bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Role of Thymic Immunity and Insulitis in the Development of Streptozocin-induced Diabetes in Mice
Authors: Nakamura Minoru , Nagafuchi Seiho , Yamaguchi Keisuke , Takaki Ryosaburo 
Published: September 2013

This article is concerned with the role of thymic immunity in the development of diabetes experimentally induced by multiple injections of subdiabetogenic doses of streptozocin (STZ). Euthymic + / +, + /nu, and athymic nu/nu mice of CD-1 and BALB/cAJcl origin were studied. Daily intraperitoneal (i.p.) injections of 30 mg /kg body wt of STZ for 5 consecutive days in CD-1 + / + and + /nu mice resulted in hyperglycemia and mononuclear cell infiltrations of islets (insulitis). The CD-1 nu/nu mice developed neither insulitis nor hyperglycemia after the same treatment. In the nu/nu mice, when thymic immunity was restored by thymus grafting, both insulitis and hyperglycemia developed, thus demonstrating that thymic immunity was a prerequisite for the development of insulitis and hyperglycemia. There was a positive correlation among the degrees of thymic immunity, insulitis, and hyperglycemia in CD-1 + /nu,nu/nu with thymus grafts, and nu/nu mice, indicating that thymic immunity may amplify the diabetogenic effect of STZ by eliciting insulitis. In contrast, in BALB/cAJcl mice, a nonsusceptible strain to insulitis, no significant differences in plasma glucose levels were observed between the + /nu and nu/nu or between the nu/nu and thymus-grafted nu/nu mice. Furthermore, no significant difference was found in plasma testosterone levels between the + /nu and nu/nu mice of both CD-1 and BALB/cAJcI origin.
In conclusion, our data indicate that thymic immunity enhances the diabetogenic effect of STZ by eliciting insulitis in susceptible mice.
New Polymorphisms at the Insulin Locus Increase Its Usefulness as a Genetic Marker
Authors: Elbein Steven C , Corsetti Lynn , Permutt M Alan 
Published: September 2013

Polymorphic sites adjacent to known genes can be used to examine the segregation of a disease relative to that gene in families, or to map the gene of interest relative to other loci. The polymorphic region 5' to the human insulin gene (5' FP) permits such analysis, but the three size classes previously identified are insufficient for many studies. More alleles are identified with restriction enzymes that generate small fragments (Pvu II). Nonetheless, sufficient polymorphism for informative family analyses is often not present.
To facilitate such analyses, we searched for other polymorphisms in over 20 KB of DNA at the insulin locus in Pima Indians, American Blacks, and Caucasians. The previously described allelic variant at a Pst I site in the 3'-untranslated portion of the gene was not polymorphic in any race. An upstream Hinc II site (−62 BP) was present in only 48% of Black alleles, but was not polymorphic in Pima Indians or Caucasians. New polymorphisms were found at a Taq I site (−11,000 BP) and a Rsa I site (−13,000 BP). The Taq I site was present in 89% of Black alleles, 87% of Pima Indian alleles, and 84% of Caucasian alleles. In contrast, the Rsa I site was present in 60% of Black and Caucasian alleles, but in only 47% of Pima Indian alleles. The Hinc II, Rsa I, and Taq I sites show no obvious linkage with each other or the 5' FP.
A fourth polymorphism, previously identified with Sac I, was found to be the creation of a new Sac I site at +2500 BP in 10% of Black alleles. This site was present only in linkage with the presence of a Hinc II site and certain sizes of the 5' FP, and only in Blacks. The usefulness of the new polymorphisms in the 5' FP (Pvu II digest) results in an increase in the number of matings that would be informative for linkage of this locus with a disease from 70% to 93%. Thus, the addition of these markers to the 5' FP permits informative linkage analysis in almost all families.
Gestational Diabetes Mellitus: Correlations Between the Phenotypic and Genotypic Characteristics of the Mother and Abnormal Glucose Tolerance During the First Year Postpartum
Authors: Metzger Boyd E , Bybee David E , Freinkel Norbert , Phelps Richard L , Radvany Ruta M , Vaisrub Naomi 
Published: September 2013

We evaluated glucose tolerance during the first year postpartum in 113 women with gestational diabetes mellitus (GDM) diagnosed according to the criteria of the First International Workshop-Conference on GDM and the National Diabetes Data Group. The high incidence of abnormal postpartum glucose tolerance (38% “diabetes mellitus” plus 19% “impaired glucose tolerance”) was correlated with certain of the heterogeneous characteristics of the population at the time of antepartum diagnosis. Virtually all women with antepartum fasting plasma glucose (FPG) &gt;130 mg/dl (GDM class BO remained abnormal postpartum (21/22 [95%]), which suggests that this group may include women with preexisting glucose intolerance unrecognized before pregnancy. In the remainder, those with FPG &gt; 105–129 mg/dl (GDM class A2) were more likely to be abnormal postpartum than those with FPG &lt;105 mg/dl (GDM class A,). Within the A, and A2 groups, increasing maternal age, relative insulinopenia, and hyperglycemia at 2 h during antepartum OGTT were also associated with a greater likelihood of abnormal glucose tolerance postpartum. The presence of HLA-DR3 and/or -DR4 antigens was not predictive of the status of glucose tolerance during the first year postpartum, although the increased frequency of cytoplasmic islet cell antibodies in A2 and B1 subjects was associated with a high incidence of abnormal postpartum glucoregulation.
The high incidence of abnormal postpartum glucose tolerance in all GDM classes makes a compelling case for careful, early, and continuing follow-up of all women with a diagnosis of GDM. The risks of abnormal glucose tolerance in the first year postpartum appear to be correlated with some of the heterogeneous characteristics of women with GDM. Differences in such genotypic and phenotypic features as we have analyzed may account for differences in the incidence of postpartum abnormality in different populations. They must be considered in all studies attempting to elucidate the pathophysiology of GDM or to evaluate therapeutic strategies designed to alter the prognosis for glucoregulation under nongravid conditions.
The Effect of Diet and Insulin on Metabolic Profiles of Women with Gestational Diabetes Mellitus
Authors: Maresh M , Gillmer M D G , Beard R W , Alderson C S , Bloxham B A , Elkeles R S 
Published: September 2013

Twenty women with abnormal glucose tolerance, detected from a routine program of antenatal screening for gestational diabetes mellitus (GDM) at 28 wk, were admitted for 24-h metabolic profiles. They were then alternately allocated to either insulin and dietary restriction or dietary restriction alone and then retested 4 wk later while on therapy. Ten normal controls were assessed twice at similar gestations to the study group. Before treatment, the 20 gestational diabetic subjects had higher mean concentrations of plasma glucose and 3-hydroxybutyrate than the controls for most of the profile, but mean insulin values were similar.
Insulin therapy was associated with a reduction in mean glucose concentrations so that the profile was similar to the controls, while in the diet-alone group the reduction was less. The 3-hydroxybutyrate concentrations rose between profiles in the normal group and also rose in those treated by diet alone, but still remained within the upper range of normal even at night. Insulin therapy resulted in a similar 3-hydroxybutyrate profile to the controls. The C-peptide response to breakfast was reduced in both groups to levels below that of the controls.
Neonatal outcome indices were similar in the two treatment groups, despite the differences in maternal metabolites, but because of the size of this study, conclusions about the neonate must be tentative.
Meal-stimulated C-Peptide and Insulin Antibodies in Type I Diabetic Subjects and Their Nondiabetic Siblings Characterized by HLA-DR Antigens
Authors: Hoogwerf Byron J , Rich Stephen S , Barbosa Jose J 
Published: September 2013

We studied serum C-peptide (CP) response 90 min after a breakfast meal and insulin antibody titers in 171 type I diabetic (IDDM) patients and 272 of their nondiabetic siblings from 169 unrelated families. HLA typing was performed in all participants.
In IDDM patients, there was a decline in CP response with increased duration of disease. CP responses of &gt;1.8 ng/ml were seen significantly less often in patients who were &lt;10 yr old at the time of diagnosis of IDDM than in patients who were &gt;10 yr old at the time of diagnosis (8% versus 21%, P &lt; 0.05). More patients with HLA-DR4 had a CP response &gt;1.8 ng/ml than did patients who lacked this antigen whether duration of IDDM was &lt;10 yr (30% versus 18%, P &gt; 0.05) or &gt;10 yr (15% versus 0%, P &lt; 0.05). Mean C-peptide was also higher in HLA-DR4-positive patients compared with HLA-DR4-negative patients both when duration of disease was &lt;10 yr (1.7 ±1.9 versus 1.4 ± 1.0, P &lt; 0.01) and &gt;10 yr (1.2 ± 1.5 versus 1.0 ± 0.4, P &lt; 0.0001). Insulin antibody binding was slightly higher in patients with HLA-DR4 compared with patients lacking this antigen (5.96 ± 7.20 versus 4.89 ± 4.74, P &lt; 0.001).
The nondiabetic male sibs had higher postprandial plasma glucose (PG) (84 ± 22 versus 79 ± 20, P &lt; 0.05) and lower serum CP values (3.8 ±1.6 versus 4.2 ± 1.7, P &lt; 0.05) than did female sibs. There were no differences in mean PG or CP values in sib groups characterized by HLA-DR type or HLA haploidentity with IDDM probands.
In conclusion, pathogenetic heterogeneity of IDDM is supported here by the following: (1) patients with earlier onset of IDDM seem to have more severe beta cell insult, and (2) DR4-positive patients give evidence of better preservation of beta cell function, even in the earlier onset classes.
Maturation of Fetal Rat Lung in Diabetic Pregnancies of Graduated Severity
Authors: Bourbon J R , Pignol B , Marin L , Rieutort M , Tordet C 
Published: September 2013

Biochemical and morphologic maturation of fetal rat lung was studied in pregnant, diabetic rats with different levels of glucose intolerance (sub-, mildly, and severely diabetic). Fetuses were almost normoglycemic and hyperinsulinemic in subdiabetic rats, both hyperglycemic and hyperinsulinemic in mildly diabetic rats, and hyperglycemic but hypoinsulinemic in severely diabetic rats. A similar delay in type II pneumocyte differentiation and a similar decrease of disaturated phosphatidylcholine (DSPC) content in lung tissue and broncho-alveolar material recovered by lung lavage occurred in the fetuses of the three diabetic groups, independently of the severity of diabetes. Phosphatidylglycerol (PG) was decreased in fetuses from severely diabetic rats only. DSPC appeared specifically affected in fetuses of sub- and mildly diabetic groups, whereas in those of severely diabetic groups, DSPC alterations accompanied a variety of abnormalities including whole lung hypoplasia and hypotrophy and decreases of sphingomyelin, unsaturated PC, and lysoPC. The mechanisms leading to abnormal lung development could therefore be different in fetuses of sub- and mildly diabetic rats on one hand and fetuses of severely diabetic rats on the other. Since hyperinsulinemia was the prominent feature of fetal “milieu interieur” in subdiabetic rats, this study presents arguments gained from in vivo experiments for an implication of hyperinsulinemia in lung developmental retardation due to maternal diabetes. However, the decrease of PG seems to depend on increased blood glucose level in itself. Diminished lung giycogen breakdown and decreased lung triglyceride content, more pronounced in fetuses of sub- and mildly diabetic rats than in those of severely diabetic rats, suggest that in the former, the decrease of DSPC biosynthesis could be due to decreased availability of substrates because of abnormal giycogen utilization.
Fetuses from sub- and mildly diabetic rats constitute experimental models most closely resembling the human fetus of the diabetic mother with respect to circulating glucose and insulin. They appear therefore more adequate for elucidating the mechanisms of abnormal lung development in the diabetic pregnancy. In contrast, fetuses from severely diabetic rats associate very high blood glucose levels and hypoinsulinemia, which are features closer to those of adult diabetic subjects than to those of the human fetus of the diabetic mother.
Recognition of Human Insulin and Proinsulin by Monoclonal Antibodies
Authors: Storch Max-Jürgen , Petersen Karl-Georg , Licht Thomas , Kerp Lothar 
Published: September 2013

High-affinity monoclonal antibodies (MAB) were obtained from lymph node cell fusions. Affinities ranging from 0.8 × 109 L/M to 5.2 ×109 L/M were calculated from binding studies with monoiodinated human, bovine, and porcine insulins and human proinsulin.
Two monoclonal antibodies were specific for human insulin, recognizing an epitope involving the amino acid B-30 (Thr). Another two monoclonal antibodies were bound to the C-terminal end of the B-chain near B-30.
The B-chain-specific monoclonal antibodies did not bind human proinsulin. One monoclonal antibody recognized the A-chain loop in the positions A-8 to A-10. This antibody bound also to human proinsulin. It was concluded that the A-chain loop is exposed on the surfaceof proinsulin, while the C-terminal B-chain is not available for binding.
The study shows that monoclonal antibodies can be used to characterize structures of insulin and proinsulin. In contrast to x-ray studies, the molecules can be used at low concentrations in soluble form. It is suggested to use monoclonal antibodies for the screening of atypical insulins in the serum of diabetic patients and for the further refinement of insulin and proinsulin measurements.
Plasma Pancreatic Polypeptide Response to Insulin-induced Hypoglycemia as a Marker for Defective Glucose Counterregulation in Insulin-dependent Diabetes Mellitus
Authors: White Neil H , Gingerich Ronald L , Levandoski Lucy A , Cryer Philip E , Santiago Julio V 
Published: September 2013

Defective glucose counterregulation occurs in some insulin-dependent diabetic subjects (IDDMs) as a result of a combined deficiency of glucagon (IRG) and epinephrine (EPI) secretionin response to insulin-induced hypoglycemia. To determine whether the deficient glucagon response, the deficient epinephrine response, or both are manifestations of autonomic dysfunction, we used the pancreatic polypeptide (PP) secretory response to insulin-induced hypoglycemia as a marker for autonomic neuropathy.
Seven nondiabetic controls and 21 IDDMs were given insulin at 40 mU/kg/h after overnight euglycemia. Eight of the IDDMs had defective counterregulation (−CR), and 13 had adequate counterregulation (+ CR) by our previously published criteria. Those with −CR had a blunted EPI (δEPI = 102 ± 16 pg/ml; mean ± SEM) and PP (δPP = 12 ± 13 pg/ml) response as compared with controls (δEPI = 310 ± 49; δPP = 498 ± 43) and IDDMs with +CR (δEPI = 291 ± 32; δPP = 521 ± 86). In controls, IRG rose by 31 ± 6 pg/ml; in IDDMs, IRG failed to rise significantly above baselineregardless of counterregulatory status. Although the PP and EPI responses correlated well (r = 0.626, P &lt; 0.001), the IRG response failed to correlate with either the EPI or the PP response.
We conclude that the deficient epinephrine, but not glucagon, secretory response to hypoglycemia in diabetic subjects is a result of autonomic neuropathy. The pancreatic polypeptide responsemay be helpful in evaluating the counterregulatory status of IDDMs before attempts at normalization of blood glucose using intensive therapeutic regimens, since a deficient pancreatic polypeptide response identifies patients with defective glucose counterregulation who have been shown previously to be at increased risk of severe hypoglycemia during intensive therapy.
Metabolic Control in Diabetic Dogs Treated with Pancreatic Autotransplants and Insulin Pumps
Authors: Albisser A M , Nomura M , Greenberg G R , McPhedran N T 
Published: September 2013

Fasting metabolite and hormonal levels were studied prospectively in pancreatectomized dogs who had received grafts of their own pancreas. The results were compared with similarly diabetic animals who received exogenous insulin pumped intravenously either peripherally or portally. All animals were studied for 48–91 wk after pancreatectomy.
In the autotransplanted animals, the fasting levels of glucose, lactate, pyruvate, alanine, pancreatic glucagon, insulin, gastric inhibitory peptide, and pancreatic polypeptide were all abnormal. In the peripherally infused animals, the fasting levels of glucose, pyruvate, alanine, free fatty acids, and insulin were also abnormal. In the portally infused animals, pyruvate, alanine, gastric inhibitory peptide, gastrin, and pancreatic polypeptide were abnormal.
These results suggest that the portal route of insulin delivery may be necessary if fasting metabolite and hormonal levels are to approximate normal most closely whether exogenous intravenous insulin is replaced by implanted pumps or endogenous insulin is replaced by pancreatic transplants.
Hormone Release, Islet Yield, and Transplantation of Fetal and Neonatal Rat Dorsal and Ventral Pancreatic Islets
Authors: Hayek A , Guardian C 
Published: September 2013

Fetal (20–21 day gestation) and neonatal (&lt;5-day-old) rat islets were isolated from the glucagon-rich (dorsal) and glucagon-poor (ventral) pancreatic regions. After 1 or 2 wk in culture, groups of islets from each region were transferred to culture dishes containing Krebs-Ringer bicarbonate buffer with low (2.4 mM) and high (16.7 mM) glucose plus aminophylline. After 2 wk in culture, insulin released into medium was higher than after 1 wk, and more so if the islets originated from dorsal tissue (P &lt; .01). Glucagon release in response to alanine (10 mM) stimulation was also significantly higher in dorsal than in ventral islets (6.38 ± 1.98 vs. 1.49 ± 0.89 pg · islet−1 · h−1 respectively; P &lt; .02).
Coincident with higher insulin and glucagon release, islet yield was greater in tissue from the dorsal neonatal pancreas than from that obtained in the fetal and neonatal ventral pancreas [range: dorsal, 131–180 (median, 153), vs. ventral, 53–127 (median, 84), islets obtained on day 5 of culture].
Neonatal islets of dorsal origin were transplanted intrasplenically (500–3000 islets) to streptozocin-induced diabetic inbred Lewis rats. Only rats receiving &gt;2500 islets were cured by transplantation.
These experiments show that dorsal fetal islets secrete more insulin than do ventral islets and that islet yield is higher when islets are isolated from dorsal rather than from ventral perinatal pancreatic tissue. Despite their in vitro behavior, more neonatal dorsal islets are required to cure experimental diabetes than are reported With adult islets.
β-Adrenergic Receptors and Adenylate Cyclase Activity in Diabetic Rat Fat Cells
Authors: Cingolani G E Chiappe De 
Published: September 2013

Our study describes the effect of norepinephrine on adenylate cyclase activity in adipocytes from control and diabetic rats. The results show that diabetes induced an increase in both basal and norepinephrine-stimulated adenylate cyclase activity. This higher activity was not suppressed when the animals were treated for 2 days with the β-blocking agent propranolol. On the other hand, adipocytes from control animals treated with propranolol showed a higher adenylate cyclase activity (basal and in response to norepinephrine).
β-Adrenergic receptors were examined in adipocytes from control and diabetic rats with and without treatment with propranolol. The results show a higher β-receptor density in adipocytes from diabetic animals. When the animals were treated with propranolol, the pblocker induced a higher receptor density in adipocytes from control animals without affecting the already increased receptor density in diabetic preparations.
The data suggest that adenylate cyclase activity in response to norepinephrine in adipose tissue is increased during at least a certain period of the diabetic state. This increase in adenylate cyclase activity is accompanied with an increase in β-receptor density, but in contrast to control animals, this receptor density is not further increased with propranolol treatment.
Apolipoprotein E Polymorphism and Hyperlipemia in Type II Diabetics
Authors: Eto M , Watanabe K , Iwashima Y , Morikawa A , Oshima E , Sekiguchi M , Ishii K 
Published: September 2013

The relationship between apolipoprotein E (apoE) polymorphism and plasma lipids and hyperlipemia was investigated in 105 male type II diabetics and 111 male nondiabetics. ApoE phenotypes were determined by a one-dimensional rapid flat gel isoelectric focusing method as described previously. The apoE phenotype frequency in diabetics was similar to that in nondiabetics.
The frequency of hyperlipemia was higher in diabetics (56.2%) than in nondiabetics (32.4%). It was highest in the apoE3/2 group of diabetics and nondiabetics, followed by the apoE4/3 and apoE3/3 groups in the order described, indicating that the susceptibility to hyperlipemia differs among the apoE phenotype groups. ApoE3/2 diabetics had significantly higher levels of apoE and very-low-density lipoprotein (VLDL) cholesterol (chol)/VLDL triglyceride (TG) ratios than apoE3/3 diabetics. The effects of diabetes mellitus on plasma lipid levels differed among the various apoE phenotype groups: i.e., plasma total chol and low-density lipoprotein (LDL) chol increased only in apoE3/2 and apoE4/3 diabetics and plasma high-density lipoprotein chol decreased only in apoE3/3 diabetics, as compared with the corresponding apoE phenotype groups of nondiabetics, whereas plasma TG, VLDL TG, and VLDL chol increased in the three apoE phenotype diabetics. Furthermore, an increase of apoEII; apoEIII ratio was observed in apoE3/3 diabetics, particularly in those with hypertriglyceridemia. This study has also shown that the increased apoEII: apoEIII ratio is due to increased sialation of apoE based on the study of sialidase digestion of apo VLDL.
We conclude that apoE polymorphism should be taken into consideration when plasma lipoprotein patterns are studied in type II diabetics and that increased sialation of apoE may at least partly contribute to an increased frequency of hypertriglyceridemia in type II diabetics.
Wound Collagen Accumulation in Obese Hyperglycemic Mice
Authors: Goodson William H , Hunt Thomas K 
Published: September 2013

We used C57-BL ob/ob mice as a model to study wound healing in type II (adult-onset) diabetes. Planimetry was used to assess rate of closure in standard open skin wounds. In agreement with previous subcutaneous wound collagen-accumulation studies, closure was slower in the ob/ob mice.
Subcutaneous implants were used to evaluate wound collagen accumulation. Weanling mice have collagen accumulation similar to lean littermates (mean 3.43 μg/ cm vs. 3.46 μg/cm), but the same ob/ob animals had decreased wound collagen (mean 2.39 μg/cm vs. 3.02 μg/cm, P &lt; 0.04) when mature. Other ob/ob animals fed a restricted diet (and thus not obese) had normal collagen accumulation at the same age. Neither insulin nor diet restriction restored wound collagen accumulation in phenotypically obese mice. Because collagen accumulation is not improved by measures that control hyperglycemia (insulin and diet restriction) and the defect was seen only in phenotypically obese ob/ob mice, the decreased wound collagen accumulation may be due in part to structural changes in adipose tissue.