bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Hyperinsulinemia on Glucose Homeostasis During Moderate Exercise in Man
Authors: Chisholm Donald J , Jenkins Arthur B , James David E , Kraegen Edward W 
Published: September 2013

Moderate exercise in man for 1 h results in a two- to threefold increase in glucose disappearance (Rd) and hepatic glucose production (Ra) so that euglycemia is maintained. The mechanism controlling the increase in Ra is not known, although circulating levels of insulin and glucagon have been suggested as important regulatory factors.
To assess the importance of circulating insulin levels on exercise-induced glucose flux, we have examined the response to 60-min exercise on a bicycle ergometer at 60% maximal oxygen uptake (Vo2 max) in five normal male subjects on two occasions. A constant i.v. infusion of insulin (20 mU/kg/h) or saline was begun 60 min before exercise. Ra and Rd were measured by a non-steady-state constant [3-3H]glucose infusion technique.
During the control (saline) study serum insulin (IRI) fell from 6.4 ± 1.8 (SEM) to 4.4 ± 1.4 mU/L (P &lt; 0.05). During the insulin infusion IRI was maintained at 23.0 ± 0.8 mU/L with a modest drop in plasma glucose before exercise, 5.4 ± 0.2 to 4.0 ± 0.4 mmol/L. Hyperinsulinemia during exercise did not affect peak responses of either Ra (control 1.88 ±0.25 versus 2.00 ± 0.17 mmol/min, NS) or Rd (control 1.89 ± 0.26 versus 1.94 ± 0.18 mmol/min, NS) nor did it result in a significant fall in plasma glucose (control −0.2 ± 0.2 versus −0.2 ± 0.4 mmol/L). Moreover, plasma glucagon (IRG) had not changed significantly after 30-min exercise during insulin infusion when Ra had increased to 195% of the pre-exercise level. Plasma cortisol, norepinephrine, and growth hormone rose during exercise, but the elevation was not significantly greater during insulin infusion than in the control study.
Thus, during moderate hyperinsulinemia in normal man, exercise does not cause a fall in plasma glucose and hepatic glucose output is undiminished. This study demonstrates that a decrease in IRI, elevation of IRG, or a change in IRI/IRG ratio are not important in initiating hepatic glucose output during exercise.
[125I]Diiodoinsulins: Binding Affinities, Biologic Potencies, and Properties of their Decay Products
Authors: Maceda Blanca Pérez , Linde Susanne , Sonne Ole , Gliemann Jørgen 
Published: September 2013

Insulin was iodinated with 0.3–0.4 mol 125I/mol insulin using the lactoperoxidase method. About one-third of the radioactivity incorporated into insulin was in diiodoinsulins and about 40% of these molecules contained diiodotyrosine in residue 14 of the A chain. Most of the remaining molecules contained one A14-monoiodotyrosine and one monoiodotyrosine in either position A19, B16, or B26. The binding affinity and biologic potency of this heterogeneous diiodoinsulin preparation was not significantly different from that of A14-[125I]monoiodoinsulin in rat adipocytes, whereas it was slightly reduced in hepatocytes and IM-9 lymphocytes. From the iodine distribution and previous data on the binding affinity of each of the four monoiodoinsulin isomers it was calculated that A14-diiodotyrosine-insulin possesses full binding affinity and biologic potency in adipocytes.
Diiodoinsulins isolated from another iodoinsulin preparation (iodate method) contained 58% A19-diiodotyrosine-insulin, and most remaining molecules contained one A19-monoiodotyrosine. The binding affinity of this mixed diiodoinsulin preparation was approximately one-fourth of that of A14-monoiodoinsulin in adipocytes, IM-9 lymphocytes, and hepatocytes. It was calculated that A19-diiodotyrosine-insulin is nearly devoid of binding affinity.
The diiodoinsulins (lactoperoxidase method) decayed to iodide (probably from diiodotyrosine-insulin) or to polymers with little specific but a markedly increased nonspecific binding. In addition, the polymers had a marked tendency to adsorb to cellulose acetate filters.
Conclusions: 1. The binding affinities of diiodoinsulins range from very low values to values at least as high as that of insulin depending on the positions of the iodine moieties. 2. The relative binding affinities vary among tissues. 3. Polymeric decay products give high nonspecific binding.
Unanticipated Amyloidosis in Dogs Infused with Insulin
Authors: Albisser A M , McAdam K P W J , Perlman K , Carson S , Bahoric A , Williamson J R 
Published: September 2013

Highly purified regular porcine insulin was given by portable insulin pumps through indwelling vena cavai catheters to 17 (13 normal, and 4 pancreatectomized) dogs initially weighing 15 ± 2 kg at rates ranging from 2 to 10 mU/min (total 17–250 mg) over time periods ranging from 37 to 252 days. During the course of the study, many of the animals lost weight and became anemic. Since these conditions persisted and weight loss progressed even after cessation of insulin infusion, as many of the dogs as possible (15 of 17) were autopsied for microscopic studies. Large amounts of amyloid were demonstrated in the liver, kidney, spleen, and/or pancreas in 55% (6/11) of normal, and in 75% (3/4) of pancreatectomized dogs. The amyloid deposits were Congo red positive, exhibited classical apple green fluorescence under polarized light, and possessed the characteristic ultrastructural features of amyloid. Massive deposits of amyloid were observed in animals receiving as little as 17 mg of insulin over a time span of 52 days. In those animals with hepatic amyloid, marked hepatomegaly was present (i.e., 1200 ± 250, X ± SD, versus 300 ± 25 g for normal animals) and preterminal serum alkaline phosphatase levels were markedly elevated (434 ± 285 versus 30 ± 14 IU/L for animals without hepatic amyloid). The magnitude of the hepatic amyloid deposits precludes the possibility that they represent insulin aggregates or insulin-derived products per se. No evidence of amyloid was present in any of the tissue biopsy specimens obtained prior to insulin infusion.
Moreover, the possibility that this represents an immune response to the injected porcine insulin has to be viewed in light of the fact that the amino acid sequences of dog and porcine insulins are identical. It is of particular interest that the affinity of the amyloid deposits for Congo red stain was totally abolished by prior permanganate treatment, suggesting that the amyloid was derived from serum amyloid A protein rather than from immunoglobulin light chains or insulin aggregates per se. Further evidence that the protein was of the AA-type came from the initial biochemical characterization. Gel filtration on Sephadex G100 in 6 M guanidine hydrochloride identified two small molecular weight peaks of about 13,000 and 25,000 daltons, both of which inhibited the radioimmunoassay for human AA protein.
The consistent finding that the insulin solutions recovered from the pump reservoirs were in an aggregated state suggests that under the conditions of these experiments insulin was physically altered in such a way as to render it amyloidogenic when administered to the dogs. Filters to trap such aggregates were not present. The relative importance of the route of administration, of the physicochemical state of the insulin, and of the status of the recipient's immune system in initiating amyloid deposition remain to be determined.
Diabetes in Pregnancy: Skeletal Malformations in the Offspring of Diabetic Rats After Intermittent Withdrawal of Insulin in Early Gestation
Authors: Eriksson U J , Dahlström E , Hellerström C 
Published: September 2013

Precise timing of the teratogenic period in diabetic pregnancy is of clinical importance since correction of the glucose intolerance during this period may protect the offspring from malformations. An experimental approach to elucidate this problem with regard to skeletal development was made in groups of pregnant streptozotocin-diabetic rats (MDI), which were treated with daily insulin injections except for a 2-day period in the first half of pregnancy. The degree of metabolic derangement was estimated by measurements of serum glucose concentrations. During the insulin-free period, the rats showed severe hyperglycemie (&gt;20 mM) while during ongoing insulin treatment, only brief periods of hyper- or hypoglycemia were observed. Insulin treatment was withdrawn successively between gestational days 3 and 12. Control groups consisted of normal pregnant rats (N) or pregnant rats with manifest diabetes (MD) without insulin treatment. The serum glucose levels of the N animals were below 6 mM while those of the MD animals were above 25 mM throughout pregnancy. Skeletal malformations in the viable offspring were recorded on gestational day 20 after Alizarin staining of calcified ossification centers, which also allowed an estimate of skeletal development as a whole.
Untreated diabetes in the MD rats induced a high rate of fetal resorptions, a decrease in fetal weight and viability, as well as retardation of skeletal development. Intermittent insulin treatment in the MDI rats ameliorated, but did not abolish, these changes. In the MD group 9 of 48 viable fetuses showed severe malformations of either the lower jaw (micrognathia) or of the lumbosacral region (caudal dysgenesis). No skeletal malformations were observed in 151 offspring of the N group. Among the MDI animals, skeletal malformations occurred in 2 of 52 viable fetuses with interruption of maternal insulin treatment on gestational days 2–3, in 7 of 118 fetuses with interruption of insulin on days 4–5, and in 4 of 77 fetuses with interruption on days 6–7. No skeletal malformations were seen in a total of 75 MDI fetuses after interruption of insulin treatment on either days 8–9 or 10–11. However, a high rate of resorptions was also seen in these two groups.
These observations strongly suggest that in rats, the teratogenic impact of maternal diabetes on embryonic skeletal development manifests itself at an unexpectedly early embryonic age and that correction of metabolism with insulin during this critical period may protect the offspring from malformations.
Diabetic Glomerulopathy: Structural Characteristics of the Early and Advanced Stages
Authors: Østerby R , Gundersen H J G , Hørlyck A , Kroustrup J P , Nyberg G , Westberg G 
Published: September 2013

Studies of the glomerular structure in diabetes mellitus have helped to elucidate the basis for some functional abnormalities. The decline in glomerular filtration occurring in many long-term diabetics is a functional disorder of great clinical importance. Quantitative structural studies of the glomeruli in diabetics at different stages of disease are necessary to learn about the development of structural changes leading to the endstage kidney disease.
Preliminary results of a study of glomeruli from longterm diabetics with clinical nephropathy are compared with those obtained in control subjects and in diabetics within the first 5 yr of disease. In the long-term diabetics the peripheral basement membrane thickness was doubled. On the average, mesangial regions occupied nearly 60% of the total tuft volume as compared with 33% in the early stages. A marked accumulation of basement membrane material in the mesangial regions had taken place so that 85% of the total basement membrane material of the tufts (i.e., peripheral basement membrane in the capillary walls plus mesangial basement membrane-like material) was localized within the mesangial regions. In the early stages equal amounts were found at these two different sites.
The distribution of the lesions within the kidney is under investigation in a light microscopic study of autopsy material from long-term diabetics with varying degrees of glomerulopathy. The severity of the diabetic glomerulopathy was quantitated separately within the superficial and the deep cortical zones. The results showed that there was no tendency toward increased severity in the deep glomeruli. It can therefore be concluded that factors related to the structural and functional differences between these two subgroups of glomeruli do not play a dominant role in the development of diabetic glomerulopathy.
Quantitative Evaluation of Fluorescein Angiograms: Microaneurysm Counts
Authors: Baudoin C , Maneschi F , Quentel G , Soubrane G , Hayes T , Jones G , Coscas G , Kohner E M 
Published: September 2013

This study describes a method for quantifying microaneurysms (MA) from fluorescein angiograms. The method was validated by the reproducibility of the number of MA in 30 angiograms read twice each by two independent observers; and by the absolute difference in MA counts between two readings by the same observer, and difference in numbers counted by two different observers. The precise location of each MA on two readings was also studied and the reproducibility of location varied from 60 to 71%, depending on the quality of the angiograms.
Clinicians and technicians working in the same or in different centers obtained similar results. The coefficient of correlation between observers and between readings was satisfactory, r &gt; 0.9.
The method is easy to learn and the reproducibility allows for its use in clinical trials.
Diabetic Nephropathy and Arterial Hypertension: The Effect of Antihypertensive Treatment
Authors: Parving Hans-Henrik , Andersen Allan R , Smidt Ulla M , Christiansen Jens Sandahl , Oxenbøll Birgitte , Svendsen Per Aa 
Published: September 2013

Our longitudinal study of urinary albumin excretion rate in long-term insulin-dependent diabetics without proteinuria (negative albustix) suggests that early detection of patients at high and low risk of developing persistent proteinuria, i.e., diabetic nephropathy, is possible by using a sensitive method for albumin determination.
Our prospective studies in young insulin-dependent diabetics with diabetic nephropathy show that the rate of decline in giomerular filtration rate (GFR) varies considerably, with a mean of 0.75 ml/min/mo and a range from 0.1 to 1.50 ml/min/mo, and that an increase in arterial blood pressure to a hypertensive level is an early feature; 43% of the patients had diastolic blood pressure &gt;100 mm Hg. Early and aggressive antihypertensive treatment reduces both albuminuria and the rate of decline in GFR in young patients with diabetic nephropathy.
Cellular Mechanisms of Insulin Release: Effects of Retinoids on Rat Islet Cell-to-Cell Adhesion, Reaggregation, and Insulin Release
Authors: Chertow Bruce S , Baranetsky Nicholas G , Sivitz William I , Meda Paolo , Webb Michael D , Shih Joyce C 
Published: September 2013

We studied the effects of retinoids on islet cell-to-cell adhesiveness and glucose-induced insulin release from rat islets. For adhesion studies, islets were dispersed using low concentrations of trypsin. Thirteen cis-retinoic acid (13 cis-RA) was added to a suspension of 15 × 105 islet cells and adhesion of cells was quantitated using a hemocytometer. For functional studies, we measured biphasic insulin release from collagenase-isolated perifused islets, dispersed cells, and single large aggregates (clumps) of islet cells.
Thirteen cis-RA (10−4 M) stimulated insulin secretion at 9.7, 12.5, 16.7, and 27.7 mM glucose. Maximal effects of 13 cis-RA (174% of control) were evident during second phase release at 9.7 mM glucose.
Thirteen cis-RA (10−7 and 10−6 M) caused cells to adhere to each other, and at higher concentrations, 13 cis-RA caused dispersed cells to reaggregate into a single clump. These retinoid-induced clumps were perifused in a Bio-Gel P-2 gel column. Secretion from the clump was twofold greater than from an equal number of perifused dispersed cells. Electron microscopic and freeze-fracture examination of the clump showed reaggregated cells to be intact and the presence of gap junctions between cells.
In conclusion, 13 cis-RA has marked effects on islet cell-to-cell adhesiveness. Trypsin-dispersed cells reaggregated by 13 cis-RA have anatomical contacts and secrete more insulin as an aggregate than as dispersed cells. Thirteen cis-RA increases insulin release possibly by increasing adhesion or interactions between β-cellS.
Insulin Gene Expression in the Developing Rat Pancreas
Authors: Kakita Keiji , Giddings Stephen J , Rotwein Peter S , Permutt M Alan 
Published: September 2013

In the developing rat pancreas from about day 15 until birth there is a marked increase in the concentration of insulin. The present experiments were designed to determine whether enhanced insulin biosynthesis is accompanied by a coordinate increment in proinsulin mRNA. Using a sensitive RNA filter hybridization technique and a cloned rat proinsulin 32P-cDNA as a hybridizing probe, the concentration of proinsulin mRNA was measured. A greater than 900-fold accumulation of proinsulin mRNA was found, which closely paralleled that of immunoreactive insulin. Proinsulin mRNA and immunoreactive insulin were highest 1–2 days after birth, more than eightfold higher than that in adult pancreas.
The patterns of digestion by a number of restriction endonucleases of the two nonallelic insulin genes were identical in adult and fetal DNA and in DNA from an insulinoma. We found no evidence of major gene rearrangement during embryogenesis as a prerequisite to insulin gene expression.
Glucose stimulated insulin biosynthesis at the earliest time examined (day 15 of gestation). Insulin biosynthesis was enhanced almost fourfold while proinsulin mRNA differed by less than 20% during a 2-h incubation. This suggested that the short-term effect of glucose on insulin biosynthesis in the developing rat pancreas occurs at the level of translation of existing mRNA, similar to that noted in adult pancreatic islets. These data taken together suggest that the same controls for insulin biosynthesis in the adult exist at these early times in pancreatic development and that the controls for insulin biosynthesis appear coordinately with the appearance of increased insulin during endocrine pancreatic differentiation.
Quantitation of Glycosylated Hemoglobin by Boronate Affinity Chromatography
Authors: Flückiger Rudolf , Woodtli Thomas , Berger Willi 
Published: September 2013

Total hemoglobin glycosylation and the contribution of glycosylation at the N-terminus of the beta-chains and at “non”-beta-N-terminal positions were quantitated by use of boronate affinity and ion exchange chromatography. Glycohemoglobin (y) was found to correlate linearly (y = 1.92x + 0.53; r = 0.96) with HbA1c (x) and to contain approximately 50% beta-N-terminally glycosylated hemoglobin. This result is in agreement with the binding on boronate agarose of the various hemoglobin components resolved by cation exchange chromatography. An amount of glycohemoglobin similar to that of HbA1c was isolatable from HbA. A slope of less than 2 results because HbA1c is retained only to 93% and the intercept of the regression line reflects the partial adherence (65%) of HbA1a+b to the resin.
These results confirm the occurrence of significant “non”-beta-N-terminal glycosylation and show that under optimal chromatographic conditions total glycohemoglobin can be determined with boronate affinity chromatography.
A Polymorphic Locus Near the Human Insulin Gene Is Associated with Insulin-dependent Diabetes Melliitus
Authors: Bell Graeme I , Horita Shiro , Karam John H 
Published: September 2013

A polymorphic region flanking the human insulin gene on the short arm of chromosome 11, the insulin-gene-linked DNA polymorphism, can be described as a locus with at least three classes of alleles: a common small “class 1” allele averaging 570 base pairs, a rare intermediate “class 2” allele of about 1320 base pairs, and a large “class 3” allele averaging 2470 base pairs in size.
We have determined the genotype at this locus of 393 unrelated diabetic and nondiabetic individuals. Differences were observed in the genotypie and allelic frequencies between groups of different races. Asians [17 nondiabetic, 2 with insulin-dependent diabetes mellitus (IDDM), and 8 with non-insulin-dependent diabetes mellitus (NIDDM)] exhibited the least variation in the size of this locus and 98% of the alleles in this group were class 1. A group of American blacks (32 nondiabetic, 5 with IDDM, and 40 with NIDDM) exhibited considerable variation in the size of this locus, and about 22% of the individuals examined had a genotype that included a rare class 2 allele. In neither of these two racial groups were the genotypie or allelic frequencies different between the nondiabetic and diabetic segments of these groups.
However, in a group of Caucasians (83 nondiabetic, 113 with IDDM, and 76 with NIDDM), there was a significantly higher frequency of class 1 alleles and genotypes containing two class 1 alleles in the diabetic patients compared with nondiabetic controls. A strikingly higher frequency of class 1 alleles (P &lt; 0.0001) and genotypes containing two class 1 alleles (P &lt; 0.0001) was observed in the IDDM group compared with nondiabetic Caucasians, whereas the difference between NIDDM and controls was only near the level of statistical significance (P = 0.025). Analysis of the combined data of our Caucasian population and those reported from studies of Caucasians from Denmark and St. Louis, Missouri, continued to show an increased frequency of class 1 alleles and genotypes containing two class 1 alleles in the IDDM group (P = 0.0001) compared with the nondiabetic group; however, there were no longer differences in genotypic or allelic frequencies between NIDDM and nondiabetic groups.
Glucose-dependent Insulinotropic Polypeptide Augmentation of Insulin Physiology or Pharmacology?
Authors: Sarson D L , Wood S M , Kansal P C , Bloom S R 
Published: September 2013

Glucose-dependent insulinotropic polypeptide (GIP) is said to be a major physiologic factor in the augmentation of the insulin response to oral glucose. Whether GIP promotes insulin release at physiologic concentrations of glucose or GIP, however, is questionable. To investigate this further, volunteers were infused with 10, 20, or 40 g intravenous (i.v.) glucose, with or without simultaneous GIP infusion, to produce plasma levels of GIP or glucose similar to those seen after oral glucose. The effect of 40 g i.v. glucose with three times the original dose of GIP was also investigated.
No significant enhancement of glucose-stimulated insulin secretion was seen when GIP was infused with 10 or 20 g i.v. glucose; however, with 40 g a doubling of the insulin response occurred. The higher dose of GIP caused a further increase in insulin response (30-min increment, 972 ±191 pmol/L; compared with glucose alone, 356 ±100 pmol/L, P &lt; 0.01; and compared with low GIP, 602 ± 247 pmol/L, P &lt; 0.02). The glucose increment after the 40-g i.v. dose was + 9.2 mmol/L.
The concentration of GIP and glucose required to produce significant potentiation of the insulin response appears to be in the pharmacologie, rather than physiologic, range.
Localization of Aldose Reductase in the Human Eye
Authors: Akagi Y , Yajima Y , Kador P F , Kuwabara T , Kinoshita J H 
Published: September 2013

The presence of the enzyme aldose reductase is increasingly being linked to diabetic complications. The distribution of this enzyme in human cornea, lens, retina, and optic nerve has been studied using specific antibodies against purified human placental aldose reductase raised in both rabbit and goat. The antisera from both animals gave equal, specific reactions.
In frozen sections of ocular tissues, significant aldose reductase localization was reproducibly demonstrated in the endothelium and epithelium of the cornea and in the basal cell layers of the conjunctiva. In the lens, staining was observed in the epithelium and superficial lens fibers. In retinal sections, the presence of aldose reductase was demonstrated in the Mueller's cells, especially near the inner limiting membrane. It was also found in some ganglion and cone cells. In the optic nerve, positive staining was observed in the axon. All other cells of the tissues examined revealed Only weak, nonspecific Staining.