bluuebunny/crossref_metadata_2025 huggingface dataset:
Postprandial Free Fatty Acid Kinetics Are Abnormal in Upper Body Obesity
Authors: Roust Lori R , Jensen Michael D
Published: September 2013

Excess free fatty acid release (rate of appearance) is seen in overnight postabsorptive, upper body obese women and, if present postprandially, could contribute to glucose intolerance. These studies examine the antilipolytic effect of a mixed meal in upper body obese, lower body obese, and nonobese women and the contribution of meal triglyceride fatty acids to circulating free fatty acids. Eight upper body obese, 8 lower body obese, and 8 nonobese age-matched, premenopausal women were studied. Systemic oleate Ra ([3H]oleate) was measured before and after an evening meal that contained triolein labeled with [14C]triolein as the only source of fat. Premeal oleate Ra was greater in both upper body obese and lower body obese women than nonobese women. The nadir of total oleate Ra occurred 90–240 min postprandially and was less (P < 0.01) in nonobese and lower body obese women (63 ± 10 and 87 ± 17 μmol/min) than in upper body obese women (140 ± 21 μmol/min). Meal oleate Ra contributed substantially to total oleate Ra. The nadir for endogenous oleate Ra in nonobese and lower body obese women was less (P < 0.01) than that observed in upper body obese women. We conclude that the antilipolytic effect of a mixed meal is reduced in upper body obese women and that meal triglyceride fatty acids contribute significantly to postprandial free fatty acid flux.
Hypoxia-Induced Sympathetic Inhibition of the Fetal Plasma Insulin Response to Hyperglycemia
Authors: Jackson Benjamin T , Cohn Herbert E , Morrison Sharon H , Baker Rex M , Piasecki George J
Published: September 2013

Large-for-delivery date babies, considered characteristic of diabetic pregnancy, are believed to result from fetal hyperinsulinemia. Paradoxically, infant birth weights tend to be low-for-delivery date in mothers with more severe diabetes. We tested the hypothesis that hypoxemia in such fetuses leads to sympathoadrenal stimulation and inhibition of insulin secretion; and, thus, produces a net reduction in the growth-promoting effects. Fetal sheep were prepared with chronic peripheral and adrenal cannulas. Fetal blood gases, lactate, norepinephrine, and epinephrine secretion rates; and plasma norepinephrine, glucose, and immunoreactive insulin concentrations were determined at 30-min intervals during a 2-h baseline period and a 4-h period of hyperglycemia divided into 2-h segments of hypoxemia (with and without alpha-blockade) and hyperoxia. Hypoxemia-hyperoxia sequences were varied randomly. Well-oxygenated fetuses responded to a threefold increase in glucose with a sixfold increase in plasma immunoreactive insulin. With hypoxemia, norepinephrine and epinephrine secretion were elevated and the insulin response was blocked. With hypoxemia and phentolamine blockade, the insulin response was enhanced with a 10-fold increase above baseline. In severe maternal diabetes with vascular disease or with poor control and very high glucose levels, the fetus is likely to be relatively hypoxemic. Our experiments suggest that in this situation, the fetal insulin response to hyperglycemia will be attenuated; this effect is mediated, at least partly, through sympathoadrenal stimulation.
Transforming Growth Factor-β1 Enhances Glomerular Collagen Synthesis in Diabetic Rats
Authors: Bollineni Jaya S , Reddi Alluru S
Published: September 2013

In vitro glomerular collagen synthesis and its response to various concentrations of transforming growth factor-β1 were studied in normal and diabetic rats. TGF-β1 increased collagen synthesis in normal glomeruli in a dose-dependent manner up to 5 ng/ml. Concentrations > 5 ng/ml showed a gradual decline in collagen synthesis. Basal collagen synthesis was increased in diabetic glomeruli, but addition of TGF-β 1 had no effect. Antibody to TGF-β1 prevented this increase in collagen synthesis. Both circulating TGF-β1 concentration and its glomerular expression of mRNA were higher in diabetic than in normal rats. Although addition of TGF-β1 did not increase synthesis in vitro, the absence of an effect is consistent with downregulation of its receptors attributable to the high circulating levels. This study clearly indicates a regulatory role of TGF-β1 in renal glomerular collagen synthesis in the normal rat, and suggests a possible causal role for enhanced collagen synthesis in the diabetic rat.
Antioxidant MDL 29,311 Prevents Diabetes in Nonobese Diabetic and Multiple Low-Dose STZ-Injected Mice
Authors: Heineke Eric W , Johnson Mary B , Dillberger John E , Robinson Keith M
Published: September 2013

Recent investigations suggest a role for antioxidants in preventing IDDM. MDL 29,311 (4,4’-[methylenebis(thio)]bis[2,6-bis(1,1-dimethylethyl)]-phenol) is an analogue of the antioxidant probucol. Administered as a 1% dietary admixture to female nonobese diabetic mice from 4 to 24 wk of age, MDL reduced the prevalence of diabetes from 49 to 4% at 24 wk of age (n = 50–61/group). Discontinuation of treatment at 24 wk of age did not result in a rapid onset of diabetes. Probucol (1%) did not prevent diabetes. Initiating MDL treatment at 4 or 8 wk of age was more effective (19 and 17%, respectively, compared with 60% in control mice) than initiating treatment at 12 wk of age (30% diabetic; n = 28–35/group). A lower dose of MDL (0.1%), started at 4 wk of age, decreased the prevalence of diabetes to 36%. Histopathology indicated that MDL did not prevent insulitis. MDL (0.1%) also was evaluated in combination with immunosuppressants. Compared with control mice (65% diabetic), the combination of MDL and deflazacort was more effective (21% diabetic) than either agent alone (39% diabetic for MDL and 59% diabetic for deflazacort), whereas the effectiveness of MDL, cyclosporin, and MDL plus cyclosporin was similar (39, 38, and 34% diabetic, respectively). In another model of IDDM, the multiple-low-dose streptozocin-injected mouse, MDL (1%) also reduced the prevalence of diabetes when administered beginning 8 wk before streptozocin (55% diabetic vs. 100% of control mice; n = 20–25/group). Probucol (1%) was ineffective. MDL appears effective in preventing the onset of disease in two mouse models of IDDM.
Relationship Between the Circadian Rhythms of Blood Pressure and Sympathovagal Balance in Diabetic Autonomic Neuropathy
Authors: Spallone Vincenza , Bernardi Luciano , Ricordi Luigi , Soldà Pierluigi , Maiello Maria Rosaria , Calciati Alessandro , Gambardella Sergio , Fratino Piero , Menzinger Guido
Published: September 2013

In diabetic autonomic neuropathy, abnormal circadian patterns of blood pressure and sympathovagal balance with reduced fall of blood pressure and prevalence of sympathetic activity during the night have been described. To correlate the abnormalities of blood pressure to those of sympathovagal balance, we simultaneously performed 24-h noninvasive monitoring of blood pressure and ECG in 25 diabetic patients (45.6 ± 13.6 yr of age with a 17.6 ± 9.1 yr duration of diabetes) with various degrees of cardiovascular reflex impairment. Autoregressive power spectrum analysis of RR interval variability was applied to 24-h ECG recordings to obtain for day and night periods the mean power of low- (0.03–0.15 Hz) and high-frequency (0.18–0.40 Hz) components, which are relative markers of sympathetic and vagal activity, respectively, and their ratio (low frequency/high frequency), assumed as index of sympathovagal balance. Diabetic patients showed a lower percentage of day-night change in systolic blood pressure (9 ± 5.48 vs. 11.6 ± 4.78%, P < 0.037), a lower day low frequency (5.9 ± 0.81 vs. 6.62 ± 0.73 In-ms2 P < 0.001), a lower night high frequency (6.06 ± 0.71 vs. 6.52 ± 0.85 In-ms2 P < 0.05), a lower day low frequency:high frequency ratio (1.82 ± 1.77 vs. 3.05 ± 1.82, P < 0.01), and a lower percentage of day-night change in low-frequency:high frequency ratio (– 13.4 ± 109.9 vs. 28.7 ± 29.7%, P < 0.05), when compared with control subjects. Day-night change in low frequency:high frequency ratio correlated to day-night change in systolic blood pressure (r = 0.52, P < 0.01) and diastolic blood pressure (r = 0.48, P < 0.015). In conclusion, in diabetic patients the degree of loss in day-night rhythm of blood pressure is associated with a proportional nocturnal sympathetic predominance. Decreased blood pressure fall combined with relative sympathetic prevalence during the night might represent a risk factor for cardiovascular accidents and could modify the circadian pattern of cardiovascular events in the diabetic population.
Metabolic Effects of Cyclosporin A and FK 506 in Liver Transplant Recipients
Authors: Krentz Andrew J , Dousset Bertrand , Mayer David , McMaster Paul , Buckels John , Cramb Robert , Smith Janet M , Nattrass Malcolm
Published: September 2013

Postoperative diabetes is a reported feature of the immunosuppressive agents cyclosporin A and FK 506. To date, however, no randomized comparative studies of the metabolic effects of these two drugs have been performed. In this study, extended (300 min) oral glucose tolerance tests (75 g) were performed a median of 8 mo (range 5–9 mo) postoperatively in 20 clinically stable liver transplant recipients randomly allocated to maintenance immunosuppression with either cyclosporin A (with or without azathioprine) or FK 506. None of the patients had clinically overt diabetes antedating transplantation. To avoid the confounding effects of corticosteroids, prednisolone was withdrawn at least 6 wk beforehand in each case. Ten healthy volunteers matched for age and body mass index served as control subjects. Overall blood glucose concentrations after the glucose challenge were significantly elevated in both groups of transplant recipients (P < 0.005 and P < 0.001 for cyclosporin A and FK 506 treatment groups, respectively) compared with the healthy control subjects. Venous whole-blood glucose concentration (mean ± SE) 120 min after the ingestion of oral glucose was significantly higher in both the cyclosporin A (P < 0.05) and FK 506 (P < 0.01) treatment groups compared with the control subjects (6.6 ± 0.5 vs. 8.8 ± 0.9 vs. 5.2 ± 0.2 mM, respectively). According to 1985 WHO criteria, 4 of 10 cyclosporin A-treated patients had impaired glucose tolerance, whereas 3 of 10 FK 506–treated patients had diabetes with 4 others having impaired glucose tolerance. Overall plasma immunoreactive insulin concentrations were significantly elevated in both the cyclosporin A (P < 0.05) and FK 506 (P < 0.01) groups, as were C-peptide concentrations (P < 0.02 and P < 0.01, respectively). By contrast, fasting lactate concentrations were significantly lower (P < 0.05) in the transplant patients compared with the control subjects. Total blood ketone body concentrations were slightly higher in both transplant groups with an increased ratio of 3-hydroxybutryate:acetoacetate in the cyclosporin A–treated (P < 0.01) and FK 506–treated (P < 0.02) patients. In conclusion, successful liver transplantation in humans is associated with significant postoperative glucose intolerance and hyperinsulinemia. These metabolic abnormalities are independent of corticosteroid therapy and are more pronounced in patients treated with FK 506 than in comparable patients receiving cyclosporin A with or without azathioprine. Alterations in the circulating ketone body ratio suggest a relatively more reduced hepatic intramitochondrial redox state in liver transplant recipients treated with these immunosuppressive agents.
Can We Really Predict IDDM?
Authors: Bingley Polly J , Bonifacio Ezio , Gale Edwin A M
Published: September 2013

Risk of progression to IDDM has been assessed extensively in first-degree relatives of IDDM patients, and highly specific prediction is possible within a small subset of this population. Because ∼90% of future cases will come from those who have no close relative with IDDM, prediction and intervention within the general population will become the main priority for the future. This review presents a decision tree analysis of risk of progression to IDDM, highlights the different prognosis of markers when applied to those with and without a family history of the disease, and proposes a strategy for disease prediction in the latter. Large collaborative studies in well-characterized populations will allow new predictive markers and models to be evaluated, and strategies of intervention to be tested with maximum efficiency and minimal delay.
Immunochemical Detection of Advanced Glycation End Products in Lens Crystallins From Streptozocin-Induced Diabetic Rat
Authors: Nakayama Hidetaka , Mitsuhashi Tomoko , Kuwajima Satoru , Aoki Shin , Kuroda Yoshihiko , Itoh Tomohiro , Nakagawa Shoichi
Published: September 2013

To reassess the significance of AGEs in cataract formation in diabetic animals, we measured amounts of AGEs in lens crystallins from STZ-induced diabetic animals with a newly developed ELISA. Lenses were removed at 5 and 20 wk after STZ injection. In 20-wk diabetic rats, all lenses were cataractous but not in control rats. In 20-wk diabetic compared with control rats, significant increases were observed in AGEs (172.3 ± 18.3 vs. 14.3 ± 1.7 All, P < 0.01) and fluorescence (2.04 ± 0.22 vs. 1.27 ± 0.10 AU, P < 0.05). The amounts of AGEs in lens crystallins, measured by the ELISA, were > 12-fold higher in diabetic rats. In agreement with earlier studies, we found that fluorescence in lens crystallins increased by 61% in diabetic rats. In 5-wk diabetic rats, all lenses were noncataractous. In 5-wk diabetic compared with control rats, significant increases were observed in AGEs (84.1 ± 7.7 vs. 9.4 ± 1.5 AU, P < 0.01) and fluorescence (1.45 ± 0.06 vs. 1.05 ± 0.06 AU, P < 0.01). Analysis of the AGE content by ELISA showed that accumulation of AGEs in diabetic lens crystallins does markedly occur with time, and a large amount of AGEs exists in the diabetic (cataractous) lens crystallins. The disproportionate elevation of AGEs, measured by the ELISA, compared with fluorescence suggests that the actual levels of AGEs in cataractous lens crystallins from diabetic animals are higher than previously anticipated, and nonfluorescent AGEs may exist in diabetic lens crystallins. With this premise, our data suggest that a newly developed ELISA for the detection of AGEs in tissue proteins may be a powerful tool for investigating the role of the advanced Maillard reaction in complications of diabetes and aging.
Antibodies to Glutamic Acid Decarboxylase Reveal Latent Autoimmune Diabetes Mellitus in Adults With a Non—Insulin-Dependent Onset of Disease
Authors: Tuomi Tiinamaija , Groop Leif C , Zimmet Paul Z , Rowley Merrill J , Knowles William , Mackay Ian R
Published: September 2013

The classification of adults with diabetes mellitus can be invalidated by patients who initially present as NIDDM but who later become frankly insulin dependent. In some of these, the pathogenesis could be similar to that in IDDM, namely autoimmune destruction of the pancreatic β-cells. We studied 102 patients >35 yr of age at diabetes onset who had initially been nonketotic and non-insulin-dependent for ≥6 mo. They were classified according to glucagonstimulated C-peptide levels into an insulin-deficient group (n = 33) and a non-insulin-deficient group (n = 69). We measured antibodies to GAD, islet cell cytoplasm, thyroid antigens, and gastric parietal cells in both groups. Anti-GAD was significantly higher in the insulin deficient group, 76% (25 of 33), than in the non-insulin deficient group, 12% (8 of 69), and this difference was substantially greater than that shown for ICAs. Thus, in a proportion of adults who present with NIDDM, a slowly evolving autoimmune insulitis can be revealed by testing for anti-GAD. This could have important connotations not only for early intervention, but also for the correct classification of diabetes.
Incidence of Gross Proteinuria in Older-Onset Diabetes: A Population-Based Perspective
Authors: Klein Ronald , Klein Barbara E K , Moss Scot E
Published: September 2013

A few population-based studies describe the incidence of gross proteinuria in people with diabetes. We performed a population-based study in southern Wisconsin of diabetic individuals diagnosed at ≥ 30 yr of age either taking insulin (n = 398) or not taking insulin (n = 441). The presence of gross proteinuria (≥ 0.3 g/L) was determined by means of a reagent strip. The incidence of proteinuria in the 4-yr interval was 17.3% (95% CI 13.6–21.0) in those taking insulin and 10.7% (95% CI 7.8–13.6) in those not taking insulin. The relative risk of developing proteinuria for those in the highest level of total pack-yr smoked compared with those who had never smoked was 2.0 (95% CI 1.2–3.3) for those taking insulin and 2.5 (95% CI 1.3–4.5) for those not taking insulin. After controlling for other risk variables, the incidence of gross proteinuria was also associated with higher GHb. These data suggest that smoking and glycemic control, both potentially modifiable factors, are significant risk factors for the development of gross proteinuria.
Race-Dependent Health Risks of Upper Body Obesity
Authors: Dowling Hillary J , Pi-Sunyer F Xavier
Published: September 2013

For Caucasian women, an excess of abdominal fat is a potent risk factor for the development of diabetes and cardiovascular disease. However, there is limited information regarding the health risks of upper body obesity for African-American women despite a higher prevalence of obesity and obesity-related diseases and a reportedly higher prevalence of abdominal fat accumulation. This study aimed to determine whether UBO, independent of total body fatness, is as potent a diabetic and CVD risk factor for black women as has been confirmed for white women. Diabetes and CVD risks and androgenic status were assessed in nondiabetic, premenopausal women of similar body fatness who differed by race (black or white) and body fat distribution (UBO or lower body obesity). In black women, high-density lipoprotein cholesterol was the only measurement adversely affected by abdominal fat; HDL cholesterol was significantly lower in the black UBO group (1.14 ± 0.05 mM) compared with the black LBO group (1.37 ± 0.08 mM). This contrasts markedly with our findings in white women. In confirmation of previous reports, white UBO women, compared with white LBO counterparts, had significantly higher glucose (967.6 vs. 709.2 mM/2 h) and insulin (120.5 vs. 52.1 pM/2 h) areas and significantly lower peripheral insulin sensitivities (0.99 vs. 2.95 × 10−4) min−1/µU/ml). In addition, HDL cholesterol levels were significantly lower in the white UBO group (1.03 mM) compared with the white LBO group (1.49 mM), whereas plasma TG levels (white UBO, 1.72 vs. white LBO, 0.88 mM) and dBPs (white UBO, 84 vs. white LBO, 75 mmHg) were significantly higher.Finally, in the white UBO group compared with the white LBO group, SHBG levels were significantly lower (27.5 vs. 51.6 nM), whereas the free testosterone levels were higher (2.21 vs. 1.49%). We conclude that an equivalent degree of UBO, independent of total body fatness, is less detrimental for black women than for white women with regard to the risks of developing diabetes and CVD.
Biological Effects and Metabolic Rates of Glucagonlike Peptide-1 7–36 Amide and Glucagonlike Peptide-1 7–37 in Healthy Subjects Are Indistinguishable
Authors: Ørskov Cathrine , Wettergren André , Holst Jens J
Published: September 2013

The biological effects and the metabolism of the intestinal hormone glucagonlike peptide-1 7–36 amide and glucagonlike peptide-1 7–37 were studied in normal healthy subjects. GLP-1 7–36 amide and GLP-1 7–37 equipotently stimulated insulin secretion (integrated hormone response 0–60 min, 631 ± 211 vs. 483 ± 177 pmol/h × L−1) and C-peptide secretion (integrated hormone response 9064 ± 1804 vs. 9954 ± 2031 pmol/h × L−1) and equipotently lowered plasma glucose (integrated decrease 48.3 ± 5.7 vs. 46.2 ± 8.4 mmol/h × L-1) and plasma glucagon (integrated decrease 80.4 ± 24.3 vs. 156.0 ± 34.6 pmol/h × L−1). Both GLP-1 7–36 amide and GLP-1 7–37 lowered the plasma concentration of free fatty acids significantly. The plasma half-lives of GLP-1 7–36 amide and GLP-1 7–37 were 5.3 ± 0.4 vs. 6.1 ± 0.8 min, and the metabolic clearance rates of the two peptides also were similar (14.6 ± 2.4 vs. 12.2 ± 1.0 pmol/kg × min). In conclusion, COOH-terminal amidation is neither important for the metabolism of GLP-1 nor for its effects on the endocrine pancreas.
Limitations in the Use of [2-14C]Acetate for Measuring Gluconeogenesis In Vivo
Authors: Consoli Agostino , Nurjhan Nurjahan , Capani Fabio , Pangburn Thomas , Lapenna Domenico , Gerich John
Published: September 2013

This study was undertaken to test two assumptions critical for use of [2-14C]acetate to measure gluconeogenesis in vivo. For the assumption that incorporation into glucose of products of [14C]acetate metabolism does not affect the distribution of label within the glucose molecule, we infused [2-14C]acetate in 17 healthy subjects and [3-14C]lactate in 10 healthy subjects and compared the ratio of the resultant specific activities of plasma glucose carbons 1, 2, 5, 6, and 3, 4 obtained with each tracer. The ratio obtained with [2-14C]acetate (2.99 ± 0.07) was significantly different from the ratio obtained with [3-14C]lactate, (3.82 ± 0.2, P < 0.01). Because the model predicts that these ratios should be identical, these results indicate that either the model is incorrect or that metabolism of [14C]acetate to other compounds affects the distribution of the label within the glucose molecule. To test the assumption that plasma 3-OH-butyrate specific activity approximates the specific activity of hepatic intramitochondrial acetyl CoA, we compared the ratio of specific activities of plasma glucose and 3-OH-butyrate obtained in 7 healthy subjects infused with [2-14C]acetate and [2-14C]octanoate. The ratio obtained with [2-14C]acetate (0.18 ± 0.03) was significantly different from that obtained with [2-14C]octanoate, (0.10 ± 0.02), P < 0.001. These results suggest compartmentalization of acetyl CoA within liver mitochondria and indicate that plasma 3-OH-butyrate specific activity may not necessarily approximate intramitochondrial acetyl CoA specific activity during [2-14C]acetate infusion. We conclude that assumptions critical for use of [2-14C]acetate to measure gluconeogenesis in vivo are not valid.
Synthesis and Expression of Transforming Growth Factor β-1, β-2, and β-3 in the Endocrine and Exocrine Pancreas
Authors: Yamanaka Yoichiro , Friess Helmut , Büchler Markus , Beger Hans G , Gold Leslie I , Korc Murray
Published: September 2013

The actions of transforming growth factor-β isoforms as potent regulators of growth and differentiation have led to the examination of their presence in the human pancreas. The cellular localization of TGF-β1, TGF-β2, and TGF-β3 was assessed in the normal human pancreas by using immunohistochemical and in situ hybridization techniques. Although cytoplasmic immunoreactivity for TGF-β1, TGF-β2, and TGF-β3 was found in islet cells, acinar cells, and ductal cells, a differential immunostaining pattern for TGF-β isoforms was observed. In the endocrine pancreas, the islet cells demonstrated diffuse cytoplasmic immunostaining for TGF-β1, TGF-β2, and TGF-β3. However, only TGF-β2 and TGF-β3 exhibited an intense pattern of immunostaining in a few endocrine cells. Most of the positive islet cells coexpressed insulin. In contrast, in the exocrine pancreas, a greater number of acinar cells showed immunoreactivity for TGF-β1 than for TGF-β2 and TGF-β3. In the ductal cells, all three TGF-β isoforms showed a similar intensity and pattern of immunostaining and were observed more frequently in the smaller distal ductules than in the larger pancreatic ducts. TGF-β1 and TGF-β3, but not TGF-β2, immunostaining was detected strongly in the smooth muscle cells and weakly in the endothelial cells of the blood vessels, whereas the fibroblasts of the interstitium were completely negative. In situ hybridization revealed that mRNA encoding all three TGF-β isoforms colocalized with their respective proteins in islets, acinar cells, and ductal cells. In contrast, mRNA expression was absent in the smooth muscle cells and endothelium of the vessels. These results suggest that TGF-β isoforms may act by both autocrine and paracrine mechanisms in the pancreas. The differential pattern of expression observed for each TGF-β isoform implies unique roles for these proteins in the regulation of the endocrine and exocrine pancreas.
Aldose Reductase Inhibition Fails to Prevent Retinopathy in Diabetic and Galactosemic Dogs
Authors: Engerman Ronald L , Kern Timothy S
Published: September 2013

To investigate a possible role of excessive polyol production in the pathogenesis of diabetic retinopathy, 16 ALX-induced diabetic dogs and 20 experimentally galactosemic dogs were randomly assigned to 5 yr of treatment with either sorbinil, an aldose reductase inhibitor, or a placebo. The severity of hyperglycemia in sorbinil-treated and placebo groups was monitored throughout the 5-yr study by assay of glycosuria and nonenzymatically glycated plasma protein and HbA1 needed in an effort to avoid confounding possible group differences in hyperglycemia severity with possible drug effects. Inhibition of polyol production by sorbinil was monitored in erythrocytes throughout the study and also in retina and other tissue obtained at autopsy. Trypsin digests of retinal vessels were compared after 60 mo of diabetes and after 42 and 60 mo of galactosemia. In diabetic dogs, development of retinopathy was not significantly influenced by a sorbinil dose (20 mg · kg−1 · day−1) sufficient to prevent elevation of sorbitol levels in retina and other tissue. Likewise, in dogs made experimentally galactosemic for 42–60 mo, administration of sorbinil (60–80 mg · kg−1 day−1) had no significant effect on the development of retinopathy notwithstanding prevention of 93–96% of the polyol elevation in retina and other tissue. Retinal capillary basement membrane was significantly thicker than normal in diabetic and in galactosemic dogs and was not significantly influenced by administration of sorbinil in either dog model. Thus, no evidence was found that the development of retinopathy is critically dependent on excessive polyol production or accumulation.
5′ Insulin Gene Polymorphism Confers Risk to IDDM Independently of HLA Class II Susceptibility
Authors: Van Der Auwera Bart J , Heimberg Harry , Schrevens Anneleen F , Waeyenberge Christine van , Flament Jocelyne , Schuit Frans C
Published: September 2013

The polymorphic variable number of tandem repeats in the 5′ upstream region of the human insulin gene is a well-known non-human leukocyte antigen locus contributing to genetic susceptibility to IDDM. Controversy exists about the question as to whether INS susceptibility haplotypes are or are not preferentially inherited together with HLA-DR4 haplotypes. We investigated whether genetic interaction between INS and the HLA complex can be better defined using DQ genotypic and phenotypic markers in addition to DR serology. The 5′ INS 1/1 genotype was positively associated with IDDM both in non-DR4 subjects (relative risk = 4.3; 95% confidence interval, 1.6–11.5) and DR4 subjects (relative risk = 4.2; 95% confidence interval, 1.9–9.0). Further subdivision of IDDM patients and matched control subjects according to HLA-DQA1 and HLA-DQB1 genotype or phenotype also failed to show any association between 5′ INS and HLA class II genes in diabetic patients. The 5′ INS and HLA class II polymorphisms therefore provide independent risk markers, which may both contribute to the genetic screening of a high-risk population among nondiabetic individuals.
Identification of Glucokinase Mutations in Subjects With Gestational Diabetes Mellitus
Authors: Stoffel Markus , Bell Katherine L , Blackburn Christine L , Powell Keesha L , Seo Tracy S , Takeda Jun , Vionnet Nathalie , Xiang Kun-San , Gidh-Jain Madhavi , Pilkis Simon J , Ober Carole , Bell Graeme I
Published: September 2013

Recent studies have shown that mutations in the glucokinase gene on chromosome 7 can cause an autosomal dominant form of NIDDM with a variable clinical phenotype and onset during childhood. The variable clinical phenotype includes mild fasting hyperglycemia (i.e., a plasma glucose value of > 110 mg/dl, a value that is at least 2–3 SDs above normal), impaired glucose tolerance, gestational diabetes mellitus, as well as overt NIDDM as defined using National Diabetes Data Group or World Health Organization criteria. Because gestational diabetes mellitus was a clinical feature associated with glucokinase mutations, we have screened a group of women with gestational diabetes who also had a first-degree relative with diabetes mellitus for the presence of mutations in this gene. Among 40 subjects, we identified two mutations, suggesting a prevalence of ∼5% in this group. Extrapolating from this result, the prevalence of glucokinase-deficient NIDDM among Americans may be ∼1 in 2500.
The Paradox Between Resistance to Hypoxia and Liability to Hypoxic Damage in Hyperglycemic Peripheral Nerves: Evidence for Glycolysis Involvement
Authors: Schneider Uwe , Niedermeier Wolfgang , Grafe Peter
Published: September 2013

Isolated ventral and dorsal rat spinal roots incubated in normal (2.5 mM) or high glucose (25 mM) concentrations or in high concentrations of other hexoses were exposed transiently to hypoxia (30 min) in a solution of low buffering power. Compound nerve action potentials, extracellular direct current potentials, and interstitial pH were continuously recorded before, during, and after hypoxia. Ventral roots incubated in 25 mM D-glucose showed resistance to hypoxia. Dorsal roots, on the other hand, revealed electrophysiological damage by hyperglycemic hypoxia as indicated by a lack of posthypoxic recovery. In both types of spinal roots, interstitial acidification was most pronounced during hyperglycemic hypoxia. The changes in the sensitivity to hypoxia induced by high concentrations of D-glucose were imitated by high concentrations of D-mannose. In contrast, D-galactose, L-glucose, D-fructose, and L-fucose did not have such effects. Resistance to hypoxia, hypoxia-generated interstitial acidification, and hypoxia-induced electrophysiological damage were absent after pharmacological inhibition of nerve glycolysis with iodoacetate. These observations indicate 1) that enhanced anaerobic glycolysis produces resistance to hypoxia in hyperglycemic peripheral nerves and 2) that acidification may impair the function of peripheral axons when anaerobic glycolysis proceeds in a tissue with reduced buffering power.
The 12th International Immunology and Diabetes Workshop: Orlando, Florida
Authors: MacLaren Noel , Lafferty Kevin
Published: September 2013

The 12th International Immunology of Diabetes Workshop was held during April 1993 in Orlando, Florida, to review research progress since the 11th Immunology of Diabetes Workshop meeting in Nagasaki, Japan, one and a half years before. The NOD mouse may have as many as 10 susceptibility genes, including its novel IA major histocompatibility complex antigen and a defective interferon-γ receptor, whereas human IDDM is so far known to be encoded by cis and trans complementation products of certain DQ genes on chromosome 6q, and a gene in the insulin-like growth factor II region on chromosome 11p. A unique protein regulator of the × box promotor of the highly susceptible DQB1*0302 allele has also been found. Islet cell antibody negative siblings of IDDM patients appear to have lower than expected abilities to secrete insulin in response to intravenous glucose. Sera from patients before and/or after developing IDDM immunoprecipitate two native proteins of 64,000- and 38,000-Mr glutamic acid decarboxylase (GAD65) reacting to conformational epitopes. However, a multitude of other autoantibodies often reacting to denatured proteins through linear epitopes have also been identified. The first workshop for GAD antibody assays was successfully completed; however, the 38,000-Mr antigen has not yet been identified. Other autoantibodies reactive to gangliosides and to sulfatides continue to be reported. Insulitis has come to be recognized as a sometimes protective event. Protective insulitis predominates in older lesions. It can be induced by as disparate means as tuberculin antigen administration, by interleukin-4 treatments, by transfer of T-cell lines generated in autologous mixed lymphocyte responses, and by immunization to insulin B-chain, whereas oral islet cell antigens, such as insulin, can delay diabetes onset in the NOD mouse. Although Th2 cells may be important in protective insulitis, the NOD may actually have a deficiency of Th1 cells. Encapsulated islets can function for months after transplantation, whereas xenogeneic islet grafts appear to be rejected through a CD4+ T-cell–mediated mechanism like the pathogenic destruction of islets seen in NOD mice. We summarize a few of the meeting highlights.
Oral Vanadate Reduces Na+-Dependent Glucose Transport in Rat Small Intestine
Authors: Madsen Karen L , Porter Valerie M , Fedorak Richard N
Published: September 2013

The effects of oral vanadate supplementation on intestinal morphometry and glucose transport were examined in STZ-induced diabetic and age-matched control male Sprague-Dawley rats. Animals received 0.1 mg/ml vanadium pentoxide in their drinking water over 14 days. Vanadate reduced intestinal glucose maximal transport capacity in both diabetic and control animals. In jejunum tissue, this decrease in glucose absorption was a direct consequence of downregulation of the glucose carrier and was not related to changes in mucosal morphometry. In the ileum tissue of control animals, the vanadate-induced decrease in glucose maximal transport capacity occurred in conjunction with an increase in carrier affinity and mucosal morphometric measurements. In the ileum tissue of diabetic animals, the vanadate-induced decrease in glucose maximal transport capacity occurred with a decrease in mucosal morphometric measurements. Na+-K+-adenosine triphosphatase activity was affected by vanadate only in diabetic animals. These results demonstrate that oral vanadate supplementation results in downregulation of the small intestinal sodium-dependent glucose carrier in both diabetic and nondiabetic rats. Furthermore, the vanadate effect may be occurring at the cellular level.
High Glucose Reduces Specific Binding for D-α-Tocopherol in Cultured Aortic Endothelial Cells
Authors: Kunisaki Makoto , Umeda Fumio , Yamauchi Teruaki , Masakado Mitunori , Nawata Hajime
Published: September 2013

We investigated the effects of glucose on specific D-α-tocopherol binding to cultured bovine aortic endothelial cells. Our results confirmed that cultured bovine aortic endothelial cells have specific binding sites for D-α-tocopherol. These binding sites exhibited time- and temperature-dependent saturation. The specific binding affinity of D-α-tocopherol was significantly lower in endothelial cells cultured in high concentrations of glucose (16.8 or 22.4 mM) for > 7 days compared with cells cultured in a physiological glucose concentration (5.6 mM). No significant reduction occurred in D-α-tocopherol binding when 11.1 mM mannitol was added to cells cultured in 5.6 mM glucose. The addition of an aldose reductase inhibitor (ICI-128436, Statil) did not significantly affect the high-glucose–induced reduction of D-α-tocopherol binding, although it reduced sorbitol levels in the cells compared with those from cells cultured in high concentrations of glucose. Moreover, significantly higher amounts of lipid peroxides were produced in aortic endothelial cells cultured in high concentrations of glucose (16.8 or 22.4 mM) for >3 days compared with cells cultured in a physiological concentration of glucose. These results indicate that high concentrations of glucose reduce D-α-tocopherol binding through mechanisms independent of putative osmotic effects of sorbitol accumulation in the cells. Possible mechanisms include glycation of protein or oxidative damage of cells and/or redox and metabolic imbalances associated with increased flux of glucose via the sorbitol pathway. A glucose-mediated reduction in D-α-tocopherol binding could diminish the beneficial effects of D-α-tocopherol to vascular endothelial cells and thereby may increase the vascular toxicity of hyperglycemia in diabetes mellitus.
Role of Prostaglandin H2 as an Endothelium-Derived Contracting Factor in Diabetic State
Authors: Shimizu Kiyokazu , Muramatsu Masahito , Kakegawa Yoshio , Asano Hiroshi , Toki Yukio , Miyazaki Yutaka , Okumura Kenji , Hashimoto Hidekazu , Ito Takayuki
Published: September 2013

This study investigated the possible involvement of prostaglandin H2, an acetylcholine-induced endothelium-derived contracting factor in rat aorta, in the development of abnormality of the vasculature in diabetes. Rings of thoracic aorta were prepared from control Wistar-Kyoto and STZ-induced diabetic rats to examine the changes in isometric tension. In 10−7 M norepinephrine-precontracted rings, acetylcholine induced relaxations, which were significantly impaired in diabetic rats. Inhibition of thromboxane A2-prostaglandin H2 receptors with ONO-3708 (10−6) M) prevented the development of the impairment of relaxation in diabetic rats. Thromboxane A2 synthesis inhibition with OKY-046 (10−5 M) did not affect the acetylcholine-induced relaxation in both control and diabetic rats. In aortic rings under resting tension, acetylcholine induced a contraction that was greater in diabetic than control rats, when the nitric oxide production was inhibited by NGxs-nitro-L-arginine methylester (10−4 M). This acetylcholine-induced contraction was observed only in the rings with intact endothelium and was completely abolished by ONO-3708 (10−6 M). The concentration of 6-keto-prostaglandin F1α in the solution bathing diabetic rat aortic rings increased significantly after acetylcholine (10−5 M) administration. Prostacyclin (10−9 · 10−6 M) did not induce contractions at all. Prostacyclin is unlikely to mediate contractions because of its low contractile potency. These findings suggest that the impairment of acetylcholine-induced relaxation in the diabetic state is not caused by the diminished production of an endothelium-derived relaxing factor or nitric oxide but rather by the increased endothelium-derived contracting factor or prostaglandin H2, which may be responsible for abnormalities of the vasculature in diabetes.
Identification in Islets of Langerhans of a New Rat α2-Adrenergic Receptor
Authors: Wang San Y , Pilkey David T
Published: September 2013

The islets of Langerhans are richly innervated, and an inhibitory effect on insulin secretion, mediated through α2-adrenergic receptors, appears to be an important physiological neural modulator of β-cell function. An α2-receptor was cloned from isolated newborn rat islets using a polymerase chain reaction (PCR) approach. This receptor was shown by sequencing to be a new rat α2-receptor very similar to the human α2-C2 receptor. No other α2-receptor subtype was identified in normal islets by the PCR using os-receptor primers. This was also the only α2-receptor subtype present in the exocrine pancreas and liver. In contrast, in the β-cell line, βTC3, the α2-C2 receptor was not detected, but the α2-C4 and α2-C10 receptor subtypes were detected. It is suggested that the α2-C2 subtype may be the principal α2-receptor mediating inhibitory autonomic nervous system activity in the gastrointestinal tract. A comparison of the rat islet, pancreas, and liver α2-receptor sequences reported here with previously reported α2-receptor sequences indicates that the rat islet α2-receptor is not the rat α2-C2 homologue previously denoted as RNGα2, but is a new, fourth rat subtype with an even higher similarity to the human α2-C2 receptor.
Peculiar T-Cell Signaling Does Not Preclude Positive Selection in the Diabetes-Prone BB Rat
Authors: Bellgrau Donald , Redd Joan M , Sellins Karen S
Published: September 2013

Various studies have provided evidence that peripheral T-cells from the diabetes-prone BB-DP rat are abnormal in function and cell surface phenotype. These characteristics have often been interpreted as indicators of immaturity and/or short life span. In this study, we describe a CD4-dependent signaling abnormality in BB-DP peripheral T-cells. In spite of the fact that CD4 plays a critical role in thymocyte development, the abnormal signaling does not appear to influence thymocyte development at the stage when the T-cell receptor is rearranged and the recombinase enzymes RAG-1 and RAG-2 transcripts are downregulated. Therefore, if a maturation defect leading to the seeding of the periphery with immature T-cells occurs in the BB-DP rat, it does not preclude the initial selection of the self major histocompatibility complex-restricted T-cell repertoire.
High Genetic Risk for IDDM in the Pacific Northwest: First Report From the Washington State Diabetes Prediction Study
Authors: Rowe Rachel E , Leech Nicola J , Nepom Gerald T , McCulloch David K
Published: September 2013

A Combination Of Immune, genetic, and metabolic markers potentially implicated in the development of insulin-dependent diabetes mellitus (IDDM) was studied in the general population. We screened 3,992 healthy schoolchildren, 12–18 years of age with no family history of IDDM, for islet cell antibodies (ICAs). Of the children, 69 (1.7%) were found to be ICA positive (ICA+), of whom 7 (0.17%) also were positive for insulin autoantibodies (lAAs). ICA+ children (group 1) were human leukocyte antigen (HLA) typed at the DQ locus along with 123 matched (group 2) and 235 random (group 3) control subjects (from the original cohort of 3,992). Of the ICA+ children, 28 underwent β-cell function (β-CF) studies. High-risk DQ types were surprisingly prevalent in all groups with 35.8% of random control subjects carrying DQB1*0302 and 8.9% carrying the highest risk HLA type for IDDM, DQB1*0302/*0201. Those individuals with higher ICA titer (>19 Juvenile Diabetes Foundation units [JDF U]) had a significantly higher prevalence of DQB1*0302 than those with lower titer ICA or normal control subjects. Six of 7 individuals positive for both ICA and IAA and typed at the DQ locus were DQB1 *0302/*0201 heterozygotes or DQB1*0302 or DQB1*0201 homozygotes, representing three of the highest risk genotypes for IDDM. No correlation was observed between ICA titer or DQ type and β-CF except that all those with β-CF below the 5th percentile carried either DQB1*0302 or DQB1*0201. Prospective follow-up is underway to determine if any combination of DQ type and immune markers predicts decline in β-CF and the development of IDDM .
Glucosamine Inhibits Glucokinase In Vitro and Produces a Glucose-Specific Impairment of In Vivo Insulin Secretion in Rats
Authors: Balkan Börk , Dunning Beth E
Published: September 2013

A characteristic feature of non-insulin-dependent diabetes mellitus (NIDDM) is the lack of an acute insulin response to intravenous glucose with maintenance of the response to other secretagogues. It has been hypothesized that impaired glucose sensing stems from defective β-cell glucokinase. It remains unclear whether decreased pancreatic glucokinase activity will produce defects of insulin secretion similar to those observed in NIDDM. In this study, the effects of glucosamine on glucokinase activity and on islet function were assessed in vitro and in vivo. Glucosamine (5 mmol/l) reduced glucokinase activity in islet homogenate and diminished the insulin response to glucose (200 mg/dl) by isolated islets, whereas the response to arginine (20 mmol/l at 100 mg/dl glucose) was unaffected. In conscious normal rats, glucosamine lowered plasma insulin, followed by an increase in blood glucose. Administration of glucosamine 10 min before an infusion of glucose (10 mg · min−1 · 15 min) reduced the insulin response. The primary effect was an attenuation of the first-phase insulin response relative to the decreased basal insulin levels. Arginine (10 mg · min−1 · 15 min) induced biphasic insulin release in both groups. Although glucosamine slightly reduced the absolute insulin response, it was normal relative to preinfusion levels. In all experiments, glucagon secretion was unaffected by glucosamine. The results indicate that glucosamine inhibits β-cell glucokinase activity in vitro. In addition, glucosamine impairs glucose- but not arginine-induced insulin secretion. We conclude that glucosamine, probably via a reduction of glucokinase activity, impairs insulin secretion in a manner comparable to that seen in NIDDM.
Nitric Oxide Produced by Macrophages Mediates Suppression of ConA-Induced Proliferative Responses of Splenic Leukocytes in the Diabetes-Prone BB Rat
Authors: Lee Ki-Up
Published: September 2013

Splenic cells from the diabetes-prone BB rat show reduced proliferative responses to concanavalin A (ConA) and other mitogens. This study was undertaken to test whether this reduced lymphoproliferation in the BB rat is mediated by an increased production of nitric oxide (NO) by macrophages. Splenic leukocytes from diabetes-prone BB rats and five strains of control rats (BB-R, Wistar-Furth, Sprague-Dawley, Wistar, and Lewis) were cultured in RPMI-1640 media containing ConA. The leukocytes from BB rats showed reduced [3H]thymidine uptake and increased release of NO compared with the control rats. Partial depletion of macrophages from the culture or incubation with NG-monomethylarginine (NGMMA), a specific NO synthase inhibitor, markedly augmented ConA-induced proliferation of the splenic leukocytes from BB but not the control rats. Enrichment of BB rat macrophages suppressed the proliferation of BB-R rat spleen cells. Excess L-arginine added to the culture reversed the NGMMA effect. These results suggest that increased production of NO by macrophages is partly responsible for the reduced proliferative responses of splenic leukocytes in the BB rat.
Monokine Antagonism Is Reduced in Patients With IDDM
Authors: Mandrup-Poulsen Thomas , Pociot Flemming , Mølvig Jens , Shapiro Leland , Nilsson Povl , Emdal Torkil , Røder Michael , Kjems Lisa L , Dinarello Charles A , Nerup Jørn
Published: September 2013

Interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α) have been implicated as immune effector molecules in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). Recently, an increased frequency of the A1/A1 genotype of an IL-1 receptor antagonist (IL-1Ra) gene polymorphism was observed in patients with IDDM. Therefore, we investigated plasma IL-1Ra and soluble TNF p55 receptor (TNFsRp55) levels in 18 men with recent-onset IDDM, 10 men with long-standing IDDM, and 35 age-matched healthy men. No differences in plasma IL-1Ra were found among the three groups. However, when the plasma IL-1Ra levels in the subjects with IDDM and the control subjects were analyzed according to IL-1Ra genotypes, we found a 30% lower level of plasma IL-1Ra in subjects with IDDM carrying the A1/A1 genotype compared with the levels in those carrying the A1/A2 genotype (372 ± 40 vs. 530 ± 54 ng/l, respectively, P = 0.025). In contrast, no significant association was seen between plasma IL-1Ra and IL-1Ra genotype in the control subjects. The TNFsRp55 level in heparinized plasma was 17% lower in patients with IDDM than in control subjects (3.93 ± 0.22 vs. 4.72 ± 0.24 μg/l, respectively, P = 0.038). These findings could not be explained by metabolic derangement in the IDDM patients. Although based on a limited number of patients, these preliminary findings suggest that μ-cells in IDDM patients may be more sensitive to the cytotoxic effects of TNF-α and IL-1 because of less production of TNFsRp55 and, in a subset of IDDM patients, of IL-IRa during the inflammatory challenge of insulitis.