids, glutamine, and serine, EBL cell protein synthesis and insulin receptor concentrations were increased compared to cells incubated without serine. Deficiency of medium isoleucine in the presence of serine rapidly decreased protein synthesis and insulin binding to intact cells. Supplementation of deficient media with serine or isoleucine had no effect on total insulin receptor numbers measured in solubilized cell preparations. Increased insulin binding following serine exposure was seen with binding assays at both 4 and 37 degrees C. Dissociation experiments to quantitate intracellular ligand after 37 degrees C binding assays showed increased in both surface binding and intracellular [125I]insulin accumulation. These data combined with previous observations suggest that amino acids essential for this cell are required for the rapid synthesis of a labile regulatory protein which facilitates the redistribution and/or recycling of insulin receptors. 相似文献
12.
Cho H Black SC Looper D Shi M Kelly-Sullivan D Timofeevski S Siegel K Yu XH McDonnell SR Chen P Yie J Ogilvie KM Fraser J Briscoe CP 《American journal of physiology. Endocrinology and metabolism》2008,295(5):E1142-E1151
c-Jun NH(2)-terminal kinase (JNK) plays an important role in insulin resistance; however, identification of pharmacologically potent and selective small molecule JNK inhibitors has been limited. Compound A has a cell IC(50) of 102 nM and is at least 100-fold selective against related kinases and 27-fold selective against glycogen synthase kinase-3beta and cyclin-dependent kinase-2. In C57BL/6 mice, compound A reduced LPS-mediated increases in both plasma cytokine levels and phosphorylated c-Jun in adipose tissue. Treatment of mice fed a high-fat diet with compound A for 3 wk resulted in a 13.1 +/- 1% decrease in body weight and a 9.3 +/- 1.5% decrease in body fat, compared with a 6.6 +/- 2.1% increase in body weight and a 6.7 +/- 2.1% increase in body fat in vehicle-treated mice. Mice pair fed to those that received compound A exhibited a body weight decrease of 7 +/- 1% and a decrease in body fat of 1.6 +/- 1.3%, suggesting that reductions in food intake could not account solely for the reductions in adiposity observed. Compound A dosed at 30 mg/kg for 13 days in high-fat fed mice resulted in a significant decrease in phosphorylated c-Jun in adipose tissue accompanied by a decrease in weight and reductions in glucose and triglycerides and increases in insulin sensitivity to levels comparable with those in lean control mice. The ability of compound A to reduce the insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1) von Ser307 and partially reverse the free fatty acid inhibition of glucose uptake in 3T3L1 adipocytes, suggests that enhancement of insulin signaling in addition to weight loss may contribute to the effects of compound A on insulin sensitization in vivo. Pharmacological inhibition of JNK using compound A may therefore offer an effective therapy for type 2 diabetes mediated at least in part via weight reduction. 相似文献
13.
H J Friesen V K Naithani H G Gattner 《Hoppe-Seyler's Zeitschrift für physiologische Chemie》1978,359(1):103-111
Two methods are described for the preparation of NalphaB1,Nepsilon29-Boc2-insulin from Nalpha A1-trifluoroacetyl-insulin and Nalpha A1-citraconyl-insulin in 80 - 90% and 65% yields, respectively. Removal of the Boc protections afforded the fully active insulin. Application of this derivative was demonstrated by the preparations of des-GlyA1-insulin and [A1-guanidinoacetyl]insulin. The former compount exhibited 2% activity in the in vitro free fat cell assay and the latter 88 +/- 5% while NalphaB1-NepsilonB29-Boc2-insulin showed 45 +/- 3% activity only. 相似文献
14.
Insulin activation of glycogen synthase in cultured human fibroblasts is not mediated solely via the insulin receptor 总被引:1,自引:0,他引:1
Insulin binds to its specific cell surface receptor in cultured human fibroblasts and also stimulates the conversion of glycogen synthase from the glucose-6-phosphate (G-6-P) dependent to the G-6-P independent form. Although these two processes are tightly coupled in most target tissues for insulin action, in the fibroblast a variety of findings question the relationship of these two events to one another. In human fibroblasts the amount of insulin required to displace half of the 125I-insulin bound to the insulin receptor is 4 ng/ml (6.6 X 10(-10)M), but the activation of glycogen synthase is not maximal until 1-10 micrograms/ml with an ED50 of 30 ng/ml insulin. Antibodies directed against the insulin receptor, which activate glycogen synthase in both fat and muscle, do not stimulate the activation of glycogen synthase in the fibroblast. Fab fragments from anti-insulin receptor antibody compete for insulin binding, but do not inhibit the insulin-stimulated rise in independent activity. The insulin-like growth factor, MSA, which is 1% as potent as insulin in stimulating glucose oxidation in rat fat cells and in inhibiting 125I-insulin binding to human fibroblasts, is 25% as potent as insulin in stimulating glycogen synthase. Proinsulin is 2-10% as potent as insulin, but behaves as a "partial agonist" of insulin action in the fibroblast, i.e. proinsulin is able to elicit only 60% of the maximal response of insulin in the glycogen synthase assay, even at high concentrations. Finally, cell lines from patients with clearly defective insulin receptors exhibit normal insulin dose response curves for the activation of glycogen synthase.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
15.
Insulin stimulates translocation of the glucose transporter isoform 4 (Glut4) from an intracellular storage compartment to the plasma membrane in fat and skeletal muscle cells. At present, the nature of the Glut4 storage compartment is unclear. According to one model, this compartment represents a population of preformed small vesicles that fuse with the plasma membrane in response to insulin stimulation. Alternatively, Glut4 may be retained in large donor membranes, and insulin stimulates the formation of transport vesicles that deliver Glut4 to the cell surface. Finally, insulin can induce plasma membrane fusion of the preformed vesicles and, also, stimulate the formation of new vesicles. In extracts of fat and skeletal muscle cells, Glut4 is predominantly found in small insulin-sensitive 60-70 S membrane vesicles that may or may not artificially derive from large donor membranes during cell homogenization. Here, we use a cell-free reconstitution assay to demonstrate that small Glut4-containing vesicles are formed from large rapidly sedimenting donor membranes in a cytosol-, ATP-, time-, and temperature-dependent fashion and, therefore, do not represent an artifact of homogenization. Thus, small insulin-responsive vesicles represent the major form of Glut4 storage in the living adipose cell. Fusion of these vesicles with the plasma membrane may be largely responsible for the primary effect of insulin on glucose transport in fat tissue. In addition, our results suggest that insulin may also stimulate the formation of Glut4 vesicles and accelerate Glut4 recycling to the plasma membrane. 相似文献
16.
17.
Semisynthetic analogues of insulin were prepared from derivatives of desoctapeptide-(B23-30)-insulin (DOI). A1, B1-(Boc)2-DOI (di-Boc-DOI) was converted to A1, B1-(Boc)2-DOI-B22-phenylhydrazide (di-Boc-DOI-NHNH-C6H5) by the trypsin-catalyzed addition of phenylhydrazine in aqueous organic solvents at pH 6.5 [Canova-Davis, E., & Carpenter, F. H. (1981) Biochemistry 20, 7053-7058]. Treatment of di-Boc-DOI-NHNH-C6H5 with BNPS-skatole produced the phenyldiimide. The latter was coupled with a variety of protected peptides that, after removal of protecting groups, yielded the following compounds whose biological activities were compared to that of insulin in binding, in stimulation of hexose transport (), and in the stimulation of lipogenesis [)), in terms of percent of insulin activity, all in the isolated epididymal fat cell: di-Boc-DOI 0.2, (0.1), [0.2]; di-Boc-DOI-NHNH-C6H5 0.5, (0.2), [0.5]; DOI 0.2, (0.2), [0.1]; DOI-(Gly)B23 0.2, (0.2), [0.1]; DOI-(Gly-Phe)B23-24 6.3, (6.3), [8.0]; DOI-(Gly-Phe-Phe)B23-25 17.0, (25.6), [24.7]; DOI-(Gly-Phe-Phe-Tyr)B23-26 59.0, (50.0), [69.0]. The semisynthetic derivatives represent a stepwise readdition of the aromatic residues near the C terminus of the B chain. A given analogue demonstrated comparable activity in all three biological assays. The results indicate that the stepwise addition of aromatic residues to the B-chain C terminus of DOI produces an increase in insulin-like activity. The biological activity of DOI-(Gly-Phe-Phe-Tyr)B23-26, the derivative in which the aromatic region has been completely reassembled, is the same order of magnitude as that of insulin. 相似文献
18.
Christopher A. Lamb Rebecca K. McCann Jacqueline Stöckli David E. James Nia J. Bryant 《Traffic (Copenhagen, Denmark)》2010,11(11):1445-1454
A major consequence of insulin binding its receptor on fat and muscle cells is translocation of the facilitative glucose transporter GLUT4 from an intracellular store to the cell surface where it serves to clear glucose from the bloodstream. Sorting of GLUT4 into its insulin‐sensitive store requires the GGA [Golgi‐localized, γ‐ear‐containing, ADP ribosylation factor (ARF)‐binding] adaptor proteins, but the signal on GLUT4 to direct this sorting step is unknown. Here, we have identified a role for ubiquitination of GLUT4 in this process. We demonstrate that GLUT4 is ubiquitinated in 3T3‐L1 adipocytes, and that a ubiquitin‐resistant version fails to translocate to the cell surface of these cells in response to insulin. Our data support a model in which ubiquitination acts as a signal for the trafficking of GLUT4 from the endosomal/trans‐Golgi network (TGN) system into its intracellular storage compartment, from where it is mobilized to the cell surface in response to insulin. 相似文献
19.
Tobin BW Welch-Holland KR Marchello MJ 《Canadian journal of physiology and pharmacology》2000,78(8):622-630
The continued development of novel insulin treatment is predicated on the hypothesis that strict glycemic control is necessary to prevent the secondary complications of diabetes. Although dramatically successful in reducing selected secondary complications, intensive insulin therapy has consequences. These include hypoglycemia, weight gain, and body fat accumulation. In the present studies we compared a model of intensive insulin therapy in diabetic rats and contrasted weight gain and body fat accumulation with pancreatic islet transplantation. Female Wistar Furth rats (173 g) administered streptozotocin (55 mg x kg(-1), iv) remained diabetic (DB) for four or nine weeks. At week three, a third group was transplanted (TRAN) with islets of Langerhans (3519 +/- 838 150 microm islets); one week later group four began intensive subcutaneous insulin therapy (ISIT; 4 x 0.5-1.0 U regular insulin x day(-1)). Within one week ISIT rats had normalized plasma glucose; levels were not different from age matched controls (CN) or TRAN animals (ISIT 10.6 +/- 1.7, CN 7.2 +/- 0.4, TRAN 7.7 +/- 0.8 mmol x L(-1), P > 0.05). The cumulative occurrence of one episode of hypoglycemia (< 2.8 mmol x L(-1)) occurred in 50% of ISIT rats. At study termination, body weight of ISIT and CN rats did not differ (199 +/- 4 vs. 207 +/- 3, P > 0.05). While carcass protein content was similar for TRAN, ISIT, and CN animals, the body fat of ISIT animals was 24% greater than in CN rats and 21% greater than in TRAN rats (P < 0.05). Correlation of body fat vs. plasma glucose illustrated hypoglycemia contributed to the body fat gain of ISIT rats (n = 8, r = -0.70, P = 0.0535). These studies illustrate a disproportionate gain of body fat from ISIT, an effect not observed with islet transplantation. Thus, the metabolic benefit ascribed to islet transplantation appears related to the absence of hypoglycemia. 相似文献
20.
Van Pelt RE Evans EM Schechtman KB Ehsani AA Kohrt WM 《American journal of physiology. Endocrinology and metabolism》2002,282(5):E1023-E1028
The aim of this study was to determine whether trunk fat mass, measured by dual-energy X-ray absorptiometry (DEXA), is predictive of insulin resistance and dyslipidemia, independently of arm and leg fat mass, in postmenopausal women. Total and regional body composition was measured by DEXA in 166 healthy, postmenopausal women (66 +/- 4 yr). Four primary markers of insulin resistance and dyslipidemia were assessed: 1) area under the curve for the insulin (INS(AUC)) response to an oral glucose tolerance test (OGTT), 2) product of the OGTT glucose and insulin areas (INS(AUC)xGLU(AUC)), 3) serum triglycerides (TG), and 4) high-density lipoprotein (HDL)-cholesterol. Trunk fat mass was the strongest independent predictor of each of the primary dependent variables. In multivariate regression models, trunk fat mass was associated with unfavorable levels of INS(AUC), INS(AUC)xGLU(AUC), TG, and HDL-C, whereas leg fat mass was favorably associated with each of these variables. Thus trunk fat is a strong independent predictor of insulin resistance and dyslipidemia in postmenopausal women, whereas leg fat appears to confer protective effects against metabolic dysfunction. 相似文献