bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Human Mononuclear Leukocytes Bearing Receptors for Somatostatin and Glucagon
Authors: Bhathena Sam J , Louie James , Schechter Geraldine P , Redman Robert S , Wahl Larry , Recant Lillian 
Published: September 2013

Mononuclear leukocytes (MNL) were isolated from human blood by Ficoll-Hypaque. These cells were further separated into lymphocyte (L) and monocyte (M) enriched fractions. L contained 99% lymphocytes and M contained 74% monocytes, a threefold enrichment over MNL. Specific binding of somatostatin, glucagon, and insulin was measured in the three fractions. Binding of all three hormones in the M fraction was increased by a factor of 3 compared with MNL and was linear with cell number. Binding of glucagon and insulin to the L fraction was very low while, in contrast, somatostatin binding was substantial and linear with lymphocyte number.
Autoradiography confirmed the binding of glucagon to monocytes and of somatostatin to both monocytes and lymphocytes.
Somatostatin is the first of the peptide hormones shown to bind to both types of circulating mononuclear cells, perhaps complicating quantification of somatostatin binding in disease states in which differential alteration of binding to lymphocytes or monocytes might occur.
Differential Time Course of Glucagon's Effect on Glycogenolysis and Gluconeogenesis in the Conscious Dog
Authors: Cherrington A D , Williams P E , Shulman G I , Lacy W W 
Published: September 2013

The evanescence of glucagon's effect on glucose production (GP) is well documented, but it is unclear (1) whether this response involves both glycogenolysis and gluconeogenesis and (2) whether the liver becomes dependent on the increased glucagon level for the maintenance of a basal supply of glucose. To answer these questions, conscious overnight-fasted dogs were given somatostatin (0.8 μg/kg · min) plus basal intraportal replacement amounts of insulin (273 μU/kg min) and glucagon (0.65 ng/kg · min) for 2 h, after which the rate of glucagon infusion was increased fourfold for 3 h and then returned to basal for 1.5 h. GP was determined using a primed infusion of [3-3H[ glucose, and gluconeogenesis (GNG) was estimatedby determining the conversion rate of alanine and lactate to glucose.
An increase in the plasma glucagon level from 55 to 206 pg/ml resulted in an initial 180% increase in GP, followed by a decline such that after 3 h of hyperglucagonemia GP was increased by only 41%. Contrary to overall GP, gluconeogenesis increased progressively throughout the hyperglucagonemic period, eventually reaching a rate 3 times basal. Restoration of the basal glucagon level (63 pg/ml) caused a marked decline in GP and GNG. In fact, GP fell to a level 29% below the initial control rate and consequently the plasma glucose level fell rapidly. The data suggest that (1) the downregulation of glucagonstimulated GP is attributable to a decline in glycogenolysis and not gluconeogenesis, and (2) following adaptation to the hormone, the liver becomes dependent on the elevated glucagon concentration for the maintenance of basal glucose production.
The Inhibition of Islet Superoxide Dismutase by Diabetogenic Drugs
Authors: Crouch Rosalie K , Gandy Samuel E , Kimsey Gary , Galbraith Richard A , Galbraith Gillian M P , Buse Maria G 
Published: September 2013

The enzyme superoxide dismutase (SOD) is a scavenger of superoxide radicals and protects the integrity of cell membranes. We previously reported that streptozotocin inhibits the SOD activity of erythrocytes and retinae in vivo and in vitro. We now report that the three major diabetogenic drugs, i.e., alloxan, streptozotocin, and Vacor (in order of increasing potency), interact with erythrocyte Cu-Zn SOD in vitro. Maximum inhibition of erythrocyte SOD of man, dog, rat, and cow is 40% and is achieved within 10 min. At submaximal doses the effect of the three drugs is additive. Inhibition induced by streptozotocin, but not by the other two agents, is reversible by dialysis. Alloxan (80 mg/kg), like streptozotocin, also inhibits erythrocyte SOD activity when injected i.v. into rats. Glucose or 3- o-methylglucose does not prevent SOD inhibition by alloxan or streptozotocin in vitro. Injection of glucose before alloxan prevents the development of diabetes, but does not prevent alloxan-lnduced inhibition of erythrocyte SOD.
SOD is present in the islets of Langerhans of rats and dogs, as demonstrated by biochemical assay of isolated islets and by immunofluorescent staining of frozen pancreases. The specific activity of SOD in the islets exceeds that of the exocrine pancreas more than 100-fold. The islet SOD is of the Cu-Zn type, since it is inhibited by KCN, and not by chloroformethanol. The mobility of the islet enzyme on polyacrylamlde disc gel electrophoresis is different from that of erythrocyte SOD. Streptozotocin, alloxan, and Vacor Inhibit the activity of islet SOD in vitro; the rate and magnitude of inhibition is the same as that observed with erythrocyte SOD. The Mn SOD of liver mitochondria is not affected by the diabetogenic drugs. It is suggested that the inhibitory effect of the diabeto- genie drugs on islet cell SOD may contribute to their cytotoxicity, and that changes in the amount or activity of this protective enzyme in β-cells may play a role in determining their vulnerability to noxious agents.
The Cellular Stimuli for the Rejection of Established Islet Allografts
Authors: Zitron Ian M , Ono Junko , Lacy Paul E , Davie Joseph M 
Published: September 2013

Previous work from our laboratory has indicated that the transplantation of pancreatic islets is a feasible approach to the problem of diabetes. A major obstacle to transplantation is presented by passenger leucocytes, which contaminate the preparations and can lead to the prompt rejection of fresh islets. We have extended our previous studies on the rejection of islet allografts by challenging transplanted animals with enriched lymphoid cell populations prepared from animals both syngeneic to the transplanted islets and third party. Rapid and complete rejection was observed when the challenge peritoneal exudate cell population was syngeneic with the transplanted islets; rejection was determined by both functional and histologic criteria. Peritoneal exudate cells from a thirdparty rat strain induced delayed and variable effects upon the function of the transplant. In contrast, splenic T-cells were capable of inducing rejection, regardless of the strain of origin, though the time course of T-cell-induced rejection was slower than that observed by syngeneic peritoneal exudate cells. Finally, splenic B-cells completely failed to induce rejection.
Our data indicate that at least two mechanisms exist by which the rejection of islet allografts may be triggered. The first is a haplotype-specific mechanism initiated by a cell type present at high frequency in peritoneal exudate cells; these are probably macrophages. The second mechanism is initiated by immunocompetent T-cells; this mechanism shows no haplotype specificity. We suggest that both macrophages and T-cells must be considered when devising protocols for the removal of passenger leucocytes from allografts.
Effects of Insulin and Insulin-like Agents on the Glucose Transport System of Cultured Human Fibroblasts
Authors: Berhanu Paulos , Olefsky Jerrold M 
Published: September 2013

We have studied the effects of insulin and insulin-like agents on glucose transport by cultured human fibro-blast monolayers. Initial rates of glucose transport were determined by measurement of 2-deoxy-D-glu-cose uptake. At physiologic concentrations, insulin stimulates 2-deoxy-D-glucose transport (average of 50% over basal) with a half-maximally effective insulin concentration of 3.3 ± 0.9 ng/ml. This effect of insulin is rapid and is half-maximal at 10 min and becomes maximal by about 30 min. Kinetic analyses showed that insulin increased the transport Vmax from 7.4 ± 0.9 nmol/min/106 cells to 11.0 ± 1.5 nmol/min/106 cells and had no effect on the Km value (2.5 ± 0.3 mM). While glucose starvation led to a higher overall rate of 2-deoxy-D-glucose transport, the relative stimulation by insulin was the same as in non-glucose-starved cells. Insulin mimickers [insulin-like growth factor (IGF), anti-insulin receptor antibody, and concanavalin A] also stimulate 2-deoxy-D-glucose transport by human fibroblast monolayers in a dose-dependent manner and the maximal effects of IGF and anti-insulin receptor antibody were the same as that of insulin, while the maximal effect of concanavalin A was only 78% of that of insulin. The maximal effects of either insulin and IGF or insulin and anti-insulin receptor antibody were not additive, suggesting that these agents all act via the same glucose transport effector system in human fibroblasts.
In conclusion, human fibroblasts possess an insulin-sensitive glucose transport system that displays many of the characteristics common to other more well studied transport systems. Thus, cultured human fibroblasts can serve as an important model for physiologic studies of insulin action and glucose transport, and for studies of pathophysiologic abnormalities of these processes in cells obtained from patients with various disease states.
The Degree of Sialylation of ApoC-III Is Altered by Diet
Authors: Patsch Wolfgang , Schonfeld Gustav 
Published: September 2013

ApoC-III, an apolipoprotein that contains from 0 to 3 or more moles of sialic acid per mole of protein, plays important roles in lipoprotein metabolism. A high carbohydrate diet alters the relative proportions of the variously sialylated isoforms of ApoC-III in the plasma VLDL of man and of rat. Hepatic perfusion experiments in the rat indicate that the diet produces its affects on plasma VLDL by altering the hepatic output of ApoC-III. Diet is a relatively long-term stimulus to VLDL secretion. Our aim was to ascertain whether the changes in ApoC-III sialylation patterns could be reproduced by an acute stimulus to increased hepatic VLDL secretion, i.e., the perfusion of rat livers with media containing high levels of free fatty acid (FFA).
Male Sprague-Dawley rats (∼250 g) were fed either Purina rat meal or a high carbohydrate formula for 3 wk. Livers were perfused with Krebs-Ringers bicarbonate, 3% bovine serum albumin containing either no added FFA, or 200 mg of added oleate. ApoB and ApoC-III3 were measured by radioimmunoassay and lipids by enzymatic assays. Lipoproteins were isolated by preparative or zonal ultracentrifugation. The relative proportions of the various isoforms of ApoC-III were quantified by isoelectric focusing. The carbohydrate diet increased the plasma levels of triglycerides and ApoC-III3 ∼ twofold. The diet also increased the proportions of ApoC-III0 relative to total ApoC-III from 33 to 42%, in plasma VLDL (P &lt; 0.02). Perfusates of livers of carbohydrate-fed rats accumulated VLDL-TG and ApoC-III3 at increased rates (93 versus 211, P &lt; 0.001, and 12.7 versus 23.5, P &lt; 0.05, μg/g/h, respectively) and the relative proportions of perfusate VLDL ApoC-lll were altered: ApoC-III0 rose from 37% to 59% and ApoC-III3 fell from 60% to 38% (P &lt; 0.02 for each). Perfusion of livers of control (meal-fed) animals with 200 mg oleate yielded twofold increases in the rates of accumulation of VLDL-TG over meal fed non-FFA perfused controls and changes in gross VLDL composition that resembled those produced by carbohydrate feeding, but ApoC-III3 levels were not increased and the relative proportions of ApoC-III0, ApoC-III, 2 and ApoC-III3 were not altered. Perfusion of livers of carbohydrate-fed rats with oleate produced fivefold and 2.5-fold increases in the rates of accumulation of VLDL-TG and ApoC-III3, respectively. The proportion of ApoC-III isoforms were identical with those seen in the livers of carbohydrate-fed rats perfused without added oleate. Thus, the changes in ApoC-lll sialylation were related more to diet than to the presence of added FFA, i.e., an acute stimulus did not reproduce the changes seen with diet. These data indicate that the sialylation of ApoC-III is under metabolic control.
Diabetes Mellitus Following Pentamidine-induced Hypoglycemia in Humans
Authors: Bouchard Ph , Sai P , Reach G , Caubarrère I , Ganeval D , Assan R 
Published: September 2013

Four patients, treated with pentamidine because of Pneumocystis carinii pneumonitis, displayed severe fasting hypoglycemia during this treatment. Diabetes mellitus appeared later, requiring insulin therapy in the three of them who survived more than a few weeks.
The metabolic study, performed in two cases during the hypoglycemic period, demonstrated inappropriately high insulin levels in the postaborptive state. 28 ± 1 μU/ml (blood glucose 41 ± 4 mg/dl) and 86 ± 5 μU/ml (blood glucose 15 ± 5 mg/dl) vs. 15 ± 3 μU/ml in 10 control subjects and 55 ± 3 μU/ml in 6 patients with a verified B-cell tumor, respectively. Poor B-cell secretory responses followed the stimulations by oral glucose (maximal increment over basal: +5 μU/ml vs. +40 μU/ml in control group and +77 μU/ml in the insulinoma group), by i.v. arginine (maximal increment +10 and +28 μU/ml, respectively, vs. +55 in the controls and +90 μU/ml in the insulinoma group) and by i.v. glucagon (+10 and +23 μU/ml, respectively) vs. +40 μU/ml in both the control and the insulinoma groups). Plasma cortisol and glucagon, and the A-cell response to arginine were higher than normal.
These high, nonsuppressible, nonstimulable insulin levels and the sequence of hypoglycemia followed by insulin-dependent diabetes mellitus is consistent with the hypothesis of a selective toxicity turned towards the B-cells. In vitro incubation of islets with pentamidine 10−10 M produced a passive release of insulin, followed by a significant decrease in B-cell response to glucose + theophylline. It is suggested that pentamidine can induce hypoglycemia because of an early cytolytic release of insulin, and then diabetes mellitus because of B-cell destruction and insulin deficiency.
Restoration of Glucose Homeostasis in Insulin-dependent Diabetic Subjects: An Inducible Process
Authors: Foss Milton C , Vlachokosta Fredericka V , Cunningham Lee N , Aoki Thomas T 
Published: September 2013

To assess the change in glucose handling capability of diabetic patients regulated with an artificial β-cell, five insulin-dependent diabetic subjects were challenged with a 100-g glucose meal while on conventional (single or split mixed insulin injections) therapy and again after 72 h on an artificial β-cell unit. It was determined that while receiving conventional therapy, the diabetic patient's capacity to oxidize glucose was severely impaired. In addition, glucose storage was markedly reduced. After 72 h on the artificial β-cell unit, the diabetic patient's capacity to oxidize glucose following the ingestion of the glucose meal significantly exceeded that of the control group, and glucose storage returned to normal.
Since the above study did not reveal the amount of time on the artificial β-cell required to restore the glucose processing capability of the diabetic patients to normal, their response to a mixed test meal ingested at noon was monitored while they were on conventional insulin therapy and during four consecutive days that they were on the artificial β-cell. This inquiry revealed a gradual increase in their capacity to oxidize carbohydrate in response to the test meal. In contrast, their ability to store carbohydrate was normalized within 24 h following initiation of artificial β-cell therapy.
These studies clearly reveal that the conventionally treated diabetic patient's capacity to both oxidize and store carbohydrate is severely impaired. Both functions can be restored to normal by the use of the artificial β-cell for 48–72 h. Most importantly, the gradual improvement in carbohydrate oxidation with respect to the daily mixed meal challenge suggests that it is an “inducible” process which requires at least 2–3 days to accomplish. Since the ability to both oxidize and store incoming carbohydrate is essential for glucose homeostasis, these observations may have significant implications for the care of diabetic patients.
Branched Chain Amino Acids as a Major Source of Alanine Nitrogen in Man
Authors: Haymond Morey W , Miles John M 
Published: September 2013

In vitro perfusion and incubation studies and recent investigations in dogs suggest that branched chain amino acids (BCAA) may be a major source of alanine nitrogen. To determine the contribution of BCAA nitrogen to the formation of alanine in man, seven postabsorptive adults received prime-dose constant infusions of 15N-leucine, L-[6,6,6-2H3] leucine, and L-[2,3,3,3-2H4] alanine; isotopic enrichment was determined in arterialized venous plasma samples by gas chromatography-mass spectroscopy. At substrate and isotope steady state, alanine flux and the rate of 15N alanine appearance were 5.4 ± 0.3 μmol/kg-min and 32 ± 2 nmol/kg·min, respectively. Leucine nitrogen flux was significantly &gt; that of leucine carbon flux (2.54 ± 0.25 vs. 1.90 ± 0.10 μmol/kg·min, respectively; P &lt; 0.001). The 30% greater flux of leucine nitrogen when compared with leucine carbon suggests significant recycling of the leucine carbon in vivo.
The percent of circulating alanine nitrogen derived from leucine was 12.5 ± 1.5%; however, the rate of leucine nitrogen transferred to alanine was 0.66 ± 0.05 mumol/kg.min, and represents a minimum of 28% of leucine nitrogen going to alanine. On the basis of these data, together with the percent of alanine and leucine in body protein, only 40% of circulating plasma alanine could come from endogenous protein, whereas 60% is derived from de novo synthesis. In addition, at least 20% of the nitrogen required for alanine synthesis is derived solely from leucine following an overnight fast. Therefore, if the contribution of isoleucine and valine nitrogen is similar to that of leucine, the BCAA may contribute to a minimum of 60% of the nitrogen required for alanine synthesis in postabsorptive man.
Sulfonylureas Do Not Affect Insulin Binding or Glycemic Control in Insulin-dependent Diabetics
Authors: Grunberger George , Ryan Janice , Gorden Phillip 
Published: September 2013

Sulfonylureas alone are ineffective in the therapy of insulin-independent diabetes mellitus (IDDM). These agents, however, might serve as an adjunct to insulin treatment if they directly affect insulin binding to its receptor. We studied 11 patients with IDDM to determine whether chlorpropamide acts directly on the insulin receptor and whether it could augment the effect of insulin on glycemic control. Mean tracer insulin binding to both peripheral monocytes and erythrocytes in 11 poorly controlled patients was normal. Optimization of glucose control by continuous subcutaneous insulin infusion for 7–10 days did not alter insulin binding to either cell type. Addition of chlorpropamide, 250–500 mg/day for another 7–10 days did not affect any aspect of insulin binding (tracer binding, number of receptor sites, insulin sensitivity, or affinity) in either cell type. Insulin binding was not changed in one patient after 3 days of 250 mg/day of the drug and in another after 500 mg/day over 3 mo. The sulfonylurea, in addition, provides no additive effect with insulin on blood glucose levels or insulin doses required to maintain euglycemia.
We conclude that short-term use of chlorpropamide in addition to insulin in IDDM does not alter insulin binding to circulating monocytes or erythrocytes. In addition, we were unable to show that this agent is a clinically useful adjunct to insulin in IDDM.
A Study of the Structural and Biochemical Development of Human Fetal Islets of Langerhans
Authors: Goldman Hy , Wong Inés , Patel Yogesh C 
Published: September 2013

The structural and biochemical ontogeny of 14 mid-trimester (12.0–19.5 wk) human fetal endocrine pancreata were examined. Each pancreas was halved at the region of the isthmus into duodenal (D) and splenic (S) portions, and islets, isolated from each of the two portions, were aliquoted and grouped according to diameter into 4 categories: (1) &gt; 300 μm (2) 300–200 μm (3) 200–100 μm (4) 100 μm.
At all fetal ages, the number of islets isolated from the splenic half was greater than from the duodenal half, and the number of islets increased as their diameter decreased. The mean total cell number per islet for each of the 4 categories are reported: (1)(D) 30,810 (S) 28,450; (2)(D) 10,970 (S) 10,250; (3)(D) 3,390 (S) 3,460; (4)(D) 1,930 (S) 1,840.
Measurement of islet insulin (IRI), glucagon (IRG), and somatostatin (IRS) by radioimmunoassay showed a progressive increase with time in the content of all three hormones in all islets from both halves of the pancreas (with the exception of the smallest islets of &lt;100 μm diameter). After 18 wk, a dramatic increase in the content of all three hormones was observed particularly in the case of the largest (&gt;300 μm) islets. In contrast, pancreatic polypeptide (IRPP) shows no significant increase. With the exception of the smallest islets (100 μm), all splenic-half islets contain a significantly greater content of IRI, IRG, and IRS compared with their duodenal-half match while the content of IRPP is significantly greater in the duodenal-half islets. In addition, all islets with the exception of the largest (&gt;300 μm), contained equal quantities of IRG and IRS and these results were apparent at 12 wk gestation.
These data provide new insights into the ontogeny of individual islet cells during the mid-trimesteric period and serve as a basis for future studies of both normal and abnormal pancreatic development.
Impaired in Vivo Insulin Clearance in Patients With Severe Target-Cell Resistance to Insulin
Authors: Flier J S , Minaker K L , Landsberg L , Young J B , Pallotta J , Rowe J W 
Published: September 2013

The concentration of insulin in plasma is determined by both its rate of secretion and its rate of clearance from the plasma compartment. The effect of marked insulin resistance on insulin clearance in vivo has not been determined in man. We have employed the euglycemic insulin clamp technique to measure insulin sensitivity and insulin clearance in 16 control subjects and in 4 subjects with marked target-cell resistance to insulin. Two insulin-resistant patients had reduced receptor concentration on peripheral mononuclear cells, and two patients had normal receptor number and affinity.
During 80-mU/m2/min insulin clamp studies, the clearance rate in each insulin-resistant patient was lower than that in any controls; the mean insulin clearance rate was 511 ± 74 ml/m2/min in control subjects and 205 ml/m2/min (P &lt; 0.001) in insulin-resistant patients. These findings demonstrate an association between marked target-cell resistance to insulin and impaired in vivo insulin clearance, and suggest an important role for receptor-mediated pathways in insulin clearance in vivo.