bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucose Modulation of Insulin and Glucagon Secretion in Nondiabetic and Diabetic Man
Authors: Hollander Priscilla M , Asplin Christopher M , Palmer Jerry P 
Published: September 2013

SUMMARY
To ascertain whether the ability of glucose to influence the pancreatic islets response to a nonglucose stimulus is normal in type II diabetics, we have evaluated the modulating effect (Md) of the plasma glucose level (PG) on the acute insulin response (IRI) and glucagon response (IRG) to intravenous arginine in noninsulin-dependent diabetics (NIDDM) and nondiabetics (ND). MdIRI or MdIRG is the change in the hormonal response to arginine resulting from changes in plasma glucose level divided by the change in plasma glucose. Md has been determined over two ranges of PG: between normal fasting PG (level I) and mild hyperglycemia (∼160 mg/dl, level II) and between mild hyperglycemia and marked hyperglycemia (∼350 mg/dl, level III). Increases in PG augmented the IRI response in both groups, but the degree of augmentation was impaired in the NIDOM group. MDIRI, for ND and NIDDM between levels I and II were 20 ± 3 and 1.9 ± 0.6, respectively, and between levels II and III were 23 ± 5 and 2.3 ± 0.5, respectively (P &lt; 0.01). MdIRI correlated with fasting PG in ND and NIDDM. Changes in PG resulted in equivalent changes in the IRG response to arginine in both groups. MdIRG for level I to II was −6.1 ±1.0 and −6.0 ± 1.2, and for level II and III was −0.9 ± 0.4 and −1.2 ± 0.5 in ND and NIDDM, respectively. The impairment of MDIRI and its relationship to fasting PG in NIDDM support the hypothesis that fasting hyperglycemia may be, in part, a compensatory mechanism for maintaining beta-cell response to nonglucose stimuli, thereby maintaining basal insulin levels. MdIRG was normal in NIDDM when evaluated at comparable glucose levels in the ND and NIDDM groups.
Partial Characterization of an Insulin-dependent Serum Factor that Regulates Ornithine Decarboxylase in Skeletal Muscle
Authors: Conover Cheryl , Jaime Rozovski S , Ruderman Neil B 
Published: September 2013

SUMMARY
We have previously shown that a factor(s) in rat serum induces ornithine decarboxylase (ODC) in incubated muscle and that its activity is diminished in sera from diabetic rats. To characterize this factor further, we have studied some of its physicochemical and biologic properties. As judged from its ability to induce ODC in the incubated rat soleus muscle, the factor is protease-sensitive and both heat- and acidstable. In untreated whole serum its activity is associated with a high-molecular-weight fraction whereas after boiling at pH 5.5, activity is principally in a fraction with a molecular weight between 3500 and 12,000 daltons. The activity of the factor is diminished in hypophysectomized, starved, and aged as well as diabetic rats. In diabetic rat serum it is restored to normal by the addition of a purified somatomedin, multiplication-stimulating activity. These findings suggest that the “ODC inducing factor” is a low-molecular- weight peptide and that it has many of the characteristics of a somatomedin.
Effects of Glucose on Proinsulin Messenger RNA in Rats In Vivo
Authors: Giddings Stephen J , Chirgwin John , Permutt M Alan 
Published: September 2013

The purpose of these studies was to determine whether glucose, the principal regulator of insulin biosynthesis in mammals, controls synthesis through alterations in levels of proinsulin mRNA in whole animals. Rats were starved for 3 days and then either refed or injected with glucose or saline for 24 h. Glucose injection raised plasma glucose levels equivalent to levels seen with refeeding but provided less than 20% of caloric replacement. Pancreatic RNA was extracted and the relative concentration of proinsulin mRNA was determined by blot hybridization with a cloned rat proinsulin cDNA probe. In starved animals proinsulin mRNA levels were 15–20% that of fed controls. Glucose injection produced a specific three- to fourfold increase in proinsulin mRNA levels relative to total pancreatic RNA, within 24 h. The effect was measurable 2 h after glucose injection and appeared largely complete by 12 h. Actinomycin D blocked the glucose-induced increase in proinsulin mRNA.
These studies demonstrate effects of changes of plasma glucose on levels of proinsulin mRNA. Their rapidity of onset and large magnitude are comparable to effects of glucose on rates of insulin biosynthesis in isolated islets and suggest that insulin biosynthesis is regulated at least in part by levels of proinsulin mRNA.
Effects of Body Composition on Insulin Sensitivity
Authors: Yki-Järvinen Hannele , Koivisto Veikko A 
Published: September 2013

We studied the effects of body composition and maximal aerobic power on insulin sensitivity in 23 normal-weight, healthy male subjects. Eight were weight lifters, eight were long-distance runners, and seven were untrained controls. In each subject, the percentage of body weight (BW) made up of muscle and fat tissue (% muscle and % fat, respectively), the maximal aerobic power (O2max), and the tissue sensitivity to insulin were measured. The weight lifters were characterized by 35% higher % muscle as compared with the runners or controls (P &lt; 0.01). O2max in the runners was 30–40% higher than in the weight lifters or controls (P &lt; 0.001). During the euglycemic clamp studies, similar steady-state plasma glucose and insulin levels were achieved in each group. When calculated per total BW, the rate of glucose metabolism (M) was virtually identical in the weight lifters (10.26 ± 1.02 mg/kg BW/min) and the runners (10.03 ± 0.86 mg/kg BW/min), and 40–45% higher than in the controls (7.10 ± 0.75 mg/kg BW/min, P &lt; 0.05). When calculated per muscle mass (Mm), only the runners had a higher than normal rate of glucose metabolism (P &lt; 0.02). M was directly proportional to % muscle (r = 0.54, P &lt; 0.01) and inversely related to % fat (r = −0.72, P &lt; 0.001). The multiple linear regression analysis revealed a highly significant multivariate correlation between M and the combined effect of % muscle, % fat, and VO2max (r = 0.78, P &lt; 0.0005). In addition, a regression equation for the predicted M was obtained as follows: M (mg/kg BW/min) = 0.697 + 0.155 % muscle − 0.312 % fat + 0.065 VO2max (ml/kg/min).
In conclusion, first, body sensitivity to insulin is directly related to muscle mass and inversely proportional to adiposity. Second, it may be possible in healthy man to predict the rate of glucose metabolism when body composition and O2max are known.
Increased Efficiency of Weight Gain and Altered Cellularity of Brown Adipose Tissue in Rats with Impaired Glucose Tolerance During Diet-induced Overfeeding
Authors: Cunningham John , Calles Jorge , Eisikowitz Leon , Zawalich Walter , Felig Philip 
Published: September 2013

We examined the relationship among glucose tolerance, efficiency of weight gain, and cellularity of brown adipose tissue (BAT) in rats (initial weight: 362 ± 1 g) made hyperphagic and obese by feeding on a highly palatable “cafeteria” (CAF) diet for 4–8 wk. As compared with chow-fed controls, CAF feeding resulted in a 45–60% increase in caloric intake (P &lt; 0.01), a 40–50% increase in weight gain (P &lt; 0.01), and hyperinsulinemia. Glucose disposal rate (K) on intravenous glucose tolerance test (IVGTT) was ≥ 1.4% in all chow-fed rats, but fell to ≤ 1.3 in 10 of 23 CAF-fed rats. As compared with the chow-fed controls, rats with normal glucose tolerance demonstrated a 12% decline in efficiency of weight gain (g/100 kcal of food consumed) in response to CAF feeding (P &lt; 0.05). In marked contrast, in rats with impaired glucose tolerance, efficiency of weight gain failed to decline in response to overfeeding and was 18% higher than in the overfed group with normal glucose tolerance (P &lt; 0.01). Although CAF feeding increased the mass of interscapular BAT by 110–130% in rats with normal as well as impaired glucose tolerance, DNA content of BAT rose only in the normal-K CAF-fed rats (0.19 ± 0.01 mg DNA/100 mg versus 0.12 ± 0.02 in chow-fed controls and 0.12 ± 0.01 in low-K rats).
We conclude that (1) impaired glucose tolerance accompanying dietary-induced obesity is associated with an increase in efficiency of weight gain and (2) failure of BAT cellularity to increase may contribute to the increase in efficiency. These data suggest that the link between obesity and diabetes may be bidirectional: obesity increases the risk of diabetes while impaired glucose tolerance may accelerate the development of obesity by enhancing efficiency of weight gain.
Anti-Islet Immunity and Thymic Dysfunction in the Mutant Diabetic C57BL/ KsJ db/db Mouse
Authors: Debray-Sachs Monique , Dardenne Mireille , Sai Pierre , Savino Wilson , Quiniou Marie-Christine , Boillot Dominique , Gepts Willy , Assan Roger 
Published: September 2013

Anti-islet immune reactions were studied in vitro in genetically diabetic homozygote C57BL/KsJ db/db mice, using murine islet cells as a target. Spleen lymphocytes inhibited insulin secretion by the islet cells. This inhibition was abolished when T-cells were eliminated by treatment with anti-Thy 1.2 monoclonal antibody in the presence of complement. Anti-islet complement-dependent antibody (CDA) and antibody-dependent cell cytotoxicity (ADCC) were also found in the sera of these mice. This anti-islet immunity was detectable as early as the tenth day of life and lasted throughout the entire life span of the animals. A significant lymphopenia was detected in thymus and spleen cell populations. None of these anomalies was found in control heterozygote mice.
Thymic function was explored in the same mice by evaluating their serum thymic factor (FTS) levels using a rosette assay. The age-dependent decline of FTS levels was significantly accelerated in diabetic mice as compared with heterozygous littermates. Futhermore, FTS inhibitory immunoglobulins were detected in db/db mouse sera, which inactivated in vitro the biologic potency of synthetic FTS. Histologically, the thymus displayed an accelerated involution. It was shown by indirect immunofluorescence using anti-FTS monoclonal antibodies that the number of FTS+ cells was reduced in db/db mouse thymuses.
Histologie study of the islets of Langerhans showed early signs of β-cell hyperactivity and hypertrophy, followed by β-cell rarefaction and profound dislocation of islet architecture. Insulitis was not detected.
Peripheral Nerve Abnormalities in the Diabetic Mutant Mouse
Authors: Sharma A K , Thomas P K , Gabriel G , Stolinski C , Dockery P , Hollins G W 
Published: September 2013

Observations were made on the genetically diabetic C57BL/KS (db/db) mouse. Morphometric observations were performed on the tibial nerve at 6, 9, and 15 mo and compared with those from nondiabetic (m/m) controls. Myelinated fiber size was less in the diabetic animals at all stages and affected cross-sectional axon area and myelin thickness equally. Unmyelinated axons were unaffected. The index of circularity of myelinated axons did not differ between diabetic and control animals. No definite absolute reduction in fiber size occurred and degenerative changes, which were slight, were equally frequent in the diabetic and control nerves. Axonal glycogenosomes, polyglucosan particles, and Schwann cell/axon networks, and Schwann cell Reich granules increased with age in both groups, but only glycogenosomes were consistently more numerous in the diabetic animals.
Counts of membrane associated particles in both P and E faces revealed that these were reduced in number in the diabetic animals in myelin and in the axolemma of unmyelinated axons, but not in the axolemma of myelinated fibers.
Growth in tibial length was also reduced in the diabetic animals and this suggested that the reduced fiber diameter probably represented a maturational deficit. The absence of a selective reduction in axonal size did not favor a primary axonopathy as the cause.
Tubular Reabsorption Rates as Related to Elevated Glomerular Filtration in Diabetic Children
Authors: Ditzel Jørn , Brøchner-Mortensen Jens 
Published: September 2013

To study renal tubular reabsorption and tubulo-glomerular balance in diabetic children, glomerular filtration rate (GFR) and tubular reabsorption rates of sodium, glucose, ultrafilterable calcium, and phosphate were measured during fasting in 26 ambulatory type I (insulin-dependent) diabetic children without clinical signs of microangiopathy (age 7–14 yr; duration of diabetes 3–14 yr). Similar measurements were made in 28 healthy school children (age 8–14 yr). Mean GFR in the diabetic children was significantly higher than in the normal children (138 versus 109 ml/min/1.73 m2, P &lt; 0.01). Mean tubular reabsorption rates of sodium, glucose, and calcium were significantly increased in the diabetic subjects (P &lt; 0.001). In contrast, tubular reabsorption rate of phosphate in the diabetic subjects was not enhanced. The renal threshold concentration of phosphate (TmPO4/GFR) was suppressed in the diabetic compared with the healthy subjects (1.23 versus 1.73 mmol/L, P &lt; 0.001). TmP04/GFR was unrelated to circulating parathyroid and growth hormone concentrations but correlated inversely with the reabsorption rate of glucose (r = -0.53, P &lt; 0.01). Sodium reabsorption was closely correlated to GFR in both diabetic (r = 0.99, P &lt; 0.0001) and healthy subjects (r = 1.00, P &lt; 0.0001), and both groups showed identical regression lines. The tubular glucose reabsorption rate was independent of GFR in the diabetics. Tubular calcium and phosphate reabsorptions correlated equally well with sodium reabsorption and with GFR in the diabetic and healthy subjects (P &lt; 0.001). The maximal reabsorption of phosphate relative to GFR was lowered in the diabetic children. Thus, in the diabetic subjects, the tubulo-glomerular balance was maintained for sodium, but not for phosphate.
These findings can be interpreted as a consequence of increased plasma (and ultrafilterate) glucose concentration inhibiting maximal phosphate reabsorption, leading to a stimulation of sodium coupled glucose reabsorption (cotransport), and thereby of solutelinked water reabsorption. The normalization of absolute phosphate reabsorption may be a consequence of the increased reabsorption of sodium. The excess sodium/solute-linked reabsorption is likely to be basic for the mechanism leading to the elevated GFR in the diabetic subjects.
Platelet Enzyme Activities in Diabetes Mellitus in Relation to Endothelial Damage
Authors: Janka H U , Standl E , Schramm W , Mehnert H 
Published: September 2013

Increased platelet reactivity has been suggested in the pathogenesis of both arteriosclerosis and diabetic microangiopathy. Therefore, platelet function and platelet enzyme activities were assessed in a large group of 357 diabetics (256 patients with IDDM, aged 16–49 and 101 patients with NIDDM, aged 50–78) and 163 matched controls, and related to photographically documented retinopathy (Rd) and to peripheral vascular disease (PVD) as well as to plasma levels of von Willebrand factor (VIII R:Ag) as an indicator of endothelial damage.
Patients with IDDM had increased platelet aggregation (PA, expressed as μM ADP threshold concentration) before Rd was detectable in comparison to control subjects (P &lt; 0.01). PA was further increased in patients with advanced Rd (P &lt; 0.01), whereas 20 newly diagnosed diabetics with IDDM exhibited normal PA. Patients with minimal Rd did not differ from patients without Rd. Plasma β-thromboglobulin (reflecting platelet consumption in vivo) was enhanced significantly in patients with Rd only (P &lt; 0.05), as was malondialdehyde (MDA) production of platelets (as a measure of platelet endoperoxide formation).
Factor VIII-related antigen in plasma was already increased in patients without Rd (P &lt; 0.05), yet more so in patients with Rd (P &lt; 0.01). Prostacyclin-stimulated adenylate cyclase activity (ACA) of platelets (as an antiaggregatory enzyme system) was twice as high in diabetics with advanced Rd compared with patients without Rd and with controls (P &lt; 0.01). Significant correlations were found between PA and plasma F VIII R: Hg, MDA production, and ACA of platelets.
Increased PA was also found in subjects with NIDDM (P &lt; 0.05). Patients with PVD, however, did not differ from patients without PVD when subjects with Rd were excluded.
These results indicate that increased platelet activity may precede clinically detectable vascular disease, but is associated with increased levels of plasma von Willebrand factor protein, suggesting that endothelial damage is already present. Increases of PA platelet enzyme activities and plasma von Willebrand factor are particularly prominent in diabetics with Rd, reflecting highly active and perhaps younger platelets in this condition.
Influence of Glucose on Insulin Handling by Rat Islets in Culture: A Reflection of Integrated Changes in Insulin Biosynthesis, Release, and Intracellular Degradation
Authors: Halban Philippe A , Renold Albert E 
Published: September 2013

Rat islets were maintained for 3 days in tissue culture at 2.8, 8.3, or 16.7 mM glucose, in the presence of [3H]leucine to label insulin stores. The immunoreactive insulin content of islets after 3 days at either 2.8 or 16.7 mM glucose was lower than that of islets exposed to 8.3 mM glucose. The specific radioactivity of stored labeled insulin, however, increased with increasing glucose. Islet insulin turnover was thus highest at 16.7 mM glucose. During a subsequent 1-day chase period at 2.8, 8.3, or 16.7 mM glucose for each of the three groups of islets prelabeled at these same three concentrations, all islets responded to glucose with increased insulin release. Release of immunoreactive insulin was highest at all three chase glucose concentrations for those islets preexposed for 3 days to 16.7 mM glucose. After 3-day labeling of islets at 8.3 mM glucose, there was an inverse relationship between the rate of release of labeled insulin and its intracellular degradation in response to the three glucose concentrations during the chase period. Those islets prelabeled at either 2.8 or 16.7 mM glucose showed much lower rates of intracellular degradation of labeled insulin stores during the chase period regardless of the ambient glucose or of the rate of release of the labeled hormone.
Adaptive changes in islet insulin handling thus occurred during the 3-day maintenance period at different glucose concentrations. Whereas glucose concentration is, of course, thought to regulate insulin biosynthesis and release directly, regulation of degradation of stored insulin within B-cells appears to reflect both the relative activity of biosynthesis and release of the hormone and the insulin content of the islets. This last and striking relation is best interpreted as reflecting two labile, exchangeable, granule pools, one preferentially available for release and the other for intracellular degradation.
Parallel Decreases in the Expression of Receptors for Insulin and Insulin-like Growth Factor I in a Mutant Human Fibroblast Line
Authors: Massague Joan , Freidenberg Gary F , Olefsky Jerrold M , Czech Michael P 
Published: September 2013

The receptors for insulin and the insulin-like growth factor (IGF) I are two structurally homologous disulfide-linked multisubunit complexes of apparent Mr = 350,000. The similar subunit structures of these two types of receptors suggested that their genetic expression might be affected by common genetic defects. We have examined this possibility in an insulinresistant, diabetic patient who exhibits decreased insulin binding activity. The receptors for IGF-I and insulin in skin fibroblasts from this patient were affinity labeled with 125I-IGF-I and 125I-insulin, respectively, and visualized by electrophoresis and autoradiography in polyacrylamide gels. Control fibroblasts exhibited the usual affinity labeling of the disulfide-linked Mr = 350,000 insulin and IGF-I receptor structures.
The intensity of labeling of both receptor types in the patient's fibroblasts was less than in control fibroblasts. Binding data indicated that this decrease is due to a decreased receptor number with little or no decrease in affinity for the respective ligands. The highaffinity bIGF-II receptor in fibroblasts affinity labeled with 125I-IGF-II or 125I-IGF-I consists of a single polypeptide not disulfide linked to any other membrane component. The molecular size and intensity of labeling of the IGF-II receptor in the patient's fibroblasts were unaltered when compared with those of controls. These observations suggest that a common genetic defect alters the expression of the homologous receptor structures for insulin and IGF-I.
Muscle Capillary Basement Membrane Width and Its Relationship to Diabetes Mellitus in Monozygotic Twins
Authors: Ganda O P , Williamson J R , Soeldner J S , Gleason R E , Kilo C , Kaldany A , Miller J P , Garovoy M R , Carpenter C B 
Published: September 2013

Quadriceps (Q) and gastrocnemius (G) muscle capillary basement membrane width (CBMW) were measured in 18 pairs of monozygotic (MZ) twins. Thirteen of these twin pairs were discordant for insulin-dependent diabetes (IDD) and five pairs were concordant for either IDD (two pairs) or for non-insulin-dependent diabetes (NIDD). In 12 of the 13 nondiabetic (ND) twin mates of IDD, 50 oral glucose tolerance tests performed in the years before or after determination of CBMW revealed mean blood glucose levels in the 36–52 percentile range, compared with normal controls.
The mean (±SD) age at the onset of IDD in discordant twins was 18.7 ± 10.1 (range 8–37) yr and the mean duration of discordance at the time of biopsy was 13.6 ± 8.3 (range 3–32) yr. CBMW data were compared within each twin (Q versus G) and between twin mates and age- and sex-matched controls. Overall, CBMW of IDD twins was greater than that of their ND twin mates. Differences between IDD and ND twins, however, were much more marked in gastrocnemius (1859 ± 643 versus 1222 ± 307 Å, P &lt; 0.0003) than in quadriceps (1291 ±319 versus 1112 ± 302 Å; P &lt; 0.04). CBMW in gastrocnemius was significantly thicker than that in the quadriceps of IDD twins (t = 4.55, P &lt; 0.0008) but not in their ND twin mates (t = 1.15, P &lt; 0.27). CMBW was significantly thicker in IDD than in their ND twin mates (in quadriceps and/or gastrocnemius) in 10 of the 12 twin pairs. Ten of 12 IDD twins (no tissue was available from 1 IDD twin) and 8 of their 13 ND twin mates had evidence of quad-riceps CBMT compared with controls. Repeat biopsies (taken 3–4 yr after the initial biopsy) of quadriceps muscle from five pairs of MZ twins (discordant for IDD) revealed only minor changes in mean CBMW in all but 1 subject.
The muscle CBMW of IDD twins is frequently, but not invariably, “thicker” than that of their ND twin mates. Although some ND twin mates of IDD may have “thick” CBM, this observation does not necessarily imply a greater propensity to development of diabetes.
Further studies are required to elucidate the interactions of genetic and local tissue-environmental factors in modulating the development of diabetic vascular disease.