bluuebunny/crossref_metadata_2025_split huggingface dataset:
Basal Glucagon Replacement in Chronic Glucagon Deficiency Increases Insulin Resistance
Authors: Bajorunas Daiva R , Dresler Carolyn M , Horowitz Glenn D , McDermott Katherine , Jeevanandam Malayapa , Fortner Joseph G , Brennan Murray F 
Published: September 2013

To evaluate the role of glucagon in insulin-mediated glucose metabolism, we studied four men and four women, ranging in age from 30–73 yr (mean ± SEM, 54 ± 5) who had undergone complete pancreatic resection for cancer or chronic pancreatitis 16–58 mo previously. The patients had undetectable C-peptide levels and established lack of biologically active 3500 mol wt glucagon. Euglycemic insulin clamp studies were performed with a 40 mU · m−2 · min−1 insulin infusion in the basal, post-absorptive, insulin-withdrawn state, before and during the last 3 h of a 72-h glucagon replacement-dose infusion (1.25 ng · kg−1 · min−1). In four patients, hepatic glucose production was determined by a primed-constant infusion of 3-[3H]glucose. Monocyte insulin-binding studies, pre- and postglucagon, were performed in all patients.
The 72-h glucagon infusion, resulting in mean plasma glucagon levels of 124 ± 7 pg/ml, caused a significant rise in the mean plasma glucose level (249 ± 8 versus 170 ± 13 mg/dl preglucagon) and a sixfold increase in mean 24-h glucose excretion. Both with and without glucagon, euglycemic hyperinsulinemia achieved identical and complete suppression of hepatic glucose production. The mean glucose utilization rate (4.70 ± 0.36 mg · kg−1 · min−1 preglucagon) was significantly decreased by glucagon replacement (3.83 ± 0.31 mg · kg−1 · min−1 P &lt; 0.02). Mean glucose clearance was also diminished with glucagon (4.49 ± 0.32 versus 5.73 ± 0.45 ml · kg−1 · min−1 preglucagon, P &lt; 0.02). After glucagon administration, no significant change in the percent specific binding of insulin to monocytes could be demonstrated. These data support a role of physiologic concentrations of glucagon in the modulation of peripheral tissue glucose utilization.
Impaired Insulin Receptor Binding and Postbinding Defects of Adipocytes From Normal and Diabetic Pregnant Women
Authors: Hjøllund Elisabeth , Pedersen Oluf , Espersen Thorkil , Klebe Joachim G 
Published: September 2013

To evaluate the relative contribution of insulin binding and postbinding defects of glucose utilization in peripheral tissue during normal and diabetic pregnancy, we have studied the in vitro insulin action of isolated adipocytes from eight nondiabetic pregnant women and nine pregnant women with insulin-dependent diabetes mellitus who were undergoing cesarian section. The pregnant women were compared with a matched group of normal nonpregnant women undergoing gynecologic surgery. Insulin binding to adipocytes measured at tracer insulin concentration was reduced by 45% (P &lt; 0.01) in normal pregnant women and by 30% (P &lt; 0.02) in pregnant women with diabetes. In contrast, no changes were found between the three groups in insulin binding to pure monocytes and erythrocytes.
The glucose transport system in fat cells from both groups of pregnant women was characterized by impaired maximal (P &lt; 0.05) and half-maximal (P &lt; 0.05) response to insulin. When fat cell glucose metabolism was studied, pregnant diabetic women exhibited decreased basal lipogenesis (P &lt; 0.05) and decreased maximal responses of lipogenesis and glucose oxidation to insulin stimulation (P &lt; 0.05). Similar but less pronounced abnormalities were seen in glucose metabolism of adipocytes from nondiabetic pregnant women.
In conclusion, both in late normal and diabetic pregnancy, insulin binding to adipocytes is significantly reduced and accompanied by decreased insulin sensitivity and reduced maximal insulin responsiveness of glucose transport and by impaired basal and maximally insulin-stimulated glucose metabolism.
Islet Secretory Granules Contain Cytochrome b561
Authors: Mackin R B , Jones D P , Noe B D 
Published: September 2013

A cytochrome has been detected in secretory granules prepared from anglerfish islets of Langerhans. The heme moiety was determined to be of the b type, and the dithionite-reduced cytochrome exhibited an α-band maximum at 561 nm with an extinction coefficient of 13.8 mM−1 · cm−1. The protein was present at a concentration of 40 ± 4 pmol/mg of secretory granule protein. The cytochrome was found to be an integral membrane protein and to be reduced by ascorbic acid but not by NADH, NADPH, reduced glutathione (GSH), or succinate.
Because of the similarity to previously characterized secretory granule cytochrome b561's from neuroendocrine tissues, this cytochrome is also referred to as cytochrome b561. Although its function has not yet been elucidated, the apparent specificity for ascorbate suggests that it may be a component of the ascorbate-de-pendent peptidyl-glycine α-amidating monooxygenase system that functions in the amidation of islet hormones.
Differential Activities of Tolbutamide, Tolazamide, and Glyburide In Vitro on Rabbit Myocardial Membrane Ca2+-Transporting ATPase Activity
Authors: Warnick P R , Davis F B , Davis P J , Mylotte K M , Blas S D 
Published: September 2013

At clinically achievable concentrations (10−9 to 5 × 10−6 M), tolbutamide and tolazamide are in vitro inhibitors of Ca2+-transporting ATPase activity in sarcolemma-enriched rabbit myocardial membranes (sulfonylurea ICM, 10−7 M). Thyroid hormone stimulation of this calcium pump-associated enzyme in vitro has been previously reported;5 in our study, this hormonal action was shown to be inhibited by tolbutamide and tolazamide. In contrast to these two sulfonylureas, glyburide (up to 5 × 10−6 M) had no effect on basal or thyroid hormone-stimulable Ca2+-ATPase activity in vitro. Studies of binding of radiolabeled purified calmodulin to heart membranes showed that tolbutamide and tolazamide inhibited this interaction, whereas glyburide had no effect on calmodulin binding. Addition of purified calmodulin (5–40 ng/μg membrane protein) to myocardial membranes incubated with 10−7 M tolbutamide or tolazamide restored Ca2+-ATPase activity and thyroid hormone responsiveness of the enzyme.
Inhibition by tolbutamide and tolazamide of myocardial sarcolemmal Ca2+-ATPase is a mechanism by which these two sulfonylureas may at least transiently raise resting sarcoplasmic Ca2+ concentration. This effect of sulfonylureas on Ca2+-ATPase is not expressed in the presence of the benzamide side chain of glyburide. The inhibitory action of certain sulfonylureas on Ca2+-ATPase is mediated by interference of the agents with the binding of calmodulin to cardiac membranes.
Enhanced Peripheral and Splanchnic Insulin Sensitivity in NIDDM Men After Single Bout of Exercise
Authors: Devlin John T , Hirshman Michael , Horton Elizabeth D , Horton Edward S 
Published: September 2013

We studied glucose metabolism in non-insulin-dependent diabetic (NIDDM) men with and without glycogendepleting cycle exercise 12 h beforehand and have compared the results to our previous data in lean and obese subjects. Rates of total glucose utilization, glucose oxidation, nonoxidative glucose disposal (NOGD), glucose metabolic clearance rate (MCR), and endogenous glucose production (EGP) were determined with a “two-level” insulin-clamp technique (100-min infusions at 40 and 400 mU · m−2 · min−1) combined with indirect calorimetry and D-3-[3H]glucose infusion. Muscle biopsy specimens from vastus lateralis were analyzed for glycogen content and glycogen synthase activity before and after insulin infusions.
After exercise, NIDDM subjects had muscle glycogen concentrations comparable with those of lean and obese subjects. The activation of glycogen synthase both by prior exercise and insulin infusion was similar to lean controls. After exercise, total glucose disposal was significantly increased during the 40-mU · m−2 · min−1 infusion (P &lt; .05), but the increase observed during the 400-mU · m−2 · min−1 infusion was not significant. These increases after exercise were the result of significantly higher NOGD duringboth levels of insulin infusion. The MCR of glucose during both insulin infusions was reduced in NIDDM compared with lean subjects but was very similar to that in obese nondiabetics. Basal EGP was significantly reduced on the morning after exercise (4.03 ± 0.27 vs. 3.21 ± 0.21 mg · kg−1 fat-free mass · min−1) (P &lt; .05) and associated with significant reductions of fasting plasma glucose (197 ± 12 vs. 164 ± 9 mg/dl). Suppression of EGP by the 40-mU · m−2 · min−1 infusion was also greater on the morning after exercise (54 vs. 90% of basal) (P &lt; .05).
This study demonstrates that a single bout of glycogen-depleting exercise significantly increases periph-eral and splanchnic insulin sensitivity 12–16 h later in NIDDM men. Increased peripheral glucose utilization after exercise is the result of increased NOGD, presumably reflecting increased glucose storage as glycogen. Insulin-stimulated rates of glucose oxidation are decreased after exercise. The lower fasting glucose concentration after exercise is due to decreased EGP rather than increased glucose utilization.
Progress Toward Standardization of Cytoplasmic Islet Cell–Antibody Assay
Authors: Gleichmann Helga , Bottazzo Gian Franco 
Published: September 2013

Cytoplasmic islet cell autoantibodies (ICAs) of 13 coded sera were determined by 26 laboratories. ICAs were determined by 24 laboratories according to a standard protocol based on the conventional indirectimmunofluorescence technique on cryostat sections of human pancreas. In addition, these 24 laboratories had performed any of 8 modifications of the assay. Test samples were titrated to end point, and the results obtained with the different methods were compared with those obtained by the standard protocol. The remaining 2 laboratories used either exclusively pancreatic sections of monkey instead of human as substrate (lab 23) or applied immunohistochemical staining (lab 22).
By following the standard protocol, interlaboratory concordance was &gt;90% for the presence or absence of islet cell antibodies in 7 of the 13 samples circulated. However, a wide variability of titers was recorded, ranging from negative to 128.
Of the modifications, prolonged incubation in the presence of aprotinin was performed by 10 laboratories and was found to improve the sensitivity in 57 of 70 (81%) determinations with samples that had been ICA positive by the standard protocol. Improved sensitivity was also noted by 2 laboratories with sections of monkey pancreas. Acetone-fixed sections, used by 6 laboratories, or a two-color immunofluorescence method, applied by 3 laboratories, did not change the titers in 27 of 35 (77%) and 14 of 25 (56%) determinations with samples that had been ICA positive by the standard protocol. In contrast, heat inactivation of the samples before testing, performed by 5 laboratories, resulted in a decrease in titers in 25 of 39 (64%) determinations. Four laboratories used fluorescein-labeled protein A as reagent and observed a decrease in ICA titers in 22 of 27 (81%) determinations. Complement-fixing antibodies were determined by 20 laboratories and were present in 66 of 136 (48%) determinations with ICA-positive samples, and in general, they were associated with high titers of the latter. Three laboratories reported results obtained by immunohistochemical staining with glucose oxidase, and at this stage, the data indicated the requirement of both method improvement and exchange of reference reagents for interlaboratory comparison.
Advanced Diabetic Glomerulopathy: Quantitative Structural Characterization of Nonoccluded Glomeruli
Authors: Østerby Ruth , Gundersen Hans Jørgen G , Nyberg Gudrun , Aurell Mattias 
Published: September 2013

Quantitative ultrastructural data were obtained from kidney biopsy material of 12 long-term insulindependent diabetics. All patients had overt diabetic nephropathy with increased urinary albumin excretion and reduced glomerular filtration rate. Renal clearance of 51Cr-EDTA was in the range of 16-50 ml · min−1 · 1.73 m−2. All patients received antihypertensive treatment.
A combined light- and electron-microscope study was performed. A significant proportion of the glomeruli was totally occluded (mean 36%, range 24-67%). Structural data presented relate only to the open, still-functioning glomeruli. Comparison with data previously obtained showed that 1) the thickness of the peripheral basement membrane [647 nm, coefficient of variation (C.V.) 0.22] was more than twice the normal value (310 nm, C.V. 0.08); 2) the width of epithelial foot processes (352 nm, C.V. 0.07) was significantly greater than in normal biopsies (224 nm, C.V. 0.06); and 3) the mean volume of the open glomeruli was markedly increased compared with normal and clearly exceeded that in the early diabetic hypertrophy. Total mesangial volume and total basement membrane material per open glomerulus were increased by 277 and 614%, respectively. However, capillary length and surface per open glomerulus were similar to those observed in early diabetic hypertrophy. These findings suggest that a late glomerular hypertrophy with preservation of capillary surface occurs as a compensatory phenomenon, prolonging renal survival for diabetic nephropathy patients.
Islet Cytotoxicity of Interleukin 1: Influence of Culture Conditions and Islet Donor Characteristics
Authors: Mandrup-Poulsen Thomas , Spinas Giatgen A , Prowse Stephen J , Hansen Birgit S , Jørgensen Dorte W , Bendtzen Klaus , Nielsen Jens Høiriis , Nerup Jørn 
Published: September 2013

We recently demonstrated that the macrophage product interleukin 1 (IL-1) is cytotoxic to isolated pancreatic islets and hypothesized that IL-1 is responsible for β-cell destruction in insulin-dependent diabetes mellitus (IDDM). We studied whether the variation in IDDM preponderance with age, sex, and genetic background in vivo is reflected in different susceptibility to IL-1 toxicity of islets in vitro. In addition, we studied the effect of preculture conditions that support endocrine islet cell function and decrease nonendocrine passenger-cell survival on the susceptibility of β-cells to IL-1 because it is unknown whether IL-1 acts directly on β-cells or via passenger cells.
No differences in susceptibility to various doses of IL-1-containing mononuclear cell supernatants were found between islets isolated from newborn or adult rats, male or female rats, or rats of four inbred strains, indicating that age, sex, and genetic background do not influence the susceptibility of the β-cell to IL-1. Preculture of islets for 1-7 days in normal atmosphere and preculture of islet clusters in 95% O2 to delete passenger cells did not affect IL-1-mediated cytotoxicity, suggesting that IL-1 acts directly on β-cells. Increasing the glucose concentration (22 mM) in the culture medium, which is known to protect β-cells against alloxan toxicity, reduced IL-1 toxicity. Five or 25% normal human serum as well as 5% normal rat serum, but not equivalent concentrations of human serum albumin, inhibited IL-1 toxicity, indicating the presence of IL-1 inhibitors, IL-1 antagonists, or β-cell-protecting factors in normal serum. The inhibitory action of serum could be counteracted by increasing the dose of IL-1.
Multiple Aspects of Insulin Resistance: Comparison of Glucose and Intermediary Metabolite Response to Incremental Insulin Infusion in IDDM Subjects of Short and Long Duration
Authors: Singh Baldev M , Palma Marion A , Nattrass Malcolm 
Published: September 2013

Glucose and intermediary metabolite responses during incremental insulin infusion (basal, 0.005, 0.01, and 0.05 U · kg−1 · h−1) were examined in IDDM subjects with duration of diabetes of &gt;5 yr (group D5: n = 8, duration 13.5 ± 3.9 yr, mean ± SD) and &lt;1 yr (group D1: n = 8, duration 0.3 ± 0.1 yr) from diagnosis.
Group D5 had significantly elevated basal plasma free-insulin levels (D5 27.4 ± 9.6, D1 15.5 ± 9.4 mU/L; P &lt; .05). Nonetheless, basal blood glucose (D5 13.8 ± 4.8, D1 7.1 ± 1.5 mM; P &lt; .01), plasma nonesterified fatty acid (NEFA) (D5 1.26 ± 0.12, D1 0.89 ± 0.10 mM; P &lt; .01), blood glycerol (D5 0.12 ± 0.05, D1 0.07 ± 0.02 mM; P &lt; .05), and blood ketones (D5 1.25 ± 0.91, D1 0.26 ± 0.20 mM; P &lt; .01) were higher in group D5.
During insulin infusion, group D5 had significantly elevated plasma free-insulin (P &lt; .05) and blood glucose (P &lt; .01) levels. Isotopically determined glucose turnover showed metabolic clearance rates were significantly diminished in group D5 during all insulin infusions, indicating a marked impairment of peripheral glucose metabolism.
In individual subjects the relationship of blood glucose, plasma NEFA, and blood total ketones (log scale) with the simultaneously occurring plasma insulin level (log scale) was linear for each metabolite. At an insulin concentration of 30 mU/L, group D5 had elevated blood glucose (D5 12.4 ± 3.1, D1 4.5 ± 1.0 mM; P &lt; .001), plasma NEFA (D5 0.93 ± 0.26, D1 0.54 ± 0.24 mM; P &lt; .01), and ketone (D5 0.97 ± 0.81, D1 0.07 ± 0.03 mM; P &lt; .02) levels.
The results demonstrate insulin resistance in lipolysis, peripheral glucose metabolism, and possibly hepatic glucose metabolism in long-duration compared with short-duration IDDM.
Kinetics of 65Zinc Uptake and Distribution in Fractions from Cultured Rat Islets of Langerhans
Authors: Figlewicz Dianne P , Formby Bent , Hodgson Alfred T , Schmid Florence G , Grodsky Gerold M 
Published: September 2013

Although large quantities of zinc have been measured in pancreatic islets and correlated with islet B-cell function, potential artifacts in histochemical techniques and theexistence of zinc-free insulin in certain species leave its role in insulin storage and secretion unclear. In this investigation, we examined the kinetics of uptake of 65zinc into isolated rat islets and the distribution of both 65zinc and endogenous islet zinc in islet subfractions. In addition, the chemically formed 65zinc-sodium insulin kinetics ofcomplexes were studied.
Net uptake of 65zinc was slow, being almost linear for the first 4 h and not reaching isotopic equilibrium over the 24 h of culture. Culture of islets in high glucose (25.6 mM) resulted in a diminished net 65zinc uptake and significantly decreased content of both endogenous zinc and insulin when compared with culture in low glucose (5.6 mM). Analysis of 65inc and endogenous zinc distribution in islet subfractions revealed a low percentage of 65zinc and endogenous zinc in the granule-enriched fractions: about 90% of total 65zinc and 80% of endogenous zinc were associated with nongranular fractions. A comparison of the specific activity of the granular fractions with the lighter sucrose fractions revealed a nonequilibration of the 65zinc taken up with the granular zinc pool. Chemical analysis of 65zinc-insulin complexes revealed an almost instantaneous binding of 65zinc to zinc-free insulin. Dissociation of preformed 65zincinsulin complexes was slow, but some dissociation occurred with a loweringof the pH.
We demonstrated that net zinc uptake by cultured islets is a slow phenomenon reducedby a high glucose environment. Although chemical analyses suggest a strong affinity of 65zinc for insulin, only small quantities of 65zinc, as well as endogenous zinc, associated with the granule-enriched fractions, and equilibration of granular 65zinc with islet 65zinc pools did not occur over 24 h. Thus, zinc may be needed in other metabolic processes besides insulin crystallization in the Bcell.
Cell-mediated Immunity in Chronically Diabetic Mice
Authors: Roth Michael D , Barg Michele , Michalski Richard , Arquilla Edward R 
Published: September 2013

A radioisotopic ear assay for delayed hypersensitivity (DH) to 2,4-dinitrofluorobenzene (DNFB) was used to investigate cellular immune function in chronic alloxan- diabetic C57BI/6 mice. The specific migration of 5-(125I)Iodo-2'-deoxyuridine-labeled monocytes to the site of antigenic challenge was employed to quantitatively measure the OH response. Although both normal and diabetic sensitized mice had a significantly greater DH response than nonsensitized controls, the response of diabetic mice was severely attenuated (23% of normal)
The effect of the delayed hypersensitivity response on spleen size was also investigated. In the nonsensitized state the spleens of diabetic mice were approximately 30% smaller than the spleens of normal mice. After sensitization with DNFB, and up to the time of antigenic challenge, the spleens from both diabetic and normal mice increased 2.1-fold in weight. After challenge, however, the diabetic spleen maintained its prechallenged size while the normal spleen increased an additional 30% in weight.
When either sensitized normal or diabetic spleen cells were passively transferred to nonsensitized normal recipient mice, a significant DH response was evoked after challenge with DNFB. This response was of equal magnitude after transfer of either the sensitized diabetic or normal spleen cells. The DH response after the passive transfer of spleencells from either normal or diabetic sensitized donors to diabetic recipients was very markedly attenuated and in fact questionably significant when compared with the nonspecific inflammatory response to DNFB.
These results indicate that an intact population of DNFB-sensitized cells exists in the diabetic, but that an inhibition of T-lymphocyte or monocyte activity is occurring during the secondary challenge. The chronic hypoinsulinemia, hyperglycemia, and catabolic metabolism of the alloxan-diabetic mouse does not qualitatively alter the immune cellular processes associated with primary sensitization but significantly attenuates the secondary response.
Retinal Vascular Reactivity to Norepinephrine and Angiotensin II in Normals and Diabetics
Authors: Rhie F H , Christlieb A R , Sandor T , Gleason R E , Rand L I , Shah S T , Soeldner J S 
Published: September 2013

Retinal arterial vasoconstriction induced by an infusion of angiotensin II or norepinephrine was investigated in eight normal controls (N), nine diabetics without retinopathy (DNR), and 10 diabetics with retinopathy (DR) by color fundus photographs taken before and after the infusions. Image analysis was done by a semiautomated computerized microdensi-tometer using a videoscanner.
Normal controls and diabetics without retinopathy had a significant reduction in diameter compared with diabetics with retinopathy, who failed to constrict arte-rioles in response to either vasopressor. The mechanism of this phenomenon is unclear.
Semiautomated computerized microdensitometry is reproducible and appears to be a sensitive technique to evaluate the vascular reactivity of the retinal vas-CUlature.
Pattern of Histocompatibility (HLA) Antigen Distribution Among Nigerian (West African Black) Diabetics
Authors: Famuyiwa O O , Nwabuebo I E , Abioye A A 
Published: September 2013

The pattern of HLA distribution was studied in 70 Nigerian diabetics. There was no association at all between HLA-B8 and insulin-dependent diabetes mellitus (IDDM). There was an increased frequency of HLA-B15 in all categories of patients: those with onset before 40 yr, those with onset after 40 yr (P &lt; 0.05), those with IDDM (P &lt; 0.05), and those with non-insulin-dependent diabetes mellitus (NIDDM). HLA-B7 was slightly increased in frequency contrary to the findings in Caucasian IDDM. HLA-A10 and HLA-Aw32 were increased in all the groups of patients, while HLA-B17 was higher in those with onset after 40 yr (P &lt; 0.02) and NIDDM (P &lt; 0.02). HLA-Bw35 was decreased in all categories of patients. However, all the observed deviations fell short of statistical significance when correction was made for the number of antigens tested for.
Comparison of the data with those in other black populations revealed that the over-all pattern of HLA distribution in black diabetics is rather disparate and still relatively ill-defined. It is concluded that the pattern of HLA and diabetes association in Nigerian diabetics would appear to be different from that in most other racial groups including North American and South African blacks. There is, however, a need to further study larger numbers of Nigerian diabetics and other black population groups so that a clearer picture may emerge.