bluuebunny/crossref_metadata_2025 huggingface dataset:
T-Lymphocyte–Receptor Repertoire of Infiltrating T Lymphocytes Into NOD Mouse Pancreas
Authors: Maeda Toshiro , Sumida Takayuki , Kurasawa Kazuhiro , Tomioka Hisao , Itoh Isao , Yoshida Sho , Koike Takao
Published: September 2013

This study analyzed T-lymphocyte–receptor Vβ genes of infiltrating lymphocytes into the pancreases of 12-to 16-wk-old NOD mice with severe insulitis and 5-wk-old mice with mild insulitis by the quantitative polymerase chain reaction method. The Vβ transcripts on infiltrating T lymphocytes into pancreases with severe insulitis in older NOD mice were diverse. In contrast, the Vβ11 gene transcript was predominantly expressed on T lymphocytes in the pancreas in younger NOD mice with mild insulitis, suggesting the possible role of Vβ11+ T lymphocytes in triggering insulitis in this species.
Effects of Tryptophan on Depression and Aggression in STZ-D Mice
Authors: Hilakivi-Clarke Leenaa
Published: September 2013

Streptozocin-induced diabetic (STZ-D) mice have reduced brain concentrations of tryptophan, a precursor substance for 5-hydroxytryptamine, and show lengthened immobility in Porsolt's swim test, a putative animal model of depression. This study investigated whether tryptophan affects behavior in Porsolt's swim test in STZ-administered male National Institutes of Health Swiss mice. In addition, the effect of tryptophan on behavior in the resident-intruder test of aggression was studied. Tryptophan is effective in the treatment of mild depression and may reduce aggressive behavior. Diabetes was induced with injection of 200 mg/kg body wt i.p. STZ. Two weeks after STZ treatment, the mice received 0, 50, and 100 mg/kg i.p. tryptophan 60 min before the swim test. The STZ-administered mice exhibited lengthened immobility in the swim test, and tryptophan caused a dose-related shortening in their immobility times. The control and STZ mice, which were isolated for 1 wk before the resident-intruder test, did not show any difference in the time spent in social investigation or aggressive or defensive behaviors. However, 100 mg/kg i.p. tryptophan 60 min before the test reduced the social interaction and aggressive behavior of the STZ-D mice but increased these behaviors in controls. Results indicate that tryptophan shortens the increased immobility time and reduces social and aggressive behavior in STZ-D mice. Therefore, the reported reductions in the brain-tryptophan concentrations in STZ-D mice may participate in regulating their behavior.
Decreased Incorporation of Long-Chain Fatty Acids into Erythrocyte Phospholipids of STZ-D Rats
Authors: Dang An Quoc , Faas Fred H , Jethmalani Sunita M , Carter William J
Published: September 2013

We studied the mechanisms for the altered fatty acid composition in erythrocytes (RBCs) derived from streptozocin-induced diabetic (STZ-D) rats. After 3-wk duration of diabetes, blood glucose, plasma triglyceride, and plasma free–fatty acid levels were all significantly increased. In the diabetic platelet-poor plasma (PPP), the most significant increases in free fatty acids were stearate, linoleate, eicosatrienoate (n-6), and docosahexaenoate (n-3). Fatty acid composition of RBC phospholipids was also altered, with significant decreases in arachidonate, docosatetraenoate (n-6), and docosapentaenoate (n-6) and increases in linoleate and docosahexaenoate. Insulin treatment of the diabetic rats resulted in normalization of docosapentaenoate, arachidonate, and linoleate levels in RBC phospholipids but not of docosahexaenoate or docosatetraenoate levels. The incorporation of [5,6,8,9,11,12,14,15-3H]arachidonate into diabetic RBC phospholipids was significantly decreased compared with the corresponding control RBC, regardless of the incubation medium used, which was the PPP derived either from the control or diabetic rats. Therefore, the decreased incorporation of [5,6,8,9,11,12,14,15-3H]arachidonate into diabetic RBC phospholipids was independent of the altered lipid composition of the PPP incubation media. Furthermore, the decreased incorporation was not specific for arachidonate, because the incorporation of other long-chain fatty acids such as [9,10-3H]oleate, [1-14C]palmitate, [2-14C]eicosatrienoate (n-6), and [1-14C]linoleate into RBC phospholipids was also comparably decreased. More important, the decreased fatty acid incorporations were reversed by insulin treatment of the diabetic rat. Our results indicate that the altered free–fatty acid composition in the diabetic plasma might not entirely account for the altered fatty acid composition of diabetic RBC phospholipids, and that the decreased incorporation or uptake of these fatty acids into the diabetic RBCs may contribute to some of these changes.
Enhanced Stimulation of Diacylglycerol and Lipid Synthesis by Insulin in Denervated Muscle: Altered Protein Kinase C Activity and Possible Link to Insulin Resistance
Authors: Heydrick Stanley J , Ruderman Neil B , Kurowski Theodore G , Adams Heather B , Chen Kim S
Published: September 2013

Denervated muscle is generally regarded as insulin resistant because the ability of insulin to stimulate glucose transport and glycogen synthesis is impaired. Previous studies indicate that insulin resistance in these muscles is likely due to a defect at a postreceptor site in the signaling pathway. Because glucose transport into cells has been reported to be linked to changes in diacylglycerol (DAG) and protein kinase C (PKC), we investigated the effect of denervation on the content and synthesis of DAG and the activity and distribution of PKC in the soleus muscle. The DAG content in muscles denervated for 24 h was 40% > in control muscles. This was associated with a two- to threefold increase in the percentage of total PKC activity that was membrane associated, with no significant change in total PKC activity, suggesting an increase in PKC activity in vivo. Studies of glucose disposition confirmed that the stimulation of glycogen synthesis by insulin and, to a lesser extent, 2-deoxyglucose uptake were impaired by denervation. However, the stimulation by insulin of glucose incorporation into DAG and other lipids was two- to threefold greater in denervated than in control muscles, and conversion of glucose to lactate and pyruvate and glucose oxidation to CO2 were unchanged. The results reveal a dichotomy in the effects of denervation on various actions of insulin, with both insulin resistance and hyperresponsiveness occurring in different pathways of glucose metabolism. They also reveal a potential mechanism for the elevation of muscle DAG after denervation. The results do not support a direct link between DAG-PKC and glucose transport. Based on these findings, a working hypothesis that links enhanced DAG-PKC signaling to insulin resistance is proposed.
Comparative Analysis of Potency of Splenic Dendritic and Adherent Cells (Macrophages) as Alloantigen Presenters In Vivo
Authors: Setum Cindy M , Serie Janet R , Hegre Orion D
Published: September 2013

Dendritic cells and macrophages have been attributed with stimulatory capacity for in vivo and in vitro immune responses. However, the relative contribution of each of these cell types has long been in dispute. Therefore, the differential ability of dendritic cells and macrophages (splenic adherent cells [SACs]) to stimulate pancreatic islet allograft rejection in reversed alloxan-induced diabetic rats was examined. Rats bearing established allografts were challenged with various dosages of donor-strain dendritic cells or SACs, and graft rejection was assessed by analysis of plasma glucose levels and/or histological criteria. Marked differences in the ability to stimulate allograft rejection were observed at the 105-cell dosage; 105 dendritic cells induced graft rejection in five of six rats (1 rat required 2 injections), whereas 105 SACs failed to induce rejection in four of four rats (P < 0.10, χ2 test). Challenge stimuli consisting of ≤ 105 SACs or ≤104 dendritic cells failed to induce graft rejection. These findings indicate that dendritic cells are potent stimulator cells for in vivo immune responses. Previous studies indicated that as few as 103 dendritic cells initiate allograft rejection in nondiabetic recipients. That more dendritic cells were required to stimulate rejection in reversed diabetic recipients compared with nondiabetic recipients suggests that other factors, such as the diabetic state and the production of a tolerant status achieved by larger amounts of grafted tissue, may influence graft survival.
O-Linked Oligosaccharides on Insulin Receptor
Authors: Collier Elaine , Gorden Phillip
Published: September 2013

The insulin receptor, an integral membrane glycoprotein, is synthesized as a single-chain precursor that is cleaved to produce two mature subunits, both of which contain N-linked oligosaccharide chains and covalently linked fatty acids. We report that the β-subunit also contains O-linked oligosaccharides. The proreceptor, α-subunit, and β-subunit were labeled with [3H]mannose and [3H]galactose in the presence or absence of an inhibitor of O-linked glycosylation. Tryptic peptides from each component were separated by reverse-phase high-performance liquid chromatography. N- and O-linked oligosaccharide chains were identified on these peptides by specific enzymatic digestions. The proreceptor and α-subunit contained only N-linked oligosaccharides, whereas the β-subunit contained both N- and O-linked oligosaccharides. The O-linked oligosaccharide chains were attached to a single tryptic fraction of the β-subunit, which also contained N-linked chains. This fraction was further localized to the NH2-terminal tryptic peptide of the β-subunit by specific immunoprecipitation with an anti-peptide antibody with specificity for this region. Binding of insulin and autophosphorylation of the β-subunit were not dependent on O-linked glycosylation, because cells grown in the presence of the inhibitor exhibited a normal dose response to insulin. Therefore, the insulin receptor contains O-linked oligosaccharides on the NH2-terminal tryptic peptide of the β-subunit, and these O-linked oligosaccharides are not necessary to the binding or autophosphorylation function of the receptor.
Decreased Growth Velocity Before IDDM Onset
Authors: Leslie R David , Lo Simon , Millward B Anne , Honour John , Pyke David A
Published: September 2013

Diabetes can retard growth. Growth was studied prospectively in 12 nondiabetic identical twins aged <14 yr and in their co-twins with insulin-dependent diabetes mellitus (IDDM) to determine whether changes in growth occur before the onset of IDDM. Seven of the 12 nondiabetic twins subsequently developed IDDM; the remainder are now unlikely to become diabetic. A significantly reduced growth velocity was observed more frequently in the nondiabetic twins (7 of 12) than in their diabetic co-twins (1 of 12; P = 0.03). Of the 7 nondiabetic twins who were prediabetic, 6 had a reduction in growth velocity to below the 3rd percentile before the onset of diabetes compared with 1 of their diabetic co-twins (P = 0.03). However, only 1 of the 5 nondiabetic twins who did not develop diabetes showed a reduction in growth velocity. The nadir of growth in the twins who developed diabetes occurred a mean of 1.2 yr before diagnosis (range 0.3–2.3 yr). All 7 of the prediabetic twins had islet cell antibodies when first seen, and 3 had them before they showed either decreased growth velocity or impaired glucose tolerance. In 4 prediabetic twins, the decreased growth preceded impaired glucose tolerance. The prediabetic twins tested had lower testosterone or estradiol levels at the time they showed decreased growth than their diabetic twins. We conclude that decreased growth velocity is an early sensitive marker of IDDM.
Follow-Up of Women With Previous GDM: Insulin, C-Peptide, and Proinsulin Responses to Oral Glucose Load
Authors: Persson Bengt , Hanson Ulf , Hartling Svend G , Binder Christian
Published: September 2013

Gestational diabetes mellitus (GDM) is a strong predictor of glucose intolerance later in life. Former GDM (n = 145) and control (n = 41) subjects were studied 3–4 yr after the index pregnancy. They were subjected to a 75-g oral glucose tolerance test (OGTT) with measurements of insulin, C-peptide, and proinsulin in the basal state and every 30 min for 180 min. In the former GDM group, 5 subjects (3.4%) had developed non-insulin-dependent diabetes mellitus (NIDDM), and 32 (22%) had developed impaired glucose tolerance (IGT; by World Health Organization criteria). In the control group, 2 (4%) had IGT. In the GDM group, IGT or NIDDM was significantly associated with obesity (body mass index [BMI] ≥25 kg/m2) and earlier diagnosis of GDM during pregnancy (P < 0.001). Nonobese (BMI <25 kg/m2) GDM subjects with normal glucose tolerance at follow-up had significantly higher mean glucose(P < 0.01), insulin (P < 0.05), and proinsulin (P < 0.001) values during the OGTT than control subjects, whereas there was no significant difference in C-peptide values. A comparison between control subjects with normal OGTT and BMI <25 kg/m2 (n = 39) and GDM subjects (n = 39) selected to have a comparable area under the glucose curve, BMI, and age demonstrated no group differences in glucose, C-peptide, or insulin levels, whereas the proinsulin levels were significantly higher (P < 0.001) during the glucose load. The molar ratio between proinsulin and insulin was also significantly higher among the former GDM subjects. We speculate that an elevated proinsulin-insulin ratio in women with previous GDM could be a marker for later development of NIDDM.
Diagnosis of Gestational Diabetes: What Are Our Objectives?
Authors: Coustan Donald R
Published: September 2013

International agreement is lacking with regard to diagnostic criteria for gestational diabetes and its treatment. Consensus is not possible without agreement on the objectives in making the diagnosis. The most commonly used criteria in North America were validated by their predictive value for the subsequent development of overt diabetes in the years after affected pregnancies. The diagnosis is also deemed by many to be important as a risk factor for adverse perinatal outcome in the present pregnancy. Attempts have been made, in various parts of the world, to derive diagnostic criteria based on pregnancy outcome; unfortunately, these have not been so intensively studied as the standards cited above. There is also a lack of agreement on whether gestational diabetes should be considered a disease or merely a risk factor. In addition, consensus has not been reached on whether population-specific criteria should be used in each location or universally accepted diagnostic thresholds should be applied. Many philosophical questions remain unanswered, and numerous opportunities for investigation present themselves. Many of these are dealt with in this workshop-conference, whereas others remain as goals to be attained.
Serum Lipids Within 36 mo of Delivery in Women With Recent Gestational Diabetes
Authors: Kjos Siri L , Buchanan Thomas A , Montoro Martin , Coulson Anne , Mestman Jorge H
Published: September 2013

We prospectively evaluated fasting serum total cholesterol (chol), low- and high-density lipoprotein cholesterol (LDL-chol and HDL-chol), and triglycerides (TGs) in a large cohort of Hispanic women during the first 36 mo after pregnancies complicated by gestational diabetes mellitus (GDM). In 1340 women studied 6–12 wk postpartum (PP-GDM group), chol and LDL-chol were similar to levels in 43 postpartum control subjects without prior GDM. Compared with control subjects (2.01 ± 1.24 mM), TG was elevated in the PP-GDM women with diabetes mellitus (DM) (2.86 ± 2.21 mM, P < 10−5) and impaired glucose tolerance (IGT) (2.64 ± 1.68 mM, P = 0.02) but not in those with normal glucose tolerance (2.00 ± 1.21 mM). HDL-chol was decreased in PP-GDM women with DM compared with those with normal glucose tolerance. A subgroup of 157 women with prior GDM returned for at least one annual follow-up test on nonhormonal contraception (FU-GDM: n = 60 at 3–11 mo after delivery, n = 78 at 12–23 mo, and n = 39 at 24–35 mo). The cumulative prevalence of DM by 36 mo was 40%. Chol or LDL-chol levels did not significantly change during the 1-yr intervals in the FU-GDM group and were similar to a control group of 36 women without prior GDM. TG was elevated and HDL-chol was decreased in the FU-GDM women with DM at 3–11 mo but not thereafter. Overall, the prevalence of moderateand high-risk LDL-chol in the FU-GDM group was not different from that of control subjects. These findings suggest that lipid abnormalities are uncommon during the first 36 mo after delivery in women with recent GDM. The abnormalities found consisted of increased TG and decreased HDL-chol in subjects who had developed DM during the study period.
New National Academy of Sciences Guidelines for Nutrition During Pregnancy
Authors: King Janet C
Published: September 2013

In June 1990, the Institute of Medicine of the National Academy of Sciences (NAS) released a report, Nutrition During Pregnancy, that recommends individualized assessment-based nutritional management for pregnant women. This is the first publication by the NAS on maternal nutrition since the Food and Nutrition Board's landmark report Maternal Nutrition and the Course of Pregnancy was published in 1970. The newer report is divided into two parts; the first part is on weight gain, and the second part deals with nutrient supplementation during pregnancy. Dr. Roy Pitkin, Chair of the Department of Obstetrics and Gyne-cology, School of Medicine, University of California, Los Angeles, chaired the Committee on Nutritional Status During Pregnancy and Lactation, which authored the 1990 report.
Energy Requirements of Pregnancy
Authors: Durnin John V G A
Published: September 2013

The energy requirements of pregnancy is a topic of considerable uncertainty because the apparent energy costs—to supply the energy required for the changes in maternal and fetal tissues and to cover the increase in basal metabolic rate (BMR), amounting to the equivalent of an extra 250–300 kcal/day—are rarely paralleled by actual findings. However, few studies have investigated this problem in a controlled longitudinal and statistically acceptable fashion. In this study, measurements of energy intake, BMR, body weight and fatness, physical activity, and mechanical efficiency of movement were made on 162 women in Scotland at 2- to 4-wk intervals throughout pregnancy, and data from 98 of these women were also obtained in the prepregnant state. Data from a parallel study in the Netherlands are also given. The gains in body weight, fatness, the fetal and placental weights, and the increase in BMR were all at the normal expected values. However, increases in energy intake were on the order of only 100 kcal/day during the second and third trimesters. Comparatively small reductions in physical activity, which would be difficult to measure precisely, are described that could account for the difference between actual energy intake and the energy costs of pregnancy.
Is Exercise Safe or Useful for Gestational Diabetic Women?
Authors: Jovanovic-Peterson Lois , Peterson Charles M
Published: September 2013

The mainstay of management of the gestational diabetic woman is dietary manipulation to achieve and maintain normoglycemia. If normoglycemia cannot be sustained by diet alone, then insulin therapy is initiated. We instituted a series of studies to observe the value and safety of a cardiovascular fitness program to improve glucose tolerance in gestational diabetic women. We first evaluated the safety for pregnant women of five aerobic exercise machines by observing the effect of these different forms of exercise on uterine activity during the third trimester. We found that upper-extremity exercise produced no uterine contractions, but lower-extremity exercise tended to produce contractions. Upper-extremity exercise, in addition to dietary therapy, was then assigned to 10 gestational diabetic women who were matched for amount of glucose intolerance to 10 gestational diabetic women managed by diet alone. The mean fasting plasma glucose ± SD after 6 wk was 4.87 ± 0.34 mM in the diet group versus 3.89 ± 0.37 mM in the diet-plus-exercise group. The mean postglucose challenge in the diet group was 10.40 ± 0.16 mM versus 5.9 ± 1.1 mM in the diet-plus-exercise group. Thus, upper-arm exercise may provide a useful treatment option for gestational diabetes and may obviate the need for insulin.
Translation Efforts in Diabetes and Pregnancy
Authors: Vinicor Frank , Olson David , Sepe Stephen
Published: September 2013

The Division of Diabetes Translation (DDT) of the National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control (CDC), has responsibility for improving the rapidity and extent of transfer of validated diabetes research findings into the practice of medicine. Three key words in this goal are rapidity, extent, and validated. The time between identification of important research findings and implementation in practice must be as short as possible, and all components of the health-care system must be aware of these findings. Furthermore, the research observations must be supported by the general scientific community. As an example, when evidence of the efficacy of photocoagulation was established, i.e., validated (1,2), this information needed to be quickly incorporated into practice, i.e., rapidity (3), by all components of the medical community, including primary-care practitioners and patients, i.e., extent (4).
The Placenta: Not Just a Conduit for Maternal Fuels
Authors: Hay William W
Published: September 2013

The placenta is a specialized organ of exchange that provides nutrients to and excretes waste products from the fetus. The exchange of nutrients between placenta and fetus involves three major mechanisms: 1) direct transfer of nutrients from the maternal to the fetal plasma, 2) placental consumption of nutrients, and 3) placental conversion of nutrients to alternate substrate forms. Although direct transfer has been considered the primary means by which placental-fetal exchange controls the supply of nutrients to the fetus and thereby fetal metabolism and growth, the considerable metabolic activity of the placenta provides a large and fundamentally important contribution to both the quality and quantity of nutrient substrates supplied to the fetus; e.g., placental O2 and glucose consumption rates approach or even exceed those of brain and tumor tissue. Other placental metabolic activities include glycolysis, gluconeogenesis, glycogenesis, oxidation, protein synthesis, amino acid interconversion, triglyceride synthesis, and chain lengthening or shortening of individual fatty acids. Thus, consideration of the metabolism of the placenta is essential for a more complete understanding of how the placenta regulates nutrient transfer to the fetus, fetal energy balance, and fetal growth.
Fetal Growth Factors as Determinants of Intrauterine Hepatic Growth
Authors: Gruppuso Philip A , Curran Thomas R , Mead Janet E , Fausto Nelson , Oh William
Published: September 2013

To understand mechanisms at the cellular level that may lead to the selective organomegaly seen in fetuses of diabetic mothers, we examined the role of insulin and autocrine-paracrine growth factors in the regulation of hepatic growth in the fetal rat. Analyses of fetal liver from the last one-third of gestation demonstrated the presence of specific mRNAs for the transforming growth factors (TGFs) TGF-α and TGF-β. TGF-α, a homologue of epidermal growth factor (EGF), acts through EGF receptors. Levels of mRNA for TGF-α increased dramatically postnatally, whereas EGF receptor number increased just before term. In contrast, levels of mRNA for TGF-β, an inhibitor of epithelial cell growth, were greater in fetal liver than in adult liver, as was TGF-β–receptor binding. Other analyses demonstrated increases in tyrosine kinase activities of the insulin receptor, EGF receptor, and insulinlike growth factor I receptor as term approached. Proliferation of fetal rat hepatocytes in primary culture did not require mitogens or serum, consistent with production and activity of autocrine-paracrine growth factors. TGF-β was a potent inhibitor of fetal hepatocyte proliferation in culture, whereas insulin potentiated fetal hepatocyte growth above “mitogen-independent” levels. The regulatory mechanisms controlling fetal hepatic growth involve a complex interaction between stimulatory and inhibitory factors. Growth factor expression, receptor expression, receptor tyrosine kinase activity, and postreceptor signal transmission represent potential loci for insulin action that might be involved in the pathogenesis of fetal macrosomia seen in diabetic pregnancies.
Gestational Diabetes Mellitus: A Survey of Perinatal Complications in the 1980s
Authors: Hod Moshe , Merlob Paul , Friedman Shmuel , Schoenfeld Alex , Ovadia Jardena
Published: September 2013

Neonatal morbidity was assessed in the offspring of 878 mothers with gestational diabetes mellitus (GDM), 132 mothers with pre-GDM, and 380 control subjects. Compared with the control group, the GDM group had a higher incidence of complications, including macrosomia, hypoglycemia, hyperbilirubinemia, hypocalcemia, polycythemia, and major congenital anomalies (P < 0.05). Although our GDM patients were stringently managed with diet or diet plus insulin, as indicated, and maintained almost euglycemic values, these neonatal complications could not be eliminated. Our data may be consistent with observations published during the last decade that even subtle degrees of maternal hyperglycemia can have a detrimental effect on perinatal outcome. Most neonatal complications readily respond to therapy if diagnosed and treated early and promptly. Macrosomia can have a detrimental effect on delivery (trauma) and later long-term implications during childhood. Tight metabolic control with diet and, when indicated, insulin treatment may be advantageous in reducing fetal birth weight. Criteria of how tight the metabolic control should be remain to be accurately defined.
Intermediary Metabolism in Pregnancy: First Theme of the Freinkel Era
Authors: Herrera Emilio , Lasunción Miguel A , Palacín Manuel , Zorzano Antonio , Bonet Bartolome
Published: September 2013

During the first half of gestation in the rat, maternal net body weight increases rapidly, whereas in the second half of gestation, the mass of maternal structures declines, coincident with the rate of maternal fat accumulation. Enhanced maternal food intake, extrahepatic tissue lipoprotein lipase (LPL) activity, and adipose tissue lipogenesis are responsible for the progressive accumulation of maternal fat. However, during late gestation, decreased fat synthesis in maternal adipose tissue, enhanced lipolytic activity, and decreased LPL activity deplete maternal fat depots. These changes, plus enhanced endogenous production of triglyceride-rich lipoproteins, are also responsible for maternal hypertriglyceridemia. This condition benefits the offspring in two ways: 1) enhanced LPL activity in maternal liver when fasting increases triglyceride consumption for ketone body synthesis, giving the basis for accelerated starvation; and 2) induction of LPL activity in the mammary gland before parturition diverts maternal circulating triglycerides to milk synthesis in preparation for lactation. The magnitude of the maternal-fetal glucose transfer was higher than that of any of the other substrates studied, including alanine, and despite actions to spare glucose, this transfer causes maternal hypoglycemia, which is especially intense in the fasting condition. This increases sympathoadrenal activity in the mother, which may contribute to her active gluconeogenesis. Glycerol was a more efficient glucose precursor than alanine and pyruvate, and whereas glycerol placental transfer is very small, it is proposed that the fetus benefits from this product of adipose tissue lipolysis when it is previously converted into glucose. In thyroidectomized pregnant rats treated with thyroxine for different periods, restraining maternal accumulation of fat depots during the early part of gestation compromises the normal metabolic adaptations during late gestation, including the capacity for accelerated starvation, which negatively affects fetal development.
Diabetic Embryopathy Studies With Animal and In Vitro Models
Authors: Eriksson Ulf J , Håkan Borg L A , Forsberg Henrik , Styrud Johan
Published: September 2013

Diabetic pregnancy is associated with an increased risk for fetal maldevelopment for a largely unknown reason. A decade ago, Norbert Freinkel suggested that the altered fuel mixture offered to the growing conceptus may be the key to most of the changes in the embryogenesis of diabetic pregnancy. He coined the term fuel-mediated teratogenesis. During early pregnancy, periods of maternal hyper- and hypoglycemia may cause marked changes in the availability of glucose to the conceptus. Also, increased concentrations of lipids, notably ketone bodies, and branched-chain amino acids in the maternal circulation contribute to a changed fuel mixture for the embryo. In a recent experimental study of diabetic rats, it was found that the maternal metabolism of all three major classes of nutrients and maternal somatic growth during gestation covaried with the development of the embryo. Consequently, the maintenance of normal concentrations of metabolites from all nutrient classes may be important for prevention of adverse fetal outcome in diabetic pregnancy. In vitro, a high glucose concentration causes embryonic dysmorphogenesis by generation of free oxygen radicals. An enhanced production of such radicals in embryonic tissues may be directly related to an increased risk of congenital malformations in diabetic pregnancy. Thus, the notion that alterations in the net transfer of cellular fuels from the diabetic mother to her offspring may cause embryonic dysmorphogenesis, which suggests that combustion of the fuel may produce compounds that impair embryonic development, has obtained experimental support. If this is also true for human diabetic pregnancy, it has therapeutic implications.
Newly Identified Pancreatic Protein Islet Amyloid Polypeptide: What Is Its Relationship to Diabetes?
Authors: Johnson Kenneth H , O'Brien Timothy D , Westermark Per
Published: September 2013

Islet amyloid polypeptide (IAPP) or amylin is a newly identified 37–amino acid COOH-terminal–amidated polypeptide that is the major protein constituent of amyloid deposits in insulinomas and amyloid deposits in pancreatic islets of non-insulin-dependent (type II) diabetic humans and adult diabetic cats. IAPP is stored with insulin in β-cell secretory vesicles and is cosecreted with insulin in response to glucose and several secretagogues. IAPP has been demonstrated in normal pancreatic islets of many species, but IAPP-derived amyloid develops commonly in the islets of only a few species (e.g., humans and cats), especially in association with age-related diabetes. IAPP from the human and cat inherently contains a short amyloidogenic sequence that is not present in species that do not form islet amyloid. Studies in animals indicate that an aberration in the synthesis or processing of IAPP, leading to a local increase in concentration of IAPP in the islet, is also required to facilitate the conversion of IAPP to amyloid. The formation of islet amyloid may contribute to the development of type II diabetes by causing disruption of islet cells and by replacement of islets. It has also been proposed that an abnormality of IAPP homeostasis underlies the pathogenesis of type II diabetes. A significant causal relationship between IAPP and type II diabetes is based on reports that IAPP inhibits glucose-stimulated insulin release by β-cells and that IAPP inhibits insulin-stimulated rates of glycogen synthesis and glucose uptake by skeletal muscle cells. These findings clearly have potentially great relevance to type II diabetes in that impaired insulin secretion and peripheral resistance to insulin are the clinical hallmarks of this form of diabetes. However, studies generally have not supported a role for IAPP as a physiologically relevant modulator of insulin secretion, and it is yet to be demonstrated whether IAPP in physiological concentrations can induce the peripheral insulin resistance that is characteristic of type II diabetes. The potential role of this newly identified pancreatic polypeptide in the genesis of type II diabetes thus needs further investigation and confirmation in model systems utilizing physiological concentrations of IAPP. The significance of the strikingly greater responsiveness of IAPP secretion relative to insulin in severely hyperglycemic states also is not clear. However, this observation may provide an important clue to the normal function of IAPP and points to an important area of future exploration.
Interaction of Ascorbic Acid and Glucose on Production of Collagen and Proteoglycan by Fibroblasts
Authors: Fisher Elizabeth , McLennan Susan V , Tada Hisaya , Heffernan Scott , Yue Dennis K , Turtle John R
Published: September 2013

Collagen and proteoglycans are two major constituents of the extracellular matrix, and their abnormalities have been incriminated in the pathogenesis of diabetic complications. A decrease of plasma ascorbic acid has been reported in diabetes and thus may play a role in the collagen and proteoglycan abnormalities in diabetes. Ascorbic acid and glucose share structural similarity, and their metabolism may interact at the level of membrane transport and cellular action. In this study, we used a fibroblast culture system to explore this possibility. Ascorbic acid increased collagen and proteoglycan both in the culture medium and the cell layer. This stimulatory action of ascorbic acid was inhibited by the presence of glucose at a concentration of 25 mM. The effect of high glucose concentration was not mediated by inhibition of ascorbic acid uptake by fibroblasts. Insulin is able to abolish this inhibitory action of glucose on collagen production, but the precise mechanism is unclear. These results show that the high glucose concentration in diabetes can impair the action of ascorbic acid at the cellular level. This may further accentuate the problem of decreased availability of this vitamin as a result of its low plasma concentration.
Nonenzymatic Glycosylation of HDL and Impaired HDL-Receptor–Mediated Cholesterol Efflux
Authors: Duell P Barton , Oram John F , Bierman Edwin L
Published: September 2013

Previous studies have shown that nonenzymatic glycosylation of high-density lipoprotein (HDL) inhibits high-affinity binding to cultured cells and the candidate HDL-receptor protein. Because binding of HDL to its receptor is required for HDL-receptor–mediated cholesterol efflux from cells, we hypothesized that glycosylated HDL3 would have reduced ability to remove cholesterol from cells. HDL3 was glycosylated in vitro to achieve up to 40–50% reductions in free-lysine residues. Glycosylated HDL3 had a slightly greater ability than control HDL3 to sequester cholesterol directly from the plasma membrane, as predicted by changes in lipid composition. This process is independent of HDL-receptor binding and should not be influenced by reduced binding of HDL3. In contrast, efflux of intracellular cholesterol from cells, which is HDL-receptor dependent, was reduced 25–40%. The ability of glycosylated HDL3 to diminish cholesterol esterification was significantly reduced, indicating reduced net cholesterol efflux. Steady-state efflux of LDL-derived cholesterol was also markedly reduced. These findings suggest that nonenzymatically glycosylated HDL is functionally abnormal and might contribute to the accelerated development of atherosclerosis in patients with diabetes mellitus.
Altered Thymic and Peripheral T-Lymphocyte Repertoire Preceding Onset of Diabetes in NOD Mice
Authors: Zipris Danny , Crow Andrew R , Delovitch Terry L
Published: September 2013

Insulitis occurs by 5 wk of age in all NOD mice. However, diabetes is detectable only after 3–5 mo of age and only in ∼50% of females and 10% of males in our colony. Therefore, it is predictable that changes in the T-lymphocyte repertoire of diabetes-prone mice occur and predispose them to disease. We demonstrate here that an altered (with respect to control BALB/cJ mice) thymic T-lymphocyte maturation reflected by a depletion (∼12%) of CD4+CD8+ T lymphocytes and a reciprocal increase in CD4−CD8− T lymphocytes precedes the onset of diabetes. This depletion was detected only ∼3 mo after insulitis and is manifested by a specific loss (∼3%) of immature T lymphocytes bearing Vβ8lo (lo is a relative level of expression) T-lymphocyte receptor. By onset of diabetes, an even greater decrease (∼35%) of CD4+CD8+ and a reciprocal increase of CD4−CD8− T lymphocytes were apparent and accompanied by the same depletion (3%) of Vβ8lo T lymphocytes. Administration of cyclophosphamide (CY), which accelerates the appearance of diabetes in NOD mice, caused similar depletions of CD4+CD8+ and Vβ8lo thymic T lymphocytes. The same alterations in the distribution of these thymic T-lymphocyte subsets were evident even earlier in insulitis- and diabetes-free NON mice, indicating that these changes in thymic T-lymphocyte development may be necessary but not sufficient to give rise to diabetes. Despite the common genetic origin of NOD and NON mice, differences at their MHC-linked and -unlinked loci may account for their differential susceptibility to diabetes. Analyses of peripheral lymph node (LN) T lymphocytes showed a decrease (6–10%) in the frequency of the CD4+ T-lymphocyte subset and a concomitant reduction (3–4%) in CD4+Vβ8+ T lymphocytes in spontaneously and CY-induced diabetic NOD mice. Interestingly, the latter reduction resulted primarily from a depletion of CD4+Vβ8.1+ LN T lymphocytes in diabetic mice and was not detectable either in prediabetic NOD mice at 16 wk of age or in nondiabetic NON mice. These data suggest that depletion of CD4+ regulatory T lymphocytes and/or the rerouting of CD4+Vβ8.1+ effector T lymphocytes from the peripheral LN to the pancreas during progression to disease onset mediate the pathogenesis of diabetes.
Metabolic Effects of IGF-I in Diabetic Rats
Authors: Rossetti Luciano , Frontoni Simona , Dimarchi Richard , DeFronzo Ralph A , Giaccari Andrea
Published: September 2013

Insulinlike growth factor I (IGF-I) stimulates glucose utilization (GU) in nondiabetic rats. We compared the effects of IGF-I and insulin on glucose metabolism in control (fed plasma glucose 7.7 ± 0.1 mM, n = 30) and partially (90%) pancreatectomized diabetic (plasma glucose 18.4 ± 0.8 mM, n = 30) awake unstressed rats. IGF-I was infused at 0.65 or 1.96 nmol · kg−1 · min−1 and insulin at 22 or 29 pmol · kg−1 · min−1 in combination with [3-3H]glucose while euglycemia was maintained by a variable glucose infusion. In controls, GU during the 0.65- and 1.96-nmol · kg−1 · min−1 IGF-I infusions (127 ± 7 and 168 ± 4 μmol · kg−1 · min−1, respectively) was similar to rates observed during the 22- and 29-pmol · kg−1 · min−1 insulin infusions (121 ± 2 and 156 ± 5 μmol · kg−1 · min−1). Whole-body glycolytic rate (3H2O generation) and muscle glycogen synthetic rate were identical during insulin and IGF-I infusions. In diabetic rats, GU was reduced by 30% versus control rats (P < 0.01) during both the low-dose (88 ± 7 vs. 121 ± 7 μmol · kg−1 · min−1) and higher-dose (109 ± 4 vs. 156 ± 5 μmol · kg−1 · min−1) insulin clamps. The defect in insulin action involved both muscle glycogen synthesis and glycolysis. In diabetic rats, IGF-I elicited rates of GU similar to controls (115 ± 10 and 164 ± 12 μmol · kg−1 · min−1 during the 0.65- and 1.96-nmol · kg−1 · min−1 infusions, respectively) and corrected the intracellular defects in glycogen synthesis and glycolysis. To determine whether the effects of IGF-I and insulin are additive in stimulating GU, euglycemic clamps were performed with supramaximal concentrations of insulin, and IGF-I was superimposed during the last 100 min. In control rats, GU during insulin alone (191 ± 11 μmol · kg−1 · min−1) was identical to that during combined insulin plus IGF-I (198 ± 9 μmol · kg−1 · min−1), whereas in diabetic rats, GU rose from 155 ± 8 (insulin alone) to 200 ± 5 (insulin + IGF-I) μmol · kg−1 · min−1 (P < 0.01). Our conclusions are that 1) in control rats, the effects of IGF-I and insulin on total-body glucose metabolism and the major intracellular pathways of glucose disposal are identical, 2) in control rats, no additive effect of the two hormones is observed, 3) in diabetic rats, insulin-mediated total glucose uptake and intracellular glucose metabolism (glycolysis and glycogen synthesis) are markedly impaired, and 4) in diabetic rats, IGF-I but not insulin is capable of reversing the cellular defects in insulin action. These results indicate that the metabolic response to IGF-I is intact in insulin-resistant diabetic rats and that the potency of IGF-I differs in control and diabetic rats.
Effects of Polyol-Pathway Inhibition and Dietary myo-Inositol on Glomerular Hemodynamic Function in Experimental Diabetes Mellitus in Rats
Authors: Goldfarb Stanley , Ziyadeh Fuad N , Kern Elizabeth F O , Simmons David A
Published: September 2013

Early functional disturbances in nerve, retina, and lens in diabetes mellitus appear to result from a common mechanism involving increased polyol-pathway activity with an associated effect on tissue myo-inositol metabolism. We tested the role of increased polyol-pathway activity in the early glomerular hemodynamic abnormalities in experimental diabetes in rats with dietary myo-inositol supplementation or the administration of sorbinil, an aldose reductase inhibitor. Each maneuver prevented the glomerular hyperfiltration of early streptozocin-induced diabetes and reversed the hyperfiltration of established diabetes of 10 days' duration. We also found that the abnormal response to captopril in diabetic rats was improved by dietary myo-inositol supplementation or sorbinil administration. Although nonhypotensive doses of captopril lowered glomerular filtration rate (GFR) in diabetic rats on a 0.01% myo-inositol diet, GFR increased substantially after captopril infusion in diabetic rats treated with sorbinil or myo-inositol supplementation. These data suggest that normalization of tissue myo-inositol metabolism restores normal responsiveness to angiotensin II; this may contribute to the reduction in GFR with the two experimental maneuvers. We also tested the interaction between polyol-pathway activation and high dietary protein intake. Aldose reductase inhibition and dietary myo-inositol supplementation had no effect on the component of increased GFR due to 50% dietary protein intake but specifically inhibited the hyperfiltration attributable to diabetes. These results suggest that hyperglycemia acts through increased polyol-pathway activity and its effects on tissue myo-inositol metabolism to play a fundamental role in the pathogenesis of the glomerular hyperfiltration characteristic of early diabetes.
Some Thoughts on the Mechanism of Action of Insulin
Authors: Exton John H
Published: September 2013

Proposed mechanisms by which insulin exerts its effects are discussed. Evidence for a role for the tyrosine kinase activity of the insulin receptor and of a phosphorylation/dephosphorylation cascade is presented. The possible roles of phospholipid breakdown, diacylglycerol, and protein kinase C are discussed. The hypothesis that insulin elicits the hydrolysis of a glycosyl phosphatidylinositol to form a mediator of certain of its actions is considered in detail. The evidence that a G protein is involved in insulin action is analyzed.
Regulation of Rat Insulin-Receptor Kinase by Glucose in Vivo
Authors: Bryer-Ash Michael
Published: September 2013

The effects of acute and chronic hyperglycemia on the kinase activity of insulin receptors in vivo were studied in the rat. Skeletal muscle–derived insulin receptors were isolated, with preservation of the in vivo phosphorylation state, from nondiabetic rats subjected to hyperinsulinemic clamps at either euglycemia (mean 5.2 mM) or hyperglycemia (14.4 mM) or from streptozocin-induced diabetic rats at euglycemia (5.1 mM) or hyperglycemia (14.2 mM). Kinase activity toward histone of insulin receptors from nondiabetic animals rendered hyperglycemic for 80–90 min was 50% higher than that of receptors from rats clamped at euglycemia (mean ± SE 4.5 ± 0.4 vs. 3.0 ± 0.3 fmol of phosphate into histone, respectively, P < 0.02), although kinase activity of receptors isolated from animals rendered diabetic for 10–14 days before hyperglycemic or euglycemic clamps showed no such effect. These results suggest that acute hyperglycemia may increase insulin-receptor kinase activity in vivo, possibly augmenting glucose disposal thereby, whereas the chronic hyperglycemia of diabetes mellitus results in metabolic derangements that nullify this effect.
Stimulatory and Inhibitory Effects of Glucose and Insulin on Rat Blastocyst Development in Vitro
Authors: De Hertogh René , Vanderheyden Ivo , Pampfer Serge , Robin Denis , Dufrasne Eric , Delcourt Jacques
Published: September 2013

The effect of glucose and insulin on the in vitro development of the rat preimplantation embryo was studied by incubating rat blastocysts recovered on days 5 or 6 of pregnancy in the absence or presence of increasing levels of glucose and/or insulin for 24 or 48 h. A differential cell-staining method allowed the separate counting of inner cell mass (ICM) and trophectoderm (TE) cells at the end of the incubation period. In a high-glucose medium (17 mM), ICM and, to a lesser extent, TE developments were significantly and irreversibly inhibited. Low insulin concentrations (3 pM) stimulated ICM and TE development in the presence of 1.1 or 6 mM glucose. Higher insulin levels (30–600 pM) in a 6-mM glucose medium, resulted in a dose-dependent inhibition of ICM and, to a lesser extent, TE development after both 24 and 48 h. This insulin-induced inhibition was reversible if insulin was removed from the medium after 24 h. In the absence of glucose in the medium, insulin was neither stimulatory nor inhibitory on ICM growth. Dead-cell occurrence in ICM after a 48-h incubation increased with increasing glucose concentration in the medium. Insulin alone did not increase dead-cell number but enhanced the effect of glucose. These results show that, in the presence of glucose, insulin might be stimulatory (at low concentrations) or inhibitory (at higher concentrations) on ICM development. A high glucose level was also inhibitory and increased dead-cell occurrence. The data suggest that insulin and glucose might interact and modulate blastocyst development as a function of their respective concentrations.