bluuebunny/crossref_metadata_2025_split huggingface dataset:
Photocoagulation for Diabetic Maculopathy: A Randomized Controlled Clinical, Trial Using the Xenon Arc
Authors:   British Multicentre Study Group
Published: September 2013

The final results of a randomized controlled clinical trial of photocoagulation for diabetic maculopathy are reported, when all patients have been followed for at least 5 yr and some for as long as 7 yr. Ninety-nine patients with two similarly affected eyes had one eye chosen by a random procedure, treated with the xenon-arc photocoagulator; the untreated eyes remained as control.
The mean visual acuity deteriorated by less than one line in treated eyes but by more than 2 lines in the controls (P &lt; 0.01). The difference in deterioration was greatest in patients whose initial vision was 6/6-6/9, and was not significant in those whose visual acuity was 6/36 or worse. Thirteen patients became blind in both eyes (visual acuity of 6/60 or less for 2 consecutive yearly assessments), 6 in the treated eye only, and 26 in the control eye only (P &lt; 0.01). Again the divergence between treated and control eyes was most marked in those whose initial vision was 6/6–6/9, (only one treated but 10 control eyes became blind). Hard exudates, microaneurysms, and hemorrhages improved more in the treated eyes (0.05 &lt; P &lt; 0.001) and more control eyes developed new vessels during the follow-up period.
Twenty-three patients died during follow-up and another 16 failed to complete the study. Though the blood pressure of those who died was higher than those who survived (P &lt; 0.05 for both systolic and diastolic) no other medical abnormalities at entry had any clear effect on visual outcome or 5-yr survival.
It is concluded that photocoagulation is of benefit in maintaining vision in diabetic maculopathy if the disease is not too far advanced.
Insulin Receptor Binding to Monocytes, Insulin Secretion, and Glucose Tolerance Following Metformin Treatment: Results of a Double-Blind Cross-Over Study in Type II Diabetics
Authors: Prager R , Schernthaner G 
Published: September 2013

We studied the effect of metformin therapy (1700 mg daily) on glucose tolerance, insulin secretion, and insulin binding to monocytes in 10 non-insulin-dependent diabetics (mean duration of disease 2.6 yr) who were treated for 4 wk with either metformin or placebo in a double-blind cross-over study.
Metformin induced a significant decrease of glucose levels during an oral glucose load compared with placebo treatment (P &lt; 0.001). All patients studied showed normal or elevated basal insulin and C-peptide levels; their responses to an oral glucose load, however, were relatively hypoinsulinemic without any significant difference between metformin and placebo. Insulin binding to monocytes was nearly identical at ail insulin concentrations tested in the placebo or metformin therapy phase.
These data indicate that the glucose-lowering potency of metformin in non-insulin-dependent diabetics cannot be associated with changes in receptor number or affinity. It is suggested that metformin might have a positive influence on postreceptor defects in non-insulin-dependent diabetics.
Glucosylated Collagen Is Antigenic
Authors: Bassiouny A R , Rosenberg H , McDonald T L 
Published: September 2013

Sera from rats inoculated with in vitro glucosylated rat skin acid-soluble collagen were evaluated for specific antibody response using the enzyme-linked immunosorbent assay. The data indicate that the altered protein is capable of eliciting the production of antibodies, but unmodified collagen is not. The specificity of the generated antibodies appears to be directed toward the glucitollysine residues of the modified collagen. Sera from streptozotocin-induced diabetic rats contain antibodies that clearly bind glucosylated collagen.
These results provide support for the hypothesis that in diabetes mellitus increased collagen glucosylation during chronic hyperglycemia may be the initiating event of an autoimmune response leading to the long-term complications.
Elevated Proinsulin Biosynthesis In Vitro from a Rat Model of Non-insulin-dependent Diabetes Mellitus
Authors: Halban Philippe A , Bonner-Weir Susan , Weir Gordon C 
Published: September 2013

Rats were injected with streptozotocin at 2 days of age. After 10–14 wk, the injected rats showed normal body weight with only modestly elevated fed plasma glucose (controls: 118 mg/dl, diabetic rats: 209 mg/dl). No significant difference between control and diabetic rats was found for overnight fasting plasma insulin levels. The diabetic rats had a retarded rate of disposal of intravenously injected glucose, with only 13% of the incremental increase in plasma insulin seen in control rats 2 min after glucose injection.
The immunoreactive insulin content of islets isolated from the diabetic rats was 14% of controls. However, these islets had 74% of the B-cell composition of controls, as estimated by quantitative morphometry. Insulin release (30 min) was lower from islets from diabetic rats than from controls, but was not lowered to the same extent as islet insulin content. Proinsulin biosynthesis was estimated by measuring the incorporation of [3H] leucine or of [3H] phenylalanine into immunoprecipitable material. Proinsulin biosynthesis was strikingly elevated in islets from diabetic rats. Although incorporation of labeled amino acids into total islet protein was also elevated for islets from diabetic rats, the elevation was less pronounced than for incorporation into immunoprecipitable material.
The diabetic state of these animals is thus associated with glucose intolerance in vivo, and an increased rate of insulin turnover in isolated islets studied in vitro.
The Pharmacokinetics of Insulin After Continuous Subcutaneous Infusion or Bolus Subcutaneous Injection in Diabetic Patients
Authors: Kobayashi Tetsuro , Sawano Shinji , Itoh Tokuji , Kosaka Kinori , Hirayama Hiroki , Kasuya Yasuji 
Published: September 2013

Pharmacokinetic models of insulin were examined in order to describe a plasma concentration-time profile after subcutaneous (s.c.) administration of insulin to the patients with insulin-dependent diabetes mellitus (IDDM) or non-insulin-dependent diabetes mellitus (NIDDM). Diabetic subjects were restricted to those with fasting plasma insulin levels around the lowest limit for insulin assay (5 μU/ml). A one-compartment open model with first-order absorption and elimination was appropriate for estimating the plasma concentration-time profile of insulin injected or infused subcutaneously. In the case of continuous s.c. insulin infusion (CSII) for 1 h at the rate of 3 ml/h (2–3 U/ml), the absorption rate constant (Ka), elimination rate constant (Ke), and distribution volume (Vd) were 0.026 ± 0.001 min−1 (mean ± SEM; absorption half-life: 27 min), 0.013 ± 0.005 min−1 (elimination half-life: 53 min), and 1.99 ± 0.49 L/kg body wt, respectively. These values did not differ significantly from those generated by single bolus s.c. injection of undiluted insulin (40 U/ml). The calculated areas under the plasma insulin concentration-time curves from time zero to infinity ([AUC]∞0) did not differ after each mode of administration, while the [AUC] ∞0 after CSII was about 32% of that following intravenous bolus injection (P &lt; 0.01).
The following conclusions can be drawn from these results: (1) the plasma concentration-time profile of insulin after CSII or bolus s.c. injection can be analyzed by pharmacokinetic modeling, (2) the absorption kinetics of insulin did ot differ significantly between two modes of s.c. insulin administration in the patients with IDDM or NIDDM, and (3) the insulin after CSII or single bolus s.c. injection seems to be degraded at the s.c. site to the same extent.
Changes in Blood Flow Close to Subcutaneous Insulin Injection Sites in Stable and Brittle Diabetics
Authors: Williams Gareth , Pickup John , Clark Adrian , Bowcock Sally , Cooke Ernest , Keen Harry 
Published: September 2013

Photoelectric Plethysmography (PPG) Was Used to investigate blood flow changes closeto superficial subcutaneous injection sites. As a validation procedure, the PPG response to subcutaneous injection of a known hyperemic agent, prostaglandin E, (10−5 M), was shown to correlate strongly with subcutaneous blood flow changes estimated by the established technique of133Xe washout.
Changes in blood flow over the subcutaneous injection sites of insulin (Actrapid) and insulin diluent were measured by photoelectric plethysmography in six nondiabetics and in six stable and seven brittle insulin-dependent diabetics. In all subject groups, an acute increase in local blood flow was seen within 2 min of both insulin and diluent injections, probably caused by injection trauma. At diluent injection sites, this acute hyperemia faded rapidly, blood flow returning to preinjection levels within 15–20 min, and there was no further increase in blood flow in any of the subjects. Insulin injected into the nondiabetics and stable diabetics caused a pronounced increase in local blood flow, sustained for at least 60 min after injection. In the brittle diabetics, however, there was no prolonged local hyperemia, the response being significantly less than that seen in both the nondiabetics and the stable diabetics.
Insulin-related hyperemia close to injection (or infusion) sites may be important in subcutaneous insulin absorption. Its near-absence in brittle diabetics may contribute to the impaired response to subcutaneous insulin characteristic of these patients.
Inhibition of Glucagon Secretion in the Human Newborn by Glucose Infusion
Authors: Grasso S , Fallucca F , Mazzone D , Giangrande L , Romeo M G , Reitano G 
Published: September 2013

Plasma glucagon, serum insulin, and blood glucose responses during a 30-min glucose (1 g/kg body wt) or saline infusion were reported in 37 full-term and 35 preterm infants. They were studied either on the first day of life before feeding was initiated or during the first week of life.
Glucose infusion promptly suppressed glucagon secretion in all infants even from the initial hours of extrauterine life. The mean maximal decrement in percentage in the full-term infants on the day of birth and older was 54 ± 4% and 61 ± 6%, respectively, while the maximaldecrement in the preterm infants on day of birth and older was significantly lower (44 ± 3% and 38 ± 4%, respectively). The insulin response to glucose was variable in all infants and most of them showed a delayed rise of serum insulin.
No change in plasma glucagon, blood glucose, and serum insulin was observed during and after saline infusion.
Endogenous Prostaglandin Synthesis and Glucose-induced Insulin Secretion from the Adult Rat Pancreatic Islet
Authors: Evans Marilyn H , Pace Caroline S , Clements Rex S 
Published: September 2013

Although exogenous prostaglandins are recognized modulators of insulin secretion, the relationship between their endogenous synthesis and insulin secretion has not been rigorously studied in isolated adult rat islets. Using 3H-arachidonic acid as a tracer, we evaluated the effect of glucose stimulation upon the incorporation of this fatty acid into islet phospholipids and prostaglandins (separated by extraction and sequential silicic acid, thin-layer and paper chromatography). We observed that 3H-arachidonic acid was incorporated into islet phospholipids and prostaglandins under basal conditions (0.3 mg/ml glucose). Furthermore, exposure of islets to a stimulatory glucose concentration led to significant increases in the recovery of 3H-arachidonic acid-derived radioactivity in islet phosphatidylethanolamine, phosphatidylserine, sphingomyelin, and phosphatidylinositol as well as into all of the measured prostaglandins (A2,B2, D2, E2, and F2α).
The most marked increases in recovered radioactivity resulting from a stimulatory glucose concentration were in islet phosphatidylethanolamine and prostaglandin A2 (which we believe to be derived, in large part, from endogenously synthesized prostaglandin E2). These glucose-induced increases in 3H-arachidonic acid-derived radioactivity in both the phospholipid and the prostaglandin fractions were eliminated by the inhibition of phospholipase A2 activity with mepacrine or by the inhibition of cyclooxygenase activity with sodium salicylate.
When islets prelabeled with 3H-arachidonic acid were exposed to a high glucose concentration in a perifusion system, there was a brisk extracellular release of radioactivity (presumably representing unidentified prostaglandins) that began within 1 min and that peaked slightly before the peak of the first phase of insulin secretion. Inhibition of either phospholipase A2 or of cyclooxygenase activity prevented the glucose-induced release of radioactivity and converted the pattern of insulin secretion from biphasic to monophasic. We conclude that the adult rat pancreatic islet rapidly incorporates arachidonic acid into phospholipids and prostaglandins and that this incorporation is markedly increased in the presence of a stimulatory glucose concentration. Studies with inhibitors of prostaglandin synthesis suggest that the endogenous synthesis of prostaglandins induced by glucose may contribute to the biphasic pattern of glucose-stimulated insulin secretion from the rat pancreatic islet.
Immunoreactivity of Human Insulin of Recombinant DNA Origin
Authors: Kumar Dinesh , Alexander Charles M , Zeidler Adina , Rhodes James J , Boarman Christopher C , Hoopes Michael T 
Published: September 2013

To evaluate possible advantages of human insulin of recombinant DNA origin (HI) in the treatment of diabetic patients, we compared cellular and humoral immunoreactivities of HI and porcine insulin (PI).
Anti-insulin IgE bound equal amounts of 125I-HI and 125I-PI. There was no difference between HI- and PI-stimulated lymphocyte transformation indices.
The binding of 125I-HI with circulating anti-insulin IgG was lower compared with 125I-PI binding (12.1 ± 1% versus 15.4 ± 1.5%, P &lt; 0.001) in 60 insulin-treated cases.
Thirteen sera were selected for high antibody titers and analyzed in detail. In the competitive inhibition assays, a 50% displacement of 125I-PI required a fourfold higher concentration of HI than PI. Although total insulin binding capacities were almost equal, 63 ± 11 nM/L for PI and 60 ± 12 nM/L for HI, the high-affinity antibodies had significantly reduced avidity for HI compared with PI. These differences in avidities suggest that HI may be useful in treatment of immune-type insulin resistance.
Quantification of Insulin Secretion and In Vivo Insulin Action in Nonobese and Moderately Obese Individuals with Normal Glucose Tolerance
Authors: Reaven Gerald M , Moore Jorene , Greenfield Michael 
Published: September 2013

Insulin secretion and in vivo insulin action were quantified in nonobese and moderately obese subjects (approximately 35% above desirable body weight) with normal glucose tolerance. Insulin secretion was estimated by determining plasma insulin responses to a 75-g oral challenge, and in vivo insulin-stimulated glucose uptake by the euglycemic clamp technique.
Plasma glucose levels of the two groups were identical during the glucose tolerance test, butthe plasma insulin response was significantly greater (P &lt; 0.01) in the bese subjects. However, insulin-stimulated glucose utilization by the two groups was equal during the euglycemic clamp studies. These results were supported by the fact that degree of obesity correlated significantly with insulin response (r = 0.61, P &lt; 0.005), but not with insulin-stimulated glucose utilization (r = −0.25, P &gt; 0.2). Thus, indirect evidence that moderately obese subjects were more insulin-resistant based on measurement of plasma insulin responsewas not supported by direct quantification of insulin action. One explanation for these findings is that the height of the plasma insulin response bears no relationship to loss of in vivo insulin action, but that seems unlikely in view of the fact that there was a significant correlation (r = −0.52, P &lt; 0.01) between these two variables in the group as a whole. Therefore, it appears that the hyperinsulinemia seen in obese individuals may not be a simple function of insulin resistance, and that the ability of insulin to stimulate glucose utilization is not significantly impaired in moderately obese subjects with normal glucose tolerance. Alternatively, the degree of impairment in insulin action seen in these individuals is insufficient to be detected by the euglycemic clamp technique.
Receptor Binding Properties of Monoiodotyrosyl Insulin Isomers Purified by High Performance Liquid Chromatography
Authors: Frank Bruce H , Peavy Daniel E , Hooker Carol S , Duckworth William C 
Published: September 2013

The four monoiodinated forms of pork insulin were prepared by lactoperoxidase catalyzed iodination followed by separation on reverse-phase high-performance liquid chromatography. The procedure was rapid and extremely reproducible, resulting in total separation of the B16, B26, and A14 monoiodinated insulins from one another and from unreacted insulin. The A19 derivative eluted closely to the unreacted insulin, requiring an additional step on ion exchange chromatography for complete purification of this derivative. The receptor binding properties of the derivatives were examined in isolated rat adipocytes and hepatocytes and in cultured human IM-9 lymphocytes. The relative binding affinities of the derivatives varied in the different cell types. At tracer concentrations, the B26 derivative had the highest apparent affinity in IM-9 lymphocytes and in adipocytes, but the A14 had the greatest affinity in hepatocytes. At equivalent concentration of each tracer, IM-9 lymphocytes bound the B26 isomer 144 ± 9% (P &lt; 0.05) and the B16 isomer 118 ± 3% (P &lt; 0.05) as well as the 125I (A14) insulin. Isolated rat adipocytes also bound the B26 to a greater extent at tracer concentrations (117 ± 6%; P &lt; 0.01) compared with A14, but bound B16 less than A14 (91 ± 2%; P &lt; 0.01). Isolated rat hepatocytes bound more of the A14 derivative than either of the B-chain labels. The B26 bound 72 ± 2% (P &lt; 0.01) and the B16 90 ± 1% (P &lt; 0.01) as well as the A14 derivative to isolated hepatocytes.
In contrast to the results obtained at tracer concentrations of the isomers, higher concentrations of native insulin were required for 50% competitive displacement (ED50) of the B26 derivative as compared with the other two derivatives in all three cell types examined.
These results indicate a higher average affinity for the B26 isomer in the three tissues, and suggest that results obtained from tracer binding alone may not provide an accurate reflection of receptor affinity for the monoiodoinsulin isomers.
Competitive displacement of the 125I-labeled derivatives by 127I (nonradioactive) labeled homologues in the IM-9 lymphocytes also showed the B26 derivative to have the highest affinity.
The present study demonstrates that monoiodoinsulin selectively labeled on each of the tyrosines can be prepared and separated on HPLC and used to examine insulin receptor binding in different cell types. Furthermore, the data demonstrate different apparent affinities of the selectively-labeled monoiodoinsulin isomers in different cell types, suggesting variability in insulin binding properties in different tissues.
Insulin Binding and Responsiveness in Fat Cells from Patients with Reduced Glucose Tolerance and Type II Diabetes
Authors: Lönnroth Peter , Digirolamo Mario , Krotkiewski Marcin , Smith Ulf 
Published: September 2013

Adipose tissue was obtained from 66 individuals including 21 patients with type II diabetes of different severity (16 SU-treated and 5 diet-treated only) as well as 9 obese subjects with reduced glucose tolerance. Adi-pocyte insulin binding, antilipolytic effect of insulin, and glucose incorporation into triglycerides were measured in the diabetic and the obese subjects and the data compared with that of normal controls of similar age and relative weight.
Insulin binding per cell was normal in the diabetic patients and was significantly increased at low insulin concentrations in the obese patients with reduced glucose tolerance, suggesting increased affinity. Furthermore, insulin binding correlated negatively with age but, when age was corrected for, did not correlate significantly with fasting insulin or glucose levels, relative body weight, or fat cell size. Insulin sensitivity, measured as the antilipolytic effect of insulin, was similar in all patient groups. Patients with the most severe type II diabetes (SU-treated group) demonstrated, in contrast to the less severely diabetic patients, a marked reduction in both basal and insulin-stimulated glucose incorporation into triglycerides showing the presence of a pronounced postreceptor defect. The insulin effect on glucose incorporation correlated negatively with the fasting glucose levels, suggesting that the postreceptor defect seen in the adipocyte reflectsperturbations in other organs, like muscle or liver, of greater importance for glUCOSe homeostasis.
Human Proinsulin-Specific Antigenic Determinants Identified by Monoclonal Antibodies
Authors: Madsen Ole D , Frank Bruce H , Steiner Donald F 
Published: September 2013

Antigenic determinants recognized by human proinsulin (HPI)-specific monoclonal antibodies (Mabs) and Mabs crossreacting with free human C-peptide (HCP) were mapped by using various forms of purified, partially converted HPI intermediates. Two HPI-specific mouse Mabs (GS-4G9 and GS-9A8) reacted with the same antigenic determinant, GS, which was localized to the site of linkage of the B-chain to the C-peptide (Arg-Arg) at positions 31–32. These antibodies bind with equal efficiency to C65-A1 split proinsulin and to intact HPI. The binding of C32-C33 split proinsulin is markedly reduced.
A rat Mab (GN-VIIB6), which crossreacts with free HCP in addition to HPI, reacted similarly with various HPI intermediates as it had with the corresponding synthetic HCP fragments, as previously reported (see ref. 9). This determinant (GN) is a three-dimensional structure composed of residues located in two separate regions in the C-peptide segment (positions 40–45 and 57–63). Reduced, carboxymethylated HPI retains the GN-determinant, whereas all insulin-like immunoreactivity identified with a conventional guinea pig insulin antiserum is completely lost. The binding of the two GS Mabs to the denatured HPI was reduced by 40–50% compared with intact HPI.
It is concluded that the strong GN-determinant can readily form in the C-peptide segment of HPI, independently of the presence of ordered structure in the insulin moiety. A predicted β-turn at position 47–50 may play an important role in bringing N- and C-terminal regions of the C-peptide segment into close proximity. The spontaneous formation of the GN-determinant could thus be a crucial step in the formation of the correct disulfide bonds in more distant parts of the newly synthesized HPI-polypeptide chain