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 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With the recent availability of biosynthetic human proinsulin there has been a renewed interest in evaluating its metabolic effects, either alone or in combination with insulin. It has been suggested that pretreatment with proinsulin enhances the hypoglycemic response to subsequently administered insulin. On the other hand, the simultaneous administration of proinsulin and insulin has additive, not synergistic, effects. To clarify this question we used the euglycemic glucose clamp technique in 10 normal subjects to compare the steady state effects on glucose disposal of combined infusions of insulin (0.54 microgram/M2 . min, equivalent to 15 mU/M2 . min) and proinsulin (2.75 micrograms/M2 . min) given both simultaneously and sequentially. The mean +/- SEM steady state glucose disposal rates were similar whether the two hormones were given simultaneously (7.2 +/- 0.7 mg/min . kg), after proinsulin pretreatment (7.7 +/- 0.7 mg/min . kg), or after insulin pretreatment (7.1 +/- 0.7 mg/min . kg). The serum proinsulin concentration of 5.39 +/- 0.3 pmol/ml during the infusion of proinsulin alone was unchanged by the simultaneous infusion of insulin, suggesting that in the doses used, insulin did not affect proinsulin clearance. We conclude that in normal subjects there is no enhancement of the combined action of insulin and proinsulin to stimulate glucose disposal by pretreatment with proinsulin or insulin.
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PMID:The effects of proinsulin pretreatment on the combined actions of insulin and proinsulin in normal man. 351 94

In this assay for immunoreactive human proinsulin (IRPI), it first is separated from plasma by use of an antiserum to human C-peptide. An immunoprecipitate is then formed by using a precipitating antiserum and polyethylene glycol, after which IRPI is dissociated from the antiserum by incubation in warm HCl, pH 2.0. The resulting mixture is assayed for insulin immunoreactivity by a double-antibody tracer-competition method involving incubation for four days with a high-affinity anti-insulin antiserum. Human proinsulin of recombinant-DNA origin is used as the standard. Added C-peptide at supraphysiological concentrations did not interfere with or react in the assay. Human insulin cross reacted by 1.5%. The detection limit for IRPI (2 SD from zero-dose binding) is 3 pmol/L. Proinsulin conversion intermediates are measured nearly as well as intact proinsulin. IRPI concentrations in 10 nondiabetic human subjects averaged 12.0 (SEM 1.6) pmol/L. The ratio of proinsulin to immunoreactive insulin averaged 14.3 (SEM 2.2)%. After intravenous arginine, the increase in proinsulin was less than that of insulin, and it declined more slowly.
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PMID:A sensitive radioimmunoassay for human proinsulin, with sequential use of antisera to C-peptide and insulin. 351 48

We compared the glucose-lowering effect of proinsulin, the precursor molecule of insulin, with that of insulin itself. In patients with non-insulin-dependent diabetes mellitus (NIDDM) in whom proinsulin (0.2 U per kilogram of body weight) was subcutaneously injected at 9 a.m., fasting glucose levels (247 +/- 22 mg per deciliter [+/- SEM]) became normal within six hours and elevated rates of hepatic glucose output were lowered. The response to regular insulin (0.2 U per kilogram) was of similar magnitude but faster. Glucose clearance was stimulated less by proinsulin, reflecting its preferential action in suppressing glucose output. Hypoglycemia occurred in five of nine insulin-treated patients, but in only one of nine proinsulin-treated patients. After proinsulin injection at bedtime (30.5 +/- 4 U), serum proinsulin concentrations reached a peak by five hours and declined gradually thereafter. Fasting hepatic glucose output became normal, and euglycemia was sustained without overnight hypoglycemia. Proinsulin reduced plasma glucose more effectively than an equal unit dosage of NPH insulin, but since higher doses of NPH insulin were not used, no conclusions could be drawn about the relative desirability of these preparations for clinical use. We conclude that subcutaneously injected proinsulin has prolonged pharmacokinetics in plasma and can normalize plasma glucose in NIDDM characterized by severe hyperglycemia; as compared with the hypoglycemic effects of regular insulin, those of proinsulin are mostly due to suppression of hepatic glucose output, with little stimulation of glucose disposal and less hypoglycemia; and proinsulin may have a role in the treatment of NIDDM.
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PMID:The effects of biosynthetic human proinsulin on carbohydrate metabolism in non-insulin-dependent diabetes mellitus. 354 79

Antibodies have been raised against biosynthetic human proinsulin that show less than 1% cross-reactivity with human insulin and C-peptide. A sensitive (IC50 0.16 pmol/ml; minimum detectable concentration 0.004 pmol/ml) radioimmunoassay has been developed using this antiserum and 125I-proinsulin that will measure proinsulin-like immunoreactivity in human serum without the need for prior separation of insulin or C-peptide. In healthy, fasted subjects (N = 23), the serum proinsulin concentration was 0.015 +/- 0.001 pmol/ml (mean +/- SEM). In six healthy subjects, serum proinsulin rose to 250% of basal after 120 min in response to 100 g oral carbohydrate, but to only 130% after 60 min following 25 g oral carbohydrate. The proinsulin/total immunoreactive insulin ratio and the proinsulin/C-peptide ratio fell sharply after both high and low carbohydrate loads. Endogenous human serum proinsulin-like immunoreactivity released into the circulation after 100 g carbohydrate was eluted from a Mono Q high-performance, ion-exchange column with the same retention time as biosynthetic human proinsulin. Treatment of biosynthetic proinsulin with trypsin under mild conditions led to a decrease in proinsulin-like immunoreactivity concomitant with an increase in C-peptide and insulin-like immunoreactivity, indicating that the proinsulin-specific antiserum did not preferentially recognize intermediates of proinsulin cleavage.
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PMID:Measurement of circulating human proinsulin concentrations using a proinsulin-specific antiserum. 388 62

A sensitive radioimmunoassay (RIA) for canine C-peptide (CCP) was established using synthetic CCP, a specific antiserum, and rabbit anti-guinea pig serum. Radioiodination was performed according to a modified chloramine-T method. Tracer preparations were used for long as 6 weeks after iodination. The standard curve ranges from 0.028 to 3.0 nmol/l. The intra-assay coefficient of variation (CV) was 3-5% and the inter-assay CV was 6-9% in the optimal range between 0.3 and 0.8 nmol/l. The average recovery of CCP added to plasma samples was 100.6% (n = 9). Canine insulin, porcine proinsulin, bovine proinsulin, and human C-peptide exhibited no cross-reactivity. The mean fasting plasma CCP concentration was 0.089 +/- 0.021 nmol/l in normal dogs and -0.005 +/- 0.007 nmol/l (mean +/- SEM) in diabetic dogs, respectively.
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PMID:Measurement of plasma canine C-peptide by radioimmunoassay. 409 33

Sera from 15 patients with the Zollinger-Ellison syndrome were subjected to gel filtration on Sephadex G-50 superfine columns (10 x 2000 mm). The concentration of gastrin in the effluent was determined by a sensitive radioimmunoassay. Immunoreactive gastrin was eluted in four components in 14 sera. (1) Component I, eluted in the same position as proinsulin, constituted 9.7 +/- 1.2 (mean +/- SEM)% of the total immunoreactivity. (2) Component II (;big gastrin') eluted between proinsulin and insulin constituted 57.8 +/- 4.1% (mean +/- SEM) of immunoreactive gastrin. In three sera with the highest concentration of gastrin, component II appeared biphasic. (3) Component III (;little gastrin') was distributed in two peaks; the first one eluted in the same position as the heptadecapeptide gastrin II made up 17.4 +/- 2.7 (mean +/- SEM)% of the total immunoreactivity; the second one eluted in the same position as gastrin I constituted 9.5 +/- 1.3 (mean +/- SEM)%. (4) Component IV (;minigastrin') was eluted immediately before the salt peak and constituted 5.6 +/- 1.4 (mean +/- SEM)%. In one serum only components I and II were present. After incubation with trypsin all immunoreactivity in components I and II was converted to heptadecapeptide-like gastrins.The findings suggest that immunoreactive gastrin in serum from Zollinger-Ellison patients is circulating in at least four components of different molecular size.
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PMID:Gel filtration studies on immunoreactive gastrin in serum from Zollinger-Ellison patients. 419 48

Insulin-like growth factor II (IGF-II) is a human plasma peptide whose sequence is homologous to both insulin-like growth factor I/somatomedin C (IGF-I/SM-C) and human proinsulin in the A and B regions. However, there is no obvious homology in the C (connecting peptide) region. The synthetic 8-amino acid C-peptide segment of IGF-II (Ser-Arg-Val-Ser-Arg-Arg-Ser-Arg) was covalently linked to thyroglobulin to render it more antigenic. Antiserum against the IGF-II C-peptide was generated which had a titer of 1:2000 determined with [125I]IGF-II C-peptide. Half-maximum displacement was by 350 pg/ml IGF-II C-peptide or 80 ng/ml IGF-II. There was no displacement by IGF-I/SM-C, insulin, or a wide variety of peptides. There was also a high degree of species specificity of this antisera. Isoelectric focusing studies of immunoreactive IGF-II showed an apparent pI of 6-6.5. The mean (+/- SEM) level of IGF-II after acid chromatography of 28 normal adult males was 687.0 +/- 31.9 ng/ml. The mean of 8 acromegalics was 600.5 +/- 57.4 ng/ml, indistinguishable from normal. The IGF-II levels of 21 hypopituitary children were significantly lower (231.5 +/- 32.3 ng/ml). Thus, GH action appears to be necessary for normal levels of IGF-II, but excess GH does not cause an elevation above normal of IGF-II, unlike what is seen with IGF-I/SM-C. These structurally related IGF peptides have different control mechanisms and ultimately may play different functional roles. The availability of specific RIAs for the measurement of IGF-II will help to clarify its role in human physiology and disease states.
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PMID:A radioimmunoassay for insulin-like growth factor II specific for the C-peptide region. 617 44

A protein-binding assay for insulin-like growth factor (IGF) was developed which preferentially measures IGF I-related peptides in serum. Binding proteins (BPs) extracted from the culture media of livers from approximately 4-week-old rats were used in the assay, with pure IGF I as tracer and a partially purified IGF preparation as standard. Serum samples were gel filtered in acetic acid to separate the IGFs from their BPs. IGFs could be detected with this assay in extracts corresponding to as little as 0.2 microliter normal serum. The affinity of these liver BPs was greatest for IGF I. IGF II, somatomedin A, and multiplication-stimulating activity were found to be 2, 3, and 10 times less potent, respectively, than IGF I in displacing [125I]IGF I. There was no cross-reaction with insulin and proinsulin, structurally the most closely related peptides. There was a highly significant correlation (r = 0.98, P less than 0.001) between IGF values obtained from simultaneous assays, using either 1) somatomedin C/IGF I antibodies, or 2) the liver BPs, for acromegalic, normal, and hypopituitary serum extracts. Nevertheless, the protein-binding assay yielded values 1.7-fold those of the RIA. The BPs therefore do not possess the specificity of the antibodies for IGF I, but they do have the advantage of being less species specific in that they permit measurement of IGFs in the rat (among others) with the same sensitivity as in man. The validity of the assay was demonstrated both by the studies of IGF levels as a function of age, which yielded a profile characteristic of IGF I, and by the GH-dependence of the IGF levels measured. Mean IGF levels (+/- SEM) were the following: 1.03 +/- 0.03 U/ml in normal adults; 2.62 +/- 0.10 in acromegalic patients; 0.19 +/- 0.01 in patients with total GH deficiency; 0.58 +/- 0.04 in patients with partial GH deficiency (the reference serum being assigned a potency of 1 U IGF/ml). Human GH administration (6 mg/m2, im) to untreated hypopituitary patients on average provoked a 2-fold increase in IGF levels within 24 h. In hypophysectomized rats there was a close relation between the IGF level attained and the dose of GH administered (P less than 0.001). IGF BPs were titrated by incubating different concentrations of the serum extracts with [125I]IGF I and comparing these with a BP preparation obtained from the reference serum used in the IGF assay and arbitrarily assigned a value of 1 U IGF BP/ml.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Preferential measurement of insulin-like growth factor (IGF) I-related peptides in serum with the aid of IGF-binding proteins (IGF BPs) produced by rat liver in culture. Estimation of serum IGF BP levels. 620 15

To assess the significance of deficiency of circulating proinsulin in patients with type I diabetes mellitus, we studied the metabolic effects of biosynthetic human proinsulin in 24 patients. After withdrawing insulin, an infusion of proinsulin to physiological plasma levels did not prevent elevations of plasma glucose or beta-hydroxybutyrate. During steady state infusions of insulin and proinsulin, 13.7 times the steady state plasma level of proinsulin compared to insulin was required to maintain euglycemia. This finding indicates that proinsulin is approximately 7.3% as biologically active as insulin on a molar basis in maintaining glucose control. The MCRs of insulin and proinsulin during these steady state infusions were 12.5 +/- 2.2 (+/- SEM) and 2.62 +/- 0.33 ml/kg X min, respectively. After maintaining euglycemia overnight with an infusion of insulin or proinsulin and then acutely stopping these infusions, the rise in plasma glucose after proinsulin was delayed significantly compared to insulin, consistent with proinsulin's slower clearance. Further studies are necessary to determine whether biosynthetic human proinsulin has a specific role in the treatment of diabetes.
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PMID:The metabolic effects of biosynthetic human proinsulin in individuals with type I diabetes. 637 14

The acute effect of fat feeding on the insulin-mediated stimulatory response of adipose tissue lipoprotein lipase (ATLPL) was examined in normal-weight subjects. After two days of isocaloric-formula feeding, subjects were divided into the following four groups: intravenous (IV) saline alone (sal) (n = 5), IV saline and 67 g of oral corn oil ingested at the outset of the infusion (sal/fat) (n = 5), IV insulin (40 mU/m2/min) and glucose to maintain euglycemia (ins/glu) (n = 9), and IV insulin and glucose and oral corn oil (ins/glu/fat) (n = 8). Triglycerides fell less in the ins/glu/fat group than in the ins/glu group (0 +/- 8% v 35 +/- 5%, means +/- SEM, at three hours, P less than 0.01; 15 +/- 8% v 43 +/- 6% at six hours, P less than 0.02). ATLPL in the sal and sal/fat groups did not change during the six-hour period. When the responsiveness of ATLPL was compared between ins/glu/fat subjects and ins/glu subjects, decreases were seen at both three and six hours (-0.3 +/- 3.0 v 15.1 +/- 5.4 nEq/g/min, P less than 0.05; 6.7 +/- 2.7 v 27.9 +/- 3.9 nEq/g/min, P less than 0.001). The glucose infusion rates needed to maintain euglycemia were also decreased by fat feeding, 229 +/- 18 v 287 +/- 20 mg/m2/min (P less than 0.05). Thus, fat feeding with insulin and glucose infusions diminishes the insulin responsiveness of ATLPL.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fat feeding decreases insulin responsiveness of adipose tissue lipoprotein lipase. 638 65


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