bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decrease of Pancreatic Somatostatin in Neonatal Nesidiobiastosis
Authors: Bishop A E , Polak J M , Garin Chesa P , Timson C M , Bryant M G , Bloom S R 
Published: September 2013

The inappropriate insulin release that is characteristic of severe neonatal hypoglycemie and nesidiobiastosis was thought to be principally due to a marked proliferation of B-cells. A possible deficiency of somatostatin, one of the factors controlling insulin release, has only recently been considered.
We report here a significant decrease of pancreatic somatostatin cells and somatostatin content in nesidiobiastosis, as compared with appropriate controls.
Pancreatic tissue from five babies with severe hypoglycemie, hyperinsulinemia, and nesidiobiastosis was examined for insulin, somatostatin, and glucagon by immunocytochemistry and radioimmunpassay. There was a variable insulin cell hyperplasia among the nesidioblastotic specimens but no significant difference from controls was detected. In contrast, there was a consistent and highly significant (P &lt; 0.02) decrease (of more than 50%) of somatostatin cells (controls, 1.29 ± 0.22%; nesidiobiastosis, 0.53 ± 0.14%, mean ± SEM).
Similarly, there was no significant alteration in insulin content, although a slight increase was found in non-microadenomatous areas of the diseased pancreata (controls, 42.3 ± 4.1; nesidiobiastosis, 58.6 ± 9.4 nmol/g wet weight of tissue, mean ± SEM). However, somatostatin content was almost 60% below control values (controls, 0.365 ± 0.038; nesidiobiastosis, 0.16 ± 0.039 nmol/g), a statistically significant difference (P &lt; 0.01).
Thus, a marked reduction in the content of somatostatin was present in the pancreata of these infants with nesidiobiastosis, resulting in a distinct alteration of the normal pancreatic hormone balance.
Diabetic Macroangiopathy and Growth Hormone
Authors: Ledet Thomas 
Published: September 2013

The large vessel disease develops slowly and progressively among most diabetics. According to the concept of a specific diabetic macroangiopathy, the alterations in the large vessels are part of the general diabetic angiopathy and are different from the spotty atherosclerosis. This hypothesis proposes that the changes develop as a consequence of the metabolic situation in diabetes. The concept is based on epidemiologic, clinical, and patho-anatomical observations.
A model of large-vessel disease in diabetes is briefly described. Diabetic serum causes proliferation of the aortic myomedial cells in culture. Growth hormone causes a similar proliferation. Type I procollagen and fibronectin elaboration is enhanced by diabetic serum. The same effect has been found with growth hormone. Insulin treatment in experimental diabetes prevents the proliferation of arterial myomedial cells in the coronary arteries. The presented data are compatible with the concept of a diabetic macroangiopathy distinct from atherosclerosis.
Hormone Regulation of Glucose Metabolism in the Genetically Obese-Diabetic Mouse (db/db): Glucose Metabolism in the Perfused Hindquarters of Lean and Obese Mice
Authors: Chan Timothy M , Dehaye J P 
Published: September 2013

Glucose metabolism and insulin sensitivity in the skeletal muscle of genetically obese-diabetic mice (db/db) 5-6 wk of age (an early stage of the diabetes-obesityc syndrome) were examined using an in situ perfused hindquarter preparation. Rates of glucose uptake, 14CO2 production from (U-14C) glucose, and lactate production from glucose were all lower in muscles from dbldb mice than those from their lean littermates. Lactate production in muscle perfused without exogenous glucose was similar in both lean and obese mouse hindquarters. Likewise, epinephrine, which activated phosphorylase equally in both lean and obese mouse muscle, also elevated the tissue glucose-6-phosphate level and lactate production from endogenous source(s) to a similar degree in the two preparations. However, epinephrine was less effective In stimulating glucose uptake in the db/db mouse preparation.
Glucose uptake was lower in the obese mouse hindquarter at all insulin concentrations tested (0-1000 μU/ml). The half-maximally effective dose of insulin (50 μU/ml) remained unaltered, however, indicating a decrease in insulin responsiveness rather than sensitivity. Both basal and insulin (1 mU/ml)-stimulated (3H)-D-allose uptake In the dbldb mouse hindquarter were below normal. No difference in assayed hexokinase activity was observed. Muscle pyruvate dehydrogenase and glycogen synthase activities were elevated by insulin (1 mU/ml) to a similar extent in both lean and obese mice.
These findings suggest that at an early phase of development when obesity, hyperglycemia, and hyperinsulinemia are moderate, a defect in glucose transport plays a major role in the “insulin resistance” of the skeletal muscles of dbldb mice.
Decreased Stimulated Glucose Oxidation and lodination by Polymorphonuclear Leukocytes from Insulin-Treated Diabetic Subjects
Authors: Qvist Rajes , Larkins Richard G 
Published: September 2013

To investigate the mechanism of the reported abnormality of polymorphonuclear leukocyte (neutrophil) function in diabetes, the burst of oxidative activity accompanying the killing reaction and the neutrophil iodination reaction were measured in 21 stable, insulintreated diabetic subjects and 32 nondiabetic subjects of similar age range. Responses to standard killed preparations of Candida albicans (C. albicans) (glucose oxidation and neutrophil iodination) and Staphylococcus aureus (S. aureus) (neutrophil iodination) were studied. The iodination reaction was studied using the subjects' neutrophils suspended both in autologous serum and in pooled normal human serum, and the glucose oxidation test was performed using the neutrophils in pooled normal human serum.
There was a significant decrease in the conversion of 14C-1-glucose to 14CO2 in the neutrophils from diabetics [0.47 ± 0.04 (SE) cf. 0.64 ± 0.04 nmol/2 × 106 neutrophils/60 min, P &lt; 0.005] and in neutrophil iodination in response to S. aureus in both autologous serum (diabetics .089 ± 0.008 cf. 0.114 ± 0.008 nmol iodine/106 neutrophils/90 min, P &lt; 0.025) and in pooled human serum (diabetics 0.086 ± 0.009 cf. 0.105 ± 0.006, P &lt; 0.05). There was no significant difference in neutrophil iodination in response to C. albicans. There was a significant negative correlation between the diabetics' fasting plasma glucose level and neutrophil iodination in response to S. aureus in pooled human serum (r = - 0.54, P &lt; 0.05), but not between fasting plasma glucose and glucose oxidation.
It is concluded that there are significant decreases in stimulated glucose oxidation and in the neutrophil iodination reaction (reflecting decreased function of the myeloperoxidase-hydrogen peroxide-halide microbicidal system) in neutrophils from insulin-treated dia-betic subjects. These abnormalities may contribute to the defective bactericidal activity of diabetic neutrophils.
Functional Evaluation of a Bioartificial Pancreas Using Isolated Islets Perifused with Blood Ultrafiltrate
Authors: Reach Gérard , Poussier Philippe , Sausse André , Assan Roger , Itoh Mitsuyasu , Gerich John E 
Published: September 2013

A new bioartificial pancreas, in which rat islets within a Millipore chamber are perifused with blood ultrafiltrate (polyacrylonitrile membrane), has been developed and its function evaluated in vitro and in vivo. Use of ultrafiltration (instead of diffusion) permitted rapid transmission of changes in blood glucose to the islet compartment (less than 10 min). To determine whether ultrafiltrate of Krebs-Ringer bicarbonate buffer (KRBB) and blood could support normal islet Bcell function, insulin secretion of freshly isolated islets in response to a 20-mM glucose challenge was examined during perifusion with KRBB and then with ultrafiltrate produced either from KRBB itself or from blood of normal and streptozotocin-induced diabetic rats. In the latter case, perifusate was reinfused to the animals, whose plasma glucose and insulin were then measured.
Insulin responses to glucose were virtually identical when the same islets were perifused with KRBB and then with ultrafiltrate of KRBB (47 ± 12 versus 41 ± 9 ng/100 islets/24 min), or when islets were perifused with KRBB and then with ultrafiltrate produced from blood of normal rats (69 ± 6 versus 73 ± 11 ng/100 islets/24 min). When five diabetic rats were connected to the device containing 600 islets, their plasma glucose decreased from 19.8 ± 1.2 to 6.1 ± 0.5 mM (P &lt; 0.001) within 120 min without overshoot hypoglycemia, and remained normal for up to 6 h. Plasma insulin increased from 2.0 ± 0.1 to 11.4 ± 1.4 ng/ml (P &lt; 0.02) at 30 min and then decreased to 2.9 ± 0.6 ng/ml. After intravenous glucose administration (0.5 g/kg, N = 4), plasma insulin increased twofold within 15 min, and glucose disappearance rates were identical to those obtained in four normal rats (K = 2.13 ± 0.18 versus 2.23 ± 0.09, NS).
These results indicate that ultrafiltrate of KRBB and blood can acutely support normal islet B-cell function, and that ultrafiltration can provide satisfactory glucose-insulin kinetics for an implantable closed-loop insulin delivery system, in which nonsyngeneic islets may be protected against immune rejection.
Irreversibility of Glomerular Basement Membrane Accumulation Despite Reversibility of Renal Hypertrophy with Islet Transplantation in Early Experimental Diabetes
Authors: Gøtzsche O , Gundersen H J G , Østerby R 
Published: September 2013

A quantitative morphologic study of the glomeruli in rats after 4 wk of streptozotocin-induced diabetes showed a number of glomerular changes, as previously described. Of particular interest was the increase in the total amount of glomerular basement membrane material [from 0.94 ± 0.13 (SD) mm3 to 1.26 ± 0.14 mm3 per kidney]. This parameter did not change after 4 wk of normoglycemia following islet cell transplantation (1.19 ± 0.17 mm3), nor was the total glomerular volume normalized. The contralateral kidney was weighed and used for estimating the total amounts of protein, RNA, and DNA. Four weeks of diabetes expectedly resulted in a 50% increase in kidney weight, and islet cell transplantation diminished this to 15% in excess of normal.
The average cell size (protein/DNA ratio) paralleled the kidney size after diabetes and following transplantation. The average amount of RNA per cell (RNA/DNA) increased significantly after induction of diabetes and was totally normalized after transplantation. Kidney protein concentration (mg protein/mg kidney) remained constant throughout the experiment. Considering that a few weeks of diabetes provokes a large increase in basement membrane material, it is especially noteworthy that 1 mo of normoglycemia is quite insufficient to reverse the accumulation.
Effects of Pregnancy and Sex Steroid Administration on Skeletal Muscle Metabolism in the Rat
Authors: Rushakoff Robert J , Kalkhoff Ronald K 
Published: September 2013

To determine whether the insulin resistance, exaggerated fasting hypoglycemia, and hypoalaninemia of late human and rat gestation may reflect altered skeletal muscle metabolism, hindlimbs of nonpregnant (NPG) and 3-wk-pregnant (PG) rats were noncyclically perfused in situ. In 12- and 24-h-fasted NPG rats, 50–500 μU/ml of insulin significantly augmented glucose uptake 3-9-fold. In PG rats uptake was suppressed 40–50% at comparable hormone concentrations. Release of alanine and phenylalanine was suppressed 20–35% by 250 μU/ml or more of insulin in NPG rats. However, comparable insulin concentrations failed to suppress their release in PG rats. No differences between groups existed with respect to oxygen uptake, glycerol, lactate, or pyruvate release. Suppression of insulin sensitivity in 12-day-pregnant rats was not observed.
Since plasma estradiol (E) and progesterone (P) are increased in pregnancy, E-benzoate (5 μg/day) and/or P (5 mg/day) were injected s.c. into female rats for 21 days. In 12-h-fasted animals, E treatment potentiated whereas P treatment mildly antagonized insulin-induced glucose uptake relative to control values. Separate effects of E and P were offset when administered in combination. Individual or combined regimens did not alter oxygen uptake, or release of alanine, phenylalanine, lactate, or pyruvate.
In late gestation, insulin action on skeletal muscle is resisted with respect to glucose uptake, alanine release, and proteolysis. Fasting hypoalaninemia is not due to impaired alanine release from muscle, but may reflect increased fetal extraction. Fasting hypoglycemia may represent, in part, maternal gluconeogenic precursor deficiency due to fetal alanine removal. E and/or P treatment do not duplicate the observed metabolic Changes.
Insulin and Glucagon Breakthrough of Somatostatin Suppression: Importance of Portal Vein Hormone Measurements
Authors: Polonsky K , Jaspan J , Pugh W , Dhorajiwala J , Abraham M , Bux P , Moossa A R 
Published: September 2013

The infusion of somatostatin (800 ng/kg/min) into anesthetized dogs leads to suppression of portal insulin concentrations from 58 ± 5 μU/ml to 18 ± 5 μU/ml and peripheral arterial concentrations from 18 ± 2 μU/ml to 8 ± 2 μU/ml, these levels remaining suppressed for the duration of the infusion (210 min). Additional experiments were performed during which somatostatin (800 ng/kg/min) was infused alone for 30 min and then together with glucose to reach steady-state glucose concentrations of 422 ± 8 mg/dl. This hyperglycemic stimulus resulted in progressive increments in portal insulin of 15 ± 3, 22 ± 8, 41 ± 11, 62 ± 14, 77 ± 17, and 88 ± 6 μU/ml at successive 10-min intervals. The corresponding increments in arterial insulin were much less, being 5 ± 2, 4 ± 1, 5 ± 2, 8 ± 2,10 ± 4, and 19 ± 6 μU/ml. In separate experiments, the rate of glucose infusion was varied so that steady-state glucose concentrations of 173 ± 3, 255 ± 8, and 359 ± 5 mg/dl were achieved in successive 60-min periods. Portal vein insulin values in each period were 100 ± 34, 262 ±117, and 596 ± 162 μU/ml, with corresponding peripheral levels of 12 ± 6, 26 ± 14, and 69 ± 45 μU/ml, respectively. Similar experiments in which a lower dose of somatostatin was used (200 ng/kg/min), in the face of similar steady-state glucose increments, resulted in portal insulin levels of 182 ± 62, 435 ± 138, and 512 ± 102 μU/ml, and corresponding peripheral levels of 34 ± 15,141 ± 55, and 188 ± 20 μU/ml, respectively.
Somatostatin infusion (800 ng/kg/min) suppressed portal vein glucagon levels to 101 ± 16 and peripheral levels to 39 ± 3 pg/ml. In these animals, hypoglycemia was then induced by infusion of insulin, and portal and peripheral glucagon levels rose to 341 ± 11 and 146 ± 27 pg/ml, respectively.
Thus, the inhibition of insuiin and glucagon secretion by pharmacologic doses of somatostatin may be overcome by an appropriate stimulus. Because of the large capacity of the liver for insulin extraction, increases in portal insulin levels may not be reflected in the periphery. However, increases in portal vein glucagon, although underestimated from peripheral levels, were always associated with changes in peripheral levels, because the liver extracts less glucagon than insulin. These findings should be considered in the interpretation of experimental studies in which somatostatin has been used to suppress endogenous pancreatic hormone secretion and peripheral hormone levels alone are used to monitor the adequacy of suppression.
The Mechanism of Impaired T3 Production from T4 in Diabetes
Authors: Gavin Laurence A , McMahon Francis A , Moeller Marie 
Published: September 2013

Uncontrolled diabetes in man is associated with low serum T3 values and impaired production of T3 from T4. Because the thiol-dependent enzyme T4-5′-deiodinase catalyzes T4-deiodination to T3, the present study was conducted to determine whether these alterations in iodothyronine metabolism consequent to diabetes were due to a reduction in the tissue content of active enzyme or thiol cofactor availability. T4-5′- deiodinase activity and nonprotein sulfhydryl (NP-SH) groups were examined in liver homogenate preparations from groups of rats (T4-treated) diabetic (streptozotocin, 100 mg/kg i.p.) for 48-96 h and compared with controls.
The mean hepatic T4-5′-deiodinase activity in the control group was 4.8 ± 0.4 pmol/min/100 mg protein (mean ± SEM). In each of the diabetic groups (48, 72, and 96 h), the mean enzyme activity was significantly less (P &lt; 0.005) than the control mean. Homogenate enrichment with the thiol reagent dithiothreitol (DTT) (5 mM) failed to reverse this diabetic effect. Moreover, although the hepatic content of NP-SH groups was significantly less than the controls after 48 and 72 h of hyperglycemia, it had spontaneously reverted to normal by 96 h. Thus, the impaired enzyme activity could not be attributed to a deficiency of thiol cofactors.
The dissociation between enzyme activity and tissue sulfhydryl groups was further illustrated by the response to insulin treatment. Insulin was given by continuous s.c. infusion to 48-h diabetic rats for 48-96 h. Although insulin therapy normalized both enzyme activity and the hepatic thiol content, the temporal profile of each response was different. Insulin therapy rapidly (48 h) corrected the hepatic content of NP-SH groups, whereas the normalization of T4-5′-deiodinase activity required 72-96 h of insulin treatment.
There was a positive correlation (r = + 0.69, P &lt; 0.025) between the serum T3 values and hepatic T4-5′-deiodinase activity. The mean serum T3 concentration was significantly reduced (P &lt; 0.001) by the diabetes after 48 h and remained low at 72 and 96 h. Insulin treatment reversed this defect but, as in the case of enzyme activity, the normalization was delayed until 72-96 h of insulin therapy.
These results indicate that (1) diabetes reduces serum T3 levels and hepatic T4-5′-deiodinase activity in T4-treated rats, (2) T4-5′-deiodinase is probably the major regulator of serum T3 levels under these conditions, and (3) the reduced T4 -5′-deiodinase activity is independent of changes in the hepatic content of NPSH groups and probably reflects a reduction in the hepatic content of active enzyme.
Characterization of Insulin-induced Receptor Loss and Evidence for Internalization of the Insulin Receptor
Authors: Marshall Stephen , Olefsky Jerrold M 
Published: September 2013

We studied the relationship between insulin-induced receptor loss and insulin internalization in isolated rat adipocytes. When cells were exposed to 100 ng/ml insulin at 37°C for times ranging from 10 min to 6 h, a monoexponential loss of insulin receptors was observed for up to 4 h, with a t½ of 75 min and a 75% maximal loss. The insulin-induced loss of receptors was dose-dependent with a % maximal effective insulin concentration of 7.6 and 1.3 ng/ml in 2- and 6-h insulin- pretreated cells, respectively. The ability of insulin to mediate receptor loss was inhibited by low temperature (16°C) and by the metabolic energy depleters dinitrophenol and NaF, suggesting that receptor loss is mediated by an 125I-insulin compared with control cells, and the relationship between insulin-induced receptor loss and insulin internalization was assessed by comparing these two processes over time and as a function of temperature. Using this approach, a significant linear relationship was observed between these partners at various temperatures (r = 0.99) and times (r = 0.94). These results suggest that the mechanism whereby insulin induces receptor loss in adipocytes is by internalization of insulin-receptor complexes.
Insulin receptors remaining on 2-h insulin, pretreated cells had identical dissociation rates and exhibited similar negative cooperative interactions when compared with control cells. Furthermore, anti-insulinreceptor antibodies inhibited binding in both groups of cells to the same extent. In contrast to these similarities, insulin-induced receptor loss was accompanied by a progressive impairment in the ability of cells to accumulate intracellular insulin in the presence ofchloroquine, which we interpret as an insulin-induced slowing of insulin internalization.
In conclusion, (1) insulin causes a time-, temperature-, dose-, and energy-dependent loss of cell-surface insulin receptors; (2) the rate of receptor loss and the extent of insulin internalization are closely correlated, suggesting that insulin-induced receptor loss in adipocytes is mediated by endocytosis of insulin-receptor complexes; and (3) insulin-induced receptor loss is accompanied by a reduced ability of residual receptors to internalize insulin.
Impaired Phagocytic Function and Increased Immune Complexes in Diabetics with Severe Microangiopathy
Authors: Iavicoli M , Mario U Di , Pozzilli P , Canalese J , Ventriglia L , Galfo C , Andreani D 
Published: September 2013

An increase in circulating immune complexes (AgAb) of medium size has been observed in diabetics with late complications. This increase may be related either to an increased formation or reduced clearance. Alternatively, both mechanisms may be involved.
As medium-sized AgAb determined by the C1q solid phase method are mainly removed from circulation by the fixed phagocytes of the reticulo-endothelial system, we investigated the function of these cells using a colloid clearance test in diabetics with various degrees of microangiopathy. Microaggregated iodinated human serum albumin was injected into 30 diabetic volunteers with severe (group 1), moderate (group 2), and absent (group 3) microangiopathy, and into 40 normal volunteers.
The colloid clearance was significantly reduced in diabetics with severe microangiopathy in comparison with patients who had no sign of microangiopathy, or with normal subjects. A significant correlation was found between reduced colloid clearance and increased levels of circulating AgAb determined by C1q solid phase method. Results of this study suggest that the increase in circulating AgAb observed in patients with severe microangiopathy may result from an impaired function of fixed phagocytes.
The Chinese Hamster as a Model for the Study of Diabetes Mellitus
Authors: Gerritsen George C 
Published: September 2013

Selection for and against diabetes and subsequent inbreeding of Chinese hamsters started in 1963. Currently there are six inbred sublines that have greater than 85% incidence of glycosuria and two control inbred nondiabetic sublines that are essentially free of glycosuria. At birth, hamsters from inbred sublines are considered prediabetic. There is phenotypic variation between diabetic sublines. Onset time, incidence of ketonuria, blood glucose, plasma insulin, glucagon and glycohydrolase levels vary from subline to subline, but pancreatic insulin and glucagon levels are consistently low and high, respectively, in all diabetic sublines compared with nondiabetics. Experimental breeding data suggest a minimum of two homozygous recessive genes for diabetes. It is not known if the inbred lines are similar diabetic genotypes, but the probability is high that modifier background genes vary from subline to subline.
Chinese hamsters have diabetes ranging from mild to severe. Animals weighing 25 g can excrete up to 75 ml of urine containing 3 g of glucose per day. Fasting blood glucose as high as 500 mg/dl and 10 μmol/ml of beta-hydroxybutyrate have been reported. Gluconeogenesis is elevated, and some glycolytic enzymes are decreased in severe diabetes. Low levels of renal acid glycohydrolase enzymes may contribute to glomerular capillary loop basement membrane thickening in diabetic hamsters. Caloric restriction per se or reduction of dietary fat prevented onset of hyperglycemia and hyperinsulinemia in prediabetics. Morphologic changes have been observed in pancreatic islets, kidney, nerve, blood vessels, eyes, brain, and genitourinary systems of diabetic Chinese hamsters. Pathogenesis of diabetes in this animal appears to be related to an increased demand for insulin. Initially there is a positive response to this demand by beta cells, but exhaustion occurs. This is followed by a decrease in beta-cell mass and relative or absolute insulin deficiency.