bluuebunny/crossref_metadata_2025 huggingface dataset:
CD5+ B Lymphocytes in High-Risk Islet Cell Antibody–Positive and Newly Diagnosed IDDM Subjects
Authors: Schatz Desmond A , Lang Francois , Cantor Alan B , Riley William J , Maclaren Noel K , Sleasman John W , Barrett Douglas J
Published: September 2013

Human CD5+ B lymphocytes produce autoantibodies that bind to self- and exogenous antigens. Extremely high percentages of CD5+ B lymphocytes are present in the fetal and newborn periods, whereas they constitute only a minority of B lymphocytes in healthy adults. Increased percentages of circulating CD5+ lymphocytes have previously been demonstrated in several autoimmune diseases, including rheumatoid arthritis, progressive systemic sclerosis, Graves' disease, and Sjögren's syndrome. We measured the percentages of B lymphocytes that expressed the CD5 determinant in 93 control subjects (age range 1 day to 59 yr, mean ± SD 22.6 ± 17.7 yr), 17 subjects with newly diagnosed insulin-dependent diabetes mellitus (IDDM; range 5'29 yr, mean ± SD 13 ± 5.9 yr), 31 high-risk islet cell antibody (ICA)-positive nondiabetic subjects (range 4–45 yr, mean ± SD 19.8 ± 14.1 yr), and 13 subjects with IDDM of >5 yr duration (range 10–43 yr, mean ± SD 24.2 ± 9.9 yr). We report that CD5+ B-lymphocyte percentages are strikingly age dependent in healthy control subjects, declining progressively from the newborn period to the middle-age years (r = −0.75, P = 0.0001). In ICA+ nondiabetic and recent-onset IDDM subjects <29 yr of age, the percentage of circulating CD5+ B lymphocytes fell within the 95% confidence intervals established for control subjects. However, the age-dependent rate of decline in the percentage of CD5+ B lymphocytes within the control range was slower in ICA+ and newly diagnosed IDDM subjects than in control subjects.
Synergism of Obesity Genes With Hepatic Steroid Sulfotransferases to Mediate Diabetes in Mice
Authors: Leiter Edward H , Chapman Harold D , Falany Charles N
Published: September 2013

Sulfotransferases controlling the intrahepatic ratio of active androgens to estrogens represent key determinants of whether an obesity mutation will be diabetogenic in C57BL/KsJ female mice. Three unlinked genes (diabetes [db], obese [ob], and fat [fat]) all produced comparable obesity in C57BL/KsJ females, but only the fat mutation was not diabetogenic. The fat gene was incapable of eliciting virilizing changes in hepatic sulfotransferase activity, whereas both db and ob accelerated estrogen and suppressed androgen sulfation. Northern-blot analysis confirmed anomalous suppression of hepatic androgen sulfotransferase transcription in db and ob but not fat females. These findings suggest the utility of obesity genes in analyzing the interaction between hyperandrogenism, hyperinsulinemia, and diabetes.
Structural and Functional Considerations of GABA in Islets of Langerhans: β-Cells and Nerves
Authors: Sorenson Robert L , Garry Daniel G , Brelje T Clark
Published: September 2013

γ-Aminobutyric acid (GABA), a prominent inhibitory neurotransmitter, is present in high concentrations in β-cells of islets of Langerhans. The GABA shunt enzymes, glutamate decarboxylase (GAD) and GABA transaminase (GABA-T), have also been localized in islet β-cells. With the recent demonstration that the 64,000-Mr antigen associated with insulin-dependent diabetes mellitus is GAD, there isincreased interest in understanding the role of GABA in islet function. Only a small component of β-cell GABA is contained in insulin secretory granules, making it unlikely that GABA, co-released with insulin, is physiologically significant. Our immunohistochemical study of GABA in β-cells of intact islets indicates that GABA is associated with a vesicular compartment distinctly different from insulin secretory granules. Whether this compartment represents a releasable pool of GABA has yet to be determined. GAD in β-cells is associated with a vesicular compartment, similar to the GABA vesicles. In addition, GAD is found in a unique extensive tubular cisternal complex (GADcomplex). It islikely that the GABA-GAD vesicles are derived from this GAD-containing complex. Physiological studies on the effect of extracellular GABA on islet hormonal secretion have had variable results. Effects of GABA on insulin, glucagon, and somatostatin secretion have been proposed. The most compelling evidence for GABA regulation of islet hormone secretion comes from studies on somatostatin secretion, where it has an inhibitory effect. We present new evidence demonstrating the presence of GABAergic nerve cell bodies at the periphery of islets with numerous GABA-containing processes extending into the islet mantle. This close association between GABAergic neurons and islet α- and δ-cells strongly suggests that GABA inhibition of somatostatin and glucagon secretionis mediated by these neurons. Intracellular β-cell GABAA and its metabolismmay have a role in β-cell function. New evidence indicates that GABA shunt activity isinvolved in regulation of insulin secretion. In addition, GABA or its metabolites may regulate proinsulin synthesis. These new observations provide insight into the complex nature of GABAergic neurons and β-cell GABA in regulation of islet function.
Adhesion Molecules in Human Islet β-cells: De Novo Induction of ICAM-1 but Not LFA-3
Authors: Vives Marta , Soldevila Gloria , Alcalde Laura , Lorenzo Carlos , Somoza Nuria , Pujol-Borrell Richardo
Published: September 2013

Understanding how T lymphocytes recognize β-cell autoantigens is essential forthe elucidation of the pathogenesis of insulin-dependent diabetes mellitus. The increased and ectopic expression of HLA class I and II molecules detected in human β-cells may facilitate this interaction. T-lymphocyte recognition of surface antigens also involves adhesion accessory molecules: intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function—associated antigen 3 (LFA-3). These molecules not only allow cell contact but can also provide costimulatory signals for T-lymphocyte activation. Levels of ICAM-1 and LFA-3 expression in normal human islet cells and regulation of their expression by cytokines interferon-γ (IFN-γ), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6 have been studied by two-color immunofluorescence staining of pancreatic cryostat sections and fluorescence-activated cell sorter analysis. Neither ICAM-1 nor LFA-3 could be demonstrated in sections or in fresh cell preparations, but after 18 h of culture, β-, α-, and δ-cells expressed spontaneously moderate levels of ICAM-1 (but not LFA-3). IFN-γ and TNF-α alone or in combination strongly enhanced this spontaneous expressionof ICAM-1 in a time- and/or dose-dependent and additive manner but had no effect on LFA-3. An SV40-transformed islet cell line showed high basal levels of both ICAM-1 and LFA-3, but the response to cytokines followed the same pattern as primary cultures.Theabsence of constitutive expression of adhesion molecules in β-cells supports the concept that they are immunologically silent cells and may also explain the failure of inducing autoimmune diabetes in transgenic mice by the sole expression of class II in theβ-cells via genetic manipulation. The induction of ICAM-1 by the same cytokines that can induce HLA class I and class II expression suggests that, in the diabetic pancreas, remaining β-cells probably express ICAM-1 concomitantly with HLA products.
Epidemiology and Immunogenetic Background of Islet Cell Antibody–Positive Nondiabetic Schoolchildren: Ulm-Frankfurt Population Study
Authors: Boehm Bermhard O , Manfras Burkhard , Seißler Jochen , Schöffling Karl , Glück Michael , Holzberger Gerhard , Seidl Siegried , Kühnl Peter , Trucco Massimo , Scherbaum Werner A
Published: September 2013

Islet cell antibodies (ICAs) were determined in a large cohort of white nondiabetic schoolchildren (n = 4287) from a homogenous population in southern Germany. The prevalence of ICA levels ≥5 Juvenile Diabetes Foundation (JDF) U was 1.05% (95% confidence interval 0.8–1.4%). Analysis of HLA-DRβ and -DQβ alleles revealed that the specificities found to be increased in insulin-dependent (type I) diabetic subjects with the same ethnic background were also associated with ICA positivity in the nondiabetic schoolchildren. HLA-DR3 (P < 0.01) and -DR4 (P < 0.01) phenotypes and absence of Asp residue (P < 0.01) at codon 57 of the HLA-DQ β-chain were significantly increased in ICA+ compared with control subjects. High levels of ICAs, which were categorized as either ≥17 or ≥30 JDF U, were found to be associated with amino acids other than Asp at position 57 of the HLA-DQ β-chain. No association of ICA level was found for HLA-DR phenotypes.
Macrophage-Specific Chemotactic Lipid Release by In Vivo Streptozocin-Administered Mouse Islets
Authors: Muir Andrew , Rovin Brad H , Lacy Paul E , Schreiner George F
Published: September 2013

The development of insulitis in animal models of immune-mediated diabetes mellitus ispreceded by an influx of macrophages into the islets. In this study, ICR mice were givenfour 30-mg/kg doses of streptozocin over 36 h to induce insulitis. The islets were subsequently isolated and cultured in suspension. A macrophage-specific islet infiltration was observed within 48 h of the first drug injection. Concurrent with this leukocyte influx, enhanced in vitro release of a macrophage-specific chemotactic lipid by isletsfrom streptozotocin-administered animals was observed. By chromatographic analysis, the islet-derived chemotactic factor appears to resemble a moderately polar complex lipid that is distinct from previously characterized lipid chemoattractants. Secretion of the factor is not dependent on cyclooxygenase activity. Identification of this lipid may provide important insights into the etiology of insulin-dependent diabetes mellitus and otherautoimmune diseases.
Receptor Binding and Tyrosine Kinase Activation by Insulin Analogues With Extreme Affinities Studied in Human Hepatoma HepG2 Cells
Authors: Drejer Kirsten , Kruse Viggo , Dahl Larsen Ulla , Hougaard Philip , Bjørn Søren , Gammeltoft Steen
Published: September 2013

The insulin-receptor affinity of five human insulin analogues with one to four amino acid substitutions was measured with human hepatoma cells (HepG2). The binding affinities ranged from 0.05% for AspB25 insulin, 18% for AspB9, GluB27 insulin, 80% for AspB28 insulin, and 327% for AspB10 insulin to 687% for HisA8, HisB4, GluB10, HisB27 insulin relative to human insulin. Binding constants obtained by competition experiments at steady state with [125I]TyrA14-labeled insulin and unlabeled analogues and by kinetic studies with [125I]TyrA14-labeled analogues and insulin gave essentially the same values. The kinetic studies showed that differences in affinity between analogues were due to differences in both dissociation and association rate constants. The affinity for insulinlike growth factor I receptor was low, ranging from <0.005% for AspB25 insulin to 0.6% for HisA8, HisB4, GluB10, HisB27 insulin. The potencies of insulin analoguesin activation of the tyrosine kinase of solubilized and partially purified insulin receptors from HepG2 cells, measured with the exogenous substrate poly(Glu80-Tyr20), ranked in the same order as the binding affinities, the actual values being somewhat elevated for the high-affinity analogues, however. We conclude that these human insulin analogues are active in insulin-receptor binding and tyrosine kinase stimulation but show wide variation in affinity.
Normotensive Diabetic BB/W Rats Show Enhanced Reflex Tachycardia
Authors: Krizsan-Agbas Dora , Buñag Ruben D
Published: September 2013

Spontaneously diabetic BB/W rats were compared with age-matched regular Wistar and nondiabetic BB/W rats to determine whether the presence of diabetes would alter cardiovascular regulation appreciably. Systolic and mean blood pressures measured with the tail-cuff method from 12 to 26 wk of age tended to be slightly higher in diabetic than nondiabetic BB/W rats, but the differences were not significant. Mean pressures recorded from indwelling catheters in the same rats at 28 wk of age also did not differ significantly, thereby verifying that the diabetic rats were not hypertensive. To measure baroreflex sensitivity, heart-rate responses were elicited reflexly by elevating blood pressure with phenylephrine or lowering it with sodium nitroprusside. Although reflex bradycardia elicited with phenylephrine was the same, reflex tachycardia elicited with sodium nitroprusside was more pronounced in diabetic BB/W than other rats. Underlying autonomic mechanisms were then assessed by repeating the baroreflex tests after either cholinergic blockade with methylatropine or β-adrenergic blockade with propranolol. Magnitude of reflex bradycardia after inhibition by either cholinergic or β-adrenergic blockade still did not differ between rat groups but that of reflex tachycardia remained significantly stronger in diabetic BB/W than other rats. These results collectively show that, although diabetic BB/W rats remained normotensive, they had enhanced reflex tachycardia that persisted even after efferent autonomic blockade. The failure to develop higher pressures with time further indicates that without additional manipulation, these rats cannot be used experimentally to simulate the simultaneous presence of hypertension in diabetic patients.
Prolonged Reversal of Diabetic State in NOD Mice by Xenografts of Microencapsulated Rat Islets
Authors: Lum Zhao-Ping , Tai Isabella T , Krestow Martin , Norton Janet , Vacek Ivan , Sun Anthony M
Published: September 2013

Transplantation of the islets of Langerhans could be the most promising approach to the clinical treatment of insulin-dependent (type I) diabetes mellitus. In this study, we report on a modified encapsulation technique that produces small alginate-polylysine capsules (0.25–0.35 mm diam). In an in vitro study, both encapsulated and unencapsulated islets showed comparable responses to glucose challenge in terms of insulin secretion. With the new capsules, 16 spontaneously diabetic NOD mice received transplants of 800 encapsulated rat islets/animal. Nonfasting blood glucose concentration decreased from 24.4 ± 1.4 to 4.0 ± 1.3 mM. At 4 and 5 mo posttransplantation, the capsules were removed from 2 recipients. Both animals regressed to a hyperglycemic state after capsule removal. However, after another islet transplantation, normoglycemia was again restored in these 2 animals. In control mice, which received unencapsulated islets, the xenografts remained functional for <10 days. A high mortality rate was observed among these animals within 2 mo of the recurrence of the hyperglycemic state. Our results clearly indicate that encapsulation of pancreatic islets in the improved capsules can effectively prolong xenograft survival without immunosuppression in an animal model that mimics human type I diabetes mellitus.
Effects of Chronic α-Adrenergic Receptor Blockade on Peripheral Nerve Conduction, Hypoxic Resistance, Polyols, Na+-K+-ATPase Activity, and Vascular Supply in STZ-D Rats
Authors: Cameron Norman E , Cotter Mary A , Ferguson Kaye , Robertson Sharon , Radcliffe Michael A
Published: September 2013

The effects of α-receptor blockade on nerve conduction, hypoxic resistance, ouabain-sensitive Na+)-K+)-ATPase, nerve polyols, and capillary density were examined in streptozocin-induced diabetic (STZ-D) rats. Nondiabetic and untreated diabetic control groups were used. Diabetes duration was 2 mo. There were two treated diabetic groups. A “prevention” group received 5 mg/kg prazosin for 2 mo from the induction of diabetes. A “reversal” group was untreated for the 1st mo and was given prazosin for the subsequent month. Conduction was measured in motor nerves supplying tibialis anterior and gastrocnemius muscles and sensory saphenous nerve. Diabetes resulted in 15–29% reductions in conduction velocity (P < 0.01). In the prevention group, conduction deficits were minimal compared with untreated diabetes (P < 0.01). In the reversal group, motor conduction was also substantially improved, although sensory conduction was not significantly affected. In vitro measurement of sciatic nerve hypoxic resistance revealed a 49% increase in the time taken for compound action potential amplitude to reach half its initial value with diabetes (P < 0.01). This was largely prevented by prazosin treatment (P < 0.01), although treatment had a lesser effect in the reversal group. Treatment had no effect on nerve polyol levels or Na+-K+-ATPase activity. Functional improvements with prazosin were probably based on increased vasa nervorum perfusion. There was a 20% elevation of endoneurial capillary density (P < 0.01) in both prevention and reversal groups. We conclude that vascular factors play an important role in the etiology of experimental diabetic neuropathy, and functional changes may be corrected by chronic vasodilator treatment.
Magnitude of Negative Arterial-Portal Glucose Gradient Alters Net Hepatic Glucose Balance in Conscious Dogs
Authors: Pagliassotti Michael J , Myers Sharon R , Moore Mary C , Neal Doss W , Cherrington Alan D
Published: September 2013

To examine the relationship between the magnitude of the negative arterial-portal glucose gradient and net hepatic glucose uptake, two groups of 42-h fasted, conscious dogs were infused with somatostatin, to suppress endogenous insulin and glucagon secretion, and the hormones were replaced intraportally to create hyperinsulinemia (3- to 4-fold basal) and basal glucagon levels. The hepatic glucose load to the liver was doubled and different negative arterial-portal glucose gradients were established by altering the ratio between portal and peripheral vein glucose infusions. In protocol 1 (n = 6) net hepatic glucose uptake was 42.2 ± 6.7, 35.0 ± 3.9, and 33.3 ± 4.4 μmol · kg−1 · min−1 at arterial-portal plasma glucose gradients of −4.1 ± 0.9, −1.8 ± 0.4, and −0.8 ± 0.1 mM, respectively. In protocol 2 (n = 6) net hepatic glucose uptake was 26.1 ± 2.8 and 12.2 ± 1.7 μmol · kg−1 · min−1 at arterial-portal plasma glucose gradients of −0.9 ± 0.2 and −0.4 ± 0.1 mM, respectively. No changes in the hepatic insulin or glucose loads were evident within a given protocol. Although net hepatic glucose uptake was lower in protocol 2 when compared with protocol 1 (26.1 ± 2.8 vs. 33.3 ± 4.4 μmol · kg−1 · min−1) in the presence of a similar arterial-portal plasma glucose gradient (−0.9 vs. −0.8 mM) the difference could be attributed to the hepatic glucose load being lower in protocol 2 (i.e., hepatic fractional glucose extraction was not significantly different) primarily as a result of lower hepatic blood flow. In conclusion, in the presence of fixed hepatic glucose and insulin loads, the magnitude of the negative arterial-portal glucose gradient can modify net hepatic glucose uptake in vivo.
Archaeology of NIDDM: Excavation of the “Thrifty” Genotype
Authors: Wendorf Michael , Goldfine Ira D
Published: September 2013

Since the 1940s, numerous cases of non-insulin-dependent diabetes mellitus (NIDDM) have been observed in certain American Indian populations. Extremely high prevalence rates of NIDDM occur most strikingly in several tribes of Paleo-Indians, whose ancestors migrated to North America >11,000 yr ago. Archaeological evidence from that period indicates that certain groups of Paleo-Indians maintained an arctic-like hunter-gatherer life-style in an area in temperate North America ranging from Wyoming to Arizona. This life-style featured a reliance on unpredictable big game species as a major food source. However, at this time, big game species were becoming extinct. It is hypothesized that those Paleo-Indians who relied on big game as a food source developed a “thrifty” genotype that allowed a selective advantage during the periods of fasting that occurred between big game kills. It also is hypothesized that this thrifty genotype in these Indians may contribute to NIDDM when a sedentary life-style is adopted and food sources are constant. Because insulin resistance in muscle is a major feature of NIDDM, it is possible that insulin resistance per se is the phenotypic expression of the thrifty genotype.
Effects of PP-56 and Vitamin E on Platelet Hyperaggregability, Fatty Acid Abnormalities, and Clinical Manifestations in Streptozocin-Induced Diabetic Rats
Authors: Ruf Jean C , Ciavatti Maryvonne , Gustafsson Torgny , Renaud Serge
Published: September 2013

The effects of vitamin E and D-myo-inositol 1,2,6-trisphosphate (PP-56) were investigated in long-term studies in streptozocin-induced diabetic rats fed a purified diet with 33% lipids and a polyunsaturated- to -saturated fatty acid ratio of 1. A supplement of vitamin E decreased plasma triglycerides, platelet lipid biosynthesis, some of the ∆6- and ∆5-desaturase abnormalities, and urine ketone bodies but did not affect the response of platelets to aggregation. PP-56 completely normalized the platelet reactivity to ADP and thrombin. This was accompanied by normalization of platelet lipid biosynthesis and diabetes-induced abnormalities in ∆6- and ∆5-desaturases. PP-56 treatment also reduced the mortality rate and to a certain extent urinary ketone bodies. The protective effect of PP-56 on platelet aggregation and mortality rate were dose related. PP-56, a molecule derived from phytic acid, seems to exert potent protective effects on some of the manifestations associated with diabetes in rats.
Effects of Exercise Training and Dietary Manipulation on Insulin-Regulatable Glucose-Transporter mRNA in Rat Muscle
Authors: Wake Samantha A , Sowden Judith A , Storlien Leonard H , James David E , Clark Peter W , Shine John , Chisholm Donald J , Kraegen Edward W
Published: September 2013

Both exercise training and dietary manipulation (increasing ω-3/ω-6 fat ratio) can ameliorate insulin resistance caused by a high-fat diet in rats. We determined whether alterations in the expression of the insulin-regulatable (IR) and/or HepG2 glucose-transporter (GT) mRNAs were similarly affected. There was a significantly higher level of IRGT mRNA in skeletal muscle from exercise-trained versus sedentary high-fat–fed rats (27% increase, P < 0.01). This difference is consistent with previously reported increases in muscle insulin-mediated glucose uptake. Skeletal muscle HepG2GT mRNA was too low to detect any training effect, but there was a tendency toward higher levels with training in cardiac muscle. In contrast, dietary manipulation, previously shown to lead to a much greater increase (100–300%) in muscle insulin-mediated glucose uptake, did not change IRGT or HepG2GT mRNA in skeletal muscle or heart. Thus, both dietary manipulation and exercise training increase insulin-stimulated glucose uptake in skeletal muscle, but only exercise training increases IRGT mRNA. Therefore, exercise training apparently increases GT production, whereas dietary manipulation improves glucose transport in skeletal muscle by other mechanisms.
Production of Inhibitor of Insulin-Receptor Tyrosine Kinase in Fibroblasts From Patient With Insulin Resistance and NIDDM
Authors: Sbraccia Paolo , Goodman Patricia A , Maddux Betty A , Wong K Y , Chen Y-D I , Reaven Gerald M , Goldfine Ira D
Published: September 2013

Although non-insulin-dependent diabetes mellitus (NIDDM) is associated with defects in insulin action, the molecular basis of this resistance is unknown. We studied fibroblasts from a markedly insulin-resistant patient with NIDDM but without acanthosis nigricans. Her fibroblasts were resistant to insulin when α-aminoisobutyric acid uptake was measured. Fibroblasts from this patient demonstrated normal insulin-receptor content as measured by both insulin-receptor radioimmunoassay and by Scatchard analysis. However, when compared with nondiabetic control subjects, insulin-receptor kinase assays of wheat-germ–purified receptors prepared from her fibroblasts showed very low basal and no insulin-stimulated tyrosine kinase activity. The insulin receptor was then removed from the wheat-germ fraction by monoclonal antibody affinity chromatography. This insulin-receptor–deficient fraction inhibited both basal and insulin-stimulated tyrosine kinase activity of highly purified insulin receptors. When the specificity of this inhibition was tested, less inhibition was seen with insulinlike growth factor I–receptor tyrosine kinase, and even less inhibition was seen with the proto-oncogene p60c-src tyrosine kinase. Thus, these studies indicate that fibroblasts from an insulin-resistant patient with NIDDM produce a relatively specific glycoprotein inhibitor of insulin-receptor tyrosine kinase. Therefore, these studies raise the possibility that this inhibitor may play an important role in the insulin resistance seen in this patient.
1990 Overview of GDM: Accomplishments of the Last Decade—Challenges for the Future
Authors: Metzger Boyd E
Published: September 2013

The First International Workshop-Conference on Gestational Diabetes Mellitus (GDM) was held in the fall of 1979 on the campus of Northwestern University Medical School. The purpose of that event was to examine the impact of mild disturbances of maternal metabolism on fetal development. The conference sought to “establish how such disturbances can be detected most effectively; whether all pregnant subjects should be examined for them; and whether positive identification justifies therapeutic attempts at rectification” (1). In his opening remarks, Norbert Freinkel (1) anticipated some of the issues that are of greatest importance more than a decade later. In particular, he stressed the public-health implications that would follow national and worldwide detection of GDM. Five years later, the Second International Workshop-Conference on GDM provided an opportunity for reappraisal of many of the same issues. The proceedings of each conference concluded with summary statements drafted by the participants (2,3). Both included the recommendation that all women (not known to have diabetes) should be screened for glucose intolerance during pregnancy by measurement of plasma glucose after an oral glucose challenge. The recommendations from the second conference formed the basis of a position statement on GDM that was adopted by the board of directors of the American Diabetes Association (4).
Long-Term Prospective Evaluation of Offspring of Diabetic Mothers
Authors: Silverman Bernard L , Rizzo Thomas , Green Orville C , Cho Nam H , Winter Robert J , Ogata Edward S , Richards Gail E , Metzger Boyd E
Published: September 2013

We have suggested that altered maternal metabolism may affect the subsequent anthropometrie and neuropsychological development of children who were in utero during disturbances in maternal fuel economy. This study reports the physical growth through 8 yr of age and the neuropsychological development through 4 yr of age in offspring of diabetic mothers (ODM). At birth, 50% of infants had weights >90th percentile for gestational age. By 12 mo, length and weight were similar to the general population. Height remained normal until 7 yr of age, when it became slightly greater than average. After 5 yr of age, relative weight increased dramatically, and by 8 yr of age, half of the ODM had weights >90th percentile. This childhood obesity in ODM is correlated with maternal prepregnant weight and independently with amniotic fluid insulin at 32–38 wk gestation. The Brazelton Neonatal Behavioral Assessment Scale (BNBAS) was administered to 185 newborn ODM. Significant correlations were found between poorer second- and third-trimester glycemie regulation and lower scores in three of four newborn BNBAS dimensions. The Stanford-Binet Intelligence Scale was measured in 102 ODM at 4 yr of age. We found an inverse correlation between childhood IQ and second- and third-trimester maternal lipid metabolism (serum free fatty acids and β-hydroxybutyrate). This correlation is not explained by adverse perinatal events, socioeconomic status, maternal IQ, ethnicity, or diabetes type. These long-range associations between altered maternal metabolism and childhood growth and development continue to support Freinkel's hypothesis of fuel-mediated teratogenesis.
Exercise in the Treatment of NIDDM: Applications for GDM?
Authors: Horton Edward S
Published: September 2013

Physical training is associated with lower plasma insulin concentrations and increased sensitivity to insulin in skeletal muscle and adipose tissue of individuals with non-insulin-dependent diabetes mellitus (NIDDM). The benefits of exercise to individuals with NIDDM in terms of increased insulin sensitivity could be applied to reversing the insulin resistance associated with gestational diabetes mellitus (GDM). Exercise may also benefit women with GDM by acting as an adjunct to diet in preventing excessive weight gain and preventing or decreasing the severity of hypertension and/or hyperlipidemia during pregnancy. Regular physical exercise should be considered as a potential approach to the prevention and treatment of GDM.
Exercise in Gestational Diabetes: An Optional Therapeutic Approach?
Authors: Bung Peter , Artal Raul , Khodiguian Nazareth , Kjos Siri
Published: September 2013

Forty-one patients with gestational diabetes requiring insulin were enrolled in a randomized study to investigate the efficacy of an exercise program in normalizing glucose tolerance. Seventeen of 21 patients completed the exercise program while maintaining normoglycemia and obviating insulin therapy. Maternal and neonatal complications did not differ between the study and control groups. The type of program described appears to be safe and can serve as a model for exercise prescription for pregnant diabetic women to attain improved glucose tolerance.
Gestational Diabetes Mellitus: Levels of Glycemia as Management Goals
Authors: Hare John W
Published: September 2013

In the United States, glucose tolerance test criteria for the diagnosis of gestational diabetes mellitus are, in plasma glucose after a 100-g challenge, as follows: fasting, >5.8 mM; 1 h, >10.6 mM; 2 h, >9.2 mM; and 3 h, >8.1 mM; any two values must be elevated. The Second International Workshop-Conference on Gestational Diabetes Mellitus recommended in 1985 that, once diagnosed, women should receive dietary therapy. If fasting or 2-h postprandial hyperglycemia later occurs (fasting, >5.8 mM; 2-h, >6.7 mM), insulin therapy should begin. Data from others have suggested both that the criteria for diagnosis may be too liberal and that the thresholds for instituting insulin therapy may be too high. We address these two issues by reviewing several papers with conflicting conclusions. There is controversy over whether women with gestational diabetes diagnosed by glucose tolerance testing, but who have fasting plasmi glucose levels <5.8 mM and 2-h postprandial values <6.7 mM, should also be insulin treated. Finally, the usual clinical criteria for making therapeutic decisions all rely on glycemia. Other fuels (amino acids, lipids, and ketones) are regulated by circulating insulin and have deleterious effects on fetal development. Further study is required to make more sound clinical decisions based not just on glycemia but on the entire metabolic milieu.
Neonatal Hypoglycemia: Back to Basics in Diagnosis and Treatment
Authors: Schwartz Robert
Published: September 2013

Hypoglycemia continues to be found in infants of diabetic mothers, although the significance of the observation remains to be defined in terms of long-term neurodevelopment and behavior. Most follow-up studies no longer identify CNS problems. The criterion, i.e., the level of blood glucose at which the diagnosis should be made, has evolved and drifted toward the adult level. No single criterion can be used dependably to make this clinical and chemical diagnosis.
Biphasic Effects of Maternal Metabolism on Fetal Growth; Quintessential Expression of Fuel-Mediated Teratogenesis
Authors: Metzger Boyd E
Published: September 2013

More than a decade ago, Norbert Freinkel postulated that alterations in the maternal metabolic milieu at any time during gestation can influence intrauterine development and also may have long-term consequences for certain tissues such as adipocytes, myocytes, pancreatic β-cells, and neurons. This review illustrates that metabolic alterations early in gestation, such as those that occur in diabetes mellitus, may impair growth of the embryo and increase the risk of dysmorphogenesis. Such delayed growth of the embryo may in turn influence size at birth. In midgestation, metabolic perturbations may accelerate functional maturation of fetal pancreatic β-cells. Fetal β-cell development is very sensitive to alterations in the nutrient milieu and may be enhanced in gestational diabetes mellitus (GDM) with only minimal elevations of plasma glucose and minor alterations in other nutrient fuels, including insulinogenic amino acids. Data are reviewed that suggest that the ensuing fetal hyperinsulinemia may promote the development of macrosomia even if metabolic control is satisfactory during late gestation. The overall potential influences of metabolic alterations on intrauterine growth are different in pregnancies complicated by diabetes mellitus throughout gestation (pregestational) and GDM. However, the implications in an individual pregnancy may be defined by the degree of metabolic control at the specific stages of gestation when growth of the embryo, development of fetal β-cell function, and growth of insulin-sensitive tissues are most critically influenced by the metabolic milieu.
Islet Cell Antibodies in Patients With Autoimmune Thyroid Disease
Authors: Yamaguchi Yoshihiko , Chikuba Nobuhiro , Ueda Yasuo , Yamamoto Hidefumi , Yamasaki Hironori , Nakanishi Toshiaki , Akazawa Shoichi , Nagataki Shigenobu
Published: September 2013

Islet cell antibodies (ICAs) were assayed in 316 patients with autoimmune thyroid disease (AITD; 190 with Graves' disease, 126 with Hashimoto's thyroiditis), 53 patients with insulin-dependent diabetes mellitus (IDDM), and 144 healthy control subjects. ICAs were measured by an immunohistochemical method with peroxidase-labeled protein A and human pancreatic tissues. The prevalence of ICAs in patients with AITD was 7.6% (24 of 316), whereas the prevalence in control subjects was 0.7% (1 of 144). Among 24 ICA+ patients, 20 (83%) had IDDM. In these 20 patients, the duration of diabetes from clinical onset was 5.4 ± 5.1 yr. ICAs in patients with IDDM alone were positive in 90.9% at 1 yr and 7.7% at 5 yr after the onset of diabetes. These data have shown that most ICA+ patients with AITD have IDDM and that the prevalence of ICAs in patients with AITD in Japanese is as high as that found among whites, whereas the incidence of IDDM in Japanese is approximately one-thirtieth or one-fiftieth of that in whites.
Effects of IP3, Spermine, and Mg2+ on Regulation of Ca2+ Transport by Endoplasmic Reticulum and Mitochondria in Permeabilized Pancreatic Islets
Authors: Lenzen Sigurd , Rustenbeck Ingo
Published: September 2013

Inositol 1,4,5-trisphosphate (IP3) increased the free-Ca2+ concentration in the incubation medium of permeabilized ob/ob mouse pancreatic islets. Spermine decreased the free-Ca2+ concentration through stimulation of mitochondrial Ca2+ uptake and attenuated the effect of IP3. Mg2+ antagonized the effects of spermine, thereby increasing the free-Ca2+ concentration and enhancing the effect of IP3 on the free-Ca2+ concentration. Because IP3 releases Ca2+ from endoplasmic reticulum, these results indicate that endoplasmic reticulum and mitochondria can interact in the regulation of the free-Ca2+ concentration in the cytosol of the pancreatic β-cell.
Blunted Diuretic and Natriuretic Responses to Central Administration of Clonidine in Streptozocin-Induced Diabetic Rats
Authors: Zhang Ping L , Patel Kaushik P
Published: September 2013

The purpose of this study was to determine whether diuretic and natriuretic effects are altered in response to intracerebroventricular (ICV) infusion of clonidine in diabetic rats. Diabetes was induced in male Sprague-Dawley rats by 65 mg/kg i.p. injection of streptozocin, and control rats were injected with vehicle 2 wk before the experiment. Blood glucose levels were significantly elevated in the diabetic group (26.3 ± 1.3 mM) compared with the control group (8.4 ± 1.6 mM). Before and during ICV infusion of clonidine (2 μg · kg−1 · min−1 for 45 min), urine flow and sodium excretion were measured from intact and denervated kidneys in anesthetized diabetic and control rats. The ICV infusion of clonidine significantly increased urine flow in both innervated and denervated kidneys from control rats but not from diabetic rats. There was a significant increase in sodium excretion during ICV infusion of clonidine from innervated kidneys of control rats, and denervation abolished this effect. In diabetic rats, clonidine failed to promote natriuresis from intact kidneys, and similar to control rats, did not promote natriuresis in denervated kidneys. This study demonstrates that 1) the diuretic response to the ICV infusion of clonidine is blunted in diabetic rats, and 2) a natriuretic response to the ICV infusion of clonidine is blunted in innervated kidneys of diabetic rats.
Role of Oxidative Stress in Development of Complications in Diabetes
Authors: Baynes John W
Published: September 2013

Nϵ-(carboxymethyl)lysine, Nϵ-(carboxymethyl)hydroxylysine, and the fluorescent cross-link pentosidine are formed by sequential glycation and oxidation reactions between reducing sugars and proteins. These compounds, termed glycoxidation products, accumulate in tissue collagen with age and at an accelerated rate in diabetes. Although glycoxidation products are present in only trace concentrations, even in diabetic collagen, studies on glycation and oxidation of model proteins in vitro suggest that these products are biomarkers of more extensive underlying glycative and oxidative damage to the protein. Possible sources of oxidative stress and damage to proteins in diabetes include free radicals generated by autoxidation reactions of sugars and sugar adducts to protein and by autoxidation of unsaturated lipids in plasma and membrane proteins. The oxidative stress may be amplified by a continuing cycle of metabolic stress, tissue damage, and cell death, leading to increased free radical production and compromised free radical inhibitory and scavenger systems, which further exacerbate the oxidative stress. Structural characterization of the cross-links and other products accumulating in collagen in diabetes is needed to gain a better understanding of the relationship between oxidative stress and the development of complications in diabetes. Such studies may lead to therapeutic approaches for limiting the damage from glycation and oxidation reactions and for complementing existing therapy for treatment of the complications of diabetes.
Production of Marked Prolongation of Islet Xenograft Survival (Rat to Mouse) by Local Release of Mouse and Rat Antilymphocyte Sera at Transplant Site
Authors: Aebischer Patrick , Lacy Paul E , Gerasimidi-Vazeou Andriani , Hauptfeld Vera
Published: September 2013

Polymer rods impregnated with lyophilized particles of mouse (M) or rat (R) antilymphocyte serum (ALS) were placed adjacent to rat islet xenografts transplanted beneath the kidney capsule of diabetic mice. Insertion of rods containing only MALS or RALS had no effect on the survival time of the rat islet xenografts. In contrast, the insertion of both MALS and RALS rods with the graft produced a marked prolongation of islet xenograft survival (mean survival time >55.5 ± 10.9 days) compared with controls (14.7 ± 2.5 days). One recipient was still normoglycemic at 100 days, and removal of the graft returned the animal to a diabetic state. The islet graft had a normal degree of β-granulation, and a slight fibrotic reaction was present around the rods. The effect of the rods in prolonging survival of the xenografts resulted from a local slow release of MALS and RALS, because implantation of the MALS and RALS rods in the right kidney and the islets in the left kidney had no effect on prolonging islet xenograft survival. These findings indicate that local immunosuppression produced marked prolongation of rat islet xenograft survival in mice. This raises the possibility of using polymer rods for the local slow release of monoclonal antibodies to lymphokines and other agents for prevention of rejection of islet allografts and xenografts and to determine the effect of lymphokines in vivo on islet function.
Effects of Insulin and Amino Acids on Leg Protein Turnover in IDDM Patients
Authors: Bennet William M , Connacher Alan A , Jung Roland T , Stehle Peter , Rennie Michael J
Published: September 2013

To determine whether the responses of muscle protein metabolism to insulin and amino acids in patients with insulin-dependent diabetes mellitus (IDDM) were different from those in nondiabetic subjects, leg tissue kinetics of [15N]phenylalanine and [1-13C]leucine and its metabolites were measured in eight insulin-withdrawn IDDM patients and eight nondiabetic subjects during basal insulinemia and during infusion of insulin (0.29 nmol · min−1 [ m−2). The diabetic patients were studied in the absence of amino acids, and both groups were studied during infusion of a mixed–amino acid solution (AA). In the diabetic patients, insulin alone and combined with additional AA reduced leg tissue phenylalanine release by 42 and 41%, respectively (both P < 0.05), but uptake was unchanged. Leg tissue leucine oxidation was unchanged by insulin alone but was increased (P = 0.012) fourfold during insulin infusion with additional AA. In the nondiabetic subjects, insulin with AA infusion increased leg tissue phenylalanine uptake (45.7 ± 7.5 to 73.1 ± 7.3 nmol · min−1 · 100 g−1, P < 0.01). Insulin-stimulated glucose uptake in the diabetic patients (1.60 ± 0.28 μmol · min−1 · 100 g−1,was impaired compared with the nondiabetic subjects (3.37 ± 0.28 μmol min −1 100 g−1, P = 0.04). These results suggest that, in IDDM patients, 1) infusion of insulin fails to stimulate muscle protein synthesis even when combined with a substantially increased provision of AA, and 2) compared with nondiabetic subjects, muscle protein synthesis as well as glucose uptake exhibit blunted responses to insulin.
Two Patients With Insulin Resistance Due to Decreased Levels of Insulin-Receptor mRNA
Authors: Imano Eiichi , Kadowaki Hiroko , Kadowaki Takashi , Iwama Norimichi , Watarai Takao , Kawamori Ryuzo , Kamada Takenobu , Taylor Simeon I
Published: September 2013

Mutations have been identified in the insulin-receptor gene in insulin-resistant patients. We studied two patients with acanthosis nigricans and insulin resistance caused by a decrease in the number of cell surface insulin receptors. Patient 1 was an 11-yr-old boy with a fasting insulin level of 2130 pM; patient 2 was a 14-yr-old girl with hyperandrogenism and a fasting insulin level of 580–740 pM. Based on Southern-blotting studies, the structure of both alleles of the insulin-receptor gene in both patients appeared to be grossly normal. There was no evidence of insertions, deletions, or major rearrangements. Moreover, the nucleotide sequences of all 22 exons of the gene were normal in both patients. Thus, the predicted amino acid sequences of both patients' insulin receptors were normal. In Epstein-Barr virus–transformed lymphoblasts from patient 1, insulin-receptor mRNA levels were so low they could not be detected with an RNase A protection assay, whereas mRNA levels from patient 2 were in the lower half of the normal range. By use of a more sensitive assay based on the polymerase chain reaction, insulin-receptor mRNA could be detected in Epstein-Barr virus–transformed lymphoblasts from both patients. Moreover, because of the existence of silent polymorphisms in the nucleotide sequences, it was possible to differentiate the two alleles of the insulin-receptor gene in both patients. In patient 2, the two alleles were expressed asymmetrically, with 90% of the mRNA molecules having been transcribed from one allele but only 10% transcribed from the second allele. This suggests that there is an unidentified mutation in the underexpressed allele that acts in a cis-dominant fashion to decrease insulin-receptor mRNA levels. However, in patient 1, both alleles were expressed symmetrically in similarly low levels. Although not proven, it seems likely that the mutations that decrease insulin-receptor mRNA levels in patient 1 also map to the insulin-receptor locus.
In Vivo Insulin Resistance Induced by Amylin Primarily Through Inhibition of Insulin-Stimulated Glycogen Synthesis in Skeletal Muscle
Authors: Frontoni Simona , Choi Soo Bong , Banduch Donna , Rossetti Luciano
Published: September 2013

We examined the in vivo mechanisms of amylin-induced resistance in concious rats (n = 18). During 180-min euglycemic insulin-clamp (21.5 pmol · kg−1 · min−1) studies, amylin (50, 200, or 500 pmol · kg−1 · min−1; plasma concentration from 3 × 10−10 to 9 × 10−9 M) infusion determined a 19–27% reduction in glucose uptake (117.8 ± 7.0 vs. 145.8 ± 11.0, 107.1 ± 9.2 vs. 145.1 ± 6.7, and 105.0 ± 7.2 vs. 144.4 ± 7.0 μmol · kg−1 · min−1 at 50, 200, or 500 pmol · kg−1 · min−1, respectively, P < 0.01) versus insulin alone, whereas 10-pmol · kg−1 · min−1 amylin infusion (plasma concn 5 × 10−11 M) failed to affect insulin-mediated glucose disposal. After amylin infusion, the contribution of whole-body glycolysis to overall glucose disposal increased from 43–48 to 62–79%, whereas muscle glycogen synthesis decreased significantly at all peptide concentrations >3 × 10−10 M, completely accounting for the decrease in glucose uptake. Skeletal muscle glucose-6-phosphate concentration rose from 0.219 ± 0.038 μmol/g (insulin alone) to 0.350 ± 0.018, 0.440 ± 0.020, and 0.505 ± 0.035 μmol/g (insulin plus amylin at 50, 200, or 500 pmol · kg−1 · min−1, P < 0.01). Suppression of hepatic glucose production by insulin was unaffected by a 50-pmol · kg−1 · min−1 amylin infusion (18.5 ± 4.3 vs. 21.7 ± 2.9 μmol · kg−1 · min−1), whereas it was slightly but significantly impaired by amylin infusion at 200 pmol · kg−1 · min−1 (17.8 ± 3.9 vs. 24.7 ± 4.5 μmol · kg−1 · min−1, P < 0.05). whereas peripheral glucose uptake and muscle glycogen synthesis were not further reduced. Our results suggest that amylin antagonizes the ability of insulin to promote total-body glucose uptake primarily by decreasing muscle glycogen synthesis, which, in turn, determines an increase in muscle glucose-6-phosphate levels and glycolysis and a reduction in glucose transport/phosphorylation.