bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucagon Immunoreactivity and Chromatographic Profiles in Pancreatectomized Humans: Paradoxical Response to Oral Glucose
Authors: Bajorunas D R , Fortner J G , Jaspan J B 
Published: September 2013

The nature and origin of plasma immunoreactive glucagon (IRG) after pancreatectomy in humans remains controversial. Low plasma IRG levels and heterogeneity hamper accurate assessment. We studied plasma IRG levels and profiles in 12 patients 2–57 mo after a total pancreatectomy (with antrectomy and duodenectomy) for cancer (N = 9) or chronic pancreatitis (N = 3).
After oral glucose, plasma IRG (with the COOH-terminal-specific 30K glucagon antibody) rose from 59 ± 7 to a peak of 113 ± 17 pg/ml at 60–120 min. Chromatographie profiles revealed four distinct IRG fractions. In every patient a plasma IRG fraction of 9000–15,000 Mr, detectable basally, increased markedly after oral glucose and accounted for the rise in total IRG observed in plasma. Nine of the 12 pancreatectomized subjects had no detectable 3500-Mr glucagon and the remaining 3 had very low levels. For the group as a whole, 3500-Mr IRG comprised 1–2% of the total recovered IRG. Two patients were also studied before pancreatectomy: sup-pressibility of glucagon (Mr 3500) was evident. After surgery this paradoxical response to oral glucose was demonstrated. Reproducibility of these responses was confirmed in two patients studied twice over 2 yr. Diabetic controls without pancreatectomy did not show this response.
The absence or marked reduction of pancreatic glucagon was confirmed in five of the pancreatectomized patients after intravenous arginine or oral protein. Normal basal plasma IRG and profiles, oral glucose sup-pressibility, and arginine stimulation were present in five control patients with unresectable pancreatic malignancies.
These findings suggest that in the chronic 3500-Mr IRG deficient state, a glucagon-related peptide arising from the gut is demonstrable by a paradoxical response to oral glucose. It is speculated that this IRG fraction might be a glucagon precursor.
Effect of Stress Hormones on Splanchnic Substrate and Insulin Disposal After Glucose Ingestion in Healthy Humans
Authors: Waldhäusl Werner K , Gasic Slobodan , Bratusch-Marrain Paul , Komjati Martin , Korn Adrienne 
Published: September 2013

To compare cortisol and epinephrine action on oral glucose tolerance, healthy humanswere infused with either cortisol (0.1 mg · kg−1 · h−1), epinephrine (5.4 μg · kg−1 · h−1), or saline before and aftera 75-g glucoseload, thereby elevating the respective plasma hormone concentrations into the pathophysiologic range. In the basal state, epinephrine increased arterial concentrations of glucose, β-hydroxybutyrate, and free fatty acids (FFA) as well as splanchnic output of glucose and β-hydroxybutyrate and splanchnic FFA more than cortisol. Postprandially, C-peptide release and hyperinsulinemia were blunted by epinephrine initially and increased less thereafter than during cortisol infusion. The rise in arterial glucose after glucose ingestion as calculated by the area under the curve was more marked (P &lt; .01) after epinephrine [(1.90 ± 0.08 M)150 min] and cortisol [(1.41 ± 0.05 M)150 min] than in the control study [(1.07 ± 0.04 M)150 min]. In parallel, the stress hormones induced an almost identical 24 and 31% rise in mean splanchnic glucose output versus control values (normal, 44.8 ± 2.5; cortisol, 55.3 ± 3.3; epinephrine, 58.9 ± 6.9 g/150 min). The associated rise in arterial concentrations and splanchnic output of insulin above control values was considerably greater during cortisol but unchanged during epinephrine exposure. Epinephrine but not cortisol induced a rise versus the control study in splanchnic uptake of lactate and FFA, as well as in pyruvate output, whereas plasma β-hydroxybutyrate and acetoacetate remained unchanged. The postprandial splanchnic glucose output-to-splanchnic C-peptide output ratio did not differ from normal during epinephrine but was reduced (P &lt; .01) during cortisol administration. Hepatic insulin uptake was proportionate to insulin production rate, whereas hepatic insulin clearance was unaffected by stress hormone action.
We conclude that besides inhibiting adequate insulin release to hyperglycemia, acute epinephrine exposure induces peripheral insulin resistance and increased splanchnic glucose output and lactate uptake. Such insulin resistance seems to be unveiled by normal but inappropriately low postprandial insulin release during epinephrine-induced basal and postprandial hyperglycemia but is partly disguised by secondary hyperinsulinemia after cortisol infusion.
Growth Hormone Regulation of Somatomedin C/Insulin-Like Growth Factor I Production and DNA Replication in Fetal Rat Islets in Tissue Culture
Authors: Swenne I , Hill D J , Strain A J , Milner R D G 
Published: September 2013

The regulation of DNA replication by growth hormone and the production of somatomedin C/insulin-like growth factor I (SM-C/IGF-I) and insulin by fetal rat islets in culture has been studied. Islets were cultured for 3 days in medium containing 2.7 or 16.7 mM glucose, various concentrations of fetal calf serum (FCS), and 100-1000 ng/ml human growth hormone (GH). DNA replication was determined by incorporation of [3H]thymidine into islet DNA; SM-C/IGF-I and insulin secreted into the medium were measured by specific radioimmunoassays.
Glucose caused a twofold stimulation of islet DNA replication in medium containing ≥ 1% FCS but failed to stimulate DNA replication at lower serum concentrations. In the presence of 16.7 mM glucose, GH (100–1000 ng/ml) stimulated DNA replication at all serum concentrations. In medium containing 2.7 mM glucose, GH was stimulatory only in the presence of 1% FCS.
Somatomedin C/IGF-I release into the culture medium could be detected in all experimental groups. Glucose alone did not affect SM-C/IGF-I release, and in serum concentrations &lt;0.1% FCS, GH also failed to increase the release of the peptide. In medium containing 1% FCS and 16.7 mM glucose, 100–1000 ng/ml GH caused a 50-100% increase in SM-C/IGF-I release into the medium.
Addition of 100 ng/ml exogenous SM-C/IGF-I to medium containing 16.7 mM glucose and 0.1–1.0% FCS caused a twofold stimulation of the islet DNA replication. This effect could be abolished by the addition of an antibody to SM-C/IGF-I. This antibody also significantly reduced GH-stimulated DNA replication, although some stimulation remained in its presence.
Glucose stimulated insulin secretion at all serum concentrations. However, with &lt; 1% FCS in the medium, insulin secretion was markedly reduced and could not be stimulated by the addition of GH. In medium containing 1% FCS and 16.7 mM glucose, 1000 ng/ml GH augmented insulin release almost twofold. We conclude that GH, but not glucose, can stimulate islet cell DNA replication by inducing the local production of SM-C/IGF-I. Apparently, however, part of the stimulation of DNA replication by GH is independent of SM-C/IGF-I and may be related to a direct effect of GH on the islets. Whether the insulin production is augmented via the mediation of somatomedins or by a direct effect of GH remains to be resolved.
Studies on Macromolecular Components of Human Glomerular Basement Membrane and Alterations in Diabetes: Decreased Levels of Heparan Sulfate Proteoglycan and Laminin
Authors: Shimomura Hiroyuki , Spiro Robert G 
Published: September 2013

Treatment of human glomerular basement membrane (GBM) with 4 M guanidine HCI resulted in a preferential extraction of noncollagenous components including laminin, fibronectin, entactin, and heparan sulfate proteoglycan, whereas effective solubilization of type IV collagen required exposure to denaturing solvents in the presence of reducing agents. The guanidine HCI–solubilized constituents were identified by immunochemical procedures after resolution by polyacrylamide gel electrophoresis, CL-6B filtration, and DEAE-cellulose chromatography. Two immunologically related heparan sulfate proteoglycans (Mr ∼350,000 and 210,000) were observed by electrophoresis, with the higher-molecular-weight form being predominant. An examination of the two proteoglycans after heparitinase digestion or chemical deglycosylation indicated that heparan sulfate chains and other carbohydrate units are attached to core proteins with Mr ∼140,000 and 110,000, respectively.
Radioimmunoassays indicated that human diabetic GBM contained significantly lower (P &lt; .005) amounts of heparan sulfate proteoglycan and laminin with average values that were 30 and 60%, respectively, of nondiabetic controls; the fibronectin content of the diabetic GBM, however, was not significantly different from the normal. These findings, together with previous studies showing increases in GBM collagen, indicate that an alteration in the macromolecular architecture of this basement membrane occurs in diabetes that may be responsible for the filtration defect and the ultimate glomerular occlusion.
Substance P and Somatostatin Content and Transport in Vagus and Sciatic Nerves of the Streptozocin-Induced Diabetic Rat
Authors: MacLean David B 
Published: September 2013

Substance P (SP) and somatostatin (SS) are two widely distributed neuropeptides that within the vagus and sciatic nerves are localized predominantly in sensory fibers. The effect of diabetes mellitus on their content or transport in sensory nerves is unknown. With the nerve ligation technique, the peripheral orthograde 24- h transport of both peptides was quantified in the vagus nerve 3 days or 1 mo after induction of streptozocin (STZ) diabetes and in both the vagus and sciatic nerves after diabetes of 3 mo duration. In acute (3-day) diabetics, neuropeptide transport in the vagus was unaltered. After 1 mo, SP transport was significantly increased; content in unligated contralateral nerve was unaltered. Transport of SS was unchanged, and content in contralateral nerve was too low to reliably quantitate. After diabetes of 3-mo duration, transport of both peptides in the vagus nerve was increased in STZ-induced diabetic (STZ-D) rats versus both weightand age-matched controls: SP 474 ± 17 (N = 10) vs. 358 ± 32 (N = 13) pg/24 h, STZ-D rats vs. controls, mean ± SE, P &lt; .03; SS 29 ± 4 vs. 20 ± 3 pg/24 h, STZ-D rats vs. controls, P &lt; .02. In the sciatic nerve, SP transport and content were unaltered. SS content was significantly reduced: 17 ± 3 vs. 30 ± 3 pg/3-mm nerve segment, STZ-D rats vs. controls, P &lt; .01. SS transport in the sciatic nerve of diabetic rats was variably reduced (P &lt; .07), and transport rates were increased (1.41 ± 0.13 vs. 0.96 ±0.10 mm/h, STZ-D rats vs. controls, P = .06), suggesting increased SS turnover within diabetic nerves.
This study indicates that the diabetic state has little short-term adverse effect on neuropeptide synthesis and transport within sensory nerves. Decreased SS content in the sciatic nerve may be a useful marker of early diabetic neuropathy.
Impaired Insulin Secretion Associated With Near Normoglycemia: Study in Normal Rats With 96-h In Vivo Glucose Infusions
Authors: Leahy John L , Cooper Henrietta E , Weir Gordon C 
Published: September 2013

We have previously demonstrated impaired glucose influence on insulin secretion in normal rats made overtly hyperglycemic with glucose infusions for 48 h. We examined the effects of a 96-h infusion period. Rats received 30, 35, or 50% glucose or 0.45% NaCI at 2 ml/h. The plasma glucose in the 30 and 35% rats peaked at 24 h but then returned to normal by 72 h. A peak followed by a gradual fall also occurred in the 50% rats, but significant hyperglycemia was maintained throughout. β-Cell responsiveness to glucose was assessed with the perfused pancreas by examining the effect of altering the perfusate glucose concentration on insulin release. Insulin secretion remained intact in the 30% rats, but the response to a glucose increase was blunted in the 35% group and totally absent in the 50% rats. In a second protocol, glucose influence on arginine-stimulated insulin release was tested by adding 10 mM arginine to the perfusate and administering it with 2.8 and 16.7 mM glucose. The ability of the different glucose backgrounds to influence the insulin response decreased as the level of infused glucose rose. On the other hand, when phloridzin was added to 50% glucose during the second 48 h of infusion, glucose modulation of insulin release was completely restored.
These data indicate that during a period of overt hyperglycemia, β-cell defects can fully evolve within 48 h in the rat. Thereafter, they are maintained by the glucose infusion even though the plasma glucose level returns to near normal. Continued minor stimulation of the β-cell may be the responsible factor.
Mechanism of Metformin Action in Non-Insulin-Dependent Diabetes
Authors: Jackson Rodwin A , Hawa Mohammed I , Jaspan Jonathan B , Sim Bushra M , DiSilvio Luciana , Featherbe David , Kurtz Antony B 
Published: September 2013

The mechanism of action of metformin was studied by comparing glucose turnover before and after a 75-g oral glucose load in 10 nonobese men with noninsulin-dependent diabetes mellitus (NIDDM) during metformin and placebo therapy by the combined application of the forearm and double-isotope techniques. During the study, 9 of the 10 patients were regularly receiving glibenclamide therapy. In 5 of the men, the first study was performed during metformin therapy, and the second study was done during placebo administration; in the other 5 subjects, the order was reversed. The interval between the studies was at least 3 mo. The metformin dosage was 1 g twice daily in 9 of the patients and 850 mg thrice daily in the 10th subject. In the basal state, metformin administration reduced plasma glucose levels from 172 ± 14 to 103 ± 9 mg/dl (P &lt; .005), hepatic glucose output (HGO) from 2.67 ± 0.15 to 2.20 ± 0.20 mg · kg−1 · min−1 (P &lt; .02), and forearm glucose uptake (FGU) from 0.106 ± 0.18 to 0.039 ± 0.016 mg · 100 ml−1 forearm · min−1 (P &lt; .005), whereas insulin (23 ± 6 μU ml) and lactate (1.56 ± 0.18 mM) levels were unchanged. Although the oral glucose tolerance curve (OGTC) was significantly lowered by metformin, the incremental area under the curve and the insulin response were unchanged. The systemic appearance of ingested glucose was unaffected by metformin; 64 ± 2% of the load was recovered peripherally in 3 h. The rise in FGU and total glucose disappearance in 3 h after glucose loading was unaffected by metformin. From 0 to 180 min after glucose loading, HGO was suppressed by 45.3 and 44.5% of the corresponding basal value without and with metformin treatment, respectively. Peak lactate levels were noted 90 min after glucose loading and were increased during metformin treatment from 2.10 ± 0.23 to 2.92 ± 0.32 mM (P &lt; .05).
We conclude that 1) metformin markedly lowers the OGTC in NIDDM; 2) lowering of the OGTC is due entirely to a fall in the basal glucose concentration; and 3) because fasting insulin levels were unchanged, the reduction in basal HGO and fasting glucose concentrations by metformin is the result of a druginduced increase in hepatic insulin sensitivity.
Estimation of Endogenous Glucose Production During Hyperinsulinemic-Euglycemic Glucose Clamps: Comparison of Unlabeled and Labeled Exogenous Glucose Infusates
Authors: Finegood Diane T , Bergman Richard N , Vranic Mladen 
Published: September 2013

Tracer methodology has been applied extensively to the estimation of endogenous glucose production (Ra) during euglycemic glucose clamps. The accuracy of this approach has been questioned due to the observation of significantly negative estimates for Ra when insulin levels are high. We performed hyperinsulinemic (300 μU/ml)-euglycemic glucose clamps for 180 min in normal dogs and compared the standard approach, an unlabeled exogenous glucose infusate (cold GINF protocol, n = 12), to a new approach in which a tracer (D-[3-3H]glucose) was added to the exogenous glucose used for clamping (hot GINF protocol, n = 10). Plasma glucose, insulin and glucagon concentrations, and glucose infusion rates were similar for the two protocols. Plasma glucose specific activity was 20 ± 1% of basal (at 120–180 min) in the cold GINF studies, and 44 ± 3 to 187 ± 5% of basal in the hot GINF studies. With the one-compartment, fixed pool volume model of Steele, Ra, for the cold GINF studies was –2.4 ± 0.7 mg · min−1 · kg−1 at 25 min and remained significantly negative until 110 min (P &lt; .05). For the hot GINF studies, Ra was never significantly less than zero (P &gt; .05) and was greater than in the cold GINF studies at 20–90 min (P &lt; .05). There was substantially less between-(78%) and within- (40%) experiment variation for the hot GINF studies compared with the cold GINF studies. An alternate approach (regression method) to the application of the one-compartment model, which allows for a variable and estimable effective distribution volume, yielded Ra estimates that were suppressed 60–100% from basal.
In conclusion, the one-compartment, fixed pool volume model of glucose kinetics is inadequate for the estimation of Ra during euglycemic glucose clamps. Two new strategies for estimating Ra from the one-compartment model, the hot GINF protocol and the regression method calculation, yielded more accurate and physiologically plausible estimates of Ra than currently used methodology.
Interleukin 1 is Potent Modulator of Insulin Secretion from Isolated Rat Islets of Langerhans
Authors: Comens Patricia G , Wolf Bryan A , Unanue Emil R , Lacy Paul E , McDaniel Michael L 
Published: September 2013

The effects of interleukin 1 (IL-1) on glucose-induced insulin secretion from isolated rat islets of Langerhans have been examined. IL-1 both inhibits and stimulates glucose-induced insulin secretion depending on the experimental design. Inhibition of glucose-induoed insulin secretion was observed after a 15-h treatment of islets with either purified IL-1, murine recombinant IL-1 (rIL-1), or human rIL-1. r IL-1 inhibition of glucose-induced insulin secretion was dose dependent with half-maximal inhibition observed at 25 pM human r IL-1. Basal insulin secretion was not affected by r IL-1 treatment. Mannose- and leucine-induced insulin secretion was also inhibited by a 15-h treatment with human rIL-1.
Islets treated 15 h with inhibitory concentrations of murine IL-1 were morphologically intact, well granulated, and retained normal concentrations of insulin compared with control islets. Furthermore, human rIL-1 treatment did not affect the islet plasma membrane permeability as assessed by the measurement of the islet intracellular volume. Finally, the viability of islets treated 15 h with murine rIL-1 was demonstrated by the observation that the inhibitory effects of murine rIL-1 on glucose-induced insulin secretion were reversible.
In addition to the inhibitory effects of IL-1 on glucose-induced insulin secretion, purified IL-1 and human rIL-1 had stimulatory effects on glucose-induced insulin secretion under the following conditions: 1) a 90-min incubation with purified IL-1 (10% vol/vol) or in the presence of human r IL-1 (1400 pM) or 2) a 15-h incubation with relatively low concentrations of human rIL-1 (0.5 or 5 pM). In conclusion, IL-1 has complex dual effects on glucose-induced insulin secretion that include both stimulation and inhibition and depend on IL-1 concentration and time of incubation. These studies suggest that IL-1 may have a physiological role as a potent modulator of insulin secretion by islets of Langerhans.
Immunochemical Studies on the Insulin-degrading Enzyme from Pig and Rat Skeletal Muscle
Authors: Yokono Koichi , Imamura Yoshimichi , Shii Kozui , Mizuno Nobuhiko , Sakai Hideyo , Baba Shigeaki 
Published: September 2013

Insulin-degrading enzyme (IDE), which proteolytically degraded insulin with a high degree of specificity, was purified from pig skeletal muscle by ammonium sulfate precipitation, chromatography on Bio-Gel P-200 and DEAE-cellulose, and finally rechromatography on Sephadex G-200 (rechromatography fraction). The enzyme was also purified by affinity chromatography (affinity fraction). Both fractions migrated as a single component at the same position on polyacrylamidegel disc electrophoresis. Antiserum against pig muscle IDE was obtained by immunization of rabbits using the rechromatography fraction. By means of antiserum, it was shown that pig muscle IDE (affinity fraction), rat muscle cytosol-, and membrane-IDE gave a precipitin band of identity in Ouchterlony double-immunodiffusion systems. Quantitative immunoprecipitin data demonstrated that the antiserum inhibited the activities of the above three IDEs compared with normal rabbit serum. These data suggest that the insulindegrading enzyme from porcine muscle and that from rat muscle have similar immunologic properties.
The antiserum described here should be a useful tool for the examination of subcellular distribution and the quantitative analysis of insulin-degrading enzyme. It may also be helpful in determining the physiologic Significance Of IDE.
Islet Electrical Pacemaker Response to Alpha-Adrenergic Stimulation
Authors: Cook Daniel L , Perara Eve 
Published: September 2013

To characterize the pancreatic islet cell response to adrenergic stimulation, membrane potentials have been recorded from isolated, perifused mouse islets of Langerhans exposed to a steady glucose level of 200 mg/dl. Various doses of epinephrine HCI from 5 to 10,000 nM have been applied for 10-15-min test periods separated by 10-15-min control periods. Epinephrine produced a dose-dependent suppression of glucose-induced membrane electrical activity. Adding epinephrine (50-100 nM) reduced the plateau fraction (the fraction of each plateau/silent phase cycle spent in the plateau phase) from 0.41 ± 0.03 (x¯ ± SEM, N = 13) to 0.28 ± 0.08 (n = 5, P = 0.05) and more markedly reduced the plateau frequency from 2.56 ± 0.32 (n = 13) to 0.80 ± 0.23 min−1 (n = 5, P &lt; 0.02). Adding 10- and 100-fold higher concentrations of epinephrine had little additional effect, indicating saturation of the epinephrine effect. There was no effect of epinephrine on the membrane potential levels of the plateau and silent phase after a new steady state was achieved and no effect on the amplitude and waveform of the rapid spikes.
The pattern of inhibition of the plateau/silent phase cycles by epinephrine is qualitatively different from the pattern seen during inhibition of electrical activity by reducing glucose level. This suggests that the electrical rhythm is controlled by more than one pathway. The persistence of electrical activity at very high levels of epinephrine (to 10,000 nM) suggests that electrical activity and, therefore, Ca2+ uptake can exist in the absence of insulin release.