bluuebunny/crossref_metadata_2025_split huggingface dataset:
An Association Between Complement-Fixing Cytoplasmic Islet Cell Antibodies and Endogenous Insulin Secretion in Children with Insulin-dependent Diabetes Mellitus
Authors: Mustonen Aki , Knip Mikael , Åkerblom Hans K 
Published: September 2013

Cytoplasmic islet cell antibodies and endogenous insulin secretion were studied in 184 children and adolescents having insulin-dependent diabetes mellitus (IDDM) in a cross-sectional study. The mean age of the subjects was 12.3 yr (range: 2.8–19.2 yr), and the mear duration of diabetes was 4.6 yr (range: 0.1–15.6 yr). Islet cell antibodies (ICA) were determined by both the indirect immunofluorescence (IF-ICA) and the complement-fixing (CF-ICA) methods. Forty-four patients (23.9%) were positive with respect to both IF- and CF-ICA, 54 patients (29.3%) had only IF-ICA, and 86 patients had no ICA. The patients having CF-ICA had a significantly higher endogenous insulin secretion in comparison with the patients who were only IF-ICA positive. The difference between the groups remained significant even when the age at onset of diabetes and the duration of the disease weretaken into account.
This finding, revealing an association between CF-ICA and endogenous insulin secretion, suggests that complement-fixing antibodies are seen only if the beta-cell mass is sufficiently preserved. The result contradicts the hypothesis, based on studies in vitro, that CF-ICA should be involved in the selective beta-cell damage in IDDM.
Rat Islet Mitochondrial Adenine Nucleotide Translocase and the Regulation of Insulin Secretion
Authors: Ewart R B L , Yousufzai S Y K , Bradford M W , Shrago E 
Published: September 2013

Employing a preparation of rat islet mitochondria, phosphoenolpyruvate has been shown to interact with the mitochondrial adenine nucleotide translocase. Thus, phosphoenolpyruvate inhibited mitochondrial uptake of [14C]ADP and exchanged with intramitochon-drial [14C]ATP. A concentration-dependent inhibition of islet mitochondrial 45Ca2+ accumulation was seen when mitochondria were exposed to phosphoenolpyruvate with half-maximal inhibition observed at a phosphoenolpyruvate concentration of 0.2 mM.
In experiments employing whole islets, phosphoenolpyruvate content was shown to be significantly elevated at both 1 and 30 min after an increase in the medium glucose concentration from 2 to 20 mM. In these experiments, the estimated islet concentrations of phosphoenolpyruvate fell in the range of maximal sensitivity of the islet adenine nucleotide translocase to phosphoenolpyruvate-induced inhibition of Ca2+ accumulation. It is concluded that increased concentrations of islet phosphoenolpyruvate resulting from increased extracellular glucose concentration may act to trigger or promote glucose-stimulated insulin secretion by modifying the distribution of Ca2+ between the islet cy-tosolic and mitochondrial compartments in a transport reaction catalyzed by the adenine nucleotide translocase.
Fuel-induced Insulin Release In Vitro from Insulinomas Transplanted into the Rat Kidney
Authors: Hoenig Margarethe , Ferguson Duncan C , Matschinsky Franz M 
Published: September 2013

We studied the release of insulin, glucagon, and somatostatin in response to glucose, glyceraldehyde (GA), and α-ketoisocaproate (KIC) from rat kidneys containing transplanted insulinomas. Kidneys were perfused about 11 wk after transplantation when the plasma glucose concentration of the fed animals had decreased from 180 ± 7 to 95.1 ± 9.9 mg/dl and plasma insulin concentrations had increased from 2.6 ± 0.5 to 14.2 ± 2.0 ng/ml. The insulin content of the tumorcontaining kidney ranged from 40 to 679 μg; the glucagon and somatostatin concentrations ranged from undetectable levels to 3.7 μg and 248 ng, respectively. The average response to 30 mM glucose and 10 mM GA was a four- to fivefold increase in insulin secretion, whereas 30 mM KIC caused a 16- to 28-fold increase. In vitro stimulation of the insulinoma with 30 mM glucose primed the β-cell response to a second stimulus following a short rest period. Cytochalasin B did not enhance this primed glucose response. Diazoxide inhibited glucose, GA, and KIC-stimulated insulin release. Glucose, GA, and KIC stimulated glucagon release in 2 of 17 insulinomas studied here.
Somatostatin release was not seen in any of the experiments. These findings show that this islet cell tumor transplanted under the kidney capsule releases insulin in response to physiologic and model fuel substances. Thus, this particular transplantable tumor offers an opportunity to study the biochemistry and biophysics that underlie fuel-stimulated insulin release.
Syngeneic Transplantation of Cryopreserved Fetal Mouse Proislets
Authors: Hegre Orion D , Simeonovic Charmaine J , Lafferty Kevin J 
Published: September 2013

Proislets, derived from fetal mouse pancreata by collagenase digestion and subsequent organ culture, can be frozen to −196°C and stored in a viable condition before successful syngeneic transplantation.
Cryopreserved proislets are relatively undifferentiated morphologically, but continue to differentiate into mature islets after transplantation.
Breathing, Sleep, and Diabetic Autonomic Neuropathy
Authors: Catterall James R , Calverley Peter M A , Ewing David J , Shapiro Colin M , Clarke Basil F , Douglas Neil J 
Published: September 2013

Sudden, unexplained deaths are relatively common in diabetic autonomie neuropathy. As disturbed autonomie function has been associated with sleep apnea, and sleep apnea with sudden death, we recorded breathing patterns, arterial oxygen saturation, and EEG during sleep in 8 male diabetic subjects with severe autonomie neuropathy and 8 age-matched, male diabetic subjects without autonomie neuropathy. None of the patients with autonomie neuropathy had more than 11 apneic episodes per night, and there were no significant differences between the two groups in the number of sleep apneas, the duration of individual apneic episodes, the total duration of irregular breathing during sleep, or the duration and quality of sleep. The arterial oxygen saturation when awake and the lowest arterial oxygen saturation during sleep were also similar in both groups.
Thus, diabetic patients with severe autonomie neuropathy have normal breathing patterns and oxygenation during sleep, and it is unlikely that sleep apnea causes these unexpected deaths.
Closed-Loop Glycemic Control with a Wearable Artificial Endocrine Pancreas Variations in Daily Insulin Requirements to Glycemic Response
Authors: Shichiri Motoaki , Kawamori Ryuzo , Hakui Nobuyoshi , Yamasaki Yoshimitsu , Abe Hiroshi 
Published: September 2013

We succeeded in miniaturizing a needle-type glucose monitoring system with characteristics suitable for application in a wearable, closed-loop control system. A wearable artificial endocrine pancreas (12 × 15 × 6 cm, 400 g) consisting of a sensor, a microcomputer system that calculates insulin and glucagon infusion rates, and two roller pumps was developed.
Continuous glucose monitoring by a glucose sensor inserted in the subcutaneous tissue of the forearm or abdomen of healthy and diabetic volunteers revealed that glucose concentrations in subcutaneous tissue were 10% lower than, but were highly correlated with, blood glucose concentrations in the range of 49–388 mg/dl.
Glycemic control was established in diabetic patients by intravenously infusing insulin in response to measured glucose concentrations on a moment-to-moment basis for a period of several days. By comparing the glycemic control obtained in each patient treated with multiple insulin injections or open-loop subcutaneous insulin infusion, the superiority of feedback control with the system was clearly demonstrated.
During continuous glycemic regulation, day-to-day variations of insulin requirements were recognized in both basal insulin infusion and postprandial insulin infusion rates in response to identical meals and exercise.
These data suggest the feasibility of long-term glycemic control in diabetic subjects with a wearable artificial endocrine pancreas, and indicate that to overcome changes in individual metabolic characteristics on a moment-to-moment basis, a closed-loop glycemic control system may be essential for ambulatory diabetic patients.
Evidence for Suppression of Hepatic Glucose-6-Phosphatase with Carbohydrate Feeding
Authors: Newgard Christopher B , Foster Daniel W , McGarry J Denis 
Published: September 2013

The mechanism by which exogenous glucose stimulates the incorporation of hepatic glucose-6-phosphate into glycogen in fasted rats has not been clearly delineated. We gave glucose intragastrically over a 3.5-h period during which liver glycogen was deposited at linear rates. Simultaneous primed continuous infusion of [2-3H] or [3-3H]glucose established that under these conditions absolute carbon flow through hepatic glucose-6-phosphatase was greatly suppressed.
After 1 h, hepatic [UDP-glucose] and [glucose-6-phosphate] had fallen by 50–60% and the former remained low throughout the experiment. By contrast, [glucose-6-phosphate] rebounded to its initial value by 2 h and remained at this level during the subsequent hour.
We interpret the data as follows. Exogenous glucose, in addition to acting as a precursor of liver glucose-6-phosphate, causes diversion of the latter away from free glucose formation and into glycogen synthesis. The fall in [UDP-glucose] is in accord with a glucose-induced activation of glycogen synthase, as proposed by Hers (Annu. Rev. Biochem. 1976; 45:167–89.). However, the fall-rise sequence of glucose-6-phosphate concentration constitutes the first direct evidence in vivo for simultaneous inhibition at the level of glucose-6-phosphatase.
Insulin Receptor Regulation and Desensitization in Rat Hepatoma Cells: Concomitant Changes in Receptor Number and in Binding Affinity
Authors: Crettaz Marco , Kahn C Ronald 
Published: September 2013

We have studied the effects of chronic exposure to insulin on the binding and the biologic activity of the hormone using a well-differentiated cell line (Fao) derived from the Reuber H35 rat hepatoma. Prolonged incubation (24 h) with 10−6 M insulin produced a 20–25% decrease in binding of tracer concentrations (2 × 10−11 M) of125I-insulin, and a leftward shift of the curve for inhibition by unlabeled insulin. Scatchard analysis of the binding data revealed that a 75–80% decrease in the number of binding sites had occurred in the insulin-treated cells, but was accompanied by an increase in apparent receptor affinity. Kinetic studies suggested negative cooperativity in insulin binding and indicated that the change in affinity was accounted for by a decrease in the rate of dissociation. Both the decrease in receptor number and the increase in affinity were dependent on time, temperature, and the insulin concentration during the treatment period. Both effects were also blocked by cycloheximide, suggesting that they required new protein synthesis. Plasma membranes isolated from downregulated cells retained both the change in receptor number and affinity. Anti-receptor antibodies present in two human sera (B-2 and B-9) inhibited 125I-insulin binding in downregulated cells with equal or slightly greater sensitivity than in control cells.
The changes in insulin binding were accompanied by changes in insulin's biologic effects in these cells. Induction of tyrosine aminotransferase (TAT) activity by insulin, an effect that is observed in control cells within 4–6 h and is half-maximal with 5 × 10−10 M insulin, was totally abolished in downregulated cells. In addition, insulin increased two- to threefold the I-form of glycogen synthase in control cells, but failed to stimulate the enzyme in downregulated cells. These results indicate that prolonged exposure of Fao hepatoma cells to insulin produces a type of downregulation characterized by a decrease in insulin receptor number and a concomitant increase in receptor affinity. This is also accompanied by a total desensitization of the cells to insulin's effects on both tyrosine aminotransferase and glycogen synthase.
Gastric Inhibitory Polypeptide (GIP) and Insulin Release in the Obese Zucker Rat
Authors: Chan Catherine B , Pederson Raymond A , Buchan Alison M J , Tubesing Karen B , Brown John C 
Published: September 2013

The involvement of the gut hormone GIP (gastric inhibitory polypeptide, glucose-dependent insulinotropic polypeptide) in the hyperinsulinemia of the adult obese Zucker rat was investigated. Glucose, insulin, and GIP responses to oral glucose were compared in lean and obese rats. The sensitivity of the isolated, perfused pancreas to glucose and GIP was studied in basal and hyperglycemie conditions in lean and obese rats. Immunocytochemical studies of the gut and pancreas were also carried out.
The glucose and GIP responses to oral glucose were similar in lean and obese rats, but obese animals were hyperinsulinemic compared with lean controls under fasting conditions and after oral glucose. The isolated, perfused pancreas of obese Zucker rats had an elevated insulin response to 300 mg/dl glucose. GIP increased the insulin response to 300 mg/dl glucose threefold in both lean and obese rats. At basal glucose levels (80 mg/dl), GIP augmented insulin release in obese but not in lean rats. Immunocytochemical studies demonstrated the presence of enlarged islets in obese rats due to an increase in the B-cell mass. A-, D-, and PP-cells appeared normal. Obese and lean rats had similar numbers of GIP-containing cells in the gut. This study suggests that GIP may contribute to the fasting hyperinsulinemia characteristic of adult obese Zucker rats. GIP infusion to achieve levels equivalent to those seen in the basal state are capable of stimulating insulin release in the absence of hyperglycemia in the obese rat, which suggests an impairment of the regulatory mechanisms controlling the glucose-dependent insulinotropic action of GIP in these animals.
Activation of Pyruvate Dehydrogenase Complex by Porcine and Biosynthetic Human Insulin in Cultured Human Fibroblasts
Authors: Buffington Cynthia K , Stentz Franke B , Kitabchi Abbas E 
Published: September 2013

Cultured human fibroblasts represent an appropriate model for studying both insulin receptor interaction and hormone responsiveness. We have investigated the properties of the pyruvate dehydrogenase multienzyme complex (PDC) and have studied the effects of various concentrations of porcine and biosynthetic human insulin (BHI) on the activity of the enzyme. Under optimal conditions of the assay, both BHI and porcine insulin activated PDC in a dose-dependent fashion in which full activation of the enzyme was achieved with 10−8 M insulin. The half-maximal concentration for porcine and human insulin was similar, occurring at the level of 5 × 10−9 M for activation of the PDC of human fibroblasts.
We conclude that the PDC of cultured human fibroblasts is activated by both human and porcine insulin at a comparable physiologic concentration. Human fibroblasts may therefore serve as a useful model to study insulin action in isolated human tissue.
Effect of Glycemic Control on Serum Insulin-like Growth Factors in Diabetes Mellitus
Authors: Merimee Thomas J , Gardner Donald F , Zapf J , Froesch E R 
Published: September 2013

We investigated the effect of improving glycemie control on serum concentrations of insulin-like growth factors I and II (IGF-I and IGF-II). In 22 adults followed during an intensive home glucose monitoring program for 6 mo, no effect of improving control was seen on either IGF-I or IGF-II. Similar results were obtained in young diabetic children &lt;10 yr of age and in diabetic adolescents with detectable puberty before entering the study. In older diabetic children without evidence of puberty before treatment (Tanner prepubertal stage 1), initial IGF-I concentrations were low, but increased during establishment of glycemie control. Puberty developed during therapy in this latter group.
Our data do not support a “global” effect of glycemie control on serum IGF-I in diabetic patients. Increases of IGF-I with better glycemie control appear most likely to occur when the metabolic consequences of diabetes have suppressed normal pubertal increases of IGF-I. IGF-II concentrations were unaffected by glycemie control in all subjects.
Impaired Insulin Action in Rats with Non-insulin-dependent Diabetes
Authors: Levy Joseph , Gavin James R , Fausto Aurora , Gingerich Ronald L , Avioli Louis V 
Published: September 2013

Studies were performed to test the hypothesis that impaired insulin action occurs as an acquired phenomenon in the streptozocin (STZ)-treated, non-insulin-dependent (NIDDM) diabetic rat model. A number of methods were used to evaluate impaired carbohydrate tolerance in these animals. Plasma glucose and insulin levels were measured at 6 and 14 wk of age, and insulin glucose tolerance tests were performed at 4 and 5 wk of age (before overt hyperglycemia ensues), and at 8 and 14 wk of age (after the animals manifest overt diabetes). The STZ-treated rats had higher plasma glucose levels than those of control animals (P &lt; 0.001) at 6 and 14 wk of age, while their plasma insulin values were decreased to levels 73% of the controls (1.7 ng/ ml versus 2.3 ng/ml, P &lt; 0.04).
Glucose disappearance rates after high (0.35 U/kg) and low (0.175 U/kg) insulin challenge were reduced in the experimental diabetic animals at all ages with both insulin doses. The data suggest that these animals have an early and progressive acquired impairment in insulin action, most compatible with a defect in cellular biologic response to insulin. The possibility that this abnormality is secondary to insulin deficiency is raised.
A Radioimmunoassay for Circulating Human Proinsulin
Authors: Cohen Robert M , Nakabayashi Tomio , Blix Petra M , Rue Paul A , Shoelson Steven E , Root Mary A , Frank Bruce H , Revers Robert R , Rubenstein Arthur H 
Published: September 2013

A radioimmunoassay for human proinsulin (hPI) has been developed using biosynthetic hPI prepared by recombinant DNA technology as immunogen, standard, and tracer. The antiserum was raised in a guinea pig and then adsorbed against insulin and C-peptide conjugated to Sepharose to improve its specificity. After adsorption of the antiserum, the cross-reactivities to insulin and C-peptide were each &lt;0.2%. Competition studies using in vitro enzymatically split forms of proinsulin demonstrated that the major antigenic determinant recognized was the junctional region between the B-chain of insulin and the C-peptide. The range of the assay extended from 10 to 150 fmol/tube, with a 50% displacement of 45–55 fmol/tube. This sensitivity proved suitable for measurements of serum hPI concentrations during infusion of biosynthetic hPI into normal subjects and type I diabetic subjects. Eightyfive of 89 serum samples from the normal subjects and each of 20 samples from diabetic subjects diluted in parallel with the hPI standard.
Since the direct assay sensitivity was not sufficient for measurement of endogenous hPI levels, a simple procedure for quantitative extraction of proinsulin-like material (PLM) from up to 40 ml of plasma on insulin antibody-Sepharose columns was developed. Log it-log slopes were calculated for dilutions of extracts of samples collected in the fasting state and 60 min after 75 g of oral glucose from eight healthy subjects. The slopes of 15 of the 16 samples did not differ significantly from the slope of the hPI standard. The fasting PLM concentration was 5.8 ± 3.0 fmol/ml (mean ± S.D, N = 8) and rose to 22.5 ± 6.7 fmol/ml (N = 6) 60 min after a 75-g oral glucose load. This assay will be useful in characterizing the metabolism and metabolic effects of biosynthetic human proinsulin and its intermediate forms and determining their therapeutic potential, and for measuring endogenous PLM in extracted plasma samples.
Platelet Function During Continuous Insulin Infusion Treatment in Insulin-dependent Diabetic Patients
Authors: Mayfield Ronald K , Halushka Perry V , Wohltmann Hulda J , Lopes-Virella Maria , Chambers Jerre K , Loadholt Claude B , Colwell John A 
Published: September 2013

Patients with diabetes mellitus manifest increased in vitro platelet aggregation andincreased synthesis of the proaggregant and vasoconstrictor, thromboxane A2 (TXA2). We studied the effects of continuous insulin infusion treatment on platelet aggregation and arachidonic acid (AA)-stimulated platelet TXA2 synthesis (15 and 30 s post-AA, 1 mM) in 16 type I diabetic patients. Strict glycemic control was induced with the Biostator for 2 days and maintained for 12–14 days with continuous subcutaneous insulin infusion (CSII). The average premeal plasma glucose level (4/day) fell from 184 ± 15, before treatment, to 107 ± 6 mg/dl on the final day (P &lt; 0.001). After control, platelet synthesis of TXA2, measured by radioimmunoassay of its stable metabolite, immunoreactive TXB2 (iTXB2), decreased in all patients (30 s: 276 ± 31 versus 199 ± 28ng iTXB2/ml/ 5 × 105 platelets; P &lt; 0.05). The reductionin platelet iTXB2 synthesis (15 and 30 s) was greater in poorly controlled patients (HbA1c&gt;12%; N = 8), and for all patients the decrease in iTXB2 (15 and 30 s) was correlated with the prestudy HbA1c level (15 s: r = 0.6; P &lt; 0.01).
In contrast, platelet aggregation responses did not improve during intensive insulin treatment. The ED50 for AA (dose producing 50% maximum aggregation at 1 min) was unchanged after 2 wk of treatment and the ED50 for aggregation induced by ADP fell significantly inpatients with HbA1c 12% (2.8 ± 1.3 versus 1.2 ± 0.6 μM; P &lt; 0.01). Other factors that were associated in this study with platelet aggregation responses were plasma lipoprotein levels and microvascular disease. In all patients before treatment, the ED50 for AA was inversely correlated with the LDL-cholesterol level(r = 0.57; P &lt; 0.01). Although platelet aggregation did not improve during the period of intensive treatment, when the relations of microvascular disease and glycemic control to platelet aggregation were analyzed together in all patients, the ED50 for AA was greatest (P &lt; 0.02) in thosepatients without microvascular disease and HbA1c &lt;12%, indicating less platelet aggregability.
Thus, a brief period of CSII treatment reduced AA-stimulated platelet iTXB2 generation; however, the effects of this treatment on platelet aggregation appear to be complex and other extraplatelet factors also seem to influence the aggregation response.
Fingerprint Analysis of Insulin and Proinsulins
Authors: Grau Ulrich 
Published: September 2013

Proteolysis of insulin or (pre)proinsulin with S. aureus protease V8 in Tris buffer at neutral pH yields a characteristic pattern of peptide fragments that is resolved using high-performance liquid chromatography. Identification of the fragments of interest was achieved by comparison of insulins of different species, of modified insulins and of proinsulin and N-extended proinsulin, and by amino acid analysis.
The fingerprint method allows, for example, the simultaneous analysis of porcine and human insulin, the identification of a modified insulin generated in dosing devices, as well as the individual analysis of the two disulfide linkages between the A- and B-chain in refolded insulins.