bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Insulin and Procaine Hydrochloride on Adipose Tissue Hexose Metabolism in ob/ob Mice: Evidence of a Postreceptor Defect
Authors: Hope-Gill Herbert F , Nanda Vinod , Kam Ting-Po
Published: September 2013

To determine if insulin resistance of obese hyperglycemic ob/ob mice might be due to an initial postreceptor defect, the effects of insulin and procaine HCI (0.1 mM) on glucose and fructose metabolism in their adipose tissue were studied. Procaine, unlike insulin, has been shown to exert its insulin-like effects on trypsinized adipocytes, suggesting an action independent of the insulin receptor. In the present study this agent, like insulin, stimulated glucose uptake, glycogenesis, pentose shunt activity, and lipid synthesis in tissue of lean littermates but not of ob/ob siblings. Prewashing has been shown to restore the sensitivity of their adipose tissue to insulin regarding antilipolysis and hexose metabolism, presumably by restoring available receptor number. In the present study, in contrast to the complete restoration of antilipolysis, prewashing only partially restored the effects of insulin (but not of procaine) on glycogenesis and lipid synthesis in tissue of ob/ob mice; no return of effects of either agent on glucose uptake or the pentose shunt occurred. Since hexose metabolism remained unresponsive to procaine and since prewashing restored only antilipolysis and a portion of the lipogenic effect of insulin (but not effects on glucose uptake or pentose shunt activity), these studies suggest an underlying irreversible defect in responsiveness of glucose uptake and the pentose shunt in adipose tissue of ob/ob mice independent of a deficiency of available insulin receptors. That portion of insulin resistance due to hyperinsulinemia and resulting receptor deficiency might be secondary to these underlying inherent defects.
Effect of Continuous Low-Dose Insulin Treatment on Subsequent Incidence of Diabetes in Genetically Prediabetic Chinese Hamsters
Authors: Frankel Barbara J , Grodsky Gerold M
Published: September 2013

In an attempt to prevent the onset of diabetes, young, genetically prediabetic (but not yet hyperglycemic) Chinese hamsters were treated continuously with insulin via minipump for 4 wk beginning 1 wk before the predicted age of onset of glucosuria (age 7 wk). Continuous insulin infusion, which increased the plasma insulin levels by 70%, did. not cause hypoglycemia, nor did it reduce the incidence or severity of diabetic symptoms over the ensuing year of observation. In fact, early treatment with exogenous insulin tended to cause increased hyperglycemia and glucosuria. No plasma anti-insulin antibodies were detected 3 and 9 months after stopping insulin treatment.
Correlation Between Morphology and Function in Isolated Islets of the Zucker Rat
Authors: Hayek Alberto , Woodside William
Published: September 2013

Obesity in the Zucker rat is accompanied by hyperlipemia, hyperinsulinism, insulin resistance, pancreatic hyperplasia, and islet hypertrophy. This study correlates the morphologic heterogeneity of isolated pancreatic islets with secretion of insulin and glucagon in a perifusion system. Islet size was arbitrarily defined as large (>0.45 mm) or small (<0.12 mm). Protein content and volume (V = 4/3πr3) were calculated for groups and individual islets, respectively. Islets from obese rats secreted more insulin in response to glucose and aminophylline than islets from lean rats (peak 7.8 ± 2.4 vs. 1.5 ± 0.37 μU/islet/min, P < 0.005). Insulin release was related directly to islet size and protein content. Small islets from lean and obese animals produced less insulin per islet than large islets (P < 0.005). In terms of islet volume, however, large islets were inefficient insulin releasers as compared to small islets (P < 0.005). Stimulation with Br-cAMP released glucagon from islets of lean but not from large islets of obese animals (peak 11 ±3.3 vs. 4.1 ± 0.3 pg/μg protein per minute, P < 0.05). Arginine produced the same effect on glucagon release (P < 0.05) as stimulation with Br-cAMP. The observed increased insulin release rates and the blunted glucagon response are related to islet size in the pancreas of the Zucker rat.
The Effect of Age on Glucose Tolerance: Studies in a Micronesian Population with a High Prevalence of Diabetes
Authors: Zimmet P , Whitehouse S
Published: September 2013

Venous plasma glucose concentrations before and two hours after a 75 g carbohydrate load were determined on 597 Nauruans, a Micronesian population with one of the highest diabetes prevalence rates yet recorded in the literature.

A marked increase in both the mean fasting and postload plasma glucose concentrations with age for both sexes was noted for the total population.

In this population the frequency distributions of fasting and two-hour plasma glucose show bimodality, separating the population into normal and hyperglycemic subpopulations. Analysis of mean fasting and two-hour glucose concentrations of subjects in the normal and hyperglycemic components shows that the increase in mean glucose with age in the Nauruan population is mainly the result of an increasing proportion of subjects falling into the hyperglycemic (diabetic) component with increasing age. Only small changes in mean glucose concentrations with age were noted in subjects in the normal component.

Percentile distributions of both fasting and postload glucose concentrations indicate that there is a dramatic age-related increase in glucose concentrations in the higher percentiles (70th and 90th) in both males and females. This finding is consistent with the hypothesis of two subpopulations in which the glucose concentrations increase significantly with age in one (higher percentiles) and remain relatively constant in the other (lower percentiles).

The data indicate that, while there is a rise in glucose concentrations with increasing age, it does not necessarily represent diabetes. The major contribution to this age-related rise is due to the increasing number of diabetics with age, and the diabetics can be separated from the rest of the population on the basis of percentile analysis and bimodality of glucose distributions.
Hepatic Effects of Chlorpropamide: Inhibition of Glucagon-stimulated Gluconeogenesis in Perfused Livers of Fasted Rats
Authors: Blumenthal Stanley A , Whitmer Kyra Riegle
Published: September 2013

In perfused livers of rats fasted for 24 h, glucagon (5 × 10−10 M) significantly elevated tissue and perfusate levels of cyclic AMP and caused a twofold increase in glucose formation from lactate. Chlorpropamide (0.8 × 10−3 M) consistently blocked these effects. Measurements of metabolic intermediates suggest that chlorpropamide may inhibit gluconeogenesis by antagonizing the action of glucagon on the phosphoenolpyruvate cycle.

In the experiments described, chlorpropamide did not lower hepatic ATP concentration or energy charge, and exerted its effects at perfusate concentrations comparable to serum concentrations reported in patients on maintenance doses of the drug.
High Plasma Norepinephrine Concentrations at Birth in Infants of Diabetic Mothers
Authors: Young James B , Cohen Wayne R , Rappaport Elizabeth B , Landsberg Lewis
Published: September 2013

Analysis of plasma norepinephrine (NE) concentrations in umbilical artery and vein from infants of diabetic and nondiabetic mothers revealed high plasma NE values in those of diabetic mothers. While birth weight and arterial plasma NE did not correlate in infants of nondiabetic mothers (r = 0.07, NS), birth weight and plasma NE were related inversely in infants of diabetic mothers (r = −0.73, P < 0.05).
Glucagon-like Polypeptides in Canine Brain
Authors: Conlon J Michael , Samson Willis K , Dobbs Richard E , Orci Lelio , Unger Roger H
Published: September 2013

Glucagon-like material has been detected by radioimmunoassay in several areas of the canine brain. High concentrations of glucagon-like immunoreactivity (GLI), measured with antibodies directed against the N-terminal region of glucagon, have been found in the hypothalamus, amygdala, and mesencephalon, but a high concentration of immunoreactive glucagon (IRG), measured with antibodies directed against the C-terminal region of glucagon, has been found only in the hypothalamus. The predominant molecular forms of GLI isolated from brain extracts by affinity chromatography are the same as those isolated from gut extracts. The predominant form of IRG in brain extracts is of the same (approximate) molecular weight as pancreatic glucagon.
Normalization of the Growth Hormone and Catecholamine Response to Exercise in Juvenile-Onset Diabetic Subjects Treated with a Portable Insulin Infusion Pump
Authors: Tamborlane William V , Sherwin Robert S , Koivisto Veikko , Hendler Rosa , Genel Myron , Felig Philip
Published: September 2013

The plasma growth hormone, epinephrine, and norephinephrine responses to cycle ergometer exercise (15 min at 1 W/kg) were examined in 10 juvenile-onset, insulin-dependent diabetics (ages 10–32 yr) during conventional insulin treatment and after 7 and 14 days of treatment with a portable subcutaneous insulin infusion system that normalizes plasma glucose. During conventional insulin treatment (mean plasma glucose, 205 ± 22 mg/dl), the growth hormone response to exercise was sevenfold greater than in normal controls (P < 0.01). After 1 wk of insulin pump treatment (mean plasma glucose, 89 ± 3), the growth hormone response fell 62% (P < 0.001); by 2 wk the growth hormone response had fallen 83% (P < 0.001) to values comparable to those of controls. Exercise resulted in a two- to threefold rise in plasma epinephrine in diabetics (P < 0.001) during conventional treatment but failed to elicit a consistent increment in epinephrine in normal control subjects or in the diabetic patients after 14 days of pump treatment. The rise in plasma norepiriephrine after exercise in conventionally treated diabetic patients was 12-fold greater than in healthy control subjects (P < 0.025) but fell 82% (P < 0.001) after 7 days and 88% (P < 0.001) after 14 days of pump treatment to values similar to those of controls. These data indicate that treatment of insulin-dependent diabetics with a subcutaneous portable insulin infusion system that normalizes plasma glucose results in normalization of the growth hormone and catecholamine response to exercise within 7 to 14 days of institution of treatment.
Variation in the Disappearance of Unlabeled Insulin from Plasma: Studies with Portal and Peripheral Infusions
Authors: Tranberg Karl-Göran , Thorell Jan
Published: September 2013

One hundred and thirty brief infusions of unlabeled insulin were given to 75 unanesthetized nondiabetic human beings. The patients were examined (1) by different doses of insulin (5−50 mU/kg), (2) by intraportal and peripheral infusion, (3) in the morning and in the afternoon, and (4) during normoglycemia and moderate, steady hyperglycemia. After intraportal infusion of insulin, the non-steady state plasma clearance rate (ml min−1 kg−1) was lowerthe largerthe dose (decreased about 50% by a 10-fold increase in insulin dose) and lower at hyper- than at normoglycemia (decreased about 30% after small insulin doses). It was also lower the higher the relative body weight, but this correlation was weak. After peripheral insulin infusion, none of the above relationships was demonstrated. Regardless of the route of insulin infusion, plasma clearance rate did not vary with fasting plasma insulin concentration, time of day, insulin sensitivity, or glucose tolerance. We conclude that the liver modifies the distribution and removal of pancreatically released insulin in response to acute increases in insulin or glucose. Otherwise the plasma clearance rate of insulin showed a notable lack of relationships with common indexes of metabolism and with insulin action.
Studies on Insulin Secreted by Isolated Islets of the Monkey, Macaca radiata radiata
Authors: Gunasekaran S , Zachariah P
Published: September 2013

The effects of various experimental conditions during the isolation of monkey islets by the collagenase method on the insulinogenic response of the isolated islets to glucose have been studied and compared with rat islets isolated under similar conditions. The monkey islets gave a normal response for at least 120 min. The results are compared with available studies on primate islets.
Morphologic Study of Cultured Pancreatic Fetal Islets During Maturation of the Insulin Stimulus-secretion Mechanism
Authors: Dudek Ronald W , Freinkel Norbert , Lewis Nancy Jo , Hellerström Claes , Johnson Robert C
Published: September 2013

We recently described a tissue culture system in which 21.5-day-old fetal rat islets underwent an in vitro maturation of insulin stimulus-secretion coupling over a period of 7 days. During the same period, the acinar part of the explanted fragments degenerated and the islets became isolated, seeming to increase in mass. In the present study, we have utilized these characteristic morphologic changes in an attempt to evaluate the extent that apparent islet growth reflects multiplication of preformed beta cells or the neogenesis of these cells from ductular or acinar cells. In the first days of culture, continuity between islets and ducts could be demonstrated, and the islets appeared to “bud” from the ducts. During this time, only insulin-and glucagon-positive cells could be demonstrated immunocytochemically, and the 3H-thymidine incorporation index of the beta cells (expressed as the percentage of beta cells labeled during 24 h of exposure to 3H-thymidine and 3 h of “chase”) in the “budding” islets was 28.7 ± 2.6. After 7 days in culture, i.e., after maturation of the insulin stimulus-secretion mechanism, the islets were no longer associated with ductular epithelium. At this stage, insulin-, glucagon-, and occasional somatostatin-positive islet cells could be demonstrated, and the 3H-thymidine incorporation index of the beta cells was significantly decreased to 16.7 ± 2.8. These observations are taken to support previous suggestions of a possible neogenesis of beta cells from duct epithelium in the rat. This tissue culture technique appears well suited for further detailed studies of this neogenesis.
Disparate Effects of Enkephalin and Morphine upon Insulin and Glucagon Secretion by Islet Cell Cultures
Authors: Kanter R A , Ensinck J W , Fujimoto W Y
Published: September 2013

Insulin and glucagon release from monolayer pancreatic islet cell cultures were inhibited in a dose-response fashion by various enkephalins. Morphine, however, stimulated insulin and glucagon release. Both effects were blocked by naloxone, while naloxone alone had no effect. In isolated and denervated islet cells, opiates directly influence secretion from islet cells.
Successful Allotransplantation of Mouse Pancreatic Islets to Nonimmunosuppressed Recipients
Authors: Bowen Kerry M , Andrus Linda , Lafferty Kevin J
Published: September 2013

Pancreatic islets from BALB/c (H-2d) mice are rejected within 14 days of transplantation to the kidney capsule of allogeneic, CBA/H (H-2k) recipients. Cyclophosphamide pretreatment of the islet donor reduced the intensity of the allograft response, and these islets undergo a more chronic rejection process. Islets from cyclophosphamide-pretreated donors can be cultured in a gas phase of 95% O2 and 5% CO2, provided the islets are aggregated into clusters of about 50 islets. After a culture period of 7–12 days, the islet tissue was transplanted to normal allogeneic recipients, where the tissue elicited little or no allograft response over a 3-mo observation period.
Cultured Hepatoma Cells as a Model System for Studying Insulin Processing and Biologic Responsiveness
Authors: Hofmann Cecilia , Marsh Jon W , Miller Bonnie , Steiner Donald F
Published: September 2013

Monolayer cultures of minimal deviation hepatoma cells (H4-II-E-C3′) bound and degraded insulin specifically, the apparent Ki value for insulin inhibition of both processes being 1 × 10−8 M, indicating that cellbound 125l-insulin is the substrate for subsequent hormone degradation in these cells as in isolated hepatocytes.1 The time course of insulin binding to its receptor depended on hormone concentration and temperature. Degradation of insulin also depended highly on temperature, with little or no degradation occurring at less than 20°C, a temperature below which a membrane–lipid phase transition may block hormone translocation or uptake. The effects of various agents on the binding and degradation of 125l-insulin also were tested. Agents believed to inhibit intralysosomal degradation of various proteins also inhibited the degradation of 125l-insulin by H4 cells (chloroquine, ammonium chloride, procaine, and lidocaine); inhibitors of energy production (dinitrophenol, sodium cyanide) inhibited degradation; an agent which inhibits microtubule function (vinblastine) blocked insulin degradation; and methylamine, reported to prevent receptor aggregation,2 also interfered with insulin processing. These findings are consistent with a model for cellular insulin processing, comprising receptor binding, clustering of receptors, endocytotic uptake, intralysosomal degradation, and extracellular release of some degradation products. H4 cells were highly sensitive to insulin. The KE for a half-maximal response of hormone-stimulated incorporation of 14Cglucose into glycogen was 10−11 M insulin, corresponding to less than 1% receptor occupancy. This response was also mimicked by concanavalin A at a concentration of 10 μug/ml. Vinblastine and chloroquine both significantly inhibited insulin-stimulated glucose incorporation into glycogen without affecting basal levels. However, since these inhibitory effects were not relieved by addition of excess insulin, it seemsunlikely that their action on glycogen synthesis was exerted only at the level of the generation of an active intermediate or degradation product from hormone-receptor complexes. The hormone-sensitive H4 cells thus provide a useful system for further studies examining the role of insulin-receptor uptake in hormone action, receptor regulation, and signal termination.
The Effect of Improved Diabetic Control on Plasma Lipid and Lipoprotein Levels: A Comparison of Conventional Therapy and Continuous Subcutaneous Insulin Infusion
Authors: Pietri Angel , Dunn Fredrick L , Raskin Philip
Published: September 2013

We studied short-term changes in plasma lipid levels in type I diabetics treated with either a conventional insulin regimen or continuous subcutaneous insulin infusion. Mean plasma glucose dropped from 260 ± 18 to 134 ± 8 mg/dl when conventional treatment was used and from 194 ± 18 to 108 ± 8 mg/dl with CSII. Both forms of therapy were associated with a significant fall in plasma triglyceride levels. However, only CSII treatment produced significant changes in total plasma cholesterol and LDL cholesterol levels. Total cholesterol fell from 195 ± 17 mg/dl to 161 ± 11 mg/dl and LDL cholesterol fell from 129 ± 13 mg/dl to 102 ± 9 mg/dl.

We conclude that improved diabetic control by any method is effective in lowering plasma triglyceride levels, but it requires almost perfect metabolic control to affect plasma cholesterol and LDL cholesterol levels. The changes in plasma lipid and lipoprotein achieved with CSII may favorably alter the prediction for the development of premature atherosclerosis in our patients.
Hypothesis: The Frequencies of Juvenile Diabetes in American Blacks and Caucasians Are Consistent with Dominant Inheritance
Authors: MacDonald Michael J
Published: September 2013

A test is described that can be used to distinguish whether a trait (in this case juvenile diabetes) is inherited in an autosomal dominant or a recessive manner. The frequencies of the trait are compared in two populations in which there has been a unidirectional influx of genes from the gene pool of one of the populations into that of the other. Before the racial admixture, the trait should be primarily a characteristic of the first population. If the trait is dominant, its frequency in the second population will be equal to the number of individuals carrying at least one gene causing the trait and thus directly proportional to the overall percentage of its genes received from the first population. If the trait is recessive, its frequency in the second population, relative to that in the first, will be far lower than the overall percentage of its genes received from the first population, because the rate of homozygotes is equal to the square of the gene frequency. The American Caucasian and black populations fulfill the criteria for the test. Racial admixture between the two groups has been entirely from the Caucasian to the black population, and juvenile diabetes was very likely nonexistent in black people before their arrival in North America. About 20% of the American black gene pool is composed of Caucasian genes and the frequency of juvenile diabetes in the American black population is 20%–30% that in American Caucasians. Because juvenile diabetes in American blacks is associated with the same HLA genes as in Caucasians, and these genes are also about 20%–30% as common in American blacks as in Caucasians, the occurrence of juvenile diabetes in American blacks is very likely due to Caucasian genes. If susceptibility to juvenile diabetes is inherited in a recessive manner, its frequency in black Americans should be about (1/5)2 or 1/25 the frequency in Caucasians. However, since the ratio of the frequency of juvenile diabetes in American blacks to that in Caucasians is roughly equal to, or certainly not lower than, the fraction of Caucasian genes in the American black gene pool, the data fit the criterion for dominant better than for recessive inheritance. Because population data are used in the test, factors that confound genetic studies in families, such as incomplete penetrance and recombination should not confound this test.
Response: Racial Differences in Juvenile-type Diabetes Are Consistent with More Than One Mode of Inheritance
Authors: Rotter Jerome I , Hodge Susan E
Published: September 2013

The ratio of the prevalences of insulin-dependent type (juvenile) diabetes (IDDM) in blacks and Caucasians is examined. It has been argued that this ratio is of the same order as the estimated proportion of Caucasian genes in the American black population. It has been further argued that this observation, together with an assumption of equal penetrances in the two races, is consistent with autosomal dominant inheritance for IDDM. The present paper shows that the ratio is equally compatible with a three-allele model which, moreover, incorporates observed immunogenetic heterogeneity within IDDM. This three-allele heterogeneity model exhibits some features of both dominant and recessive inheritance. The model predicts that, compared with Caucasians, there will be less pancreatic autoimmunity in the black IDDM population and lower recurrence risks to relatives of black diabetics. These predictions can be tested in future studies.
Short-term Regulation of Insulin Receptor Affinity in Man
Authors: Insel J R , Kolterman O G , Saeko M , Olefsky J M
Published: September 2013

We have studied the short term regulation of insulin receptors by serially measuring insulin binding to erythrocytes during 5 h of infusions of glucose and insulin. Two infusion protocols were employed: (1) Hyperinsulinemic study. Subjects were infused with insulin (80 mU/min) to induce sustained hyperinsulinemia, while euglycemia was approximated by infusion of glucose (8 mg/kg/min). (2) Hyperglycemic study. Subjects were infused with glucose (7 mg/kg/min) and a small amount of insulin (10 mU/min), while endogenous insulin secretion was inhibited with epinephrine and propranolol. Insulin binding to erythrocyte insulin receptors was measured serially during both of these infusion protocols for 5 h. The results demonstrated no change in insulin binding during the first 3 h of either infusion. However, by 5 h of either infusion, a striking 36% decrease in insulin binding, from 6.3 ± 0.5% to 4.0 ± 0.6%, was observed. Scatchard analysis and average affinity analysis of the binding data demonstrated that this decrease in insulin binding was entirely caused by a decrease in receptor affinity. Insulin binding to circulating monocytes was also measured, and comparable effects were observed. When cells were removed from the in vivo environment at 3 h and were incubated in vitro for a subsequent 2 h, decreased insulin binding developed during the incubation. Thus, this short term regulation of insulin receptor affinity occurred in vivo or in vitro, and cells that were programmed during the first 3 h of the infusion study could develop a decrease in insulin receptor affinity in vitro in the absence of plasma factors.
Defective Regulation of Cl− Permeability in Islets of Diabetic Mice [C57BL/KsJ(db/db)]
Authors: Berglund Ove , Sehlin Janove
Published: September 2013

Efflux of 36Cl− from prelabeled, collagenase-isolated islets of noninbred ob/ob mice, inbred diabetic [C57BL/KsJ(db/db)] mice, and nondiabetic [C57BL/KsJ(+/+)] mice was studied by nonrecirculating perifusion. Islets of both ob/ob mice and nondiabetic KsJ mice showed similar rates of basal 36Cl efflux, D-glucose stimulation of the 36Cl− efflux, and net uptake of 36Cl− at apparent isotope equilibrium. The 36Cl− efflux in islets from both young and old KsJ-db/db mice was almost insensitive to the D-glucose concentration. The basal rate of 36Cl− efflux in islets from young and old db/db mice was increased, indicating an abnormally high Cl− permeability. It is suggested that the defective regulation of the membrane potential in B-cells from [C57BL/KsJ(db/db)] mice may at least partly be caused by a db-mediated defect in the regulation of Cl− permeability.
Influence of the Age of Erythrocytes on Their Insulin Receptors
Authors: Eng John , Lee Lilly , Yalow Rosalyn S
Published: September 2013

Specific binding of 125I-insulin to erythrocyte receptors increased linearly with reticulocyte count in routine blood specimens from hospitalized patients. Specific binding as high as 30–35% is observed in patients with reticulocyte counts in the range of 20–25% compared with 9.0 ± 0.5% specific binding in healthy control subjects with normal reticulocyte counts. It is concluded that care must be exercised in interpreting elevations of specific 125I-insulin binding to erythrocyte receptors as due to specific disease processes without considering how the disease itself may alter mean erythrocyte age at the time of sampling.
Reduced Perikaryal Volume of Lower Motor and Primary Sensory Neurons in Early Experimental Diabetes
Authors: Sidenius P , Jakobsen J
Published: September 2013

The volume of nerve cell bodies of the anterior horn of the fifth lumbar segment and of the fifth lumbar dorsal root ganglion were measured by stereological methods in rats with 4-wk duration of streptozotocin diabetes and in age-matched controls. The perikaryal volume of motor and sensory neurons was reduced by 18% in diabetic rats and a shift between the number of A- and B-cells was observed in the dorsal root ganglion.

The findings are in accordance with our earlier observation of reduced axonal size of myelinated fibers in the common peroneal nerve. Furthermore, the data lead us to suppose that the nervous system abnormalities in early diabetes are not exclusively restricted to the peripheral nerves.
Abnormal Sciatic Nerve Myo-inositol Metabolism in the Streptozotocin-diabetic Rat: Effect of Insulin Treatment
Authors: Clements Rex S , Stockard Cecil R
Published: September 2013

The metabolism of myo-inositol and its hospholipids has been studied in the sciatic nerves of control, two weeks' streptozotocin-diabetic, and insulin-treated diabetic rats. The concentrations of glucose, fructose, and sorbitol were increased and the concentration of myo-inositol was decreased in the sciatic nerves of the diabetic animals; these abnormalities were only partially corrected by insulin therapy that was adequate to obviate hyperglycemia. Whereas the space of distribution of 2-3H-myo-inositol was found to exceed the total water space of the nerves of control animals, the 2-3H-myo-inositol space approximated the water space in the nerves of diabetic animals and was only slightly increased after insulin therapy. During the first 2 h after the intraperitoneal injection of 2-3H-myo-inositol, the recovery of radioactivity in nerve lipids was decreased by 69% in the untreated diabetics and by 77% in the insulin-treated diabetics. Analysis of the individual phosphoinositides revealed a proportional increase in the radioactivity recovered with phosphatidylinositol and a decrease in the recovery with triphosphatidylinositol in the diabetic nerves.

CDP-diglyceride:inositol transferase activity was decreased by 44% in homogenates of sciatic nerves from untreated diabetic rats, but it was normal in nerve homogenates from insulin-treated diabetics. The pattern of incorporation of radioactivity into phospholipids after 1 h of incubation of nerve homogenates with 2-3H-myo-inositol was similar to that observed in vivo. The fractional recovery of radioactivity with phosphatidylinositol was increased, whereas the recovery of label as triphosphatidylinositol was decreased by 11% in the presence of homogenates of sciatic nerves from diabetic rats.

These observations indicate that 2 wk of acute streptozotocin diabetes results in a decrease in the sciatic nerve content and space of distribution of myo-inositol and suggests that nerve myo-inositol transport may be defective in the diabetic animal. The observed abnormalities in the amount and pattern of incorporation of 2-3H-myo-inositol into diabetic nerve phospholipids could be explained, in part, by decreased activities of CDP-diglyceride:inositol transferase and phosphatidylinositol 4-phosphate kinase activities in the diabetic nerves. However, the fact that the incorporation of 2-3H-myo-inositol into phospholipids was decreased in the nerves of insulin-treated—diabetic animals despite a normal CDP-diglyceride:inositol transferase activity suggests that defective myo-inositol transport may also contribute to the abnormal neural phosphoinositide metabolism in this model. The possibility that these abnormalities are related to the development of the structural and functional changes associated with diabetic neuropathy requires further investigation.
Nonaggregating Insulin Solutions for Long-Term Glucose Control in Experimental and Human Diabetes
Authors: Albisser A Michael , Lougheed William , Perlman Kusiel , Bahoric Andrej
Published: September 2013

A physiologic additive for dissolving insulin crystals for parenteral application has been found. Insulin crystals are relatively insoluble in simple aqueous solutions. They will dissolve, however, in highly acidic solutions, but these are not suitable for parenteral use. Both neutral and acid pH insulin solutions have a tendency for the dissolved hormone to reaggregate. Notwithstanding possible changes in biologic activity, such formed aggregates must be prevented because they interfere with the flow in portable insulin delivery devices and result in the loss of glycemic control. The addition of 1.5% autologous serum to the aqueous diluent for insulin has eliminated these difficulties and increased by 37% the apparent biologic activity of insulin solutions prepared in this way. With this additive, continuous uninterrupted intravenous insulin infusion has provided near ideal blood glucose control in four pancreatectomized dogs for 5 mo and four patients with juvenile-onset diabetes for 18–23 days. Serum apparently contains factor(s) that promote the dissolution of insulin and prevent the formation of peptide aggregates in dilute solutions.
Beta-Cell Electrical Activity in Response to High Glucose Concentration
Authors: Beigelman Paul M , Ribalet Bernard
Published: September 2013

Glucose-induced β-cell electrical activity, recorded with glass microelectrodes, is characterized by trains of fast action potentials (“spikes”). The membrane depolarizes before each train of spikes and then depolarizes. This pattern is termed a “burst.” There is a characteristic biphasic response to a square wave of 11.1 mM glucose. Pulses at higher glucose concentrations (22.2 mM or more) evoke transient, constant spike activity. The duration of this activity is lengthened and the lag period shortened in proportion to the concentration and length of the glucose pulse. The lag period between removal of glucose and the cessation of spike activity is also proportional to the glucose concentration.
Glycosylation of Plasma Protein and its Relation to Glycosylated Hemoglobin in Diabetes
Authors: Yue D K , Morris K , McLennan S , Turtle J R
Published: September 2013

Glycosylation of plasma proteins was studied in diabetic and normal subjects by an adaptation of a thiobarbituric acid method previously used for glycosylated hemoglobin. There was a highly significant correlation between the degree of glycosylation in vivo of plasma protein and hemoglobin. The process of glycosylation depended on time and temperature and was not mediated enzymatically. Plasma protein of all molecular sizes could be glycosylated. At 37°C, 4.6% of 14C-glucose became attached to plasma protein after 24 h of incubation in vitro; no difference between normal and diabetic plasma protein could be demonstrated. After glycosylation, glucose dissociated from protein slowly; 72% remained attached after dialysis for 24 h. As an estimate of diabetic control, measurement of glycosylation of plasma protein is a suitable alternative to determination of glycosylated hemoglobin. Results of each method correlated equally well with the degree of diabetic control when this was assessed by calculation of the M-factor, mean plasma glucose concentrations, or variance of the plasma glucose determinations. In hemolytic anemia, hemoglobinopathy, and recent transfusion, measurement of glycosylation of plasma protein may be more accurate than that of glycosylated hemoglobin. It may also provide an estimate of diabetic control between that provided by short-term blood glucose determination and long-term glycosylated hemoglobin.
A Detailed Study of Risk Factors for Retinopathy and Nephropathy in Diabetes
Authors: West Kelly M , Erdreich Linda J , Stober Judy A
Published: September 2013

Indexes of retinopathy and nephropathy were studied in a large population of diabetics using standardized methods. In each of 973 subjects, more than 100 other variables were also measured: this made It possible to take into account many confounding factors when we examined the relationships of these variables to microangiopathy.

The most powerful risk factor for microangiopathy was duration of diabetes, but frequency of both retinopathy and nephropathy was impressively related to the level of plasma glucose at the time of examination. This latter relationship was independent of the effects of other variables. Risk of retinopathy was also related to factors that were probably associated with higher previous plasma glucose levels—need for insulin therapy, history of ketonuria, present level of plasma triglyceride, leanness, and younger age of onset of diabetes. In subjects with a systolic blood pressure of less than 170 mm Hg and who did not have proteinuria, no significant relationship was found between blood pressure and frequency of retinopathy, but, when the systolic pressure was greater than 169 mm Hg, rates of retinopathy were excessive, even In those subjects without proteinuria. Several other factors had no significant relationship to retinopathy or nephropathy: these included age, level of education, smoking, and plasma cholesterol. Rates of severe nephropathy were somewhat greater In men than in women, but this difference was not statistically significant. Rates of retinopathy and of mild proteinuria were similar in men and women. After adjustment for duration of diabetes, the risk of retinopathy was no higher in the 102 subjects with two diabetic parents than in the 254 who had no family history of diabetes.
Immunologic Features of Mice with Streptozotocin-induced Diabetes: Depression of Their Immune Responses to Sheep Red Blood Cells
Authors: Ishibashi Tsuneo , Kitahara Yoshinari , Harada Yasuko , Harada Susumu , Takamoto Masahiro , Ishibashi Tatsuro
Published: September 2013

The immune responsiveness in streptozotocin (SZ)-induced diabetic mice was studied using the immune responses to sheep red blood cells (SRBC) as an indicator system. In SZ-diabetic mice, the weights of such lymphoid organs as the thymus and spleen were significantly decreased with time after SZ administration, whereas the weight of liver was markedly increased. In SZ-diabetic mice, the level of delayed type hyper-sensitivity (DTH) to SRBC was not lower than that in normal controls in most cases, although the level of DTH was significantly depressed, on occasion, in SZ-diabetic mice. In contrast, antibody-forming activity, measured as the number of plaque-forming cells (PFC), was markedly decreased in SZ-diabetic mice. It seems that antibody production is more profoundly depressed than is DTH in SZ-diabetic mice. The transfer of normal thymus and bone marrow cells into SZ-diabetic mice caused only a partial restoration of PFC activity. When normal spleen cells were transferred into diabetic irradiated mice, proliferation of spleen cells and production of splenic PFC was greatly reduced as compared with normal irradiated mice. Treatment with insulin completely reversed such depression in the transfer system. These findings suggest that the chronic insulin-deficient diabetic state caused a depression and delay in the proliferation and differentiation of lymphoid cells.
Diabetes Mellitus Induces Changes in Cardiac Myosin of the Rat
Authors: Dillmann Wolfgang H
Published: September 2013

Decreased contractility has been reported in the diabetic heart. Because a close correlation exists between contractility and the activity of Ca2+ AT Pa se of purified actinomyosin and myosin, Ca2+ ATPase activity was determined in control and diabetic rats. In control rats, actinomyosin ATPase was 0.59 ± 0.05 μmol Pi/mg protein/min and had decreased by 35% to 0.38 ± 0.04 in diabetic rats (P < 0.025). Myosin ATPase activity was 1.25 ± 0.09 μmol Pi/mg protein/min in control rats and had decreased by 45% to 0.67 ± 0.05 in diabetic animals (P < 0.01). To investigate the decrease in myosin ATPase activity further, ventricular myosin was separated by pyrophosphate polyacrylamide electrophoresis into its three authentic components, V1, V2, and V3 myosin. V1 has the highest mobility and Ca2+ ATPase activity (1.27 ± 0.3 arbitrary units) and represents 72% of control myosin, whereas V3 has the lowest mobility and Ca2+ ATPase activity (0.16 ± 0.08 units) and constitutes 13% of myosin. A marked change in the predominance of V1 and V3 myosin components occurs in diabetic rats where V3 myosin predominates, representing 68% of total myosin with V1 myosin constituting only 15%. Ca2+ ATPase activities of V1, V2, and V3 myosin in control and diabetic hearts are similar; however, the predominance of V3 myosin in diabetic rats can account for the decreased Ca2+ ATPase activity of diabetic myosin. The diabetes-induced changes in myosin ATPase activity and myosin isoenzyme distribution can be reverted to control levels by insulin administration.
Glucagon Precursors Identified by Immunoprecipitation of Products of Cell-free Translation of Messenger RNA
Authors: Lund Pauline K , Goodman Richard H , Jacobs John W , Habener Joel F
Published: September 2013

Polyadenylated RNA extracted from anglerfish islets was translated in a wheat germ cell-free system containing [35S]methionine in the presence and absence of microsomal membranes prepared from a canine pancreas. Labeled translation products were analyzed by immunoprecipitation with an antiserum to porcine glucagon, followed by electrophoresis of the translation products and immunoprecipitated proteins on SDS polyacrylamide gels. In the absence of microsomal membranes two proteins of Mr = 14,500 and Mr = 12,500 were specifically immunoprecipitated with antiglucagon serum. Addition of microsomal membranes to the translation reactions resulted in a diminution of the labeled protein of Mr = 14,500 and a marked increase in the immunoreactive protein of Mr = 12,500. The protein of Mr = 12,500 was resistant to degradation by proteolytic enzymes added to translation reactions, indicating that it was segregated within microsomal vesicles. These results are consistent with synthesis of anglerfish islet glucagon in the form of a pre-prohormonal precursor (Mr = 14,500) containing a leader sequence that is cotranslationally cleaved from the protein by enzymes associated with microsomal membranes to produce a smaller intermediate prohormonal precursor (Mr = 12,500) of pancreatic glucagon (Mr = 3500).
Development of Insulin Release by Fetal Rat Pancreas In Vitro: Effects of Glucose, Amino Acids, and Theophylline
Authors: Kervran Alain , Randon Jacques
Published: September 2013

The dynamics of insulin release by pieces of fetal rat pancreas from 17.5 to 21.5 days of gestation was measured in an in vitro perifusion system. Interactions between glucose, theophylline, and a mixture of 12 amino acids at physiologic concentration (mix. A.A.) were studied.

On day 17.5, 13.9 m M glucose induced only a small (10 min) early phase of insulin release. The late phase of insulin secretion appeared on day 18.5 and gradually increased as the gestation proceeded. The mix. A.A. (9 mM) or theophylline (5 mM) potentiated the two phases of insulin release induced by 13.9 mM glucose from days 18.5 to 21.5 of gestation. On day 21.5, the combination of theophylline and mix. A.A. at 2.2 mM glucose stimulated insulin release by fetal pancreas.

The dose-dependent curves of the early phase of insulin release, due to glucose or glucose and mix. A.A. (9 mM), showed half maximal responses in the term fetal pancreas at glucose concentrations of 7.2 and 4 mM, respectively. The values were 7.9 and 5.9 mM for the late phase.

The results indicate that the mechanisms controlling biphasic insulin release develop during the late fetal life in the rat. Transition from the fetal to adult type of insulin secretion more likely parallels quantitative, rather than qualitative, changes within the B cells.
Androgen Sensitization of Streptozotocin-induced Diabetes in Mice
Authors: Maclaren Noel K , Neufeld Michel , McLaughlin Judith V , Taylor Glen
Published: September 2013

Male mice are more sensitive to the diabetogenic effect of streptozotocin (SZ) than female mice. These studies were designed to determine whether sex hormones could be responsible.

A single intraperitoneal (i.p.) dose of 80 mg SZ/kg regularly induced acute severe diabetes in 45 day old male CD-1 mice beginning after 1 day, whereas females of the same age and strain remained euglyce-mic for 75 days after the same SZ dose. With 120 mg SZ/kg, similar female mice developed a mild, delayed hyperglycemia 41 days after injection. Inbred strains (DB A/2 J) demonstrated a similar sex relationship.

In 45 day old male CD-1 mice, pretreatments with antiandrogen (SCH.13521) reduced the hyperglycemie effect of SZ when compared with control male mice given the same SZ dose (P < 0.001). Castration of male CD-1 mice before SZ also caused a milder hyperglycemia than in sham-operated control mice (P < 0.001). Pretreatment with estrogens before SZ in male CD-1 mice had little effect.

Female CD-1 mice, given 10 mg testosterone twice before the 120 mg SZ/kg injection, showed an increased sensitivity to SZ-induced diabetes when compared with female control mice or with female mice pretreated with only 1 mg testosterone (P < 0.001). Examination of the pancreases of these animals showed that the testosterone effect was accompanied by enhanced β cell destruction and increased and more centrally placed α cells within islets.

Phenobarbital when given daily for 7 days before the SZ injection potentiated the diabetogenic effect of SZ in male CD-1 mice and in female mice.

These studies are consistent with an important action of testosterone in potentiating the pancreatic /3 cell toxicity of SZ. The similar synergistic effect of phénobarbital may help to clarify the biochemical mechanism of SZ-induced pancreatic β cell destruction.
Insulin Activates Glycogen Synthase in Cultured Human Fibroblasts
Authors: Podskalny Judith M , Kahn C Ronald
Published: September 2013

To develop a technique for examining short term insulin effects in cultured human fibroblasts, the effect of insulin on glycogen synthase was determined. Fibroblasts contain detectable glycogen synthase activity which can be converted from the D form, dependent on glucose-6-phosphate for activity, to the I form, which is independent of glucose-6-phosphate, in the presence of insulin. In the basal state, about 6–20% of the glycogen synthase is independent activity. This increases to between 30 and 60 %l activity after insulin stimulation. Stimulation Is seen with insulin concentrations as low as 10−9 M, although maximal stimulation requires 10−7 – 10−6 M insulin. The effect of insulin is rapid, reaching a maximum within 20 min of incubation. Incubating the cells in fresh media without serum and glucose for up to 24 h before assay enhances the cellular response to insulin. Glucose has only a small, transient effect on the conversion of the enzyme from the D to the I form in the absence of insulin. These data demonstrate that human fibroblasts possess insulin-sensitive glycogen synthase, which may be used as a marker of metabolic response in disease states.
Glucose Stimulation of Somatostatin and Insulin Release from the Isolated, Perfused Rat Pancreas
Authors: Sorenson Robert L , Lindell Debra V , Elde Robert P
Published: September 2013

Insulin and somatostatin release from the isolated perfused rat pancreas was studied under conditions of 50 and 300 mg/dl glucose as well as a linear 50–300 mg/dl glucose gradient. The glucose-stimulated response profile of somatostatin was nearly parallel to that of insulin in both the acute and gradient dose experiments. Antisomatostatin serum was without significant effect on glucose-stimulated insulin release. In spite of the marked, fifteenfold stimulation of somatostatin release (1.5 × 1010 M in the perfusate effluent) by glucose, the concentration of somatostatin was insufficient to significantly alter glucose-stimulated insulin release in the isolated perfused rat pancreas.
Modifications of Glucose Storage and Oxidation in Nonobese Diabetics, Measured by Continuous Indirect Calorimetry
Authors: Meyer H U , Curchod B , Maeder E , Pahud P , Jequier E , Felber J-P
Published: September 2013

A new application of continuous indirect calorimetry is described for measuring the disposal of a glucose load. In a group of 10 normal subjects, 3 h after a 100 g oral glucose load, 20 g glucose was oxidized at basal rate, 19 g in response to the load and 63 g stored, while a decrease of 2 g was observed in the glucose space (GS). In a group of four type I, insulin-dependent diabetics, both glucose oxidation (9 g at the basal rate and 4 g in response to the load) and glucose storage (9 g) were markedly decreased, with the remainder either being lost in the urine (36 g) or remaining in the glucose space (42 g). In a group of eight nonobese type II, non-insulin-dependent diabetics, glucose oxidation both at the basal rate and in response to the load was slightly decreased (13 and 14 g, respectively) and glucose storage decreased to 40 g. These results suggest that, in type I diabetics, complete insulin deficiency seriously impairs two major mechanisms regulating glucose homeostasis, i.e., glucose storage and oxidation, while, in type II diabetics, the remaining insulin secretion attentuates these disturbances.