bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-CD8 Abrogates Effect of Anti-CD4–Mediated Islet Allograft Survival in Rat Model
Authors: Seydel Karl , Shizuru Judith , Grossman Davida , Wu Anna , Alters Susan , Fathman C Garrison
Published: September 2013

We studied the effects of anti-CD4 treatment of diabetic ACI rats on the induction oftolerance to allogeneic (Lewis) islet allografts. When given as a 4-day treatment regimen, OX38, a mouse anti-rat CD4 antibody, caused depletion of >80% of CD4+ cells from the peripheral blood of treated rats. After induction of diabetes (a single high-dose bolus of streptozocin) and 3 days after the initiation of anti-CD4 immunotherapy, recipient ACI rats were transplanted with fully allogeneic (Lewis) islets of Langerhans via the portal circulation. These transplanted islets were capable of returning the anti-CD4–treated ACI recipients to normoglycemia, which was maintained indefinitely in the absence of further immunosuppression. In contrast, treatment of recipient rats with OX8, an anti-CD8 monoclonal antibody (MoAb), induced only a slight prolongation of graft survival (≤30 days). Further characterization of the cellular requirements for the induction of long-term transplantation survival revealed thatsuccessful pretransplantation anti-CD4 therapy could be ablated by the coincident treatment of recipient rats with depleting levels of anti-CD8 MoAb. These data point to the necessity of a regulator CD8+ cell in the induction of anti-CD4–mediated transplantation survival in this rat model of islet transplantation.
Diminished in Situ Glucose-6-Phosphate Flux in Permeabilized Adipocytes From Streptozocin-Induced Diabetic Rats
Authors: Mick Gail J , Tousley Kristen , McCormick Kenneth L
Published: September 2013

With metabolically active, saponin-permeabilized adipocytes, in situ pathway metabolism, which was distal to glucose transport, was examined in acute streptozocin-induced diabetic (STZ-D) rats. Metabolic reactions were initiated with selectively radiolabeled glucose-6-phosphate (G6P), an otherwise inert substrate with intact cells. Thus, the membrane pores permitted a direct comparison of cellular flux between control and STZ-D adipocytes at identical initial substrate concentrations. Three metabolic pathways were studied: 1) proximal glycolysis through the triosephosphates ([3-3H]G6P to 3H2O), 2) glycolysis-Krebs ([6-14C]G6P) oxidation, and 3) lipogenesis ([6-14C]G6P incorporation into triglyceride). The extent of membrane porosity was assessed by both propidium iodide staining and lactate dehydrogenase leakage to assure that porosity was comparable between the cell groups. Porous adipocytes from STZ-D rats had markedly attenuated rates of G6P metabolism compared with controls. At enzyme-saturating concentrations of G6P (4 mM), this deficit ranged from 44% for glycolysis-Krebs oxidation to 88% for lipogenesis. The reduction in glycolysis-Krebs oxidation was also evident between 0.5 and 6 mM G6P. These porous-cell data were compared with parallel studies of glucose metabolism and clearance in intact adipocytes. Finally, several glycolytic enzymes and acetyl-CoA carboxylase were measured in cell-free (sonicated) extracts with traditional in vitro methods under Vmax conditions. Overall, the in situ porous-cell flux measurements uncovered larger deficits in posttransport cellular metabolism than were apparent in the cell-free, in vitro assays. We conclude that, in actively metabolizing porous rat adipocytes, there exists a striking and unequivocal transport-independent defect in intermediary metabolism after acute STZ-D.
Diminished Specific Activity of Cytosolic Protein Kinase C In Sciatic Nerve of Streptozocin-Induced Diabetic Rats and Its Correction by Dietary myo-Inositol
Authors: Kim Jean , Rushovich Errol H , Thomas Thomas P , Ueda Tetsufumi , Agranoff Bernard W , Greene Douglas A
Published: September 2013

The impaired Na+-K+-ATPase activity in peripheral nerve from diabetic rats is prevented by dietary myo-inositol (MI) supplementation in vivo and corrected by protein kinase C (PKC) agonists in vitro, suggesting that PKC may mediate the effects of nerve MI depletion on Na+-K+-ATPase activity. However, little is known about the effect of diabetes on PKC activity or peptide in rat peripheral nerve. Therefore, the effect of streptozocin-induced diabetes and dietary MI supplementation on the activity and distribution of PKC in rat sciatic nerve homogenates and cytosolic and particulate fractions was explored with histone phosphorylation assay and Western-blot analysis. PKC activity but not peptide was selectively decreased in the cytosolic fraction by streptozocin-induced diabetes, and this abnormality was partially corrected by dietary MI supplementation. These results suggest that altered MI metabolism may affect nerve PKC specific activity, and this alteration may play a role in reduced Na+-K+-ATPase activity and blunted regenerative response in diabetic nerve.
Effect of Diabetes on Cytosolic Free Ca2+ and Na+-K+-ATPase in Rat Aorta
Authors: Ohara Takeshi , Sussman Karl E , Draznin Boris
Published: September 2013

We examined Na+-K+-ATPase activity and the levels of αI-, αII-, and β-subunit mRNA and protein in aortic cells of diabetic rats. Diabetes was induced by streptozocin. Na+-K+-ATPase activity was significantly reduced on the 2nd day of diabetes (9.4 ± 1.3 vs. 17.5 ± 2.1 μmol NADH · mg−1 protein · h−1, P < 0.05) and remained depressed on days 7 and 14. The levels of 5.3-kilobase (kb) mRNA band of the catalytic αII-subunit of Na+-K+-ATPase were also decreased on the 2nd day of diabetes, whereas the second band, 3.4 kb, was not affected. Both bands were significantly decreased on days 7 and 14. This was followed by a reduction in the levels of αII-protein (day 14). The levels of αI- and β-subunit mRNA and alpha I- protein were not affected by diabetes. A decrease in Na+-K+-ATPase activity was accompanied by a significant (P < 0.001) increase in the cytosolic free Ca2+ concentrations ([Ca2+]i) in diabetic aortic cells (221 α 18 nM on the 7th day and 242 ± 17 nM on the 14th day vs. 153 ± 7 nM in controls). These findings are consistent with the hypothesis that decreased Na+-K+-ATPase activity and gene expression in vascular smooth muscle cells with accompanied rises in [Ca2+]i may be an important pathogenetic factor in the development of hypertension and atherosclerosis in diabetes.
Diabetes Mellitus and Glucagon Alter Ouabain-Sensitive Na+-K+-ATPase in Rat Small Intestine
Authors: Fedorak Richard N , Cortas Nadim , Field Michael
Published: September 2013

Na+-K+-ATPase provides the driving force for cellular Na+ transport and exists in multiple isoforms that differ in ouabain sensitivities. We report that the Ki for ouabain inhibition of glucose-evoked short-circuit current, determined in intact rat ileal mucosa mounted in Ussing chambers, is higher in streptozocin-induced chronically diabetic rats than in age–matched controls. The changes in ouabain sensitivity seen in diabetes also occurred when intact ileum of age-matched controls was incubated in vitro with 2.8 × 10−5 M glucagon for at least 80 min. The effect of glucagon was blocked by cycloheximide, indicating a role for protein synthesis. This suggests that changes in ouabain sensitivity seen in diabetes are produced by glucagon, the serum concentration of which increases in diabetes. Ouabain-dependent phosphorylation of Na+-K+-ATPase (backdoor phosphorylation) revealed a higher Km for phosphate in intestinal basolateral membranes obtained from diabetic rats compared with age-matched controls, again confirming a decrease in ouabain sensitivity. Furthermore, the mRNA encoding the α1-isoform was upregulated 2.6-fold in chronically diabetic intestines. This suggests that the ouabain sensitivity seen during diabetes may be due to upregulation of the α1-isoform, known to be less sensitive to ouabain than the other isoforms.
Risk of IDDM in Children of Diabetic Mothers Decreases With Increasing Maternal Age at Pregnancy
Authors: Warram James H , Martin Blaise C , Krolewski Andrzej S
Published: September 2013

Offspring of women with insulin-dependent diabetes mellitus (IDDM) have a significantly lower risk of IDDM than the offspring of men with IDDM. Furthermore, a negative association of the risk of IDDM in the offspring with maternal age at delivery has been reported. This study tested the association with maternal age in an independent set of families (n = 103) in which the mother had at least one pregnancy before and after the onset of IDDM. In the 304 offspring, the mean ± SE risk of IDDM by age 20 was 6.0 ± 2.4% for those born at maternal ages < 25 yr, whereas, the risk was significantly lower (0.7 ± 0.7%) for those born at older maternal ages (P = 0.03). These 304 offspring were combined with a sample of 1391 offspring previously reported for a multivariate analysis of other factors related to pregnancy (4). In the combined analysis, the risk of IDDM in offspring born at maternal ages > 25 yr was one-fifth that for offspring born to younger mothers. The risk of IDDM in the offspring was not significantly related to birth order, mother's age at first pregnancy, or the interval between pregnancies for subsequent ones. The risk for the children born before the mother's onset of diabetes was higher than that for those exposed in utero to her diabetes, but the difference did not reach statistical significance. In conclusion, although genetic factors are important determinants of susceptibility to IDDM, exposure to maternal diabetes protects offspring from IDDM during the first 2 decades of life. Moreover, a child born to an IDDM mother >25 yr old has an even lower risk than a child born to that mother at a younger age. The combined result is that a child born to a >25-yr-old woman with IDDM has a very low risk of developing IDDM, almost as low as the children of nondiabetic parents. This has immediate practical implications for women with IDDM who are considering pregnancy and important implications for hypotheses regarding the mechanism that underlies the protective effect of exposure to maternal diabetes.
Islet Amyloid Polypeptide and Insulin Secretion From Isolated Perfused Pancreas of Fed, Fasted, Glucose-Treated, and Dexamethasone-Treated Rats
Authors: O'Brien Timothy D , Westermark Per , Johnson Kenneth H
Published: September 2013

Rats from four experimental treatment groups, including fed controls, 24- to 30-h fasted, dexamethasone-treated, and intraperitoneal glucose-treated, were used to assess the effects of these treatments on the immunohistochemically detectable islet amyloid polypeptide (IAPP) content in the pancreatic islets. Isolated perfused pancreases from additional animals in these groups were used to assess insulin and IAPP secretion and relative amounts of these hormones secreted into the perfusate under low-glucose (2.75 mM) and high-glucose (16.7 mM) conditions. Insulin and IAPP concentrations in the perfusate were measured by radioimmunoassays. Titration of immunohistochemical staining revealed the highest levels of IAPP in the dexamethasone- and glucose-treated groups, followed by the fed controls; the least amount was observed in the fasted group. In the perfusion experiments, the dexamethasone-treated group had significantly higher IAPP secretion than did all of the other groups under stimulation with 16.7 mM glucose. In addition, both dexamethasone treatment and glucose treatment increased the relative amount of IAPP to insulin secretion during 16.7 mM glucose stimulation in comparison with fed controls and fasted groups. Fasting tended to have the opposite effect and significantly decreased the relative amount of IAPP to insulin secreted under stimulation with 16.7 mM glucose. In all groups, IAPP and insulin secretion were generally parallel, which is consistent with their colocalization in the β-cell secretory vesicle and co-release after glucose stimulation. However, significant differences in the insulin-IAPP ratios between experimental groups is consistent with the hypothesis that production of IAPP and insulin are regulated differently in the β-cell. The increased secretion of IAPP in severe hyperglycemia may also facilitate the formation of IAPP-derived islet amyloid deposits, thus contributing to progressive worsening of the diabetic state.
Molecular Scanning of Insulin-Responsive Glucose Transporter (GLUT4) Gene in NIDDM Subjects
Authors: Choi Woong-Hwan , O'Rahilly Stephen , Buse John B , Rees Alan , Morgan Ruth , Flier Jeffrey S , Moller David E
Published: September 2013

We investigated the prevalence of mutations in the gene encoding the major insulin-responsive facilitative glucose transporter (GLUT4) in patients with non-insulin-dependent diabetes mellitus (NIDDM). All 11 exons of the GLUT4 gene from 30 British white subjects with NIDDM were amplified using the polymerase chain reaction and screened for nucleotide sequence variation using the single-stranded conformation polymorphism (SSCP) method. No variation between the study subjects was detected in exons 1–3, 4b–8, and 10. Variant SSCP patterns were detected in exons 4a and 9. SSCP variation in exon 4a was revealed by direct nucleotide sequencing to be due to a common silent polymorphism (AAC→AAT at Asn130). One NIDDM patient demonstrated a variant SSCP pattern in exon 9. This was caused by a point mutation (GTC→ATC) at codon 383, which leads to the conservative substitution of isoleucine for valine in the putative fifth extracellular loop of the transporter. Allele-specific oligonucleotide hybridization was used to examine the frequency of this mutation in 240 Welsh white subjects (160 with NIDDM and 80 controls). The Val→lle383 mutation was found in the heterozygous state in two diabetic subjects and no control subjects. We conclude that mutations of the GLUT4 coding sequence are very uncommon in this population of subjects with typical NIDDM. Determining whether the lle383 GLUT4 variant present in 3 diabetic subjects contributes in any way to their disease will require further study.
Impaired Expression of Glycogen Synthase mRNA in Skeletal Muscle of NIDDM Patients
Authors: Vestergaard Henrik , Bjørbæk Christian , Andersen Per H , Bak Jens F , Pedersen Oluf
Published: September 2013

Based on recent studies of the abnormal physiology and biochemistry of the glycogen synthesis in skeletal muscle of non-insulin-dependent diabetes mellitus (NIDDM) patients and their first-degree relatives, the key enzyme of this pathway, glycogen synthase (GS), is considered a candidate gene in the pathogenesis of insulin resistance. Comparing matched groups of 14 NIDDM patients with 14 control subjects, we found that impaired insulin-stimulated nonoxidative glucose metabolism of peripheral tissue (P < 0.02) and reduced total GS activity (P < 0.05) of vastus lateralis muscle from patients with NIDDM were accompanied by a 39% reduction (P < 0.02) in the steady state level of GS mRNA per microgram DNA of muscle. In both diabetic and control subjects, the mRNA expression of GS was unaffected after euglycemic-hyperinsulinemic clamp for 4 h. With single-stranded conformation polymorphism analysis of the entire coding sequence of the GS gene, we were unable to detect any genetic variants in a subset of eight NIDDM patients. We conclude that abnormal pretranslational regulation of the GS gene may contribute to impaired glycogen synthesis of muscle in NIDDM. Our studies give no evidence for structural changes in the coding region of the GS gene, and it is unknown if the decreased mRNA expression is due to impaired transcription or accelerated degradation of the transcript.
Effect of Diabetes and Aging on Carboxymethyllysine Levels in Human Urine
Authors: Knecht Kevin J , Dunn John A , McFarland Kay F , McCance David R , Lyons Timothy J , Thorpe Suzanne R , Baynes John W
Published: September 2013

Carboxymethyllysine (CML) has been identified as a modified amino acid that accumulates with age in human lens proteins and collagen. CML may be formed by oxidation of fructoselysine (FL), the Amadori adduct formed on nonenzymatic glycosylation of lysine residues in protein, or by reaction of ascorbate with protein under autoxidizing conditions. We proposed that measurements of tissue and urinary CML may be useful as indices of oxidative stress or damage to proteins in vivo. To determine the extent to which oxidation of nonenzymatically glycosylated proteins contributes to urinary CML, we measured the urinary concentrations of FL and CML in diabetic (n = 26) and control (n = 28) patients. The urinary concentration of FL correlated strongly with HbA1 measurements and was significantly higher in diabetic compared with control samples (9.2 ± 6.5 and 4.0 ± 2.8 μg/mg creatinine, respectively; P < 0.0001). There was also a strong correlation between the concentrations of CML and FL in both diabetic and control urine (r = 0.67, P < 0.0001) but only a weakly significant increase in the CML concentration in diabetic compared with control urine (1.2 ± 0.5 and 1.0 ± 0.3 μg/mg creatinine, respectively; P = 0.05). The molar ratio of CML to FL was significantly lower in diabetic compared with control patients (0.25 ± 0.12 and 0.43 ± 0.16, respectively; P < 0.0001). The correlation between urinary FL and CML and the increase in CML in diabetic urine suggests that urinary CML is derived in part from autoxidation of FL in nonenzymatically glycosylated proteins, whereas the decreased ratio of CML to FL in diabetic urine suggests that oxidative stress is decreased in diabetes. The ratio of CML to FL showed no correlation with age in either diabetic or control populations, arguing against an increase in oxidative stress to proteins with age.
Altered Behavior and Neurochemistry During Short-Term Insulin Withdrawal in Streptozocin-Induced Diabetic Rats
Authors: Bellush Linda L , Reid Sally G
Published: September 2013

Amphetamine-induced stereotypy and turnover of dopamine (DA) and serotonin (5-HT) in the CNS were assessed in streptozocin-induced diabetic rats 48 h after withdrawal from insulin treatment and compared with nondiabetic controls, diabetic rats receiving continued insulin treatment, and chronically hyperglycemic diabetic rats. Stereotypy was attenuated in chronically hyperglycemic diabetic rats but normalized in insulin-treated diabetic rats. Stereotypy in insulin-withdrawn rats was intermediate, being attenuated significantly relative to controls but not significantly different from either insulin-treated diabetic rats or chronically hyperglycemic diabetic rats. DA turnover was significantly reduced in striatum and hypothalamus in all diabetic groups. 5-HT turnover was reduced in chronically hyperglycemic diabetic rats in all four brain regions but normalized in insulin-treated diabetic rats. Insulin-withdrawn diabetic rats had significantly reduced 5-HT turnover in frontal cortex. Taken together, the findings indicate that insulin replacement does not normalize diabetes-induced reduction in DA turnover and that short-term insulin withdrawal, e.g., occurring clinically with noncompliance, affects both 5-HT turnover in some brain regions and behavior.
Impairment of Glycerol Phosphate Shuttle in Islets From Rats With Diabetes Induced by Neonatal Streptozocin
Authors: Giroix Marie-Helene , Rasschaert Joanne , Bailbe Danille , Leclercq-Meyer Viviane , Sener Abdullah , Portha Bernard , Malaisse Willy J
Published: September 2013

In islets from adult rats injected with streptozocin during the neonatal period, the oxidative and secretory responses to D-glucose are more severely affected than those evoked by L-leucine. A possible explanation for such a preferential defect was sought by comparing the rate of aerobic glycolysis, taken as the sum of D-[3,4-14C]glucose conversion to labeled CO2, pyruvate, and amino acid, with the total glycolytic flux, as judged from the conversion of D-[5-3H]glucose to 3H2O. A preferential impairment of aerobic relative to total glycolysis was found in islets from diabetic rats incubated at either low or high D-glucose concentration. This coincided in islet mitochondria of diabetic rats with a severe decrease in both the basal (no-Ca2+) generation of 3H2O from L-[2-3H]glycerol-3-phosphate and the Ca2+-induced increment in [3H]glycerophosphate detritiation. The mitochondria of diabetic rats were also less efficient than those of control animals in generating 14CO2 from [1-14C]-2-ketoglutarate. The diabetes-induced alteration of 2-ketoglutarate dehydrogenase in islet mitochondria was less marked, however, than that of the FAD-linked glycerophosphate dehydrogenase and was not associated with any change in responsiveness to Ca2+. Sonicated islet mitochondria of diabetic rats displayed normal to slightly elevated glutamate dehydrogenase activity. We propose, therefore, that the preferential impairment of the oxidative and secretory responses of islet cells to D-glucose in this experimental model of diabetes may be at least partly attributable to an altered transfer of reducing equivalents into the mitochondria as mediated by the glycerol phosphate shuttle.
Altered Expression of Diabetes in BB/Wor Rats by Exposure to Viral Pathogens
Authors: Thomas Valerie A , Woda Bruce A , Handler Eugene S , Greiner Dale L , Mordes John P , Rossini Aldo A
Published: September 2013

Autoimmune diabetes mellitus affects >50% of diabetes-prone BB (DP BB) rats but <1% of diabetes-resistant BB (DR BB) rats. We report an outbreak of spontaneous diabetes among DR BB rats that coincided with serologic evidence of the onset of viral infection. This apparent link between a change in the environment and the expression of diabetes then led us to study the interaction of environmental exposure to viral pathogens in this disorder with virally seropositive and seronegative populations of BB rats and polyinosinic–polycytidylic acid (poly I:C), an interferon inducer known to accelerate diabetes onset in DP rats. We administered a cytotoxic anti-RT6 monoclonal antibody, poly I:C, or both to DR rats. Depletion of the RT6.1+T-lymphocyte population has previously been shown to induce diabetes and thyroiditis in DR rats. RT6 alone did not induce diabetes in seronegative DR rats, and poly I:C was only weakly effective, but nearly all animals given both reagents became diabetic. When given to seropositive DR rats, either reagent alone induced diabetes; when given to non-BB rats, neither agent was effective. Poly I:C also accelerated the onset of DP diabetes to a greater extent in seropositive than in seronegative rats. We conclude that expression of the genetic predisposition to diabetes present in all BB rats depends on cellular factors that include the presence or absence of regulatory (RT6+) T lymphocytes and modulatory environmental factors including exposure to viral pathogens.
Influence of Protease on Inhibitory and Stimulatory Effects of Interleukin 1β on β-Cell Function
Authors: Welsh Nils , Bendtzen Klaus , Sandler Stellan
Published: September 2013

To elucidate the putative role of proteases in the action of interleukin 1β (IL-1β) on pancreatic β-cells, we studied the effects on islet function of different protease inhibitors when added together with recombinant IL-1β to isolated rat pancreatic islets. It was found that the trypsin inhibitor Nα-p-tosyl-L-lysine chloromethyl ketone (TLCK) counteracted the acute stimulatory effects of IL-1β on islet glucose oxidation, insulin release, and biosynthesis. TLCK also partially or completely counteracted the long-term inhibitory effects of IL-1β on islet glucose oxidation, insulin biosynthesis, content, and release. This protease inhibitor also counteracted IL-1β–induced β-cell cytotoxicity as assessed by DNA content measurements. Of the other group-specific protease inhibitors investigated, only N-tosyl-L-phenylalanine chloromethyl ketone, Nα-p-tosyl-L-arginine methyl ester, and chloromercuriphenylsulfonic acid were found to partially protect against IL-1 β action. We concluded that protease activation, putatively a serine protease, may be an early and perhaps primary event in the action of IL-1β on β-cells.
Insulin Secretion in Adult Rats After Intrauterine Exposure to Mild Hyperglycemia During Late Gestation
Authors: Gauguier Dominique , Bihoreau Marie-Therese , Picon Luc , Ktorza Alain
Published: September 2013

We investigated the effects of intrauterine mild hyperglycemia during late fetal life on glucose regulation and insulin secretion in adult rats. Unrestrained pregnant rats were continuously infused with glucose during the last week of pregnancy to induce mild hyperglycemia (6.5–8 mM). Control rats were infused with a glucose-free solution. The offspring were studied, as adults, from 1 to 20 mo by performing glucose tolerance and insulin secretion tests. Young-adult rats from hyperglycemie dams showed mild glucose intolerance and impairment of glucose-induced insulin secretion. This situation gradually evolved to basal hyperglycemia and severe impairment of glucose tolerance and insulin secretion. Insulin secretion was also studied in vitro in 20-mo-old rats with the isolated perfused-pancreas technique. Insulin release in response to glucose stimulation from pancreases of hyperglycemic dams was similar to that of controls, and the response to arginine was increased but not significantly. The possible involvement of enhanced sympathetic nervous system activity in the impairment of insulin secretion in adult rats from hyperglycemic mothers was then investigated by performing glucose tolerance and insulin secretion tests in the presence of the α2-blocker idazoxan in 8-mo-old rats. Under these conditions, rats from hyperglycemic dams recovered almost normal glucose tolerance, and glucose-induced insulin secretion was greatly improved. These data show that mild hyperglycemia induced in the fetus during late pregnancy leads to persistent impairment of glucose regulation and insulin secretion. They suggest that the impairment of insulin secretion in vivo results from a perturbation of the neuroregulation of insulin secretion rather than an intrinsic pancreatic β-cell defect.
Islet Function in Offspring of Mothers on Low-Protein Diet During Gestation
Authors: Dahri Saloua , Snoeck Anne , Reusens-Billen Brigitte , Remacle Claude , Hote Joseph J
Published: September 2013

A low-protein diet (8 vs. 20%) administered during pregnancy affects the structure and function of the endocrine pancreas of the offspring. At 21.5 days of gestation, we reported a reduction of cell proliferation, islet size, islet vascularization, and pancreatic insulin content. In this study, we demonstrated an impairment of insulin secretion of these fetal islets when stimulated in vitro with amino acids such as arginine and leucine. If the offspring is kept on the same low-protein diet during suckling, weaning, and adulthood, fasting insulin levels remain low in the presence of normal blood glucose levels. Glucose tolerance at 70 days is impaired, with lower insulin response. In addition, permanent functional damage seems to be induced in utero by a low-protein diet, because a normal diet given from birth to adulthood does not restore normal insulin response after a glucose challenge. Our experimental results stress the impact of a balanced diet with qualitative and quantitative amino acid composition for the fetal endocrine pancreas to develop normally, without lasting functional and structural consequences in adulthood.
Abnormal Glucose Tolerance During Pregnancy in Pima Indian Women: Long-Term Effects on Offspring
Authors: Pettitt David J , Bennett Peter H , Saad Mohammed F , Charles Marie A , Nelson Robert G , Knowler William C
Published: September 2013

The long-term effects on offspring of abnormal glucose tolerance detected during pregnancy were examined in 552 Pima Indian offspring 5–24 yr of age. Fasting hyperinsulinemia, presumably reflecting increased insulin resistance, occurred at an earlier age in the offspring of women who had abnormal glucose tolerance during pregnancy, and these offspring were more obese and had higher rates of abnormal glucose tolerance. When confounding factors were controlled, a 1 mM higher 2-h postload glucose concentration during pregnancy resulted in a significantly higher prevalence of diabetes in the offspring (odds ratio = 1.62). Maternal 2-h glucose concentration during pregnancy was also a significant predictor of glucose concentration during pregnancy in the offspring (P = 0.011). Thus, the metabolic abnormalities associated with the diabetic pregnancy result in long-term effects on the offspring, including insulin resistance, obesity, and diabetes, which in turn may contribute to transmission of risk for developing the same problems in the next generation.
Diabetes Mellitus After GDM
Authors: O'Sullivan John B
Published: September 2013

The impact of factors that influence diabetes mellitus (DM) and impaired glucose tolerance (IGT) incidence rates among former gestational diabetes mellitus (GDM) patients undermine attempts at interstudy comparisons. The recommended diagnostic standards for GDM by oral glucose tolerance test (OGTT) are the O'Sullivan and Mahan criteria and the World Health Organization (WHO) criteria for IGT, which result in prevalence rates of 2.5 and 7.2%, respectively, when applied to 752 unselected pregnant women. In applying the O'Sullivan and Mahan criteria, the current open-ended definition of GDM without rules either to exclude overt diabetes uncovered by pregnancy or to require a return to a normal OGTT after pregnancy is shown to be a major source of differences in subsequent incidence rates of diabetes. For subsequent nonpregnant diagnoses, the differences between WHO and National Diabetes Data Group criteria and the allowable modifications within each of the diagnostic standards all result in different incidence rates of diabetes. Review of 12 worldwide studies of diabetes among former GDM patients indicated a wide range of incidence rates, from 19 to 87% for combined DM and IGT and 6 to 62% for DM. In applying WHO DM criteria to GDM patients and control subjects, the excess risk of diabetes among GDM patients was 18% in Copenhagen and 30.9% in Boston, MA. The potential impact of varying observation periods within studies was seen when the application of an actuarial method added a further 50% to the Boston incidence rates of both GDM patients and control subjects. Although the variability in diabetes incidence rates is wide, there is broad general agreement on the predictive nature of gestational blood glucose levels.
Monitoring the Severity of Metabolic Disturbances and Effectiveness of Management of Gestational Diabetes Mellitus
Authors: de Hertogh René
Published: September 2013

To monitor the severity of metabolic disturbances during gestational diabetes mellitus (GDM), some risk factors existing at the time of diagnosis must be considered, including age of the pregnant women, early gestational age at diagnosis, high fasting blood glucose level, high HbA1c or fructosamine levels, or high amniotic fluid insulin level. The degree of OGTT abnormality will also influence the therapeutic approach, although the insulin response to the glucose challenge seems to be of little discriminating value. Effectiveness of the treatment can be appreciated by self-monitoring of blood glucose, although the practical precision of these measures and their necessary repetitions will limit clear-cut evaluation of borderline cases. HbA1c and fructosamine are of little help because of lack of sensitivity and time delay between changes in blood glucose and associated glycosylated protein changes. Whether other parameters such as amino acids, growth factors, or related compounds are more specifically linked to the physiopathology of GDM complications remains to be established but would help in monitoring GDM metabolic disturbances in the future. Meanwhile, prophylactic insulin treatment may still constitute a pragmatic approach, taking into account possible and poorly appreciated drawbacks from overtreatment, e.g., maternal hyperinsulinism and chronic hypoglycemia.
Calorie Restriction for Treatment of Gestational Diabetes
Authors: Dornhorst Anne , Nicholls Jonathan SD , Probst Fay , Paterson Catherine M , Hollier Kaye L , Elkeles Robert S , Beard Richard W
Published: September 2013

Birth weights of infants of 35 gestational diabetic mothers treated with calorie restriction alone (1200–1800 kcal) were compared with those of infants of 2337 nondiabetic women, including two control groups (A and B) matched for race, body mass index, age, and parity. All women were screened for gestational diabetes with the O'Sullivan screening method, and a 3-h oral glucose tolerance test was performed on all abnormal results. Control group A mothers had a normal screen, and control group B mothers had an abnormal screen with a normal glucose tolerance test. Pregnancy weight gain was significantly less for the gestational diabetic mothers (mean ± SD 4.6 ± 4.9 kg) than for the general prenatal population (9.3 ± 5.3 kg), group A control subjects (9.7 ± 5.3 kg), and group B control subjects (9.7 ± 5.4 kg; P < 0.0005). No infant of a gestational diabetic mother was below the 10th percentile for weight, and birth weights were similar to those of the control groups even though weight gain after the 28th wk of gestation was only 1.7 ± 1.6 kg. The frequency of macrosomia (birth weight ≥ 4000 g) was similar among the gestational diabetic mothers (9.3%), the general prenatal population (7.4%), and group A mothers (11.6%) but significantly higher for the group B control subjects (20.9%; χ2 = 8.57, P < 0.005). This study demonstrated that gestational diabetic mothers who are calorie restricted have infants with normal birth weights and a frequency of macrosomia less than that of screen-positive nondiabetic women with similar macrosomic risk factors.
Metabolic Effects of Hypocaloric Diets in Management of Gestational Diabetes
Authors: Knopp Robert H , Magee M Scott , Raisys Vidmantas , Benedetti Thomas
Published: September 2013

Although hypocaloric diets have been advocated for the management of the obese gravida and the obese mother with gestational diabetes, there is no general agreement on how severely calories should be restricted or on how this therapeutic approach compares with insulin therapy. The lack of consensus is in part because of the lack of studies comparing insulin management with the effects of different degrees of hypocaloric feeding and its effects on metabolism and glycemic status. We review the effects of 50 and 33% calorie restriction on glycemic status and intermediary fuel status in obese gestational diabetic subjects and compare the results with the administration of 20 U NPH and 10 U regular insulin every morning, a therapy of proven value in reducing macrosomia in gestational diabetes. When the two calorie-restriction regimens were compared after a 9-h overnight fast, glycemic status improved 10–20% on both. Ketonuria increased about twofold with 50% calorie restriction, but on average no increase in ketonuria was seen on the 33% calorie-restriction regimen. Both calorie-restriction programs led to a reduction in levels of plasma triglyceride, a correlate of infant birth weight. In contrast, the insulin regimen diminished ketonuria, but glycemic status improved little, and plasma triglyceride concentrations did not decline. Although more studies are needed to confirm these trends, the beneficial effect of 33% calorie restriction, which occurred without marked ketonuria, is consistent with previous studies in gestational diabetes. In addition, the simultaneous improvements observed in plasma glucose and triglyceride concentrations suggest that moderate calorie restriction may be valuable in preventing macrosomia in the offspring of the obese subject with gestational diabetes. A clinical trial to test this hypothesis is warranted.
Rationale for Insulin Management in Gestational Diabetes Mellitus
Authors: Langer Oded , Berkus Michael , Brustman Lois , Anyaegbunam Akolisa , Mazze Roger
Published: September 2013

A prospective study was undertaken to test the hypothesis that insulin treatment in patients with gestational diabetes mellitus (GDM) with fasting plasma glucose (FPG) >5.3 mM significantly reduces adverse perinatal outcome. Assigned to insulin or diet treatment based on FPG were 471 GDM women. Four factors believed to be associated with infants large for gestational age (LGA) were evaluated: FPG, overall glycemic control, maternal weight, and treatment regimen. We found that when glycemic control was optimized, the key factors related to large infants were FPG and treatment modality. In the low-FPG group (<5.3 mM), diet therapy achieved an incidence of 5.3% LGA. When insulin therapy was used to optimize control, an incidence of 3.5% LGA was found. Patients in the mid-FPG group (5.3–5.8 mM) had a higher increased rate of LGA (28.6%) for diet-treated versus insulin-treated women (10.3%). In addition, a fourfold increased risk for LGA was found in the diet-treated obese subjects in the mid-FPG group compared with insulin-treated obese women. Finally, treatment with insulin resulted in similar incidence of LGA within all FPG groups. We concluded that FPG >5.3 mM can be the basis for initiation of insulin treatment in GDM subjects with optimization of glycemic control as the goal. This approach may contribute significantly to reduced neonatal risk and may foster a standardized method for rapid and effective assignment to treatment.
Gestational Diabetes Mellitus: Influence of Race on Disease Prevalence and Perinatal Outcome in a U.S. Population
Authors: Dooley Sharon L , Metzger Boyd E , Cho Nam H
Published: September 2013

We explore whether racial differences in a United States population influence disease prevalence and perinatal outcome in gestational diabetes mellitus (GDM). The data presented are based on 3744 consecutive patients who underwent universal screening at 24–28 wk gestation; those with a 1-h plasma glucose ≥7.2 mM underwent a 100-g 3-h oral glucose tolerance test (OGTT). The overall prevalence of GDM was 3.5 cases/100 with the standard O'Sullivan-Mahan diagnostic criteria derived for plasma, whereas use of the Carpenter-Coustan modification of the O'Sullivan-Mahan criteria yielded a prevalence of 5.5. The population was 39.1% white, 37.7% black, 19.8% Hispanic, and 3.45% Oriental/other. For those patients with a nondiagnostic test, mean plasma glucose at each time point of the OGTT was similar for all racial groups. Because of demographic and phenotypic heterogeneity between different racial groups, the influence of these different variables on the prevalence of GDM was tested by multiple logistic regression. Black and Hispanic race, maternal age, and percentage ideal body weight were found to have significant independent effects on the prevalence of GDM (P < 0.05, 0.001, 0.001, and 0.001, respectively). The adjusted relative risk of GDM was significantly higher in black (1.81, 95% confidence interval [;CI] 1.13–2.89, P < 0.05) and Hispanic (2.45, 95% CI 1.48–4.04, P < 0.001) patients compared with whites. The influence of race on infant birth weight was examined in the 92 patients with GDM controlled with diet. Despite comparable degrees of carbohydrate intolerance across racial groups, mean birth weight was found to be highest in Hispanics and lowest in blacks and Orientals. By analysis of covariance, race was found to have a significant independent effect on birth weight (P = 0.017), with maternal percentage ideal body weight a significant covariate (P = 0.009). These results suggest that race as well as maternal age and degree of obesity must be taken into account when comparing the prevalence of GDM in different populations and assessing the impact of specific therapeutic interventions on perinatal outcome.
Comparison of Diagnostic Criteria of IGT, Borderline, and GDM: Blood Glucose Curve and IRI Response
Authors: Omori Yasue , Minei Satomi , Uchigata Yasuko , Shimizu Meimi , Sanaka Mayumi , Honda Masashi , Hirata Yukimasa
Published: September 2013

A 75-g oral glucose tolerance test (OGTT) was performed in 615 nonobese pregnant women (mean ± SD age 29.7 ± 4.3 yr) who were referred to the Division of Internal Medicine at our diabetes center because of glycosuria. Seventy-seven cases were found to have urinary glucose at the first trimester, 185 at the second trimester, and 353 at the third trimester. With their 75-g OGTT results, the diagnostic criteria of borderline (formulated by the Japan Diabetes Society), impaired glucose tolerance (IGT; defined by the World Health Organization [WHO]), and gestational diabetes mellitus (GDM; determined by the Japan Society of Obstetrics & Gynecology standards) were compared through blood glucose (BG) curves and immunoreactive insulin (IRI) responses. Borderline (fasting BG ≥6.1 and <7.8 mM and 2-h BG ≥6.7 and <11.1 mM) is neither diabetes nor normal. IGT is as referred to by the WHO. GDM exceeds two points of fasting BG ≥5.6 mM, 1-h BG ≥10.0 mM, or 2-h BG ≥8.3 mM. Diabetes mellitus (DM) is as referred to by the Japan Diabetes Society (same as the WHO). The prevalence of abnormal glucose tolerance among all 615 pregnant women was 54.6% in borderline, 24.5% in IGT, 7.3% in GDM, and 3.4% in DM. The 2-h BG levels in IGT during the first trimester were higher than in borderline (P< 0.01). The 1- and 2-h levels in GDM without DM in a given trimester were higher than in borderline (P< 0.001–0.05). However, there were low responses of IRI at the early phase in each group. The prevalence of low responders whose 30-min ΔIRI (pM)/ΔBG (mM) was < 54 was 47% in borderline, 52% in IGT, 83% in GDM, and 100% in DM at the first trimester. Moreover, among 7 cases who were low-IRI responders during their first pregnancy, 3 developed GDM or DM during their second pregnancy. Although it is difficult to clarify which criteria for GDM are better, these data indicate that a low 30-min ΔIRI/ΔBG on 75-g OGTT is an important piece of evidence predicting the future onset of non-insulin-dependent DM.
Incidence and Severity of Gestational Diabetes Mellitus According to Country of Birth in Women Living in Australia
Authors: Beischer Norman A , Oats Jeremy N , Henry Olivia A , Sheedy Maryt T , Walstab Janet E
Published: September 2013

Gestational diabetes mellitus (GDM) was diagnosed in 1928 of 35,253 (5.5%) tested pregnancies at the Mercy Maternity Hospital in Melbourne between 1979 and the end of 1988. Compared with women born in Australia and New Zealand, the incidence of GDM was significantly greater in women born on the Indian subcontinent (15%); in women born in Africa (9.4%), Vietnam (7.3%), Mediterranean countries (7.3%), and Egypt and Arabic countries (7.2%); and in Chinese (13.9%) and other Asian (10.9%) women. There was no significant difference for women born in the United Kingdom and northern Europe (5.2%), Oceania (5.7%), North America (4.0%), or South America (2.2%). With the World Health Organization criteria as a guide to the severity of hyperglycemia, compared with mothers born in Australia and New Zealand, there were significant increases in the incidences of the more severe grades of GDM in parturients born in the Mediterranean region, Asia, the Indian subcontinent, Egypt, and Arabic countries. The incidence of GDM increased significantly in all racial groups, rising from 3.3% during 1979–1983 to 7.5% during 1984–1988.
Altered Diastolic Function in Asymptomatic Infants of Mothers With Gestational Diabetes
Authors: Mehta Sudhir , Nuamah Isaac , Kalhan Satish
Published: September 2013

Left and right ventricular filling was studied prospectively in 50 full-term (39.4 ±1.3 wk) asymptomatic newborns of mothers with gestational diabetes mellitus (GDM). Their data were compared with those of 80 asymptomatic full-term (39.8 ±1.2 wk) infants who served as control subjects. Infants were examined in the immediate newborn period (<48 h) and then again at 2–4 and 6–9 wk. Although mean weight, length, and gestational age did not differ, the mean ± SD left ventricular dimensions during diastole (1.73 ± 0.15 vs. 1.81 ± 0.18 cm, P = 0.007) and systole (1.22 ± 0.15 vs. 1.31 ± 0.17 cm, P = 0.004) were significantly lower in infants of mothers with GDM compared with control infants. Diastolic measurements suggested a shift from the early diastolic filling of the ventricle to the later period of atrial systole in infants of mothers with GDM. A lower initial one-third area fraction and a higher peak flow velocity and velocity time integral during atrial systole were noted at the mitral valve in infants of mothers with GDM. These changes had resolved by 2–4 wk of age. The altered diastolic filling patterns in infants of mothers with GDM indicate poor myocardial relaxation and/or decreased passive compliance of the ventricular myocardium. These alterations were observed in asymptomatic infants in the absence of left ventricular or septal hypertrophy. If exposed to significant stress such as asphyxia or sepsis, the observed myocardial dysfunction could lead to higher morbidity in these infants.
Obstetric Complications With GDM: Effects of Maternal Weight
Authors: Goldman Mindy , Kitzmiller John L , Abrams Barbara , Cowan Ronald M , Laros Russell K
Published: September 2013

Obstetric complications recorded prospectively were assessed retrospectively in 150 women with gestational diabetes mellitus (GDM) and 305 control subjects matched for age, parity, and ethnicity. Intensive diet therapy and self-monitoring of capillary blood glucose were used to obtain postprandial euglycemia; 22% of GDM subjects required insulin. GDM and control subjects were grouped by body mass index to detect any influence of maternal prepregnancy weight on outcome. Polyhydramnios, preterm labor, and pyelonephritis were not more frequent in GDM, but hypertension without proteinuria (7.3 vs. 3.3%) and preeclampsia (8 vs. 3.9%) were more frequent in GDM. The frequency of hypertensive complications in GDM was not totally attributable to being overweight. Abnormalities of labor, birth trauma, and fetal macrosomia were not more common in GDM; 6.7% of the infants of mothers with GDM weighed >4200 g at birth compared with 3.6% of control infants (NS), and 10% were large for gestational age and sex compared with 6.6% of control infants (NS). Despite this, cesarean delivery was more common in GDM (35.3 vs. 22%, P < 0.01), mostly due to significantly more cesarean births without labor.
Functional Maturation and Proliferation of Fetal Pancreatic β-Cells
Authors: Hellerström Claes , Swenne Ingemar
Published: September 2013

We review some key aspects of the maturation of stimulus-secretion coupling and the regulation of DNA replication in the fetal β-cell. During fetal life, the β-cell shows a poor insulin response to glucose, although it responds to several other nonnutrient stimuli. However, chronic exposure to glucose in excess of basal levels can induce maturation of the stimulus-secretion coupling. Studies of glucose metabolism and the transmembrane flow of K+ and Ca2+ indicate that the attenuated glucose-stimulated insulin release is due to an immature glucose metabolism resulting in impaired regulation of ATP-sensitive K+ channels in the plasma membrane of the fetal β-cell. In late fetal life, glucose is also a strong stimulus to β-cell replication, and metabolism of glucose is a prerequisite for this process. Glucose stimulates proliferation by recruiting β-cells from a resting state into a proliferative compartment composed of cells in an active cell cycle. The proliferative compartment comprises <10% of the total islet cell population even at maximal stimulation. The proliferation of fetal β-cells is also regulated by several peptide growth factors such as growth hormone, insulinlike growth factor I, and platelet-derived growth factor. The observation that glucose can both induce precocious maturation of the stimulus-secretion coupling and stimulate proliferation of the fetal β-cell explains the intrauterine hyperinsulinemia and β-cell hyperplasia of the offspring of diabetic mothers with relatively mild hyperglycemia. However, severe hyperglycemia, at least when induced in rats, seems to retard rather than stimulate β-cell growth.