bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variable Deterioration in Cortical Function During Insulin-induced Hypoglycemia
Authors: Herold Kevan C , Polonsky Kenneth S , Cohen Robert M , Levy Jerre , Douglas Frank 
Published: September 2013

Cortical function during insulin-induced hypoglycemia was studied in 14 normal controls and 12 type I diabetic patients by measuring the reaction time to a visual stimulus. Each subject was studied on two occasions, during insulin-induced hypoglycemia and under euglycemic conditions. The mean reaction time during euglycemic conditions was 260 ± 6 ms in the controls and 309 ± 11 ms in the diabetic subjects (P &lt; 0.001) and did not change significantly over a 2-h period. Intravenous (i.v.) insulin administration to both groups of subjects resulted in similar reductions in glucose concentrations, which were maintained below 50 mg/dl for at least 30 min. Under these conditions, the reaction time increased significantly (mean increase 104 ± 37 ms [P &lt; 0.02] in the controls and 75 ± 28 ms [P &lt; 0.02] in the diabetic subjects). However, significant variability in responsiveness was observed in individual subjects. Three of the 14 controls and 4 of the 12 diabetic subjects showed no significant change in reaction time during hypoglycemia, while the remainder demonstrated significant increases. Individual differences were not correlated with severity or duration of hypoglycemia or counterregulatory hormone responses. The maximum increase in reaction time occurred as long as 60 min after the nadir glucose and returned to baseline 10–40 min after normalization (&gt; 60 mg/dl) of the plasma glucose level. Subjective awareness of hypoglycemia was unrelated to the change in reaction time.
These studies demonstrate that: (1) the reaction time to a visual stimulus is an objective, reproducible measure of cortical function during insulin-induced hypoglycemia; (2) control and diabetic subjects demonstrate variable sensitivity to the effects of hypoglycemia on cortical function, which is unrelated to the counterregulatory hormone responses; (3) the deterioration of cortical function observed during induction of hypoglycemia and the recovery of cortical function after euglycemia is restored may lag behind the changes in plasma glucose level (these findings help explain the frequently observed lack of correlation between the neurologic effects of hypoglycemia and simultaneous peripheral glucose levels); and (4) individual differences in cortical sensitivity as reflected by the reaction time response to hypoglycemia may parallel the variable clinical picture associated with hypoglycemia in insulin-treated diabetic subjects.
Insulin-induced Desensitization at the Receptor and Postreceptor Level in Mitogen-activated Human T-Lymphocytes
Authors: Ercolani Louis , Lin Hsin Lee , Ginsberg Barry H 
Published: September 2013

Human T-lymphocytes activated by phytohemagglutin acquire insulin receptors in culture. Saturation analysis of insulin-binding activity in the presence of competing ligand revealed curvilinear Scatchard plots. Insulin receptorswere not regulated by insulin before mitogen activation and culture of T-lymphocytes. However, insulin-induced downregulation of insulin receptors was: (1) demonstrable in receptor-positive cells, (2) dependent on insulin concentration, (3) temporally unrelated to insulin internalization, and (4) prevented by culture at 4°C but not by cycloheximide at 37°C. Recovery of insulin receptors required further culture of cells in media depleted of insulin for 24 h. Scatchard analysis revealed loss of receptor number without changes in receptor affinity.
Insulin-induced increases in glucose transport and oxidation were demonstrable in receptor-positive cells but not in receptor-negative cells. However, these effects were extremely time-dependent. After a 2-h exposure of cells to 10−8 M insulin, increases in glucose transport were no longer demonstrable. Elution of bound insulin from these cells followed by re-exposure to insulin depressed glucose transport in them. Recovery from this hyporesponsive, desensitized state required a 6-h culture in insulin-depleted media. Glucose oxidation of desensitized cells couldbe stimulated by spermihe but not by insulin. These studies demonstrate the activated human T-lymphocyte is an insulinsensitive tissue that is capable of limiting its physiologic response to insulin by receptor- and postreceptor-mediated mechanisms.
Sex Steroid Dependency of Diabetes-induced Changes in Polyol Metabolism, Vascular Permeability, and Collagen Cross-Linking
Authors: Williamson Joseph R , Rowold Edwin , Chang Katherine , Marvel Joyce , Tomlinson Martha , Sherman William R , Ackermann Karen E , Berger Richard A , Kilo Charles 
Published: September 2013

The effects of castration on diabetes-induced increases in collagen cross-linking and vascular permeability and on polyol levels in new granulation tissue formed after induction of streptozocin (STZ) diabetes were examined in male Sprague-Dawley rats. New granulation tissue formation was induced by implanting sterile polyester fabric subcutaneously (s.c.) at the time of STZ injection 3 wk before assessment of vascular permeability and collagen cross-linking. Castration was performed 10 days before implanting the fabric. The characteristic increases in collagen cross-linking (manifested by decreased solubility in 0.5 M acetic acid) and in albumin permeation of the vasculature seen in intact diabetic rats were completely prevented by castration. Net collagen accumulation was not affected by diabetes or castration. Castration also markedly diminished diabetes-induced increases in tissue levels of sorbitol and completely prevented the decreases in tissue levels of myo-inositol and scyllo-inositol observed in intact diabetic rats, but had no effect on serum glucose levels, nonenzymatic glycosylation of plasma and granulation tissue proteins, or plasma somatomedin-C levels.
The demonstration that castration prevents diabetesinduced increases in vascular permeability and collagen cross-linking as well as imbalances in tissue levels of sorbitol, myo-inositol, and scyllo-inositol in this model indicates that all of these changes are sex steroid-dependent phenomena. While the pathogenesis of these vascular permeability and collagen cross-linking changes is clearly multifactorial, these new findings: (1) indicate that the role of sex steroids in the development of late complications of diabetes may be far more important than hitherto suspected, and (2) suggest an explanation for the clinical observation that diabetic complications are uncommon in prepubertal diabetic subjects regardless of duration of diabetes.
Lower Prevalence of Diabetes in Female Former College Athletes Compared With Nonathletes
Authors: Frisch R E , Wyshak G , Albright T E , Albright N L , Schiff I 
Published: September 2013

The prevalence rate of diabetes was determined for 5398 living college alumnae (2622 former college athletes and 2776 nonathletes) from data on medical history, athletic training, and diet. For all ages, the prevalence rate among the former athletes was 0.57% (15/2622) and among the nonathletes was 1.3% (37/2776). The former college athletes and the nonathletes had similar percentages in family history of diabetes, i.e., 12.0 and 13.5%, respectively.
For cases occurring at age ≥20 yr (thus assessing the effects of college athletic training), 0.5% (13/2622) of the former college athletes had diabetes compared to 1.2% (32/2776) of the nonathletes; the relative risk is 2.24 [95% confidence limits (CL), 1.19 and 4.74, respectively]. Omitting cases of gestational diabetes, the relative risk of diabetes in nonathletes versus athletes is 3.41 (95% CL, 1.33 and 8.70). The percentages of former athletes and nonathletes that are insulin-using, non-insulin-using, and gestational diabetics did not differ significantly. The athletes were leaner than the nonathletes at all ages up to 70 yr. Of the former college athletes, 82% had been on precollege teams, compared to 25% of the college nonathletes; 74% of the former athletes were exercising regularly, compared to 57% of the nonathletes. We conclude that long-term athletic training is associated with a lower risk of the development Of diabetes.
Insulin Receptors in Embryo and Extra Embryonic Membranes of Early Somite Rat Conceptus
Authors: Unterman T , Goewert R R , Baumann G , Freinkel N 
Published: September 2013

Intact rat conceptuses were cultured from day 9.5 of gestation on. Individual components of the conceptus, including the embryo and the extraembryonic membranes (consisting of yolk sac, amnion, and allantoic placenta), were isolated and examined for insulin receptors at two time points during organogenesis: 1) day 10.4 of gestation (∼10–12 somites) when the yolk sac had become vascularized and just before closure of the anterior neuropore and 2) day 11.6 (∼27–31 somites) when vascularization of the chorioallantoic placenta had been established and the neural tube was closed completely. The studies were designed to provide inferential insights about the possible role of insulin in embryogenesis during different phases of nutrient delivery.
Active insulin degradation occurred with embryo as well as membrane homogenates during incubation at 37°C. Degradation was markedly reduced at 4°C, and binding of 125I-labeled insulin by embryo or membrane homogenates prepared on day 10.4 or 11.6, respectively, of gestation approached equilibrium after a 20-h incubation at this temperature. Values for the specific binding of tracer (0.4 ng/ml) or carrier (10.4 ng/ml) insulin by embryo and membrane homogenates were the same on days 10.4 and 11.6; specific binding was significantly greater with preparations of membranes than embryo at both time points. Full binding curves on day 11.6 showed similar affinities for insulin by embryo and membranes (Ke = 1.2 × 108/M and 4.6 × 108/M, respectively). Specificity of the binding was confirmed by comparison with proinsulin, desoctapeptide insulin, and insulin-like growth factor I and by the demonstration that maximally effective amounts of human antiinsulin receptor antiserum inhibited insulin binding ∼75% in embryos and 92% in membranes on both days. Photoaffinity cross-linking studies confirmed the presence of a major insulin-binding moiety in embryos and membranes similar to that found in rat liver plasma membranes (L) but different in apparent molecular weight (liver plasma membranes &gt; membranes &gt; embryo).
Our studies indicate that specific insulin receptors are present in the embryo and membrane components of the early postimplantation rat conceptus at two different stages in the development of nutrient delivery systems. However, the embryos and extraembryonic membranes display some differences with regard to the number and binding characteristics of their specific insulin receptors at both time points. The functional significance of these differences remains to be elucidated.
Fine Structural Abnormalities of the Placenta in Diabetic Rats
Authors: Gewolb I H , Merdian W , Warshaw J B , Enders A C 
Published: September 2013

In the streptozocin-induced diabetic rat, the placenta is larger and the fetus is smaller than normal. To study cellular differences that might contribute to the size and functional disparity between diabetic and control placentas, a light- and electron-microscopic analysis was performed on 14-, 18-, and 22-day (term) control and diabetic placentas.
Diabetic placentas, especially later in gestation, were marked by the presence of large numbers of glycogendistended cells in the basal zone. Within the placental labyrinth, the trophoblastic layers of the interhemal membrane were significantly thicker in the diabetic placentas on days 18 and 22, and large accumulations of lipid droplets were present, especially in the inner two trophoblastic layers. In normal placentas there is a marked thinning of the placental barrier in the labyrinth by day 22 of gestation, making the thickness of the labyrinthine layers in age-matched diabetic placentas even more impressive. Finally, the labyrinth of 22-day diabetic placentas contained more glycogen and rough endoplasmic reticulum in the inner trophoblastic layer, a feature that is found in less-mature (18-day) control placentas.
Thus, the diabetic placentas have a number of features that are consistent with functional immaturity/ dysmaturity. Cytologic evidence confirms the presence of increased glycogen and lipid reserves in both the junctional zone and the cellular area between maternal and fetal blood. The thickening and modification in the interhemal membrane of the labyrinth of the diabetic placentas increase the diffusion distance between the maternal and fetal circulations and thus may adversely affect placental exchange functioning and result in the fetal growth retardation seen in this model of the diabetic pregnancy.
Metabolic Consequences of Prolonged Hyperinsulinemia in Humans: Evidence for Induction of Insulin Insensitivity
Authors: Marangou A G , Weber K M , Boston R C , Aitken P M , Heggie J C P , Kirsner R L G , Best J D , Alford F P 
Published: September 2013

Hyperinsulinemia is frequently associated with a variety of insulin-resistant states and has been implicated causally in the development of insulin resistance. This study examines the metabolic consequences of prolonged hyperinsulinemia in humans. Basally and 1 h after cessation of a 20-h infusion of insulin (0.5 mU · kg−1 · min−1, aimed at elevating plasma insulin levels to ∼30 mU/L) or normal saline, subjects were assessed for 1) glucose turnover with 3-[3H]glucose; 2) insulin sensitivity, as measured by either the euglycemic glucose-clamp technique or the intravenous glucose tolerance test (IVGTT) minimal model method of Bergman; and 3) monocyte insulin-receptor binding. Hepatic glucose production (Ra) was suppressed by &gt;95% during each euglycemic clamp and during the 20-h insulin infusion. After the insulin infusion, Ra and glucose utilization rate returned to the initial basal level within 1 h, as did insulin levels. At that time, insulin sensitivity was significantly decreased, as measured by the “insulin action” parameter during the 40- to 80-min phase of the clamp (0.049 ± 0.003 vs. 0.035 ± 0.007 min−1 P &lt; .05) and during the 80- to 120-min phase (0.047 ± 0.005 vs. 0.039 ± 0.007 min−1, .05 &lt; P &lt; .1). The IVGTT minimal model analysis revealed a fall in the rate of glucose disposal (KGTT) (2.8 ± 0.6 vs. 1.9 ± 0.2 min−1 P &lt; .05), which was entirely explained by a decrease in insulin sensitivity (SI, 9.4 ± 0.3 vs. 3.8 ± 0.2 min−1 · μU−1 · ml−1, P &lt; .02); there was no change in glucose-mediated glucose disposal (SG, 0.029 ± 0.004 vs. 0.029 ± 0.004 min−1) or pancreatic Ybgr;-cell responsiveness (ø1, 2.7 ± 0.4 vs. 2.6 ± 0.5 μU · ml−1 · min mg−1 · dl−1; ø2, 7.8 ± 2.4 vs. 7.8 ± 2.4 μU · ml−1 · min−2 – mg−1 · dl−1). Monocyte insulin-receptor binding was unaffected by the prolonged hyperinsulinemia.
Our studies indicate that modest sustained hyperin- sulinemia may lead to decreased insulin action in the presence of normal monocyte insulin-receptor binding and normal pancreatic insulin secretion. If the monocyte reflects insulin binding in the key insulin-sensitive tissues, this defect in insulin action probably lies at a postreceptor level.
Functional Characteristics of Decreased Insulin Receptors on Fibroblasts Obtained from a Subject with Severe Insulin Resistance and Acanthosis Nigricans
Authors: Prince Melvin J , Smith Fannie E , Peters Edward J , Stuart Charles A 
Published: September 2013

In a patient with severe insulin resistance and acanthosis nigricans, a decrease in the number of insulin receptors has been found on freshly isolated monocytes and cultured fibroblasts compatible with a primary or genetic decrease in cell-surface insulin receptors. To determine the functional characteristics of the remaining receptors on these cells, insulin-stimulated glucose uptake, insulin internalization, and insulin-induced receptor loss were evaluated in monolayer fibroblasts obtained from this subject. Maximal insulin stimulation of 2-deoxyglucose was markedly blunted, compatible with abnormal insulin responsiveness due to a functional impairment of the remaining receptors. In the presence of chloroquine, the acanthotic subject's fibroblasts internalized more insulin per available receptor compared with the normal cell line, suggesting an accelerated rate of insulin internalization. When the rate of insulin internalization was more directly determined by assessing the rate of appearance of acid-resistant, cell-associated radioactivity at 37°C, a similar increase in insulin internalization rate was evident. When downregulation was assessed, insulin's ability to induce receptor loss in the acanthotic subject's cell line was augmented.
Thus, a primary or genetic decrease in insulin receptors on cultured fibroblasts from a patient with acanthosis nigricans and insulin resistance is associated with functional impairment of the remaining receptors leading to significant alterations in ligand processing and subsequent insulin action.
Islet Cell Antibodies Identify Latent Type I Diabetes in Patients Aged 35–75 Years at Diagnosis
Authors: Groop Leif C , Bottazzo Gian Franco , Doniach Deborah 
Published: September 2013

One hundred fifty-four selected patients with nonketotic diabetes diagnosed between the ages of 35 and 75 yr and treated with diet or oral hypoglycemie agents for at least 1 yr were investigated for parameters of glycemie control (weight loss, blood glucose, and glycosylated hemoglobin), islet cell function (fasting and glucagon-stimulated C-peptide responses), and immunologie markers of insulitis (total ICA and CF-ICA) or autoimmunity (thyroid and gastric antibodies). These parameters were all repeated in 9 of 22 ICA-positive patients after a 2-yr follow-up and correlated with secondary drug failure. The antibody tests were also done on 51 nondiabetic controls matched for age and body weight.
The 22 (14%) diabetic subjects having positive islet cell antibodies (ICA) included more women than men with a shorter duration of symptoms, lower body weight, more associated thyroid autoimmunity, and a tendency to have more type I diabetes in their families, although glycemic control, age at onset, and family history of type II diabetes were the same as in the 132 ICA-negative cases.
Patients with ICA had lower initial C-peptide levels and showed little rise after glucagon stimulation. Beta cell function deteriorated significantly during the 2-yr follow-up in 9 of 22 positive patients and more ICA-positive patients required insulin. It is suggested that these latent type I diabetic patients are characterized by persistent ICA, progressive loss of beta cells, and a high frequency of thyrogastric autoimmunity. The determination of ICA may be of clinical value in the diagnosis and treatment of nonketotic diabetes with onset in later life.
Putative Hypothalamic Glucoreceptors Play No Essential Role in the Response to Moderate Hypoglycemia
Authors: Cane Patricia , Artal Raul , Bergman Richard N 
Published: September 2013

The response to insulin-induced hypoglycemia includes increased plasma levels of glucagon, epinephrine, norepinephrine, cortisol, and growth hormone. This integrated response is thought to be mediated via sympathetic afferent pathways emanating from the ventromedial hypothalamus. However, the precise loci of the receptors that sense glucopenia are not known. In this study, we investigated the importance of putative forebrain glucoreceptors to the systemic response to hypoglycemia. Three protocols were performed. Protocol 1: the systemic response was observed in conscious dogs to hypoglycemia induced by infusion of insulin at a high rate (150 mU/min). Protocol 2: the effect of concomitant bilateral, intracarotid glucose infusion on the response to intravenous insulin was examined. Intracarotid glucose infusion rates were chosen to yield central euglycemia in the face of systemic hypoglycemia. Protocol 3: as a control for protocol 2, glucose was infused at low rates into the systemic circulation, yielding hypoglycemia in both central and systemic blood. When insulin was infused at 150 mU/ min, without glucose replacement (protocol 1; N = 6), plasma insulin increased from 14 ± 3 to 335 ± 35 μU/ ml at 60 min (P &lt; 0.001). Glucose fell from basal (104 ± 3 mg/dl) to 38 ± 3 mg/dl (P &lt; 0.001). Significant increases were observed in epinephrine (basal, B: 63 ± 8; steady state, SS: 1762 ± 582 pg/ml; P &lt; 0.007), norepinephrine (B: 209 ± 33, SS: 650 ± 133 pg/ml; P &lt; 0.01), and glucagon (B: 256 ± 35, SS: 467 ± 35 pg/ml; P &lt; 0.03). In addition, endogenous glucose production (Ra) increased from 72 ± 4 to 108 ± 9 mg/min (P &lt; 0.02) despite frank hyperinsulinemia. Infusing glucose into the carotid arteries at 204 ± 10 mg/min (protocol 2; N = 7) during a 4-h systemic insulin infusion was sufficient to prevent jugular hypoglycemia [jugular glucose, Gj, B: 100 ± 3, SS (90–160 min): 101 ± 3 mg/ dl; P &gt; 0.70], but not peripheral hypoglycemia (Gp, B: 102 ± 2, SS: 55 ± 3 mg/dl; P &lt; 0.001). Despite carotid glucose replacement, counterregulatory responses were still observed in epinephrine (B: 98 ± 14, SS: 466 ± 127 pg/ml; P &lt; 0.04) and norepinephrine (B: 213 ± 19, SS: 474 ± 133 pg/ml; P &lt; 0.05). Moreover, the magnitude of counterregulatory responses was not different when the glucose was given peripherally rather than centrally [protocol 3: epinephrine (B: 84 ± 18, SS: 523 ± 105 pg/ml; P &lt; 0.004), norepinephrine (B: 277 ± 65, SS: 445 ± 71 pg/ml; P &lt; 0.02)].
Counterregulatory responses to modest systemic hypoglycemia are not altered by the concomitant prevention of central hypoglycemia. Apparently, hypothalamic glucoreceptors are not essential for the sympathetic response to hypoglycemia, implying that important glucose-sensitive receptors are located elsewhere in the body.