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Biomedical subjects

J W Eriksson

Publications and source records attributed to J W Eriksson.

At least 55 records · Page 3Linked to original sources
PubMed1999

Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients: is cellular insulin resistance a secondary phenomenon?

To elucidate potential mechanisms for insulin resistance occurring early in the development of type 2 diabetes, we studied 10 young healthy individuals, each with two first-degree relatives with type 2 diabetes, and 10 control subjects without known type 2 diabetic relatives. They were pairwise matched for age (35 +/- 1 vs. 35 +/- 1 years), BMI (23.6 +/- 0.6 vs. 23.1 +/- 0.4 kg/m2), and sex (four men, six women). Glucose turnover was assessed during a euglycemic clamp at two insulin levels (low approximately 20 mU/l; high approximately 90 mU/l), and abdominal subcutaneous adipose tissue (SAT) lipolysis and blood flow were concomitantly studied with microdialysis and 133Xe clearance. HbA1c was higher in patients with type 2 diabetic relatives than in control subjects (4.8 +/- 0.1 vs. 4.5 +/- 0.1%, P < 0.02), but fasting glucose, insulin, and C-peptide levels were similar. During the clamp, the insulin sensitivity index for glucose disposal was lower (P < 0.03) in relatives than in control subjects (low 12.0 +/- 1.6 vs. 18.1 +/- 1.4; high 9.4 +/- 0.8 vs. 12.9 +/- 0.6 [100 x mg x l x kg(-1) x mU(-1) x min(-1)]). This difference was partially attributed to slightly higher clamp insulin levels in the relatives (P < 0.03), suggesting an impaired rate for insulin clearance. SAT lipolysis measured as in situ glycerol release did not differ under basal conditions (2.0 +/- 0.2 vs. 2.1 +/- 0.2 micromol x kg(-1) x min(-1)), but the suppression during the insulin infusion was less marked in relatives than in control subjects (glycerol release: low 0.92 +/- 0.09 vs. 0.68 +/- 0.16; high 0.71 +/- 0.10 vs. 0.34 +/- 0.10 micromol x kg(-1) x min(-1); P < 0.03). Plasma nonesterified fatty acids also tended to be higher in relatives than in control subjects during the insulin infusion (NS). In contrast, in vitro experiments with isolated subcutaneous adipocytes displayed similar effects of insulin in relatives and control subjects with respect to both glucose uptake and antilipolysis. In conclusion, insulin action in vivo on both lipolysis and glucose uptake is impaired early in the development of type 2 diabetes. Since this impairment was not found in isolated adipocytes, it may be suggested that neural or hormonal perturbations precede cellular insulin resistance in type 2 diabetes.

Adipocytes↗
PubMed1999

Islet cell and glutamic acid decarboxylase antibodies present at diagnosis of diabetes predict the need for insulin treatment. A cohort study in young adults whose disease was initially labeled as type 2 or unclassifiable diabetes.

OBJECTIVE: To clarify the predictive value of islet cell antibody (ICA) and GAD65 antibody (GADA) present at diagnosis with respect to the need for insulin treatment 6 years after diagnosis in young adults initially considered to have type 2 or unclassifiable diabetes. RESEARCH DESIGN AND METHODS: The patient material was representative of the entire Swedish population, consisting of patients who were 15-34 years old at diagnosis of diabetes in 1987-1988 but were not considered to have type 1 diabetes at onset. At follow-up, 6 years after the diagnosis, it was noted whether the patient was treated with insulin. The presence of ICA was determined by an immunofluorescence assay, and GADAs were measured by a radioligand assay. RESULTS: Six years after diagnosis, 70 of 97 patients were treated with insulin, and 27 of 97 patients were treated with oral drugs or diet alone. At diagnosis, ICAs and GADAs were present in 41 (59%) of 70 patients and 41 (60%) of 68 patients, respectively, of those now treated with insulin, compared with only 1 (4%) of 26 patients and 2 (7%) of 27 patients who were still not treated with insulin. For either ICA or GADA, the corresponding frequencies were 50 (74%) of 68 for patients who were later treated with insulin and 3 (12%) of 26 for those who were still not treated with insulin, respectively. The sensitivity for later insulin treatment was highest (74%) for the presence of ICA or GADA, and the specificity was highest (100%) for ICA and GADA. The positive predictive value was 100% for the combination of ICA and GADA, 98% for ICA alone, and approximately 95% for GADA alone. CONCLUSIONS: Determination of the presence of ICA and GADA at diagnosis of diabetes improves the classification of diabetes and predicts the future need of insulin in young adults.

Adult↗
PubMed1998

Successful treatment with plasmapheresis, cyclophosphamide, and cyclosporin A in type B syndrome of insulin resistance. Case report.

CASE HISTORY: A woman born in 1949 was diagnosed in 1990 with systemic lupus erythematosus. She was treated with prednisolone, and < 1 year later she presented with marked hyperglycemia. Large doses of insulin were given four times per day. Even though the patient was thin (BMI 17.4 kg/m2), very little improvement was seen. INVESTIGATIONS AND TREATMENT: Serum insulin levels were high, and a euglycemic clamp investigation confirmed severe insulin resistance. The patient's serum contained insulin receptor antibodies inhibiting insulin binding, and thus the patient had a type B syndrome of insulin resistance. After diet and exercise, glycemic control stabilized and insulin treatment was withdrawn. However, in late 1993 she was in a catabolic and hyperglycemic state even though prednisolone doses were increased and azathioprin was added. In early 1994 she was treated with plasmapheresis and cyclophosphamide i.v. Subsequently, cyclosporin A was started as a maintenance therapy in addition to azathioprin. There was a rapid and sustained clinical improvement. Since late 1994 and onward, there is no sign of diabetes or glucose intolerance and there are no demonstrable insulin receptor antibodies in the patient's serum. DISCUSSION: Severe type B insulin resistance may respond favorably to treatment with plasmapheresis and cyclophosphamide followed by cyclosporin A in combination with azathioprin.

Adipocytes↗
PubMed1997

[Report of a case. Inhalation steroids caused adrenal cortex suppression].

In one of two cases of systemic effects of high-dose inhaled corticosteroid treatment with fluticasone propionate, adrenal suppression was demonstrated in a young man, and in the other retarded growth and severe general effects were observed in connection with infection in a child. These cases illustrate the risk of systemic effects of inhaled corticosteroids, and the importance of using the lowest possible maintenance dose.

Administration, Inhalation↗
PubMed1997

Peroxovanadate and insulin action in adipocytes from NIDDM patients. Evidence against a primary defect in tyrosine phosphorylation.

We studied the effects of insulin and the stable peroxovanadate compound potassium bisperoxopicolinatooxovanadate (bpV(pic)), a potent inhibitor of phosphotyrosine phosphatases, on lipolysis and glucose uptake in subcutaneous adipocytes from 10 male patients with non-insulin-dependent diabetes mellitus (NIDDM) and 10 matched non-diabetic control subjects. Lipolysis stimulated by isoprenaline or the cAMP analogue, 8-bromo-cyclic AMP (8-br-cAMP), was reduced by approximately 40% in NIDDM compared to control subjects. In both groups bpV(pic) exerted an antilipolytic effect that was similar to insulin (approximately 50 % inhibition). 14C-U-glucose uptake was dose-dependently increased by bpV(pic) treatment, but this effect and also that of insulin were impaired in NIDDM compared to control (bpV(pic) 1.6-fold vs 2.4-fold and insulin 2.2-fold vs 3.4-fold). Furthermore, low concentrations of bpV(pic) did not affect insulin-stimulated glucose uptake, although tyrosine phosphorylation of the insulin receptor beta-subunit was clearly increased by bpV(pic). In conclusion, 1) beta-adrenergic stimulation of lipolysis in vitro is attenuated in NIDDM adipocytes due to post-receptor mechanisms. 2) Both insulin and bpV(pic) decrease lipolysis and enhance glucose uptake in control as well as NIDDM adipocytes. The effect on glucose uptake, but not that on lipolysis, is impaired in NIDDM cells. 3) Peroxovanadate does not improve sensitivity and responsiveness to insulin in NIDDM adipocytes, showing that insulin-resistant glucose uptake in NIDDM is not overcome by phosphotyrosine-phosphatase inhibition and, thus, probably is not caused by impaired tyrosine phosphorylation events alone.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

Insulin promotes and cyclic adenosine 3',5'-monophosphate impairs functional insertion of insulin receptors in the plasma membrane of rat adipocytes: evidence for opposing effects of tyrosine and serine/threonine phosphorylation.

The aim of the present study was to elucidate events in the plasma membrane (PM) associated with the previously described effect of insulin to rapidly enhance the number of cell surface insulin binding sites in rat adipocytes. [125I]insulin was cross-linked to cell surface insulin receptors of intact cells that had been preincubated with or without insulin. Subsequently prepared PM displayed a approximately 3-fold increase in bound [125I]insulin when cells had been pretreated with 6 nM insulin for 20 min compared to membranes from control cells, and SDS-PAGE with autoradiography showed that this occurred at the insulin receptor alpha-subunit. The magnitude of the effect was similar to that found for insulin binding to intact cells that had been preincubated with insulin. In contrast, the insulin binding capacity in the PM was not affected by prior treatment of cells with insulin when assessed with the addition of [125I]insulin directly to solubilized PM; this suggests an unchanged total number of PM receptors. Thus, the enhancement of cell surface insulin binding capacity produced by insulin is not due to the translocation of receptors, but instead appears to be confined to receptors already present in the PM. The addition of phospholipase C (from Clostridium perfringens), which cleaves PM phospholipids, mimicked the effect of insulin to enhance cell surface binding in adipocytes, and this suggests a pool of cryptic PM receptors. Both the nonmetabolizable cAMP analog N6-monobutyryl cAMP (N6-mbcAMP) and the serine/threonine phosphatase inhibitor okadaic acid abolished the effect of concomitant insulin treatment to increase binding capacity. In contrast, the tyrosine phosphatase inhibitor vanadate increased insulin binding even in the presence of okadaic acid or N6-mbcAMP. The effect of N6-mbcAMP to impair cell surface insulin binding was also evident in the presence of a peptide derived from the major histocompatibility complex type I that effectively impairs receptor internalization, but the amount of PM receptors assessed by immunoblot was unaltered. Taken together, the data suggest that insulin exposure leads to the uncovering of cryptic receptors associated with the PM. It is also suggested that tyrosine phosphorylation promotes this process, whereas enhanced serine phosphorylation, e.g. produced by cAMP, impairs the functional insertion of the receptors, rendering them unable to bind insulin.

Adipocytes↗
PubMed1996

Cryptic receptors for insulin-like growth factor II in the plasma membrane of rat adipocytes--a possible link to cellular insulin resistance.

To further elucidate the mechanisms for short-term regulation of the receptor for insulin-like growth factor II (IGF-II), we investigated effects of insulin, cAMP and phosphatase inhibitors on cell surface 125I-IGF-II binding in rat adipocytes. Preincubation with the serine/threonine phosphatase inhibitor okadaic acid (OA, 1 microM) or the non-hydrolysable cAMP analogue N6-mbcAMP (4 mM) markedly impaired insulin-stimulated 125I-IGF-II binding. Furthermore, addition of OA enhanced the inhibitory effect exerted by N6-mbcAMP. N6-mbcAMP also induced an insensitivity to insulin which was normalized by concomitant addition of the tyrosine phosphatase inhibitor vanadate (0.5 mM). In contrast, vanadate did not affect the impairment in maximal insulin-stimulated 125I-IGF-II binding produced by either OA or N6-mbcAMP. Phospholipase C (PLC), which cleaves phospholipids at the cell surface, markedly enhanced cell surface 125I-IGF-II binding in a concentration-dependent manner. Scatchard analysis demonstrated that the effect of PLC was due to an increased number of binding sites suggesting that "cryptic' IGF-II receptors are associated with the plasma membrane (PM). PLC (5 U/ml) also reversed the N6-mbcAMP-induced decrease of 125I-IGF-II binding at a low insulin concentration (10 microU/ml). Taken together, these data indicate that cAMP, similar to its effects on the glucose transporter GLUT 4 and the insulin receptor, may increase the proportion of functionally cryptic IGF-II receptors in the PM through mechanisms involving serine phosphorylation, possibly of a docking or coupling protein. Tyrosine phosphorylation appears to exert an opposite effect promoting the full cell surface expression of receptors.

Adipocytes↗
PubMed1996

Effects of peroxovanadate and vanadate on insulin binding, degradation and sensitivity in rat adipocytes.

The effects of vanadate and the stable peroxovanadate compound bpV(pic) on insulin binding and degradation were investigated in rat adipocytes under conditions of ongoing receptor cycling. Both bpV(pic) and vanadate increased 125I-insulin binding to intact cells through an increase in apparent receptor affinity. The maximal effect of bpV(pic) was to increase binding approximately 4-fold (EC50 0.06 +/- 0.01 mM), whereas vanadate increased binding approximately 2-fold (EC50 1.4 +/- 0.2 mM). Removal of cell surface insulin-receptor complexes with trypsin showed that the effects on binding exerted by bpV(pic) and vanadate were due to a similar increase in both cell surface binding and intracellular accumulation of radioactivity. Both bpV(pic) and vanadate inhibited the degradation of 125I-insulin in medium containing 1% bovine serum albumin. The ratio of degraded/intact intracellular 125I-insulin was also markedly reduced by these agents, suggesting that they inhibit intracellular insulin-degrading proteases. Similar to previous findings with vanadate, bpV(pic) stimulated glucose transport and, at low concentrations, enhanced insulin sensitivity. Taken together, these data demonstrate that both bpV(pic) and vanadate inhibit insulin degradation. In addition, they significantly enhance cell surface insulin binding in rat fat cells and this is associated with an improved insulin sensitivity.

3-O-Methylglucose↗
PubMed1996

A stable peroxovanadium compound with insulin-like action in human fat cells.

Aqueous solutions of peroxovanadium (pV) compounds are potent insulin-mimics in various types of cell. Since chemical instability is a problem with these agents, we studied the insulin-like action in human fat cells of a stable pV complex, bpV(pic). It enhanced 14C-U-glucose uptake in a dose-dependent manner by approximately twofold which was slightly less than the effect of insulin (approximately threefold). The pV complex did not alter cell-surface insulin binding and submaximal concentrations did not influence cellular sensitivity to insulin action on glucose uptake. The bpV(pic) inhibited the lipolytic effect of isoprenaline to the same extent as insulin; however, when the cGMP-inhibitable low-K(m) phosphodiesterase (cGI-PDE) was blocked with the specific inhibitor OPC 3911, the antilipolytic effect of insulin, but not that of bpV(pic), was completely prevented. Moreover, when lipolysis was stimulated by the non-hydrolysable cAMP analogue N6-monobutyryl cAMP, bpV(pic), in contrast to insulin, maintained an antilipolytic effect. These findings indicate that bpV(pic) exerts its antilipolytic effect not only through cGI-PDE activation, similar to the effect of insulin, but also by means of other mechanisms. The tyrosine kinase activity of insulin receptors from human placenta was not altered by the pV compound itself, whereas bpV(pic) clearly enhanced insulin-stimulated activity. In contrast, in situ tyrosine phosphorylation of the insulin receptor beta-subunit as well as that of several other proteins was clearly increased in cells which were treated with bpV(pic), whereas vanadate only amplified insulin-stimulated tyrosine phosphorylation. In conclusion, bpV(pic) exerts powerful insulin-like effects in human fat cells and may be a new and potentially useful agent in the management of insulin-resistant states.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1996

Insulin sensitivity following treatment with the alpha 1-blocker bunazosin retard and the beta 1-blocker atenolol in hypertensive non-insulin-dependent diabetes mellitus patients.

OBJECTIVE: To compare the effects of the alpha 1-blocker bunazosin retard and the beta 1-blocker atenolol (Uniloc) on insulin sensitivity and glucose and lipid homeostasis in patients with type-2 diabetes and hypertension. METHODS: Patients with controlled type-2 diabetes (non-insulin-dependent diabetes mellitus), treated by diet or oral sulphonylurea derivatives, and with mild-to-moderate hypertension were include in a randomized, parallel group, double-blind, multicentre study. After a single-blind placebo run-in period lasting 4-6 weeks, the patients were treated either with bunazosin retard or with atenolol for a further 16 weeks including an initial dose titration period to achieve blood pressure control. Treatment involved 3, 6 or 12 mg bunazosin retard tablets or 25, 50 or 100 mg atenolol tablets, administered orally once a day and prescribed according to blood pressure response. The euglycaemic hyper-insulinaemic clamp technique was used to assess insulin sensitivity both after the placebo period and after the active treatment. A total of 95 patients was enrolled in the study (placebo phase). Forty-eight patients were withdrawn from the placebo phase, mainly due to their blood pressures being outside the required range (seated diastolic blood pressure 90-114 mmHg) and 47 patients were allocated randomly to active treatment. Of these, 23 were administered bunazosin retard and 24 atenolol. All evaluations were on an intention-to-treat basis. RESULTS: Insulin sensitivity assessed as glucose utilization during the clamp was significantly higher following bunazosin retard compared with following atenolol administration (3.52 +/- 0.27 versus 2.86 +/- 0.19 units of metabolic clearance rate of glucose index, P < 0.05). The insulin level attained during clamps (infusion rate 56 mU/m2 per min) was higher (P < 0.05) following atenolol (117 +/- 5 mU/l) than it was following bunazosin retard administration (102 +/- 5) or placebo (108 +/- 3), possibly due to an impaired insulin clearance. Compared with placebo, atenolol treatment resulted in significantly increased glucosylated haemoglobin whereas bunazosin retard had no significant effect. The two drugs did not show any consistent differences in lipid profile or fibrinogen and plasminogen activator inhibitor 1 levels. During the study seven serious adverse events were reported and one was reported shortly after completion of the study. All except one were classified as not related to the study drug and five of them occurred during placebo treatment. The non-serious side effects were in general considered to be either unrelated to the test drugs or expected effects of the two respective drug classes. Both bunazosin retard and atenolol displayed acceptable safety profiles. CONCLUSION: Bunazosin retard treatment in hypertensive non-insulin-dependent diabetes mellitus patients appears to be associated with a slightly higher insulin sensitivity than is atenolol.

Adrenergic alpha-Antagonists↗
PubMed1996

A new non-invasive method using pulse oximetry for the assessment of arterial toe pressure.

We evaluated a novel, simple non-invasive method to assess systolic arterial toe pressures (ATP). It was employed in 63 subjects, of which 37 had suspected or established lower extremity arterial disease (LEAD) and 26 did not. 48 of the subjects had diabetes and 15 were non-diabetic. Pulsatile toe blood flow was monitored with a regular pulse oximeter (Biox 3700TM, BOC Ohmeda, Helsingborg, Sweden) (POX) with the sensor on the tip of the great toe. A small blood pressure cuff was placed around the proximal part of the toe and was connected to a sphygmomanometer (TycosTM, Levimed AB, Höganäs, Sweden). Systolic pressure was estimated as the cuff pressure at which pulsatile blood flow ceased during cuff inflation. Toe pressure measurement was obtained, in parallel, using the established strain gauge plethysmographic technique. There was a good concordance between the two methods (linear regression: r = 0.93; y = 1.1 x x-6.4; y = pressure obtained with the pulse oximeter, x = pressure obtained with strain gauge, in mmHg). However, patients with very low systolic toe pressures, < 20 mmHg, could not be reproducibly assessed using the POX method. In conclusion, the POX method was found to be a simple and reliable method for the estimation of systolic toe pressures, at least for those above the severely ischemic level. It may provide an easily accessible and cost-effective means of vascular assessment at the bedside, as well as for out-patients.

Adult↗
PubMed1994

The cGMP-inhibitable phosphodiesterase modulates glucose transport activation by insulin.

To assess the role of the cGMP-inhibitable phosphodiesterase (cGI-PDE) in the action of insulin on glucose transport, adipocytes from young, lean rats were preincubated for 20 min at 37 degrees C with and without OPC 3911, a specific inhibitor of cGI-PDE, and 3-O-methylglucose uptake was measured. Insulin-stimulated glucose transport was impaired by OPC 3911 (approximately 15%) and this impairment became more pronounced in the presence of the degradable cAMP-analogue 8-bromo-cAMP (approximately 45%). This analogue alone did not significantly decrease glucose transport. Furthermore, insulin sensitivity was impaired by the combination of OPC 3911 and 8-bromo-cAMP. Maximal insulin-stimulated glucose transport in adipocytes from aging, obese rats was affected similarly by OPC 3911 and 8-bromo-cAMP, suggesting that cGI-PDE activity is not markedly altered in this insulin-resistant state. In conclusion, cGI-PDE exerts a modulating effect on the stimulatory action of insulin on glucose transport. This effect is particularly pronounced when the cellular cAMP levels are elevated.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1994

Insulin concentrations and insulin sensitivity after short-term amiloride in healthy subjects.

We have evaluated the short-term effects of amiloride on insulin action in vivo, since amiloride is known to impair insulin action in vitro. Seven healthy subjects were treated according to a randomized, double-blind, cross-over protocol. The treatment periods were 3 days each with amiloride 15 mg daily and placebo. Insulin action on glucose turnover was assessed directly after each treatment period with the hyperinsulinaemic euglycaemic glucose clamp technique. At the two insulin concentrations studied (approximately 30 mU.l-1 and approximately 200 mU.l-1), the glucose infusion rate required to maintain constant euglycaemia did not differ after either amiloride or placebo. The rates of glucose production and utilization were also similar, whereas the so-called insulin sensitivity index at the lower insulin concentration was significantly reduced (by about 15%) after amiloride. Moreover, amiloride produced significantly higher fasting insulin and C-peptide concentrations, whereas fasting glucose and NEFA concentrations were unaltered. In conclusion, these data suggest that short-term amiloride slightly impairs insulin sensitivity with respect to glucose uptake. However, overall glucose homoeostasis does not appear to be affected, probably due to a compensatory rise in plasma insulin.

Adolescent↗
PubMed1993

Cellular cyclic AMP levels modulate insulin sensitivity and responsiveness--evidence against a significant role of Gi in insulin signal transduction.

Treating rats with pertussis toxin (PTX) both elevated the adipocyte cAMP levels and impaired sensitivity and responsiveness to the antilipolytic effect of insulin in the presence of different beta-adrenergic agonists. However, in the presence of a fixed medium concentration of the degradable cAMP analogue, 8-bromo-cAMP, the effect of insulin was similar in PTX- and control cells. Elevating the cAMP levels in control cells either through different concentrations of the cAMP analogue or addition of adenosine deaminase impaired both insulin sensitivity and responsiveness to a similar extent as that seen in PTX-treated cells. The antilipolytic effect of insulin was exerted through the activation of the cGMP-inhibitable phosphodiesterase (cGI-PDE) as it was dose-dependently impaired by the specific cGI-PDE inhibitor OPC 3911. The results show the importance of the cellular cAMP levels in modulating insulin sensitivity and action. Gi plays a minor role, if any, for the signal transduction of the antilipolytic effect of insulin.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1993

Peroxovanadate but not vanadate exerts insulin-like effects in human adipocytes.

Vanadate and peroxovanadate were recently reported to exert maximal or even supramaximal (peroxovanadate) insulin-like effects in rat adipocytes. To evaluate the response in human cells, isolated human adipocytes were exposed to insulin or various concentrations of vanadate (0-10 mmol/l) or peroxovanadate (0-5 mmol/l). Neither vanadate nor peroxovanadate affected 125I-insulin binding and insulin sensitivity. Vanadate exerted no apparent effect on 14C-U-glucose uptake, whereas 0.1 mmol/l peroxovanadate exerted a full insulin-like response (p < 0.001). No additive response was observed by combining either vanadate or peroxovanadate with insulin. Peroxovanadate at 0.1 mmol/l was as effective as insulin in inhibiting isoproterenol-stimulated lipolysis. Neither peroxovanadate nor insulin-inhibited lipolysis stimulated by N6-monobutyryl-cAMP, an analogue which is not hydrolysed by the cAMP-phosphodiesterase. It is concluded that peroxovanadate, but not vanadate, elicits a full insulin-like response in human adipocytes.

Adipose Tissue↗
PubMed1992

Cyclic AMP impairs the rapid effect of insulin to enhance cell-surface insulin-binding capacity in rat adipocytes.

The aim of this study was to characterize further the interaction between cyclic AMP (cAMP) and insulin binding and action. Rat adipocytes were preincubated at 37 degrees C for 20 min, and after energy depletion with KCN, cell-surface 125I-insulin binding was measured. As recently reported [Eriksson, Lönnroth & Smith (1992) Diabetes 41, 707-714], preincubation with insulin rapidly increased the number of cell-surface insulin binding sites up to approximately 5-fold through recruitment within the plasma membrane. This was completely abolished by the presence of 4 mM-N6-monobutyryl cAMP (a non-hydrolysable cAMP analogue) or 1 microM-isoprenaline, without any apparent change in receptor internalization. Insulin-stimulated receptor tyrosine kinase activity was attenuated by the cAMP analogue only if the exposure of the adipocytes was prolonged to 60 min. The cellular sensitivity to insulin, assessed as 3-O-methylglucose uptake, was markedly decreased by the cAMP analogue, and this could be attributed to the impaired cell-surface binding. However, evidence for post-receptor interactions between cAMP and insulin was also found: an impairment of maximal insulin-stimulated 3-O-methylglucose transport and a delay in the rate of activation of the glucose transport system by insulin. In conclusion, these data demonstrate that beta-adrenergic stimulation and elevated cAMP levels markedly impair the ability of insulin to enhance cell-surface insulin-binding capacity. This novel interaction may be an important mechanism for the cellular insensitivity to insulin produced by cAMP.

Adipose Tissue↗