Basal Glucose Metabolism Research Articles

Sulphonylureas-induced increase in insulin binding and glucose metabolism by isolated rat adipocytes.

The effects of oral hypoglycaemic drugs, SPC-703 (n-/p-toluenesulphonyl/-5-methyl-2-pirazoline-1-carbonami de) and tolbutamide on insulin binding and glucose metabolism by isolated adipocytes were studied. After 10 days of administration of both sulphonylurea derivatives, no differences were observed in insulin concentration between both experimental and the control groups of animals, despite a significant fall in blood glucose level. SPC-703 and tolbutamide in concentrations of 1 mM added in vitro to the suspension of adipocytes had no effect on insulin binding or on basal and insulin simulated glucose metabolism. Daily administration of 300 mg/kg body weight of SPC-703 or tolbutamide for 10 days resulted in 48% and 34% increase of specific binding of insulin by adipocytes, respectively. From the Scatchard plot analysis we noted that the increase of binding resulted from increased affinity of insulin receptors for hormone. Simultaneous increase in basal and insulin stimulated glucose metabolism by adipocytes, as measured by 14CO2 production and 14C incorporation into cellular lipids, was observed. The results indicate that hypoglycaemic action of sulphonylureas may be explained by increased affinity of insulin receptors and the stimulating action of these compounds on peripheral glucose metabolism.

Effects of food restriction on lactate production from glucose by rat adipocytes.

We investigated the effects of acute food deprivation on the rates of glucose metabolism and lactate production by epididymal fat cells isolated from 2- and 8-mo-old Wistar rats in one of three nutritional states: fed ad libitum, restricted to 50% of ad libitum, or fasted for 48 h. Food restriction did not affect total rates of basal glucose metabolism but significantly altered its pattern. In small fat cells from 2-mo-old rats, donor's food restriction led to decreased basal and insulin-stimulated glucose oxidation and fatty acid synthesis but led to increased lactate production, which increased from 4% of total glucose metabolized by cells from fed rats to 62% by cells from fasted rats. In large fat cells from 8-mo-old rats, donor's food restriction produced minimal changes in basal glucose metabolism and lactate production (already elevated at 37% of total) but caused insulin-stimulated lactate production to increase. These findings indicate that adipose tissue can produce significant amounts of lactate (with adipocyte enlargement and/or food deprivation) and may play an important role in extrahepatic generation of triose intermediates and in the Cori cycle.

Hyperglucagonemia and insulin-mediated glucose metabolism.

The effect of chronic physiologic hyperglucagonemia on basal and insulin-mediated glucose metabolism was evaluated in normal subjects, using the euglycemic insulin clamp technique (+50, +100, and +500 microU/ml). After glucagon infusion fasting glucose increased from 76 +/- 4 to 93 +/- 2 mg/dl and hepatic glucose production (HGP) rose from 1.96 +/- 0.08 to 2.25 +/- 0.08 mg/kg X min (P less than 0.001). Basal glucose oxidation after glucagon increased (P less than 0.05) and correlated inversely with decreased free fatty acid concentrations (r = -0.94; P less than 0.01) and decreased lipid oxidation (r = -0.75; P less than 0.01). Suppression of HGP and stimulation of total glucose disposal were impaired at each insulin step after glucagon (P less than 0.05-0.01). The reduction in insulin-mediated glucose uptake was entirely due to diminished non-oxidative glucose utilization. Glucagon infusion also caused a decrease in basal lipid oxidation and an enhanced ability of insulin to inhibit lipid oxidation and augment lipid synthesis. These results suggest that hyperglucagonemia may contribute to the disturbances in glucose and lipid metabolism in some diabetic patients.

Postreceptor myocardial metabolic defect in a rat model of non-insulin-dependent diabetes mellitus.

Hearts isolated from non-insulin-dependent diabetic rats were found to exhibit reduced rates of basal and insulin-stimulated glucose metabolism. Since tissue levels of fructose 1,6-bisphosphate are significantly reduced in the diabetic heart, it was concluded that phosphofructokinase may be inhibited. However, neither glycogen nor glucose 6-phosphate accumulated in the myocyte, indicating that the phosphofructokinase reaction was not a bottleneck diverting substrate away from glycolysis. The other major factor contributing to decreased glycolytic flux in the diabetic heart is the impairment in glucose transport. Both basal and insulin-stimulated transport of 3-O-methyl-D-glucose was 30% less in the diabetic heart. While insulin sensitivity was unaltered in the diabetic rat, insulin responsiveness was decreased, indicating that the impairment in insulin-stimulated hexose transport was caused by a post-receptor defect. The net result of these abnormalities in glucose metabolism is a significant reduction in the rate of ATP synthesis by the diabetic heart.

In vivo insulin resistance in individual peripheral tissues of the high fat fed rat: assessment by euglycaemic clamp plus deoxyglucose administration.

We have examined peripheral insulin action in conscious rats chronically fed high fat (60% calories as fat) or high carbohydrate (lab chow) diets using the euglycaemic clamp plus 3H-2-deoxyglucose technique. A response parameter of individual tissue glucose metabolic rate (the glucose metabolic index, based on tissue deoxyglucose phosphorylation) was used to assess diet effects in eight skeletal muscle types, heart, lung and white and brown adipose tissue. Comparing high fat with high carbohydrate fed rats, basal glucose metabolism was only mildly reduced in skeletal muscle (only diaphragm was significant, p less than 0.05), but was more substantially reduced in other tissues (e.g. white adipose tissue 61% and heart 33%). No evidence of basal hyperinsulinaemia was found. In contrast, widespread insulin resistance was found during the hyperinsulinaemic clamp (150 mU/l) in high fat fed animals; mean whole body net glucose utilization was 34% lower (p less than 0.01), and the glucose metabolic index was lower in skeletal muscle (14 to 56%, p less than 0.05 in 6 out of 8 muscles), white adipose (27%, p less than 0.05) and brown adipose tissue (76%, p less than 0.01). The glucose metabolic index was also lower at maximal insulin levels in muscle and fat, suggesting the major effect of a high fat diet was a loss of insulin responsiveness. White adipose tissue differed from muscle in that incremental responses (maximal insulin minus basal) were not reduced by high fat feeding. The heart showed an effect opposite to other tissues, with an increase in insulin-stimulated glucose metabolism in high fat versus chow fed rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of hyperketonemia to alter basal and insulin-mediated glucose metabolism in man.

The effect of physiologic elevations of plasma hydroxybutyrate induced by the infusion of sodium D,L-beta-hydroxybutyrate (15 mumol X kg-1 X min-1) on carbohydrate metabolism was examined with the euglycemic insulin clamp technique in nine healthy volunteers. Plasma insulin concentration was acutely raised and maintained at 126 +/- 6 microU/ml and plasma glucose was held constant at the fasting level by a variable glucose infusion. Glucose uptake of 6.53 +/- 0.80 mg X kg-1 X min-1 was unchanged by hyperketonemia when compared with an intraindividual control study using saline instead of beta-OH-butyrate infusion (6.26 +/- 0.59 mg X kg-1 X min-1). In studies, in which the degree of metabolic alkalosis accompanying butyrate infusion was mimicked by the continuous administration of bicarbonate, glucose uptake was also unaffected (6.25 +/- 0.45 mg X kg-1 X min-1). Furthermore, hyperketonemia had no effect on basal glucose production or the suppression of hepatic glucose production following hyperinsulinemia. It is concluded that moderate elevations in plasma beta-hydroxy-butyrate do not alter hepatic or peripheral glucose metabolism.

Control of glucose balance in the perfused rat liver by the parasympathetic innervation.

Electrical stimulation of the nerve bundles around the hepatic artery and the portal vein activates both the sympathetic and parasympathetic liver nerves; the sympathetic effects clearly predominate. Parasympathetic effects were therefore studied in the rat liver perfused in situ by perivascular nerve stimulation in the presence of both an alpha- and a beta-blocker. In the presence of the alpha-blocker phentolamine and the beta-blocker propranolol all sympathetic nerve effects were prevented; the remaining parasympathetic stimulation had no influence on the basal glucose and lactate metabolism nor on the hemodynamics. Insulin alone, with both alpha- and beta-blockade, provoked a small, parasympathetic nerve stimulation in the presence of insulin a more pronounced enhancement of glucose utilization. In the presence of an alpha- and beta-blocker perivascular nerve stimulation antagonized the glucagon stimulated glucose release, but did not affect lactate exchange. The nerve effect was abolished by the parasympathetic antagonist atropine. Acetylcholine or insulin, with both an alpha- and beta-blocker present, mimicked the effects of nerve stimulation antagonizing the glucagon-stimulated glucose release. Nerve stimulation in the presence of insulin was more effective than either stimulus alone. The present results show that in rat liver stimulation of the parasympathetic hepatic nerves has direct effects on glucose metabolism synergistic with insulin and antagonistic to glucagon.

Defective non-insulin-mediated and insulin-mediated glucose transport and metabolism in adipocytes from obese and lean patients with untreated type 2 diabetes mellitus.

Insulin binding, glucose transport, and glucose metabolism were investigated in isolated adipocytes from 11 lean and 13 obese patients with non-insulin-dependent diabetes mellitus. Insulin binding at 15 degrees C was reduced by 35% (p less than 0.01) in both lean and obese diabetic patients, whereas insulin binding (or uptake) at 37 degrees C was similar in diabetic patients and healthy controls. In lean diabetic patients both non-insulin-mediated (basal) and maximally insulin-stimulated glucose transport and metabolism were significantly reduced (all p less than 0.01). The percentage responses to insulin were also markedly reduced (p less than 0.05, p less than 0.02). In obese diabetic patients basal glucose transport was reduced (p less than 0.01) but basal glucose metabolism was not. Insulin-stimulated glucose transport and metabolism were significantly reduced (p less than 0.01, p less than 0.05). The percentage responses were reduced compared to healthy controls (p less than 0.05, p less than 0.05) but higher than in lean diabetic patients (p less than 0.05). We conclude that adipocytes isolated from both lean and obese patients with non-insulin-dependent diabetes mellitus are characterized by severely depressed non-insulin-mediated and insulin-mediated glucose transport and depressed insulin-mediated glucose metabolism. The major defect seems to be a reduced maximal effect of insulin on glucose metabolism, suggesting post-binding and post-transport abnormalities.

Regulation of glucose utilization in adipose cells and muscle after long-term experimental hyperinsulinemia in rats.

The effects of chronic insulin administration on the metabolism of isolated adipose cells and muscle were studied. Adipose cells from 2 and 6 wk insulin-treated and control rats, fed either chow or chow plus sucrose, were prepared, and insulin binding, 3-O-methylglucose transport, glucose metabolism, and lipolysis were measured at various insulin concentrations. After 2 wk of treatment, adipose cell size and basal glucose transport and metabolism were unaltered, but insulin-stimulated transport and glucose metabolism were increased two- to threefold when cells were incubated in either 0.1 mM glucose (transport rate limiting) or 10 mM glucose (maximum glucose metabolism). Insulin binding was increased by 30%, but no shift in the insulin dose-response curve for transport or metabolism occurred. After 6 wk of treatment, the effects of hyperinsulinemia on insulin binding and glucose metabolism persisted and were superimposed on the changes in cell function that occurred with increasing cell size in aging rats. Hyperinsulinemia for 2 or 6 wk did not alter basal or epinephrine-stimulated lipolysis in adipose cells or the antilipolytic effect of insulin. In incubated soleus muscle strips, insulin-stimulated glucose metabolism was significantly increased after 2 wk of hyperinsulinemia, but these increases were not observed after 6 wk of treatment. We conclude that 2 wk of continuous hyperinsulinemia results in increased insulin-stimulated glucose metabolism in both adipose cells and soleus muscle. Despite increased insulin binding to adipose cells, no changes in insulin sensitivity were observed in adipose cells or muscle. In adipose cells, the increased glucose utilization resulted from both increased transport (2 wk only) and intracellular glucose metabolism (2 and 6 wk). In muscle, after 2 wk of treatment, both glycogen synthesis and total glucose metabolism were increased. These effects of hyperinsulinemia were lost in muscle after 6 wk of treatment, when compared with sucrose-supplemented controls.

Acute growth hormone deficiency rapidly alters glucose metabolism in rat adipocytes. Relation to insulin responses and binding.

To investigate cellular aspects of the antagonism between endogenous GH and insulin in adipose tissue, we examined glucose metabolism, insulin responses, and insulin binding in adipocytes isolated from rats made GH deficient by treatment with antibodies to rat GH (ArGH), which neutralize the biological actions of GH. Adipocytes were incubated in the presence or absence of insulin, and their ability to convert [14C] glucose to CO2 and lipid was measured. Basal glucose utilization was significantly elevated in adipocytes from ArGH-treated rats after 6, 3, or even 1 h of serum treatment compared to that in controls treated with nonimmune serum. This suggests that endogenous GH suppresses glucose metabolism in adipocytes from normal rats. In the presence of insulin, the absolute values of glucose utilization were also higher in cells from ArGH-treated rats than in controls. However, because basal glucose oxidation was higher with GH deficiency, the percent stimulation by insulin was not different in adipocytes from ArGH-treated rats and controls. In keeping with this, the binding of [125I]iodoinsulin was not altered by GH deficiency. These findings indicate that endogenous GH suppresses basal glucose metabolism in adipocytes, and that this effect is rapidly reversed by treatment of normal rats with ArGH. Furthermore, this effect of GH on adipocyte metabolism is independent of changes in insulin binding and appears to account for the enhanced responses to insulin observed with GH deficiency.

Effects of prostaglandin E 2, indomethacin and adenosine deaminase on basal and insulin-stimulated glucose metabolism in human adipocytes

The effects of prostaglandin E 2 were studied on glucose metabolism (3- O-methylglucose transport, CO 2 production and lipogenesis) in human adipocytes. Initially, the effects of endogenously produced adenosine and prostaglandins were indirectly demonstrated by using adenosine deaminase and indomethacin in the incubations. From these studies it was found that adenosine deaminase (5 μg/ml) had a pronounced effect on adipocyte glucose metabolism in vitro. In the basal (nonhormonal-stimulated) state, glucose transport, CO 2 production and lipogenesis were inhibited by about 30% ( P<0.05). Furthermore, adenosine deaminase significantly inhibited the isoproterenol- and insulin-stimulated CO 2 production and lipogenesis ( P<0.01). Indomethacin (50 μM) had a consistently inhibitory effect on the insulin-stimulated CO 2 production ( P<0.05), whereas indomethacin had no significant effects on basal or isoproterenol-stimulated glucose metabolism. In contrast to the relatively minor effect of endogenous prostaglandins, the addition of exogenous prostaglandin E 2 significantly stimulated the glucose transport, glucose oxidation and lipogenesis in human adipocytes, especially in the presence of adenosine deaminase. Half-maximal stimulation was obtained at prostaglandin E 2 concentrations of 2.2, 0.8 and 0.8 nM, respectively. The effect of prostaglandin E 2 was specific, since the structurally related prostaglandin, prostaglandin F 2α, had practically no effect on glucose metabolism. The maximal effect of prostaglandin E 2 (1 μM) on glucose metabolism was 30–35% of the maximal insulin (1 nM) effect. When insulin and prostaglandin E 2 were added together, the effect of prostaglandin E 2 on glucose metabolism was additive at all insulin concentrations tested.

The relationship of insulin production to glucose metabolism in severe sepsis.

Basal glucose metabolism was evaluated in eight stable, infected patients by measuring hepatic glucose production rates in relation to stress endocrine profile and by comparing these data to five injured, noninfected patients. All patients exhibited normal total-body oxygen consumptions and cardiac indices. Fasting basal insulin values were similar in both groups (6 microU/cc) despite a significantly higher plasma glucose level in septic patients (106 +/- 14 mg/dL) compared to nonseptic patients (88 +/- 10 mg/dL). Septic patients exhibited splanchnic glucose production and calculated glucose clearance rates, 53% and 34% higher, than injured nonseptic patients, respectively. In addition, septic patients exhibited a decreased pancreatic insulin secretory response to an intravenous glucose tolerance test as evidenced by a significantly depressed peak insulin value (17 microU/cc) relative to injured patients (77 microU/cc). These findings indicate that insulin suppression is evident in sepsis even in the absence of shock and suggest that sepsis-related basal hyperglycemia does not appear to be associated with peripheral insulin resistance.

Dysregulation of glucose transport in hearts of genetically obese (fa/fa) rats.

Overall D-glucose metabolism and 3-0-methylglucose transport were measured in the perfused heart preparation of lean and genetically obese (fa/fa) rats. Absolute values of basal and insulin-stimulated glucose metabolism were decreased in hearts of 15-week-old obese rats when compared to lean age-matched controls. Basal and maximally stimulated (i.e., by the combined addition of insulin and increasing perfusion pressure) 3-0-methylglucose transport was normal in hearts from young obese rats (5-week-old). However, when only one stimulus was used (insulin or increasing perfusion pressure alone), 3-0-methylglucose transport was stimulated to values that were lower than those of lean rats. Basal 3-0-methylglucose transport was four times lower in hearts from older obese rats (15-week-old) than in lean ones of the same age. At this age, stimulation of 3-0-methylglucose transport by insulin alone, by increasing perfusion pressure alone or by the combination of both stimuli, reached values in obese rats that were only half those of lean animals. It is concluded that: (a) in the early phase of the syndrome, the basal glucose transport system in hearts of obese rats is normal, but its response to stimulation becomes abnormal and; (b) at a later phase of obesity, the glucose transport system becomes abnormal even under basal conditions and its responsiveness to various stimuli is markedly impaired.

Effects of streptozotocin diabetes and insulin treatment on adipose tissue glucose utilization in the rat.

[U-14C] glucose utilization by pieces of epididymal fat-pad was studied in streptozotocin-diabetic rats, food-restricted animals, and normal controls. Both CO2 and fatty acids formation were greatly reduced in tissues from the diabetic animals treated or not with insulin and this change was milder in tissues from food-restricted rats. A positive correlation was found between [14C] glucose utilization in vitro and plasma RIA-insulin levels when values from all animals were pooled. The percentual response to high doses of insulin was small in adipose tissue from streptozotocin-diabetic animals for CO2 and total lipids formation, but it was high for fatty acids synthesis; the response in food-restricted animals was high and was greatly augmented in tissues from the streptozotocin-diabetic rats treated with insulin. Results indicate that in adipose tissue from streptozotocin-diabetic animals the alteration of insulin responsiveness occurs distal to the receptor events and that impaired basal glucose metabolism is a direct consequence of their hypoinsulinemia.

Effect of cross-linking agents on insulin associated responses in adipocytes.

The effect of 10 bifunctional cross-linking agents and four monofunctional analogues was studied on isolated adipocytes. [125I]Insulin binding and degradation, basal and insulin-stimulated glucose oxidation, and 3-O-methyl glucose uptake were measured. Two cross-linkers, which possess succinimide ester residues (disuccinimidyl suberate and dithiobis(succinimidyl propionate)) and react selectively with amino groups, appeared to react relatively specifically with the insulin receptor. Both produced a slight stimulation of basal glucose transport and metabolism, a marked inhibition of insulin-stimulated glucose transport and metabolism, and a marked decrease in insulin binding. Pretreatment of cells with unlabelled insulin partially blocked the effect of disuccinimidyl suberate, and as has been previously shown, disuccinimidyl suberate cross-linked insulin to its receptor. A monofunctional analogue of these compounds was 100-fold less active in altering cellular metabolic activity. Bisimidates, such as dimethyl suberimidate, dimethyl adipimidate, and dimethyl dithiobispropionimidate, also react with free amino groups but are more hydrophilic. These agents produced similar effects on glucose oxidation as the succinimide esters, but had little or no effect on insulin binding. The effects of these agents are not blocked by insulin and they do not cross-link insulin to its receptor. Mixed bifunctional reagents containing either a succinimide ester or an imidate and a group which reacts with thiols produced effects similar to the cross-linkers containing two succinimide groups or bisimidates, respectively. The bifunctional arylating agents difluorodinitrobenzene and bis(fluoronitrophenyl)sulfone produce marked effects on insulin binding and glucose oxidation at micromolar concentrations, but the monofunctional analogue fluorodinitrobenzene is almost equally active suggesting that with these compounds chemical modifications and not cross-linking was important. With neither the mixed bifunctional reagents, nor the arylating agents, did insulin pretreatment alter the effect of cross-linker and none of these agents cross-linked [125I]insulin to its receptor. These data suggest that the insulin receptor possesses a free amino group in a hydrophobic environment in its active site. A reactive amino group in a hydrophilic environment as well as other reactive groups are also present in some component of the insulin receptor-effector complex. Chemical modification or cross-linking of these functional groups results in an inhibition or mimicking of insulin action. Further study will be required to identify the exact locus of these sites.

Influence of dexamethasone on insulin action: inhibition of basal and insulin-stimulated hexose transport is dependent on length of exposure in vitro.

Rat adipose tissue was exposed to 0.1 μ M dexamethasone in a biochemically defined environment for up to 48 h in order to characterize the cellular alterations in insulin action resulting from long term glucocorticoid treatment. After treatment, adipocytes were isolated by collagenase digestion, and insulin action was determined by acute experiments that examined insulin binding, hexose transport, and glucose metabolism. Neither 2-h nor longer 10- to 48-h exposures to dexamethasone influenced insulin receptor number or affinity. Conversely, steroid treatment directly reduced both hexose transport and glucose metabolism, and the extent of the effects was dependent on the length of exposure. Two-hour treatment with dexamethasone reduced glucose transport and metabolism in the absence but not the presence of insulin. However, after 10- to 48-h exposures to dexamethasone, both basal and insulin-stimulated hexose uptake and glucose metabolism were significantly inhibited. For example, after 24-h treatment, -de...

Local effect of burn on skeletal muscle insulin responsiveness

Basal and insulin-stimulated glucose metabolism by skeletal muscle were studied 3 days after a 3-sec scald of one hindlimb of the rat. Soleus muscles from the burned and unburned limb of the burned rats, as well as from timed controls, were incubated with [U- 14C]glucose and 0, 0.1, 1.0, or 10.0 mU insulin/ml. Basal glucose uptake by soleus muscle from the burned limb was 144% ( P < 0.001) greater than that of the controls. The glucose uptake by muscle from the unburned limb did not differ from that of controls. Insulin increased glucose uptake in control and unburned muscles but had no effect in burned muscles. Basal lactic acid release by soleus muscle from the burned limb and the contralateral unburned limb of burned rats was 123% ( P < 0.001) and 24% ( P < 0.01) higher, respectively, than that of soleus muscle from control rats. Of the lactic acid released by muscles from control rats or the unburned limb of burned rats, 35% was derived from exogenous glucose. In contrast, 50–55% of the lactic acid released by muscles from the burned limb was derived from exogenous glucose reflecting a predominant conversion of glucose to lactic acid. Insulin had no effect on the rate of lactic acid release and did not change the proportion of glucose converted to lactic acid by any of the three muscle groups. The basal rate of glucose conversion to CO 2 by muscle from the burned limb was elevated 133% ( P < 0.01) and that by muscle from the unburned limb was not altered as compared to controls. Insulin did not stimulate the conversion of glucose to CO 2 by any of the three muscle groups, and in the presence of insulin the release of CO 2 by burned, unburned, and control muscle did not differ. The basal rate of glucose incorporation into glycogen was the same in all three muscle groups. Insulin stimulated glucose incorporation into glycogen to a similar degree in muscles from control rats and the unburned limb of burned rats. However, the stimulatory effect of insulin was completely absent in soleus muscle from the burned limb. It is concluded that thermal injury suppresses the insulin-induced augmentation of glucose uptake and glucose incorporation into glycogen in skeletal muscles in the region of the burn but does not alter insulin sensitivity of skeletal muscles in the unburned region.

Effect of maturation and senescence on carbohydrate utilization and insulin responsiveness of rat adipose tissue

The aim of the present investigation was to study the effect of aging upon the metabolism and the responsiveness to insulin of epididymal adipose tissue from rats (6 weeks, 6 and 24 months). Basal glucose metabolism by these tissues and adipocytes was positively related to cell size, for each age group. But age per se plays an important role: for the same diameter, the U-14C-glucose oxidation to CO2 and its incorporation into triglycerides described markedly between 6 weeks and 6 months, as reported peviously, and decreased still further between 6 months and 24 months, for any diameter. In contrast, insulin responsiveness of adipose tissue fragments and fat cells was negatively correlated to adipose cell size, when we analyzed the role of cell diameter for a group of given age. When comparing the sensitivity to hormone for a given cell volume but at different ages, it appeared that insulin resistance increased considerably between 6 weeks and 6 months and was still more marked in old age. The mechanisms underlying these facts have been discussed.

Desensitization of the insulin receptor at an early postreceptor step by prolonged exposure to antireceptor antibody

We have used an adipocyte-like cell line, the 3T3-L1 fatty fibroblasts, to compare acute and chronic effects of autoantibodies directed against the insulin receptor. Acute exposure of the cells in tissue culture to the antibodies resulted in a blockade of insulin binding and stimulation of 2-deoxy-glucose transport and glucose oxidation. Maximal acute effects were reached within 30-120 min. Subsequently, the stimulatory response decayed and, after 6 hr in the continuous presence of the antibodies, basal glucose metabolism had returned to the level observed with unexposed cells and a state of severe insulin resistance prevailed. In contrast to the decay of bioresponse, no change in insulin binding was detectable over the same time period. The mechanism of desensitization seemed to involve events early after insulin binding to receptor because cells exposed to antibody for prolonged periods of time, although unresponsive to insulin and antireceptor antibodies, responded normally to both spermine and vitamin K(5), agents that stimulate glucose metabolism independently of the insulin receptor. These data suggest that prolonged or continuous occupancy of the insulin receptor by a ligand, in this case antireceptor antibodies, does not produce a continuous biological response. Instead, there is desensitization at some early step in the pathway for insulin action. These observations have important implications with respect to the mechanism of insulin action and to other situations in which there is long-term exposure of cells to antibodies that react with membrane components.

The effect of age on the in vitro insulin response in the rat. II. Glucose metabolism in epididymal adipose tissue (author's transl)

A decrease of the basal glucose metabolism with sensescence in the isolated rat adipose tissue has been demonstrated. In the presence of insulin, the oxidation of (U14C)-D-glucose and its incorporation into triglycerides are significantly increased at all ages studied. No significant difference between groups of animals was noted when the insulin-stimulating effect was related to basal metabolism. The synthesis of fatty acids from glucose is highly enhanced by insulin at 6 weeks, poorly at 6 months and no more at 24 months. It is concluded that the insulin sensitivity of the rat adipose tissue is not affected by ageing. Nevertheless, as far as fatty acid synthesis is concerned, a different metabolic pathway could be involved.