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PubMedDate not supplied

Insulin-specific IgE in serum of 67 diabetic patients against human insulin (Novo), porcine insulin, and bovine insulin. Four case reports.

We have investigated the binding of insulin-specific IgE (IgE1) to porcine, bovine, and human insulin (Novo), pancreatic polypeptide, and a-component in serum samples from type I diabetic patients treated with insulin preparations of different purity. Patients treated with porcine or mixed-species purified insulin (monocomponent) did not differ significantly from a nondiabetic control group. Hence, in these groups no IgE1 could be detected against any of the components investigated. Serum samples from patients treated with five-times recrystallized insulin preparations and patients with insulin allergy showed a significantly greater binding of IgE1 to the three species of insulin; IgE1 binding was greatest to bovine insulin and least to human insulin. The difference in binding was most significant in the allergic patients (P less than 0.001), probably due to differences in the affinity. It is concluded that conventional (recrystallized) insulin induces more IgE1 than monocomponent insulin. Data are presented on confirmed allergy in four diabetic patients whose allergy disappeared upon transfer to human insulin.

Aged↗
PubMed2000

Combined use of insulin and endothelin-1 causes decrease of protein expression of beta-subunit of insulin receptor, insulin receptor substrate-1, and insulin-stimulated glucose uptake in rat adipocytes.

Previously, we reported that insulin-stimulated glucose uptake (ISGU) can be inhibited by endothelin (ET-1). However, the mechanism by which ET-1 impairs ISGU in adipocytes remains unclear. This study investigated the effects of ET-1 on insulin action in rat adipocytes in order to elucidate the molecular mechanism of action of ET-1 on ISGU. The results show that ISGU was increased fivefold after 3-h treatment with 1 nM insulin. Treatment with 100 nM ET-1 had no effect on basal glucose uptake. However, ET-1 inhibited approximately 25% of ISGU and 20% of insulin binding after 3-h treatment in the presence of 1 nM insulin. Expression of the beta-subunit of the insulin receptor (IRbeta) and the insulin receptor substrate-1 (IRS-1) in adipocytes was not significantly affected by 1 nM insulin or by 100 nM ET-1, even after 3-h treatment. However, expressions of IRbeta and IRS-1 were dramatically decreased in a dose- and time-dependent manner when adipocytes were treated with both insulin and ET-1. Approximately 50% of IRbeta and 65% of IRS-1 expression levels were suppressed when adipocytes were simultaneously treated with both 1 nM insulin and 100 nM ET-1 for 3 h. These results suggest that the inhibitory effect of ET-1 on ISGU may be mediated via the insulin receptor and suppression of IRbeta/IRS-1 expression.

Adipocytes↗
PubMed1986

Fasting and feeding variations of insulin requirements and insulin binding to erythrocytes at different times of the day in insulin dependent diabetics--assessed under the condition of glucose-controlled insulin infusion.

Nine insulin-dependent diabetic patients were examined for insulin requirement, counterregulatory hormones, and receptor binding during their connection to glucose-controlled insulin infusion system. They were of 103% ideal body weight. A diet of 45% carbohydrate, 20% protein and 35% fat was divided into three meals and three snacks averaging the daily calorie intake of 1859 kcal. Following an equilibrating phase of 14 hours after the connection to the glucose-controlled insulin infusion system the blood samples were taken at 0800, 1200 and 1800. The insulin infusion rate increased at 0300 in the early morning from 0.128 mU/kg/min to 0.221 mU/kg/min (P less than 0.02). The postprandial insulin infusion rate jumped from 0.7 U/h (0700-0800) to 7.5 U/h (0800-0900). The calorie related and carbohydrate related insulin demands after breakfast were also highest and declined after lunch respectively (1.16 uU/kg/min kj vs. 0.61 uU/kg/min kj, P less than 0.05 and 236 mU/g CHO vs. 129 mU/g CHO and 143 mU/g CHO). Of the counterregulatory hormones the cortisol showed a significant diurnal rhythm to insulin demands. The insulin tracer binding was higher at 0800 before breakfast than that at 1200 before lunch (P less than 0.05). The increased binding could be better attributed to receptor concentration change than to affinity change. The cause of insulin relative insensitivity in the morning could be due to altered liver response to the cortisol peak in type 1 diabetics. The preserved variation of insulin binding in our patients might be referred to feeding.

Circadian Rhythm↗
PubMed1995

Insulin-induced activation of phosphatidylinositol (PI) 3-kinase. Insulin-induced phosphorylation of insulin receptors and insulin receptor substrate-1 displaces phosphorylated platelet-derived growth factor receptors from binding sites on PI 3-kinase.

Phosphatidylinositol (PI) 3-kinase is an enzyme that functions in the signaling pathways downstream from multiple cell surface receptors. The p85 regulatory subunit of PI 3-kinase binds to phosphotyrosine residues of various phosphoproteins including the platelet-derived growth factor (PDGF) receptor, the insulin receptor, and insulin receptor substrate-1 (IRS-1). Using NIH-3T3 cells overexpressing the human insulin receptor, we demonstrate that the p85 regulatory subunit of PI 3-kinase binds to phosphorylated PDGF receptor in cells incubated in the absence of insulin. When insulin is added, p85 is released from phosphorylated PDGF receptors and binds to phosphorylated insulin receptors and insulin receptor substrate-1. Moreover, insulin-induced dissociation of PDGF receptors from binding sites on PI 3-kinase requires a functional insulin receptor and is not prevented by vanadate treatment. In contrast, insulin activation does not displace PDGF receptors from binding sites on Ras GTPase-activating protein. This competition for binding to PI 3-kinase provides a mechanism for cross-talk among signaling pathways initiated by distinct peptide hormones and growth factors such as insulin and PDGF.

3T3 Cells↗
PubMed1996

Thyrotropin via cyclic AMP induces insulin receptor expression and insulin Co-stimulation of growth and amplifies insulin and insulin-like growth factor signaling pathways in dog thyroid epithelial cells.

Despite the similarity of their receptors and signal transduction pathways, insulin is regarded as a regulator of glucose, protein, and lipid metabolism, whereas insulin-like growth factors (IGF-I and IGF-II) mainly act as mitogenic hormones. In the dog thyroid primary culture model, the triggering of DNA synthesis by thyrotropin (TSH) through cAMP, or by cAMP-independent factors including epidermal growth factor, hepatocyte growth factor and phorbol esters, requires insulin or IGFs as comitogenic factors. In the present study, in TSH-treated cells, IGF-I receptors and insulin receptors were paradoxically equivalent in their capacity to elicit the comitogenic pathway, which, however, was mediated only by IGF-I receptors in dog thyroid cells stimulated by cAMP-independent mitogens. Moreover, prior cell exposure to TSH or forskolin increased their responsiveness to insulin, IGF-I, and IGF-II, as seen on DNA synthesis and activation of a common insulin/IGF signaling pathway. To understand these observations, binding characteristics and expression of insulin and IGF-I receptors were examined. To analyze IGF-I receptor characteristics, the unexpected interference of a huge presence of IGF-binding proteins at the cell membrane was avoided using labeled Long R3 IGF-I instead of IGF-I. Strikingly, TSH, through cAMP, time-dependently induced insulin binding and insulin receptor mRNA and protein accumulation without any effect on IGF-I receptors. These findings constitute a first example of an induction of insulin receptor gene expression by a cAMP-mediated hormone. In dog thyroid cells, this allows low physiological insulin concentrations to act as a comitogenic factor and might explain in part the enhanced responsiveness to IGFs in response to TSH. This raises the possibility that TSH-insulin interactions may play a role in the regulation of thyroid growth and function in vivo.

Animals↗
PubMed2000

The combination of insulin-like growth factor I and insulin-like growth factor-binding protein-3 reduces insulin requirements in insulin-dependent type 1 diabetes: evidence for in vivo biological activity.

Insulin-like growth factor-I (IGF-I) enhances insulin action in normal subjects and in patients with both type 1 and 2 diabetes; however, its administration is associated with significant side effects in a high percentage of patients. The coadministration of IGF binding protein-3 (IGFBP-3, the predominant IGF binding protein in serum) with IGF-I limits IGF-I inducible side effects, but it does not attenuate the ability of IGF-I to enhance protein synthesis and bone accretion; therefore, we determined whether IGF-I/IGFBP-3 would retain biological activity in type 1 DM and limit side effects associated with free IGF-I administration. Twelve patients received recombinant human IGF-I plus IGFBP-3 (2 mg/kg-day) by continuous sc infusion for 2 weeks. Each subject served as his own control; and, during a paired 2-week period, each received a placebo infusion. The order of the treatments was randomized. Subjects were placed on a constant caloric intake but were allowed to adjust insulin doses to maintain appropriate levels of glycemic control. Subjects measured blood glucose four times per day at home and kept a log of their insulin use. Frequent sampling for glucose, insulin, and GH was conducted during four inpatient study periods, one at the beginning and one at the end of each 2-week study interval. During IGF-I/IGFBP-3, insulin doses were reduced by 49%, and mean serum glucose was reduced by 23%. Free insulin levels obtained during frequent sampling in hospital fell 47% on IGF-I/IGFBP-3, compared with control, but showed no change with placebo. Concomitant glucose measurements did not differ in the two treatment groups. There was no change in body weight. Fructosamine levels decreased by 12%, but this was not significant (P < 0.1). Fasting triglyceride was unchanged, but cholesterol declined from 170 +/- 24 to 149 +/- 31 mg/dL (P < 0.05). IGFBP-2 (an IGF-I-dependent responsive variable) rose from 141 +/- 56 to 251 +/- 98 ng/mL (P < 0.01) on IGF-I/IGFBP-3. To analyze the mechanism by which IGF-I/IGFBP-3 might reduce insulin requirements, the change in serum GH was quantified. Mean GH levels were reduced by 72%, from 2.48 to 0.55 ng/mL (P < 0.001). An equal number (40%) of drug- and placebo-treated subjects had minor hypoglycemic episodes at home that required adjustment of insulin doses. No episode was classified as severe. In contrast to previous studies with free IGF-I, there were no cases of edema, headache, jaw pain, retinal edema, or Bell's palsy. No subject withdrew because of drug complications. These findings indicate that IGF-I/IGFBP-3 is biologically active on carbohydrate metabolism, as measured by a decrease in insulin requirements in patients with type 1 diabetes. Further studies will be required to determine the long-term safety and efficacy of this combination in patients with insulin resistance and diabetes.

Adult↗
PubMed1986

[Comparison of biosynthetic human insulin and purified pork insulin. Studies in insulin-resistant obese patients using the insulin suppression test].

An insulin suppression test performed in random order with either biosynthetic human insulin or purified pork insulin was used to compare biological activity of these two insulins in obese patients suffering from varying degrees of glucose intolerance. Blood glucose curve, steady-state blood glucose levels, insulin sensitivity indices and steady-state plasma insulin levels were identical during the two sets of tests. Furthermore endogenous insulin and glucagon secretion were similarly suppressed. The insulin suppression test is a simple and rapid procedure to compare the biological activity of fast-acting insulins. Our results confirm the insulin-resistance in obesity and clearly show that biosynthetic human and porcine insulins have similar biological potency.

Adult↗
PubMedDate not supplied

Switch to multiple daily injections with insulin glargine and insulin lispro from continuous subcutaneous insulin infusion with insulin lispro: a randomized, open-label study using a continuous glucose monitoring system.

OBJECTIVE: To evaluate the safety and efficacy of the transition from a continuous subcutaneous insulin infusion (CSII) regimen with insulin lispro to 1 of 2 dose regimens of multiple daily injections (MDI) with insulin lispro and insulin glargine in patients with type 1 diabetes. METHODS: The study group consisted of 38 patients with type 1 diabetes who had been using CSII with insulin lispro for > or =6 months. These patients were randomized to receive insulin glargine at a dose equal to (group 1:1) or 1.2 times (group 1:1.2) the mean of their total daily CSII basal insulin dose. Data were obtained by continuous interstitial glucose measurement at baseline and for 7 days of MDI. RESULTS: The switch to MDI was associated with a transient deterioration in glycemic control on day 1 in the 1:1 treatment group, which stabilized thereafter. Glucose variability did not increase significantly from baseline in either group on days 1 and 2 after the switch in treatment but increased significantly on day 4 in the 1:1 group for mean amplitude of glucose excursion and in the 1:1.2 group for SD, M-value, and mean amplitude of glucose excursion. Rates of hypoglycemia did not change significantly in either study group after the switch in treatment, but the 1:1 group showed a trend toward less nocturnal hypoglycemia. There were no episodes of severe hypoglycemia, and patients in both groups experienced significantly less time at glucose values <70 mg/dL on day 1 after the switch in comparison with baseline. CONCLUSION: MDI with insulin glargine and insulin lispro provide a safe transition for patients taking "pump holidays" without clinically significant disruptions of glycemic control. The recommended dose of insulin glargine after the switch in treatment is equal to the total daily basal dose on CSII.

Adolescent↗
PubMed1991

The relationship between insulin binding, insulin activation of insulin-receptor tyrosine kinase, and insulin stimulation of glucose uptake in isolated rat adipocytes. Effects of isoprenaline.

We have studied the relationship between insulin activation of insulin-receptor kinase and insulin stimulation of glucose uptake in isolated rat adipocytes. Glucose uptake was half-maximally or maximally stimulated, respectively, when only 4% or 14% of the maximal kinase activity had been reached. To investigate this relationship also under conditions where the insulin effect on activation of receptor kinase was decreased, the adipocytes were exposed to 10 microM-isoprenaline alone or with 5 micrograms of adenosine deaminase/ml. An approx. 30% (isoprenaline) or approx. 50% (isoprenaline + adenosine deaminase) decrease in the insulin effect on receptor kinase activity was found at insulin concentrations between 0.4 and 20 ng/ml, and this could not be explained by decreased insulin binding. The decreased insulin-effect on kinase activity was closely correlated with a loss of insulin-sensitivity of glucose uptake. Moreover, our data indicate that the relation between receptor kinase activity and glucose uptake (expressed as percentage of maximal uptake) remained unchanged. The following conclusions were drawn. (1) If activation of receptor kinase stimulates glucose uptake, only 14% of the maximal kinase activity is sufficient for maximal stimulation. (2) Isoprenaline decreases the coupling efficiency between insulin binding and receptor-kinase activation, this being accompanied by a corresponding decrease in sensitivity of glucose uptake. (3) Our data indicate that the signalling for glucose uptake is closely related to receptor-kinase activity, even when the coupling efficiency between insulin binding and kinase activation is altered. They thus support the hypothesis that receptor-kinase activity reflects the signal which originates from the receptor and which is transduced to the glucose-transport system.

3-O-Methylglucose↗
PubMed1995

Studies on an insulin-stimulated insulin receptor serine kinase activity: separation of the kinase activity from the insulin receptor and its reconstitution back to the insulin receptor.

In cells insulin stimulates autophosphorylation of the insulin receptor on tyrosine and its phosphorylation on serine and threonine by poorly characterized kinases. Recently we have achieved co-purification of the insulin receptor with insulin-stimulated insulin receptor serine kinase activity. We now show that the co-purified serine kinase activity can be removed by NaCl washing and reconstituted by adding back the NaCl eluate. Reconstitution enabled higher serine phosphorylation than achieved with the co-purified preparation. Myelin basic protein was discovered to be a potent substrate for insulin-stimulated serine phosphorylation by the co-purified preparation, with the activity responsible having similar properties to the serine kinase activity towards the receptor. Myelin basic protein was also phosphorylated on serine by the NaCl eluate. Myelin basic protein phosphorylated by the co-purified preparation or the NaCl eluate gave the same set of phosphoserine peptides. The major myelin basic protein serine kinase activity in the NaCl eluate co-purified exactly on Mono Q with the activity that restored insulin-stimulated insulin receptor serine phosphorylation. These results provide strong evidence for the true separation of the serine kinase from the insulin receptor and the distinctiveness of the serine kinase activity from the insulin receptor tyrosine kinase and mitogen-activated protein kinases. The procedures developed for the isolation of the serine kinase and the establishment of an effective in vitro substrate should allow purification of the kinase. The protocols also provide flexible systems for identifying the functions of the insulin-stimulated serine phosphorylations and the respective kinase(s).

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1996

Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice.

We and others recently generated mice with a targeted disruption of the insulin receptor substrate 1 (IRS-1) gene and demonstrated that they exhibited growth retardation and had resistance to the glucose-lowering effect of insulin. Insulin initiates its biological effects by activating at least two major signalling pathways, one involving phosphatidylinositol 3-kinase (PI3-kinase) and the other involving a ras/mitogen-activated protein kinase (MAP kinase) cascade. In this study, we investigated the roles of IRS-1 and IRS-2 in the biological action in the physiological target organs of insulin by comparing the effects of insulin in wild-type and IRS-1-deficient mice. In muscles from IRS-1-deficient mice, the responses to insulin-induced PI3-kinase activation, glucose transport, p70 S6 kinase and MAP kinase activation, mRNA translation, and protein synthesis were significantly impaired compared with those in wild-type mice. Insulin-induced protein synthesis was both wortmannin sensitive and insensitive in wild-type and IRS-1 deficient mice. However, in another target organ, the liver, the responses to insulin-induced PI3-kinase and MAP kinase activation were not significantly reduced. The amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) was roughly equal to that of IRS-1 (in wild-type mice) in the liver, whereas it only 20 to 30% of that of IRS-1 in the muscles. In conclusion, (i) IRS-1 plays central roles in two major biological actions of insulin in muscles, glucose transport and protein synthesis; (ii) the insulin resistance of IRS-1-deficient mice is mainly due to resistance in the muscles; and (iii) the degree of compensation for IRS-1 deficiency appears to be correlated with the amount of tyrosine-phosphorylated IRS-2 (in IRS-1-deficient mice) relative to that of IRS-1 (in wild-type mice).

Adaptor Proteins, Signal Transducing↗
PubMed1996

Insulin-like growth factor II (IGF-II) inhibits insulin-like growth factor binding protein I (IGFBP-1) production in luteinized human granulosa cells with a potency similar to insulin-like growth factor I (IGF-I) and higher than insulin.

Insulin-like growth factor binding protein I (IGFBP-I) is produced by human granulosa cells and may be important in follicular development. Production of IGFBP-I in human granulosa cells is under inhibitory control of insulin and insulin-like growth factor-I (IGF-I). It had not been known if IGF-II affected IGFBP-I production in these cells. We examined the effect of IGF-II on IGFBP-I production in human granulosa cells and compared this effect of IGF-II to similar effects of insulin and IGF-I. Human granulosa cells were obtained during in vitro fertilization and plated at a density of 10(5) cells/mL in McCoy 5A tissue culture medium supplemented with 10% fetal calf serum. After 48 h of preincubation at 37 C, 90% humidity, 5% CO2, the medium was removed, and serum-free medium was added. After 24 h of incubation in the serum-free medium, the medium was removed, cells were washed, and new serum-free medium supplemented with various concentrations of insulin, IGF-I, or IGF-II was added. After 24 h of incubation with insulin, IGF-I, or IGF-II, the medium was removed and frozen at-20 C until assayed for IGFBP-I. IGFBP-I was measured using kits from Diagnostic System Laboratories, Webster, Texas. Concentrations of IGFBP-I in the medium were 4.4 +/- 1.7 ng/mL for control cells; 3.0 +/- 0.8, 3.0 +/- 0.7, 3.1 +/- 0.7, 1.8 +/- 0.5, and 1.1 +/- 0.3 ng/mL for 1, 10, 10(2), 10(3), and 10(5) ng/mL insulin respectively; 1.4 +/- 0.6, 2.1 +/- 0.5, 0.3 +/- 0.1, 0.1 +/- 0.02, and 0.01 +/- 0.02 ng/mL for 0.5, 1, 5, 10, and 10(2) ng/mL of IGF-I, respectively; and 2.3 +/- 2.2, 1.2 +/- 0.8, 0.9 +/- 0.3, 0.7 +/- 0.2, and 0.04 +/- 0.02 ng/mL for 0.5, 1, 5, 10, and 10(2) ng/mL of IGF-II, respectively. Concentration of IGFBP-I in the medium collected from cells incubated with hormones was statistically lower than that for control cells starting at 10(3) ng/mL of insulin (P < 0.05), 0.5 ng/mL of IGF-I (P < 0.05) and 1 ng/mL of IGF-II (P < 0.05). Within the range of hormone concentrations tested, the P-values (independent groups t-test) never reached less than 0.01 levels for insulin, but reached this level at 5 ng/mL for both IGF-I and IGF-II. We conclude that IGF-II inhibits IGFBP-I production in luteinized human granulosa cells in a dose-dependent manner and with potency similar to IGF-I and higher than insulin. Further studies are needed to determine the physiological significance of this and other effects of IGF-II in the human ovary in both normal and pathological states.

Culture Media, Conditioned↗
PubMedDate not supplied

Comparison of biosynthetic human insulin and pork insulin during rest, food ingestion, and physical work in insulin-dependent diabetic subjects using a glucose controlled insulin infusion system.

In six insulin-dependent diabetic subjects, we investigated whether differences between biosynthetic human insulin (BHI) and pork insulin are present as measured by an automatic glucose controlled insulin infusion system (GCIIS) (Biostator). The parameters measured were basal insulin requirement and food-dependent insulin requirement, as well as the blood sugar-lowering and insulin-saving effect of standardized physical work. The results show that BHI does not reveal any differences with regard to the basal food-independent and food-dependent insulin requirement compared to pork insulin in insulin-requiring diabetic subjects. Delayed food-dependent initial rise in blood sugar and insulin during physical work, which was observed with BHI, does not show any differences in the integral over 180 min. These investigations confirm the results found in vitro and in animal experiments. At the same time, they indicate discrete differences in the activity spectrum.

Animals↗
PubMed1989

Immunological relationships between receptors for insulin and insulin-like growth factor I. Evidence for structural heterogeneity of insulin-like growth factor I receptors involving hybrids with insulin receptors.

The receptors for insulin and insulin-like growth factor-I (IGF-I) are closely related in primary sequence and overall structure. We have examined the immunological relationships between these receptors by testing the reactivity of anti-(insulin receptor) monoclonal antibodies with IGF-I receptors in various tissues and cell lines. Antibodies for six distinct epitopes reacted with a subfraction of IGF-I receptors, as shown by inhibition of 125I-IGF-I binding, precipitation of 125I-IGF-I-receptor complexes or immunodepletion of receptor from tissue extracts before binding assays. Both immunoreactive and non-immunoreactive subfractions displayed the expected properties of 'classical' IGF-I receptors, in terms of relative affinities for IGF-I and insulin. The proportion of total IGF-I receptors which was immunoreactive varied in different cell types, being approx. 40% in Hep G2 cells, 35-40% in placental membranes and 75-85% in IM-9 cells. The immunoreactive fraction was somewhat higher in solubilized receptors than in the corresponding intact cells or membranes. A previously described monoclonal antibody, alpha-IR-3, specific for IGF-I receptors, inhibited IGF-I binding by more than 80% in all preparations. When solubilized placental receptors were pretreated with dithiothreitol (DTT) under conditions reported to reduce intramolecular (class I) disulphide bonds, the immunoreactivity of IGF-I receptors was abolished although total IGF-I binding was little affected. Under the same conditions insulin receptors remained fully immunoreactive. When solubilized receptor preparations were fractionated by gel filtration, both IGF-I and insulin receptors ran as symmetrical peaks of identical mobility. After DTT treatment, the IGF-I receptor was partially converted to a lower molecular mass form which was not immunoreactive. The insulin receptor peak showed a much less pronounced skewing and remained fully immunoreactive in all fractions. It is concluded that the anti- (insulin receptor) antibodies do not react directly with IGF-I receptor polypeptide, and that the apparent immunoreactivity of a subfraction of IGF-I receptors reflects their physical association with insulin receptors, both in cell extracts and in intact cells. The most likely basis for this association appears to be a 'hybrid' receptor containing one half (alpha beta) of insulin receptor polypeptide and the other (alpha' beta') of IGF-I receptor polypeptide within the native (alpha beta beta' alpha') heterotetrameric structure.

Antibodies, Monoclonal↗
PubMed1988

Characterization of the stimulatory action of insulin on insulin-like growth factor II binding to rat adipose cells. Differences in the mechanism of insulin action on insulin-like growth factor II receptors and glucose transporters.

Insulin is known to increase the number of cell surface insulin-like growth factor II (IGF-II) receptors in isolated rat adipose cells through a subcellular redistribution mechanism similar to that for the glucose transporter. The effects of insulin on these two processes, therefore, have now been directly compared in the same cell preparations. 1) Insulin increases the steady state number of cell surface IGF-II receptors by 7-13-fold without affecting receptor affinity; however, insulin stimulates glucose transport activity by 25-40-fold. 2) The insulin concentration required for half-maximal stimulation of cell surface IGF-II receptor number is approximately 30% lower than that for the stimulation of glucose transport activity. 3) The half-time for the achievement of insulin's maximal effect at 37 degrees C is much shorter for IGF-II receptor number (approximately 0.8 min) than for glucose transport activity (approximately 2.6 min). 4) Reversal of insulin's action at 37 degrees C occurs more rapidly for cell surface IGF-II receptors (t1/2 congruent to 2.9 min) than for glucose transport activity (t1/2 congruent to 4.9 min). 5) When the relative subcellular distribution of IGF-II receptors is examined in basal cells, less than 10% of the receptors are localized to the plasma membrane fraction indicating that most of the receptors, like glucose transporters, are localized to an intracellular compartment. However, in response to insulin, the number of plasma membrane IGF-II receptors increases only approximately 1.4-fold while the number of glucose transporters increases approximately 4.5-fold. Thus, while the stimulatory actions of insulin on cell surface IGF-II receptors and glucose transport activity are qualitatively similar, marked quantitative differences suggest that the subcellular cycling of these two integral membrane proteins occurs by distinct processes.

3-O-Methylglucose↗
PubMed2003

Randomized cross-over trial of insulin glargine plus lispro or NPH insulin plus regular human insulin in adolescents with type 1 diabetes on intensive insulin regimens.

OBJECTIVE: To compare blood glucose control and incidence of nocturnal hypoglycemia in adolescents with type 1 diabetes on multiple injection regimens managed with either an insulin analog combination or NPH insulin plus regular human insulin. RESEARCH DESIGN AND METHODS: In a randomized cross-over study, 28 adolescents with type 1 diabetes on multiple injection therapy received either insulin glargine prebedtime plus lispro preprandially (LIS/GLAR) or NPH insulin prebedtime plus regular human insulin preprandially (R/NPH). During each 16-week treatment arm, subjects completed home blood glucose profiles, and at the end of each treatment arm, they were admitted for an overnight metabolic profile. A total of 25 subjects completed the study. RESULTS: Compared with R/NPH therapy, LIS/GLAR was associated with lower mean blood glucose levels (LIS/GLAR versus R/NPH): fasting (8.0 vs. 9.2 mmol/l, P < 0.0001), 2 h postbreakfast (8.1 vs. 10.7 mmol/l, P < 0.0005), prelunch (8.9 vs. 10.1 mmol/l, P < 0.01), and 2 h postlunch (8.0 vs. 9.5 mmol/l, P < 0.002). However, there was no difference in mean blood glucose levels before or after the evening meal. Incidence of nocturnal hypoglycemia on overnight profiles was 43% lower on LIS/GLAR compared with R/NPH therapy; however, there was no difference in rates of self-reported symptomatic hypoglycemia. Total insulin dose required to achieve target blood glucose control was lower on LIS/GLAR (1.16 IU/kg) compared with R/NPH therapy (1.26 IU/kg, P < 0.005), but there was no significant difference in HbA(1c) levels (LIS/GLAR versus R/NPH: 8.7 vs. 9.1%, P = 0.13). CONCLUSIONS: Combination therapy with insulin glargine plus lispro reduced the incidence of nocturnal hypoglycemia and was at least as effective as R/NPH insulin therapy in maintaining glycemic control in adolescents on multiple injection regimens.

Adolescent↗
PubMed1984

Effects of insulin antibodies on bioavailability of insulin: preliminary studies using 123I-insulin in patients with insulin-dependent diabetes.

Bovine insulin was labelled with carrier-free Na 123I and the species labelled on the A14 tyrosyl residue was purified by reverse phase high pressure liquid chromatography. After sterilization by filtration through a 0.22 micrometer millipore filter, the labelled hormones (123I-insulin) was injected intravenously into normal volunteers and into two insulin-immunized insulin-dependent diabetic patients. Patient 1 was treated with 74 U insulin/day, whereas, despite daily insulin doses greater than 100 U, patient 2 remained hyperglycaemic and continued to lose weight. Plasma insulin binding capacity was 10 U/l in patient 1 and greater than 20 U/l in patient 2. In both diabetic patients, heart activity (i.e. blood pool) decreased more slowly than in control patients, an observation consistent with the reduction of plasma insulin clearance rate in immunized patients. Kidney activity was decreased in patient 1 and undetectable in patient 2, suggesting that most of the circulating 123I-insulin was bound to antibodies and not filtrable. Finally, in both patients, the profile of liver radioactivity was markedly altered. Maximum liver activity was delayed and the liver image persisted for greater than 45 min. According to analysis of the time activity profile in various organs, we consider that specific antibodies act predominantly either as 'carrier-proteins' retarding the action of soluble insulin as in patient 1 or as insulin 'scavengers', the immune complexes being cleared by the reticulo-endothelial system as in patient 2.

Adult↗
PubMed1995

A comparison of the effects of insulin-like growth factor-I, insulin and combined infusions of insulin and insulin-like growth factor-I on glucose metabolism in dogs.

The effect of infusions of recombinant insulin-like growth factor-I (IGF-I) (34, 103 or 688 pmol kg-1 min-1), insulin (3.4, 10.3 or 68.8 pmol kg-1 min-1) or combined infusions (34 pmol IGF-I + 3.4 pmol kg-1 min-1 insulin or 103 pmol IGF-I + 3.4 pmol kg-1 min-1 insulin) on glucose metabolism was investigated in dogs using a [3-3H]-glucose infusion and euglycaemic clamp. All insulin doses decreased glucose production rate (Ra) in a dose-dependent manner (P < 0.05). All IGF-I doses decreased glucose Ra (P < 0.05) but this decrease was not dose dependent. The decrease in glucose Ra with the combined infusion of 34 pmol kg-1 min-1 IGF-I + 3.4 pmol kg-1 min-1 insulin was greater than 34 pmol kg-1 min-1 IGF-I (P < 0.05) but not different from 3-4 pmol kg-1 min-1 insulin. All insulin and IGF-I doses increased glucose utilization rate (Rd) in a dose-dependent manner (P < 0.01). The increase in glucose utilization was greater following both combined infusions than with either component infused alone (P < 0.05). Although at the doses selected, insulin and IGF-I had similar effects on glucose utilization with additive effects when the two peptides were combined, IGF-I was less effective than insulin in suppressing glucose production.

Animals↗