bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Streptozotocin-induced Diabetes on Renal Ornithine Decarboxylase Activity
Authors: Levine Jon H , Buse Maria G , Leaming A B , Raskin Philip
Published: September 2013

The effects of streptozotocin(SZ)-induced diabetes on renal ornithine decarboxylase (ODC) activity, the rate-limiting enzyme in polyamine biosynthesis, were studied. Sixteen hours after the injection of SZ, renal ODC activity increased 50% above that of the vehicle-injected controls. The maximum increase in activity—600%—was observed from 24 to 72 h after SZ. Within a week, ODC activity fell below control levels and remained suppressed during a 3 wk follow-up period. Insulin treatment within 10 h of the SZ injection prevented the increase of ODC activity; however, insulin given after enzyme activity had increased did not restore ODC activity to control levels. The early increase of ODC activity occurred in the presence of mild hyperglycemia without ketosis or hyperglucagonemia, but the levels were much higher in severely diabetic animals. Adrenalectomy, performed before the initial increase in enzyme activity, prevented the subsequent increase in diabetic animals; however, when adrenalectomy was performed after the enzyme had increased, enzyme activity did not normalize.
Streptozotocin Diabetes in the Monkey: Plasma Levels of Glucose, Insulin, Glucagon, and Somatostatin, with Corresponding Morphometric Analysis of Islet Endocrine Cells
Authors: Jones Carl W , Reynolds W Ann , Hoganson George E
Published: September 2013

Streptozotocin (STZ) was administered to 20 female rhesus monkeys at a dose of between 30 and 55 mg/kg. Depending on the severity of the resultant diabetic-like state, these animals were divided into two groups: insulin-dependent monkeys requiring daily insulin injections and carbohydrate-disturbed animals not requiring insulin. STZ-treated monkeys exhibited significantly higher fasting glucose levels or increased glucose disappearance times after an intravenous glucose tolerance test than did controls. In the insulin-dependent monkeys, fasting plasma glucagon levels were elevated when compared with the carbohydrate-disturbed or control monkeys. Glucagon levels did not differ between carbohydrate-disturbed and control animals. Fasting somatostatin levels were also significantly elevated in insulin-dependent animals when compared with controls. Morphometric analysis was performed on the alpha, beta, and delta cell populations of the pancreatic islets in three control and three diabetic animals. Significant decreases in beta cell percent volume and numerical percent and increases in both alpha and delta cell percent volume and numerical percent were observed in relation to control values after STZ diabetes lasting from 17 to 31 mo. Thus, the diabetic-like state induced by STZ in the monkey resembles juvenile-onset human diabetes mellitus with respect to plasma hormone levels and to morphometric changes in the islets of Langerhans.
Islet Cell and Other Organ-specific Antibodies in U.S. Caucasians and Blacks with Insulin-dependent Diabetes Mellitus
Authors: Neufeld Michel , Maclaren Noel K , Riley William J , Lezotte Dennis , McLaughlin Judith V , Silverstein Janet , Rosenbloom Arlan L
Published: September 2013

Islet cell antibodies (ICA) were detected in 168 (33%) of 504 patients with insulin-dependent diabetes mellitus (IDDM). Mean age of onset of IDDM was 8.6 ± 0.2 yr and mean age at testing was 13.4 ± 0.3 yr. None of 162 controls without diabetes (mean age 21.8 ± 0.9 yr) had ICA. Caucasian patients (404) had a 74% frequency of ICA within 3 mo of diagnosis and an overall ICA frequency of 36%. These results were similar to those reported from Europe. Black patients (100) had lower frequencies of ICA (P < 0.01) and thyroid antibodies (P < 0.05). Caucasian patients with onset of IDDM before 5 yr of age (107) had a lower frequency (P < 0.01) of ICA (21%) than those (297) with a later age of onset (42%). Patients with persistent ICA beyond 5 yr of IDDM had increased frequencies of gastric parietal and adrenal cortex cell antibodies. Thyroid microsomal antibodies were less frequent (P < 0.05) in blacks (4%) than in Caucasians (20%). The former did not have adrenal antibodies. Similar ICA frequencies among Caucasians with IDDM in the U.S. and in Europe suggest that etiologie factors are similar in the two geographic regions. The lower frequencies of ICA in patients with IDDM onset before 5 yr of age suggest that some of these patients may have a different etiology and/or a more rapid disappearance of islet cell antigens than patients with a later onset. The lower ICA frequencies in black patients can be explained by heterogeneity of IDDM in this group and by admixture of IDDM susceptibility genes from the Caucasian genome to the black genome.
The Prevalence of Diabetes in the Rural and Urban Polynesian Population of Western Samoa
Authors: Zimmet P , Faaiuso S , Ainuu J , Whitehouse S , Milne B , Deboer W
Published: September 2013

Rural-urban comparisons of diabetes prevalence were made in the Polynesian population of Western Samoa. The prevalence of diabetes in the urban population was almost three times that in the rural (10.1% versus 3.6%).

While the urban male and female subjects were significantly more obese than their rural counterparts, the difference in prevalence rate could not be wholly explained on this basis. Diabetes prevalence was still approximately double in urban subjects when we compared the rural and urban populations after removing the differences in obesity and age. The results suggest that, apart from age and obesity, other factors, e.g., differences in diet, physical activity, or stress (or a combination of these), may participate in the rural to urban difference in diabetes prevalence.
Responses of Neonatal Rat Islets to Streptozotocin: Limited B-Cell Regeneration and Hyperglycemia
Authors: Bonner-Weir S , Trent D F , Honey R N , Weir G C
Published: September 2013

Streptozotocin (SZ) was given to 2-day-old neonatal rats, and, during their subsequent development, the interrelationships between plasma glucose, plasma insulin, pancreatic islet morphology, and hormone content were examined.

At 4 days of age, a peak of hyperglycemia was observed (SZ, 349 ± 8 mg/dl versus control (C), 127 ± 2) that was associated with a marked reduction of B-cell numbers (SZ, 26.5 ± 2.6% B-cell per islet versus C, 72.8 ± 0.8%). By 10 days of age the SZ animals became normoglycemic with partial recovery of the B-cell number (SZ, 39.6 ± 2.1% versus C, 64.0 ± 2.6%). By 6 weeks hyperglycemia returned (SZ, 345 ± 5.2 mg/dl versus C, 171 ± 6.2) with B-cell number of the SZ being 72% of the C (SZ, 48.8 ± 2.4% versus C, 67.5 ± 1.5%). This hyperglycemia and reduced B-cell number persisted to at least 13 wk age. Despite a marked reduction of pancreatic insulin content observed during development, there was little effect upon glucagon or somatostatin content.

At 6 wk of age, the plasma insulin concentration was only 30% of C, which suggests an insulin secretory defect beyond that which could be accounted for by the modest B-cell reduction. The present study indicates that even though active regeneration of B-celle occurred after early injury, the capacity for ultimate normalization was limited. The resultant moderate reduction in B-cell number may be associated with a functional defect in glucose-stimulated insulin secretion.
Glucose Disposal is Not Proportional to Plasma Glucose Level in Man
Authors: Best James D , Taborsky Gerald J , Halter Jeffrey B , Porte Daniel
Published: September 2013

Metabolic clearance rate (MCR) of glucose has been defined as the rate of glucose utilization divided by the glucose concentration. This model of glucose transport has been widely used as a measure of hormonally regulated glucose disposal, on the assumption that glucose disposal rate is proportional to glucose concentration. To test this assumption, the relationship between glucose concentration and disposal rate was studied in man during infusion of somatostatin ± exogenous insulin to achieve fixed plasma insulin levels of 1,18, and 46 μU/ml on separate days. When glucose concentration was increased to more than twice basal fasting levels, the glucose disposal rate increased significantly at all three insulin levels. However, the increase was not proportional to the rise in glucose concentration, and MCR fell by 38%, 16%, and 11% at the low, medium, and high insulin levels, respectively. These results are explained by an alternative model of glucose transport in which insulin-independent tissues such as brain have a relatively fixed glucose uptake, while other tissues have glucose transport systems which take up glucose at a rate proportional to its plasma concentration. We conclude that MCR of glucose is not a good measure of hormonally regulated glucose disposal because it is partially dependent on the glucose concentration, particularly at low insulin levels.
Effect of Pubertal Stage and Recent Blood Glucose Control on Plasma Somatomedin C in Children with Insulin-dependent Diabetes Mellitus
Authors: Blethen Sandra L , Sargeant Daniel T , Whitlow Margaret G , Santiago Julio V
Published: September 2013

One hundred and fifty-five children with insulin-dependent diabetes mellitus were studied to determine the relationship of plasma somatomedin C concentrations to pubertal stage, recent blood glucose control, duration of diabetes, and daily insulin dosage. Plasma somatomedin C, as measured by radioimmunoassay, increased with age and the progression of puberty in both boys and girls, but was not different from those of normal children aged 5–18 yr. In diabetic children under 5 yr of age, plasma somatomedin was significantly lower than in normal children. These results are different from those reported previously in diabetic children, in which somatomedin activity was measured using a pig cartilage bioassay.

In boys, puberty was accompanied by an increase in hemoglobin A1c from 11.6 to 14.1% despite a 36–44% increase in total daily insulin dosage adjusted for body weight. In girls, puberty was also associated with an increase in hemoglobin A1c (12.1–15.1%) without a change in weight-adjusted insulin dose. Although there was no apparent correlation between hemoglobin A1c and somatomedin C in the group as a whole (r = −0.078), multiple regression analyses demonstrated a significant negative correlation between these two variables (P < 0.001) when considered independently of age, sex, pubertal stage, duration of diabetes, and insulin dose. Pubertal status had a significant (P < 0.01) effect on plasma somatomedin C; plasma somatomedin C was also significantly positively correlated with the duration of diabetes (P < 0.01) but not with weight adjusted insulin dose. SMC concentration was not correlated with age when this variable was considered independently of puberty (P = 0.26). The data indicate that puberty and metabolic control both have significant yet independent effects on somatomedin C in children with insulin-dependent diabetes. In addition, the increased somatomedin C associated with puberty may contribute to the accelerated development of diabetic complications seen at this time, while the lowering of somatomedin C associated with worsening metabolic control may adversely affect linear growth.
Evidence for the Hormonal Status of Somatostatin in Man
Authors: Zyznar Edward S , Pietri Angel O , Harris Virginia , Unger Roger H
Published: September 2013

To determine the hormonal status of somatostatin in man, plasma levels of ∼1600-dalton somatostatin-like immunoreactivity (SLI) were measured before and after a mixed meal. Plasma was subjected to gel filtration and the fractions coeluting with somatostatin were concentrated ninefold before radioimmunoassay. In this system the recovery of synthetic somatostatin added to plasma averaged 71 ± 4.6% (mean ± SE, N = 5). Synthetic somatostatin infused into normal volunteers gave a dose-related increase in the measured SLI value. Fasting SLI in 13 normal volunteers was 8.0 ± 0.7 pg/ml (mean ± SE) and rose to 18.6 ± 1.5 pg/ml and 20.3 ± 2.0 pg/ml at 60 and 120 min, respectively, after the meal (P < 0.001). In seven type I diabetics, the fasting level was 11.5 ± 1.6 pg/ml and the 60- and 120-min postprandial levels were 21.4 ± 2.5 and 22.3 ± 2.9 pg/ml, respectively. The meal-induced rise in ∼1600 M.W. SLI approximated that produced by infusing somatostatin at 2 μg/h, a rate that significantly suppressed glucagon levels. These results are therefore consistent with a hormonal role for somatostatin in man.
A New Genetically Obese-Hyperglycemic Rat (Wistar Fatty)
Authors: Ikeda Hitoshi , Shino Akio , Matsuo Takao , Iwatsuka Hisashi , Suzuoki Ziro
Published: September 2013

The fa-gene was transferred from the Zucker rat (13 M strain) to the Wistar Kyoto (WKY) rat. The survey, performed at the 10th generation of backcrossing, showed that Wistar fatty rats (fa/fa), a congenic strain of WKY, developed obesity and obesity-related features, such as hyperinsulinemia and hyperlipemia, in the same manner as Zucker fatty rats. Males, but not females, showed hyperglycemia, glucosuria, and polyuria as early as 8 wk of age. Tolerance and insulin response to oral glucose were decreased with advancing age in males.

The diabetic changes appeared to be caused by an interaction between predisposition to develop diabetes in the WKY rat and fa-induced obesity. This is because WKY rats were found to be less sensitive to insulin than Zucker rats by both the glucose tolerance test and the steady-state blood glucose method which estimates overall insulin sensitivity.
Lymphocytic Thyroiditis and Diabetes in the BB/W Rat: A New Model of Autoimmune Endocrinopathy
Authors: Sternthal Elliot , Like Arthur A , Sarantis Kosmas , Braverman Lewis E
Published: September 2013

The Bio Breeding/Worcester (BB/W) rat develops spontaneous insulin-dependent diabetes mellitus secondary to lymphocytic infiltration and destruction of the pancreatic beta-cells. This destructive process in the pancreas has been postulated to be based on a thymus-dependent cell-mediated autoimmune process. In view of the well recognized association in man of diabetes mellitus and another autoimmune endocrinopathy, chronic thyroiditis (Hashimoto's thyroiditis), the present studies were carried out to determine whether lymphocytic thyroiditis occurred with increased frequency in the diabetic, insulin-treated BB/W rat. The incidence of lymphocytic thyroiditis was strikingly increased in 8–10-mo-old diabetic rats (59%) as compared with their nondiabetic cohorts (11%) (P < 0.001). Relative thyroid weight was significantly greater in diabetic as compared with nondiabetic rats (P < 0.01) and in diabetic rats with thyroiditis than in diabetic rats without thyroiditis (P < 0.025). Lymphocytic thyroiditis was not accompanied by any consistent changes in serum T4, T3, and TSH concentrations or in the serum TSH response to thyrotropin-releasing hormone (TRH) suggesting that the thyroiditis was not of sufficient severity or duration to induce primary thyroid gland failure. The BB/W rat represents the first animal model of multiple autoimmune endocrinopathies and provides a unique opportunity to study the pathogenesis of these disorders.
Enhanced Intestinal Absorption of Insulin in Rats in the Presence of Sodium 5-Methoxysalicylate
Authors: Nishihata Toshiaki , Rytting J Howard , Kamada Akira , Higuchi Takeru
Published: September 2013

Sodium 5-methoxysalicylate, previously shown to enhance the rectal absorption of several drugs, facilitates the absorption of insulin from the upper gastrointestinal tract, resulting in significantly elevated insulin levels and lowered glucose concentrations in the plasma of rats. Restricting the movement of insulin and adjuvant down the intestine by either ligation or use of a more viscous vehicle further increased the absorption of insulin.
Glucose Utilization During Exercise in Normal and Diabetic Subjects: The Role of Insulin
Authors: Krzentowski Georges , Pirnay Freddy , Pallikarakis Nicolas , Luyckx Alfred S , Lacroix Marcel , Mosora Florentina , Lefèbvre Pierre J
Published: September 2013

Due to selective isotopic effects occurring during photosynthesis, certain natural sugars are enriched in 13C Using such “naturally labeled 13C-glucose,” we studied glucose oxidation during exercise in seven normal volunteers and in six insulin-dependent diabetics after an overnight fast. In the diabetics, blood glucose was monitored the night before the test and adjusted to about 100 mg/dl by intravenous insulin infusion. The insulin infusion was withheld 15 min before exercise in four diabetics and maintained at 0.9 U/h for 2 h; then it was maintained at 0.6 U/h for 2 h in five diabetics. Three patients underwent both tests. All subjects exercised on a treadmill for 4 h at about 45% of their max. After 15 min adaptation, all received 100 g 13C-labeled glucose orally. Total glucose oxidation was derived from non-protein RQ and exogenous glucose oxidation evaluated as previously described. The diabetics had no residual B-cell function as indicated by negligible plasma C-peptide values and a lack of Cpeptide response to the oral glucose challenge. Total glucose oxidation averaged 230 ± 14 g/4 h in the normal subjects. It was similar (238 ± 19 g/4 h) in the diabetics receiving an intravenous insulin infusion, but decreased to 176 ± 14 g/4 h when no insulin was infused. Exogenous glucose oxidation was 92 ± 3 g/4 h and 84 ± 8 g/4 h (not statistically different) in the controls and in the insulin-infused diabetics, respectively. It was 43 ± 11 g/4 h in the diabetics exercising without being infused with insulin. We conclude that (1) in well-insulinized diabetic patients, prolonged muscular exercise can be performed under metabolic conditions which are basically similar to those of normal subjects; (2) during prolonged exercise, well-insulinized diabetic patients are able to oxidize up to 85–90% of a 100-g exogenous glucose load given orally and oral glucose can thus be ingested during prolonged exercise in well-controlled juvenile insulintreated diabetics; (3) even in the absence of insulin administration during exercise, juvenile diabetics who start exercising when blood glucose is near normal are able to perform a 4-h exercise at 45–50% of their max. Under these conditions, however, they are unable to utilize more than 40–45% of a 100-g glucose load given orally. They rely more upon lipid stores than the normal subjects or the well-insulinized diabetics.
Pneumococcal Immunization in Adult Diabetics
Authors: Lederman Michael M , Schiffman Gerald , Rodman Harvey M
Published: September 2013

The antibody responses of 102 adult insulin-treated diabetics who received 14-va lent pneumococcal polysaccharide vaccine were measured. Grand mean preimmunization antibody levels were similar for diabetics, 255 ng protein N/ml, and controls, 234 ng protein N/ml. Postimmunization, the values in the diabetics, 1009 ng protein N/ml, and 834 ng protein N/ml in 48 healthy controls, were not significantly different. The height of antibody response in the diabetic group did not correlate with age, sex, duration of diabetes, insulin dose, concentration of glycosylated hemoglobin, fasting or 2-h postprandial glucose concentrations, or the presence of retinopathy. Side effects were minimal and occurred in 26%. Antibody response to pneumococcal polysaccharide vaccine is not impaired in adult diabetics. Pneumococcal immunization is safe and may reduce the frequency of pneumonia and its complications in the diabetic population.
Studies on the Cellular Basis of Atherosclerosis: The Effects of Atherosclerosis Risk Factors on Platelets and the Vascular Endothelium
Authors: Wall Robert T , Rubenstein Martin D , Cooper Suzanne L
Published: September 2013

Thrombosis is a well-recognized complication of atherosclerosis and may be a factor in initial lesion formation. Experimental endothelial cell injury results in activation of the coagulation mechanism and therefore may be a critical aspect of the pathogenesis of occlusive vascular disease. If this is so, then risk factors for atherosclerosis should affect the endothelium either by causing cell injury, inhibiting repair mechanisms, or altering its thromboresistant properties. To test this, we studied the effect of several risk factors on endothelial cell behavior in vitro. Since the smooth muscle cell is the major cellular component of human atherosclerotic plaque and since a primary smooth muscle cell lesion is suggested by the clonal nature of human plaque, we also studied the effect of risk factors on arterial smooth muscle behavior. We have found that homocysteine directly injures human endothelium, which may account for the premature arterial disease in homocystinuria. Serum from patients with familial hypercholesterolemia inhibits the critical function of endothelial cell migration, as well as arterial smooth muscle cell migration. Moderate hypoxia has no effect on endothelial cell or smooth muscle cell viability, proliferation, or migration. Platelet factors are shown to affect human smooth muscle cell proliferation and both endothelial cell and smooth muscle cell migration. Preliminary study of platelet activation in diabetes with retinopathy suggests a relation to glucose control, but might reflect underlying vessel disease rather than direct platelet effect.
Diabetic Hypertriglyceridemia: Evidence for Three Clinical Syndromes
Authors: Reaven Gerald M , Greenfield Michael S
Published: September 2013

Based on studies of both man and rat, it is proposed that at least three distinct syndromes of hypertriglyceridemia occur as the result of abnormalities of carbohydrate metabolism. We believe that these syndromes are the predictable results of the changes in plasma insulin and/or free fatty acid (FFA) concentration that occur in patients with impaired glucose tolerance (IGT), non-insulin-dependent diabetes mellitus (NIDDM), and insulin-dependent diabetes mellitus (IDDM). In patients with IGT the basic defect is postulated to be loss of normal insulin sensitivity, leading to compensatory hyperinsulinism, increased very low density lipoprotein (VLDL)-triglyceride (TG) secretion, and hypertriglyceridemia. In contrast, patients with NIDDM have ambient insulin concentrations that are “normal” in absolute terms, and in these subjects we believe that the elevated circulating FFA concentrations increase hepatic VLDL-TG secretion, which, in turn, is responsible for the hypertriglyceridemia. However, elevated FFA levels do not stimulate hepatic VLDL-TG secretion in insulin-deficient patients with IDDM, presumably because the livers of such individuals are not capable of responding to the increased FFA flux. In these subjects, the development of hypertriglyceridemia, when it does occur, is secondary to the existence of a profound defect in the removal of VLDL-TG from plasma. These generalizations are consistent with results in both man and rat, and provide models that account for the development of hypertriglyceridemia in the three major clinical categories of abnormal carbohydrate metabolism.
Effect of Insulin and Glucose Infusions on Sympathetic Nervous System Activity in Normal Man
Authors: Rowe John W , Young James B , Minaker Kenneth L , Stevens Arthur L , Pallotta Johanna , Landsberg Lewis
Published: September 2013

Recent studies indicate a link between carbohydrate intake and the functional state of the sympathetic nervous system. Fasting or carbohydrate restriction decreases sympathetic activity, while glucose ingestion or dietary supplementation with sucrose increases sympathetic nerve activity. To examine the potential contributions of hyperglycemia and hyperinsulinemia to sympathetic stimulation, sympathetic activity was assessed by measurement of plasma norepinephrine (NE) levels and concomitant cardiovascular indices in nonobese young men during glucose and insulin infusions using glucose clamp techniques. In the insulin infusion studies (euglycemic glucose clamp), insulin was administered at 2 mU/kg/min and 5 mU/kg/min for 2 h while blood glucose was maintained at basal levels by a variable rate of glucose infusion. In the hyperglycemic studies, blood glucose was raised 125 mg/dl above basal and maintained at that level for 2h.

In response to both insulin infusions, plasma NE rose progressively over the course of the study, increasing 50% with the 2-mU infusion (from mean basal value of 240 ± 34 pg/ml to 360 ± 41 at 150 min, P < 0.001 for changes over time by analysis of variance) and 117% with the 5-mil infusion (from 254 ± 20 pg/ml to 551 ± 88 at 150 min, P < 0.001). The plasma NE response was greater with the 5-mll than with the 2-mU insulin infusion (P < 0.001), and similarly, was greater during the 2-mU insulin infusion than during a control test in which neither insulin nor glucose was infused (P < 0.001). Associated with the elevations in plasma NE In the 2-mU insulin infusion were increases in pulse rate (P < 0.05), pulse pressure (P < 0.005), and pulse rate - systolic blood pressure product (P < 0.01), and during the 5-mU insulin infusions there were increases in pulse pressure (P < 0.001), mean arterial blood pressure (P < 0.001), and pulse rate - systolic blood pressure product (P < 0.001). Plasma NE did not change during the hyperglycemic glucose clamp nor during control tests, and pulse pressure in the hyperglycemic studies (P < 0.005) was the only cardiovascular measurement increased by these two infusion protocols. The clearance of NE in three subjects was unaffected by the 2-mU insulin infusion. Thus, insulin infusion increases sympathetic nervous system activity in the absence of changes in blood glucose.
Insulin Release In Vitro from Islet Tissues and Adenomas of Rats Treated with Nicotinamide and Streptozotocin: The Effects of Glucose
Authors: Frigo I , Younoszai R , Dixit P K , Matta S G , Bauer G E
Published: September 2013

Young male Holtzman rats injected with nicotinamide and streptozotocin develop grossly visible tumors of pancreatic islet tissue. Using ah i.v. glucose tolerance test, some tumor-bearing animals exhibited a vigorous (or fast) response to glucose loading (Diabetic Index = 0.47), whereas others showed a subdiabetic (or slow) response (Diabetic Index = 2.34). In vitro perifusion studies demonstrate that tumor pieces from both groups of rats released immunoreactive insulin (IRI) in response to glucose; tumors from fast responding rats showed a rapid monophasic release of IRI (i.e., rapid transient release with little secondary phase), while tumors from slow responders released IRI in a biphasic pattern resembling that of normal islets.

A population of large islet masses (or microscopic tumors), isolated from drug-treated rats by collagenase digestion of the pancreas of tumor-containing rats, exhibited glucose-stimulated IRI release that resembled the pattern of the tumor from the same animal. Isolated islets of Langerhans of ordinary size from the pancreas of tumor-bearing rats, on the other hand, usually exhibited a normal (biphasic) IRI release pattern in response to glucose. Analysis by gel filtration suggests that the predominant form of IRI released from perifused tumor preparations, under either basal or glucose-stimulated conditions, eluted at a rate corresponding to rat insulin.
The Absence of Cryptic Insulin Receptors on Resting Lymphocytes
Authors: Gozes Yehoshua , Caruso Joanne , Strom Terry B
Published: September 2013

Previous experiments have demonstrated that insulin receptors emerge upon stimulated lymphocytes while resting lymphocytes lack insulin receptors. The appearance of insulin receptors is totally dependent on RNA and protein synthesis. The results suggest that insulin receptors are synthesized de novo or that new protein is synthesized that is responsible for activation of the receptor. In this study, we investigated the possibility that cryptic membrane receptors are present before lymphocyte activation. As a precedent, hypertonic salt solutions or enzymatic digestion have been reported to uncover cryptic insulin receptors in liver and fat cell membranes. Similar treatment of lymphocytes failed to reveal cryptic, stereospecific receptor sites, although nonspecific insulin binding did increase.
Alteration of Glycolytic Intermediary Metabolism in Erythrocytes During Diabetic Ketoacidosis and Its Recovery Phase
Authors: Kono Norio , Kuwajima Masamichi , Tarui Seiichiro
Published: September 2013

The concentrations of glycolytic intermediates and adenine nucleotides were determined in erythrocytes from patients with diabetic ketoacidosis before and during insulin treatment. Ketoacidosis resulted in an increase in the levels of intermediates above the phosphofructokinase (PFK) step and a marked decrease in the levels of those below this step. Thus, a “crossover” point was seen at the PFK step in a crossover plot. This indicated that the rate of glycolytic flow during ketoacidosis was controlled by PFK and that the reduced level of 2,3-bisphosphoglycerate (2, 3-BPG) was attributed to the inhibition of this enzyme. In vitro studies revealed that acidemia is mainly responsible for the inhibition of PFK, whereas elevated levels of ketone bodies and free fatty acids have no direct bearing on it.

Insulin administration produced hypophosphatemia within 8–12 h and it persisted for 24 h or longer. The levels of fructose-6-phosphate and glucose-6-phosphate were decreased transiently during this hypophosphatemic phase, while those of fructose bisphosphate and triose phosphates were increased. This indicated that PFK was activated. Thus, it is no longer reasonable to think that the inhibition of PFK is a factor responsible for a delay in normalization of the 2, 3-BPG level during the recovery phase. The levels of these glycolytic intermediates, including 2, 3-BPG, were normalized within 4 days by appropriate therapy.
Nonenzymatic Glycosylation of Basement Membranes: In Vitro Studies
Authors: Cohen Margo P , Urdanivia Enrique , Surma Maria , Ciborowski C James
Published: September 2013

Incubation of purified rat glomerular basement membrane (GBM) with [14C]-glucose in vitro resulted in the incorporation of [14C] into acid-precipitable radioactivity in a reaction that was time and temperature dependent. Findings with rat lens capsule basement membrane (LCBM), an anatomically distinct but chemically similar extracellular matrix, incubated for varying times at different temperatures with [14C]-glucose at constant specific activity were similar. Nonenzymatic glycosylation of basement membrane, documented by hydroxymethylfurfuraldehyde generation after incubation with unlabeled glucose, increased in proportion to the ambient glucose concentration over a range of 5–100 mM. Acid-precipitable radioactivity also increased in proportion to [14C]-glucose concentration, although this method overestimated glycosylation about 15-fold at 5–20 mM glucose and 50-fold at 50–100 mM glucose. Coupled with recent in vivo studies, these findings indicate that exposure to increased glucose concentration alters the chemistry of glomerular and other basement membranes. Since accumulation of basement membrane characterizes several of the micrbangiopathic sequelae of diabetes, the role of increased nonenzymatic glycosylation on the structure, function, and metabolism of basement membrane warrants investigation.
Insulin and Its Secretagogues Activate Ca2+-dependent Phosphatidylinositol Breakdown and Amylase Secretion in Rat Pancreas In Vitro
Authors: Farese Robert V , Larson Ronald E , Sabir Mohammad A
Published: September 2013

We studied the effects of insulin and insulin secretagogues on pancreatic phospholipids and the release of amylase from pancreatic fragments incubated in vitro. Insulin provoked rapid, dose-related increases in amylase release, and these were accompanied by decreases in phosphatidylinositol and increases in phosphatidic acid. Glucose and other insulin secretagogues elicited similar changes in amylase release and pancreatic phospholipids; epinephrine blocked these effects of glucose, presumably via inhibition of glucose-induced insulin secretion. Effects of insulin and glucose on phospholipids and amylase release were dependent on Ca2+ in the incubation medium. These findings suggest that, in the pancreas, insulin enhances Ca2+-dependent phosphatidylinositol breakdown, which in turn influences amylase secretion. The effects of insulin on phospholipids may also explain certain other actions of insulin.
Effect of Somatostatin on the Flow Rate and Triglyceride Levels of Thoracic Duct Lymph In Normal and Vagotomized Dogs
Authors: Nakabayashi Hajime , Sagara Hosaku , Usukura Noriomi , Yoshimitsu Kohei , Imamura Toshinori , Seta Takashi , Yanase Eimei , Kawato Masanori , Hiraiwa Yoshio , Sakato Shunichi , Takeda Ryoyu
Published: September 2013

The role of circulating somatostatin (SRIF) in triglyceride (TG) homeostasis was evaluated in fasting and postprandial lymph of the canine thoracic duct. Cyclic SRIF at a very low, near physiologic (50 ng/min), and pharmacologic (5 μg/min) doses was infused into the portal or the femoral vein, and lymph was collected every 10 min through a cannula inserted into the duct under neuroleptanalgesia. The intraportal (IP) and intrafemoral (IF) SRIF infusion, but not saline infusions, significantly and almost identically reduced the rates of fasting lymph flow to levels of 87% and 91% of the preinfusion values, respectively, at a dose of 50 ng/min, and to 78% and 80%, respectively, at both rates at a dose of 5 μg/min. The attenuating effect of the IP and IF SRIF infusions at both rates upon lymph flow was completely abolished by vagotomy at the diaphragmatic level. The flow rate, TG concentration, and TG content (flow × concentration) of lymph obtained 3 h after a fat- and protein-rich meal ingestion were significantly and almost identically reduced during the IP and IF SRIF infusions at 50 ng/min, but not during saline infusions. Greater attenuation of these parameters was observed with 5 μg/min infusions, regardless of the route of administration. These results indicate that SRIF in near physiologic as well as pharmacologic doses can inhibit lymph flow after traversing the liver in the presence of the vagus nerve. They suggest the the other splanchnic organs may have a physiologic influence upon TG entry from the gut through alterations of dynamics of the splanchnic lymph system.
Preparation of Viable islet Cells from Dogs by a New Method
Authors: Horaguchi Atsushi , Merrell Ronald C
Published: September 2013

A new method for the preparation of viable islet cells from the normal dog pancreas is described, based on the perfusion of the pancreatic duct with collagenase. Exposure of the acinar tissue to the highest concentrations of collagenase results in improved islet yield with decreased acinar contamination. After the selective digestion of the gland by ductal perfusion, mechanical dissociation liberates single cells and clumps. Analysis of the procedure by insulin yield and amylase attrition indicates a 57% B-cell recovery and a sixfold enrichment in B-cell concentration. The cells have been transplanted as autografts into dogs after pancreatectomy. In 5 of 7 transplanted dogs, normoglycemia was achieved postoperatively.
Increase in Capillary Basement Membrane Width in Parents of Children with Type I Diabetes Mellitus: Association with HLA-DR4
Authors: Marks James F , Raskin Philip , Stastny Peter
Published: September 2013

Hereditary factors related to HLA antigens are known to play a role in determining risk for the development of type I diabetes. In the present investigation, asymptomatic first degree relatives of diabetic patients were investigated to determine whether any abnormalities could be associated with the HLA haplo-types. Muscle biopsies were performed to obtain measurements of the width of the capillary basement membranes in 16 type I diabetic children, 20 of their unaffected siblings, and 38 parents. Only two diabetic children had capillary basement membranes greater than 2000 Å. The mean width of the capillary basement membranes was not different in affected compared with unaffected siblings. In contrast, the capillary basement membranes in the parents were considerably larger, with 14 of the 38 parents (37%) having measurements greater than 2000 Å. Moreover, the width of the capillary basement membranes in the parents correlated with the presence of the antigen HLA-DR4. The mean capillary basement membrane width in DR4 positive parents was 2026 ± 350 Å; that of DR4 negative parents was 1642 ± 333 Å. The difference was highly significant (P < 0.001). There was no correlation of capillary basement membrane width with HLA-DR3. The results suggest that a risk factor for type I diabetes associated with HLA-DR4 was associated in parents of type I diabetic patients with an asymptomatic increase in capillary basement membrane width in the absence of any clinical evidence of diabetes. The possible role of these abnormalities in the pathogenesis of type I diabetes and of the vascular complications of the disease require further study.
Insulin Binding, Internalization, and Insulin Receptor Regulation in Fibroblasts from Type II, Non-insulin-dependent Diabetic Subjects
Authors: Prince Melvin J , Tsai Phoebe , Olefsky Jerrold M
Published: September 2013

The ability of insulin to bind, internalize, and regulate its own receptor was investigated in cultured human fibroblasts obtained from 8 normal subjects and 8 patients with type II, non-insulin-dependent diabetes mellitus (NIODM). The ability of the cells from the two groups to bind insulin was the same, and Scatchard analysis demonstrated identical curvilinear plots. When cells were incubated at 37°C with the lysosomotropic agent, chloroquine, and 125I-insulin, the drug led to a marked, but comparable, increase in cell-associated radioactivity in both control and diabetic fibroblasts (236 and 245% increase, respectively). Insulin pretreatment leads to a loss of insulin receptors in cultured human fibroblasts and preincubation with insulin led to a comparable dose-dependent decrease in subsequent insulin binding in both normal and diabetic fibroblasts. Scatchard analysis demonstrated that this decrease in binding was entirely due to a decrease in receptor number with no change in receptor affinity. These data demonstrate normal insulin binding, insulin internalizatidh, and insulin-mediated receptor loss in fibroblasts from patients with NIDDM, and these cells are several generations removed from the in vivo milieu. Thus, these results provide direct evidence that the well-known decrease in insulin binding in freshly isolated cells from patients with NIDDM is a reflection of environmental factors rather than an intrinsic (genetic) cellular abnormality.
Kinetic Analysis of the Response of Plasma Glucose, Insulin, and C-Peptide to Glucagon Injection in Normal and Diabetic Subjects
Authors: Turco Gianluigi , Brossa Claudio , D'alberto Micaela , Regis Giorgio , Segre Giorgio , Bianchi Enrica , Bruni Bruno , Gamba Silvia
Published: September 2013

A compartmental model formed by plasma glucose, proinsulin, insulin, and C-peptide was proposed to allow a quantitative evaluation of the interrelationship among the different components of the system and to obtain a better discrimination between normal and pathologic subjects. In 11 control subjects, in 6 mild diabetics, and in 9 severe diabetics (insulin-dependent), the kinetics of plasma glucose, insulin, and C-peptide after an i.v. injection of glucagon (sampling for about 120 min) were fitted to the model which was solved with digital computing techniques. Since biphasic plasma insulin and C-peptide kinetics were demonstrated in many normals and mild diabetics, the effect of glucagon in the model was represented by a differential plus a proportional effect. The model (formed by 6 compartments and 14 transfer constants) takes into account the fact that insulin and C-peptide derive monomolecularly from proinsulin and that liver inactivates insulin.

The values of the parameters obtained were submitted to stepwise discriminant analysis in order to obtain their relative importance in discriminating among the three groups of subjects.

With respect to normal subjects, we found in diabetics an increased inflow of glucose into plasma; a decreased effect of glucagon in promoting the proinsulin response; a decreased effect of glucose in promoting the proinsulin response; a decreased glucose utilization; a lower coupling effect of insulin on glucose; and a higher disappearance rate of C-peptide. We observed a lower formation of insulin and C-peptide from proinsulin in severe diabetics.
Insulin Binding and Glucose Uptake Differences in Rodent Skeletal Muscles
Authors: Bonen A , Tan M H , Watson-Wright W M
Published: September 2013

Insulin binding and 2-deoxy-d-glucose uptake were compared in the soleus, plantaris, and extensor digitorum longus (EDL) muscles, in vitro, since the known biochemical profile of the soleus differs markedly from the other two. The present study showed that insulin binding increased in all three muscles with increasing concentrations of insulin in the range of 0.2- 30 nM. However, the increase in binding of insulin to soleus at each insulin concentration exceeded that observed in the other two muscles (P < 0.05). Differences between the plantaris and EDL were not significant. The quantity of insulin bound at each concentration also increased more rapidly in the soleus than in either the plantaris (P < 0.05) or EDL (P < 0.05). Basal and insulin-stimulated uptake of 2-deoxy-d-glucose was also greater in the soleus than in the other muscles (P < 0.05). Maximal 2-deoxy-d-glucose uptake occurred at 1 nM insulin in each of the three muscles. These results indicate that in metabolically distinct types of skeletal muscles glucose uptake can differ markedly, and this is related to differences in the insulin binding capacities of these muscles.
Reversal of Increased Gastric Somatostatin in Streptozotocin-diabetic Rats by Whole Pancreas Transplantation
Authors: Chiba Tsutomu , Taminato Tomohiko , Kadowaki Seizo , Chihara Kazuo , Matsukura Shigeru , Nozawa Masumi , Seino Yutaka , Fujita Takuo
Published: September 2013

Changes in both the content and the release of gastric somatostatin after amelioration of streptozotocin (SZ)-induced diabetes by whole pancreas transplantation were investigated in the present study. Highly inbred male Lewis rats were divided into three groups:normal, control rats; SZ-induced diabetic rats; and SZdiabetic rats after whole pancreas transplantation. Fundic as well as antral somatostatin content in the streptozotocin-diabetic rats was significantly increased compared with the controls. Whole pancreas transplantation in SZ-diabetic rats markedly lowered the increased somatostatin content both in the fundus and the antrum. On the other hand, the exaggerated somatostatin release induced by glucagon from the isolated, perfused stomach observed in the SZ-diabetic rats was reduced to the level of normal rats by whole pancreatic transplantation. From these results, it is concluded that the hyperfunction of gastric D-cells in the SZ-diabetic rats is reversed by transplantation of Whole pancreas.
A Direct In Vitro Demonstration of Insulin Binding to Isolated Brain Microvessels
Authors: Frank Harrison J L , Pardridge William M
Published: September 2013

Recent in vivo autoradiographic studies have suggested that circulating insulin may bind to the capillary wall, i.e., the blood-brain barrier. In the present study the blood-brain barrier insulin receptor was examined directly by measuring [125I]-iodoinsulin binding to capillaries isolated from fresh bovine cerebral cortex. Microvessels were prepared by gentle hand homogenization and trapping on nylon mesh. The binding was rapid, specific, and reversible with one-half maximal binding attained in 7 min and maximal binding achieved in 45 min at room temperature. The high affinity site has an affinity constant of 2.3 ± 0.3 nM−1, and 50% displacement of [125I]-iodoinsulin occurred at approximately 9 ng/ml. [125I]-lodoinsulin was not displaced by excess thyrotropin, prolactin, or growth hormone, and proinsulin was much less potent than porcine insulin. These studies confirm the presence of a specific insulin receptor on brain microvessels. Although insulin does not cross the blood-brain barrier, the presence of an insulin receptor provides a possible mechanism by which blood-borne insulin can influence brain cell metabolism.
Hepatic Extraction of Plasma Immunoreactive Glucagon Components: Predilection for 3500-dalton Glucagon Metabolism by the Liver
Authors: Jaspan J B , Polonsky K S , Röjdmark S , Ishida T , Field J B , Rubenstein A H
Published: September 2013

This Study examines quantitatively the extraction of plasma immunoreactive glucagon (IRG) components by the liver. It was shown that the liver has a predilection for removal of the 3500-dalton biologically active IRG component with virtually no extraction of the other IRG fractions. Hepatic extraction of whole plasma IRG was 25.2 ± 2.5%. Analysis of the hepatic extraction of the four plasma immunoreactive components, separated by gel filtration, revealed variable but quantitatively insignificant extraction of all components other than the 3500-dalton fraction, which was 33.4 ± 3.2% (P < 0.001). Hepatic extraction of whole plasma IRG was significantly less than that of the 3500-dalton component during periods of basal glucagon secretion when IRG fractions other than the 3500-dalton fraction contribute substantially to the whole plasma IRG level. However, during periods of stimulation of glucagon secretion by arginine or arginine plus cholecystokinin-pancreozymin, when the 3500-dalton component accounts for virtually all of the whole plasma IRG level, hepatic extraction of whole plasma IRG was similar to that of the 3500-dalton fraction.
Diabetic Retinopathy in Identical Twins
Authors: Leslie R D G , Pyke D A
Published: September 2013

The prevalence and features of diabetic retinopathy have been examined in 95 pairs of identical twins, 31 concordant for insulin-dependent diabetes (IDD), 27 discordant for IDD, and 37 concordant for non-insulin-dependent diabetes (NIDD). Optic fundi were examined after pupillary dilatation and retinopathy was classified as nil, background, or severe. In the NIDD twins, 35 of the 37 pairs were in the same category including all but one of the 15 pairs with the same duration of diabetes. However, in insulin-dependent diabetic pairs the situation was quite different; only 21 of 31 pairs were in the same retinopathy category, and of the 10 pairs of co-twins with the same duration of diabetes 5 pairs showed a striking difference for retinopathy. There was no significant difference in the prevalence of retinopathy in the concordant and discordant IDD twin pairs. Diabetic retinopathy was not observed in 32 unaffected co-twins of diabetics.

We conclude that genetic factors may be important in the etiology of retinopathy in non-insulin-dependent diabetes but that nongenetic factors must be important in the pathogenesis of retinopathy in insulin-dependent diabetes.