bluuebunny/crossref_metadata_2025_split huggingface dataset:
Perfect Normalization of Excessive Glucagon Responses to Intravenous Arginine in Human Diabetes Mellitus With the Artificial Beta-Cell
Authors: Kawamori Ryuzo , Shichiri Motoaki , Kikuchi Mikio , Yamasaki Yoshimitsu , Abe Hiroshi 
Published: September 2013

To elucidate the precise significance of pancreatic A-cell hypersécrétion in the pathogenesis of diabetes mellitus, the change in the immunoreactive glucagon (IRG) response to intravenous arginine was studied in both nonobese, hypoinsulinemic non-insulin-dependent (NIDDM) and insulin-dependent diabetic (IDDM) subjects whose blood glucose responses and plasma immunoreactive insulin (IRI) simulated those of healthy subjects with the aid of the artificial beta-cell system that we originally developed.
In both five NIDDM and five IDDM subjects, blood glucose responses and plasma IRI after arginine challenges were made equivalent to those seen in healthy subjects by infusing insulin in response to blood glucose, revealing that previously exaggerated IRG responses were made completely similar to the responses in healthy subjects.
In summary, these results clearly demonstrate that the exaggerated response of A-cell secretion against arginine challenges in insulin-deficient diabetics is secondary to insulin lack, and the perfect normalization of its response is achieved only when both plasma insulin concentration and glycemie control simulate those of healthy subjects.
Tyrosine A14 [125I]monoiodoinsulin: Preparation, Biologic Properties, and Long-term Stability
Authors: Linde Susanne , Hansen Bruno , Sonne Ole , Holst Jens J , Gliemann Jørgen 
Published: September 2013

125I-insulin was prepared by reacting 17.4 nmol porcine insulin (100 μg) with 5 mCi 125I (about 2.4 hmol) using the lactoperoxidase method. The reaction product was subjected to gel electrophoresis and the band containing A14 [125I]monoiodoinsulin was eluted. This preparation showed a specific activity of about 1.5 Ci/μmol as evaluated by radioimmunoassay and bioassay, i.e., about 75% of the theoretical maximum. The content of radioactive derivatives other than A14 monoiodoinsulin was less than 2%.
The binding affinity of tracer A14 monoiodoinsulin to adipocytes, hepatocytes, and cultured human lymphocytes was about twice as high as that of A19 monoiodoinsulin. Binding to antibodies was examined in 10 guinea pig anti-insulin sera. Three sera did not distinguish between the two tracers, whereas seven exhibited higher binding of the A14 tracer. A detailed analysis of one of the discriminating sera showed that the average affinity constant was about 2.5 times lower for the A19 tracer than for the A14 tracer.
The A14 monoiodoinsulin tracer is remarkably stable. After 200 days the specific activity had declined to about half of its original value which is consistent with the hypothesis that the physical decay of [125I]monoiodoinsulin (T12 = 60 days) extinguishes the activity of the molecule without causing major damage of other molecules. By this time 96% of the radioactivity migrated with insulin when subjected to gel filtration on Sephadex G-50, 4% was in the void volume, and nothing in the total column volume or later. Binding to receptors was indistinguishable from that obtained at time zero.
It is concluded that Tyr A14 [125I]monoiodoinsulin represents an advance in biologic work as compared with previous tracers for insulin.
A Familial Form of Obesity Without Hyperinsulinism at the Outset
Authors: Maruhama Yoshisuke , Abe Ryuzo 
Published: September 2013

A total of 32 pairs of obese fathers or mothers and their obese offsprings, aged 20 yr or younger, from 25 families with established hyperinsulinemic obesity was studied. Although the obese pairs with offsprings aged 11-20 y r equally showed an insulin hyperresponse to glucose, the offsprings 10 yr or younger revealed a rather normal insulin response, despite the presence of obesity, and this contrasted with their fathers or mothers. No difference was found in the estimated age of onset between the two groups of offspring. The offsprings in both age groups ate a similar high carbohydrate, high calorie diet.
The results suggest that the insulin hypersecretion is not the primary trait in this form of familial obesity and that the insulin response to glucose becomes augmented during the maturation years of 11-20, thus resulting in the accumulation of hyperinsulinemic and hyperlipidemic adults in the family.
Lymphocytotoxic Antibodies and Histocompatibility Antigens in Juvenile-onset Diabetes Mellitus
Authors: Serjeantson S , Theophilus J , Zimmet P , Court J , Crossley J R , Elliott R B 
Published: September 2013

Cold-reacting serum lymphocytotoxic antibodies (LCAs) were measured in sera from 230 insulin-dependent juvenile-onset diabetes mellitus (IDDM) patients and from 116 control subjects. LCAs were present in only 4% of control sera compared with 19% in IDDM patients. The most significant determinant of LCAs was time since onset of diabetes; within the first 12 mo, 55% of IDDM sera had LCAs, compared with 25% after one year and 15% after five years of diabetes. LCAs were absent in sera from patients with IDDM for 10 yr or more.
Genetic factors were also implicated in susceptibility to occurrence of LCAs. HLA antigen B8 and B18 were associated with an increased risk for LCAs, whereas HLA-B7 was associated with a decreased risk. The relative risk for LCAs in patients positive for HLA-B8 but not B7 was 2.3, compared with 0.0 in HLA-B7/B8 heterozygotes. In contrast, B7 did not provide protection from LCAs in B18/B7 IDDM patients.
Properdin factor B (Bf) alleles, which are in linkage disequilibrium with alleles of the HLA-B locus, were also associated with LCAs. IDDM patients with alleles BfS1 or BfF had a prevalence of LCAs of 7%, significantly less than the 39% in Bf-F1S or -F1 patients.
LCAs were not identical or closely correlated to pancreatic islet cell antibodies. Our findings indicate genetic heterogeneity in, yet, another autoimmune process in IDDM.
Islet Cells Grow after Transplantation of Fetal Pancreas and Control of Diabetes
Authors: Brown Josiah , Heininger Diane , Kuret Jeffrey , Mullen Yoko 
Published: September 2013

The capacity of a fetal rat pancreas to grow and function was assessed after its transplantation into adult diabetic rats. One month after induction of diabetes by streptozotocin (SZ) (72.5 mg/kg) in adult Lewis rats, one syngeneic 17-17½ day fetal pancreas was transplanted under the kidney capsule. Insulin, initially 3 U/day and decreasing to 0.5 U every other day, was given for 27.5 ± 1.7 (× ± SEM) days (total dose, 48 ± 4 U) until the diabetes reversed (45 ± 3 days). Plasma glucose, 481 ± 10 mg/dl after SZ, fell after transplantation and cessation of insulin injections during a 4-mo period to 129 ± 2 mg/dl. Urine volume fell from 82 ± 4 ml per day to normal (12 ± 2), and glucose excretion, which was 7.7 ± 0.4 g per day after SZ, completely disappeared from the urine. The disappearance rate of glucose injected into the circulation, which was 0.50 ± 0.07% per minute in untreated diabetes, reverted to normal, 2.78 ± 0.18% per minute, not different from that in the normal control, 2.55 ± 0.13% per minute. Plasma insulin in control diabetic rats was totally unresponsive to glucose injection, despite a rise in plasma glucose concentration from 471 ± 5 mg/dl to 621 ±18 mg/dl. In transplanted rats, plasma insulin was moderately higher than normal before and at most time points after glucose injection. After removal of the transplanted pancreases, plasma glucose, urine volume, and glucose excretion returned to pretransplant levels and ketones appeared in the urine of all rats. Analysis of the insulin content of the pancreases removed 77 to 279 days after transplantation gave a value of 818 ± 43 mil, which is 22% of the insulin content of normal rats.
To achieve optimal growth and function of a transplanted fetal pancreas, careful control of the blood glucose is necessary during the period of growth and development.
The Effect of Prostacyclin and 6-Keto-Prostaglandin F1α on Insulin Secretion and Cyclic Adenosine 3′, 5′-Monophosphate Content in Isolated Rat Islets
Authors: Heaney Thomas P , Larkins Richard G 
Published: September 2013

The effects of prostacyclin (PGI2) and its degradation product 6-keto-prostaglandin F1α (6-keto-PGF1α) on insulin secretion and cyclic adenosine 3′, 5′-monophosphate (cAMP) production were investigated in isolated rat islets. At a glucose concentration of 5.6 mM, addition of both PGI2 and 6-keto-PGF1α in a concentration range of 10−8–10−4 M significantly stimulated insulin secretion. The effects were concentration dependent, being maximal at an initial PGI2 concentration of 10−6M (2.7-fold increase, P &lt; 0.001) and an initial 6-keto PGF1α concentration of 10−7 M (2.1-fold increase, P &lt; 0.005). Lesser stimulation was observed at higher concentrations of both agents. In contrast to their relative effects on insulin secretion, PGI2 was approximately 100-fold more potent at increasing islet cAMP content.and higher concentrations were progressively more effective in raising islet cAMP content.
The effect of PGI2 on insulin secretion was dependent on the medium glucose concentration. At an initial PGI2 concentration of 40 μM, significant stimulation of insulin secretion was seen at glucose concentrations of 3.3 and 5.6 mM, but no effect was seen either in the absence of glucose, or at high glucose concentrations (10 and 16.7 mM). In contrast to the glucose dependency of the effect of PGI2 on insulin secretion, it caused a comparable increase in islet cAMP content at all glucose concentrations tested.
In the presence of 0.5 mM 3-isobutyl-1-methylxanthine (IBMX), PGI2 inhibited insulin secretion at glucose concentrations of 5.6–16.7 mM. However, in this situation PGI2 caused a further increase in islet cAMP above that found with IBMX alone. It is concluded that both PGI2 and 6-keto-PGF1α affect insulin secretion in vitro, although the effects of PGI2 may depend on its conversion to 6-keto-PGF1α. The effects of PGI2 can be either stimulatory or inhibitory, depending on the concentrations of glucose and IBMX in the medium, and cannot be explained solely by its effect on islet cyclic AMP content.
Production of 6-Oxo-Prostaglandin F1α by Rat Aorta: Influence of Diabetes, Insulin Treatment, and Caloric Deprivation
Authors: Rogers Susan P , Larkins Richard G 
Published: September 2013

The production of 6-oxo-prostaglandin F1α (6-oxo-PGF1α), a stable metabolite of prostacyclin (PGI2), was examined in three separate series of experiments in aortae from rats with diabetes induced by streptozotocin (SZ) and aortae from nondiabetic control rats.
In the first series, it was shown that production of 6-oxo-PGF1α by aortae from rats with diabetes of 4–6-wk duration was significantly decreased compared with nondiabetic rats (0.77 ± 0.07 ng/mg wet weight aorta vs. 1.23 ± 0.11 ng/mg wet weight aorta, P &lt; 0.001). Diabetic rats were treated with two doses of insulin, a lower dose of 8 U/kg/day that only partially corrected their plasma glucose and body weight compared with nondiabetic rats, and a higher dose of 25 U/kg/day that completely corrected their plasma glucose and body weight. Both insulin regimens completely reversed the defect in 6-oxo-PGF1α production.
In the second series, the time course of development of the defect in 6-oxo-PGF1α production was examined. It was found that two weeks after induction of diabetes, the aortic production of 6-oxo-PGF1α did not differ between control and diabetic rats. However, 4 and 7 wk after induction of diabetes, 6-oxo-PGF1α production was significantly reduced, even though the degree of hyperglycemia and hypoinsulinemia was the same as at 2 wk.
In the third series, the effect on aortic 6-oxo-PGF1α production of weight loss caused by restricted dietary intake was compared with the effect of a comparable weight loss caused by experimental diabetes. Again, the diabetic rats had significantly reduced 6-oxo-PGF1α production compared with control rats, but 6-oxo-PGF1α production in nondiabetic rats which had lost weight as a result of limited feeding was the same as nondiabetic control rats fed ad libitum.
It is concluded (1) that insulin treatment, even if insufficient to achieve perfect control of plasma glucose, can restore 6-oxo-PGF1α production to normal, (2) diabetes of greater than 2-wk duration is required to produce the abnormality, and (3) the reduced 6-oxo-PGF1α production is not a nonspecific consequence of weight loss.
The Influence of Genetic Background on the Expression of Mutations at the Diabetes Locus in the Mouse: IV. Male Lethal Syndrome in CBA/Lt Mice
Authors: Leiter Edward H 
Published: September 2013

To assess whether db-induced pathogenetic changes in beta-cells were restricted to mice with H-2d haplotype, the db gene from BL/Ks was transferred into the CBA/Lt subline (H-2k). A marked sexual dimorphism was observed in the diabetes syndrome in db/db animals. Young adult db/db males exhibited an early onset and completely lethal diabetes (100% mortality by 6 mo). At 3 mo db/db males were moderately obese (43 ± 4 g) but severely hyperglycemic (475 ±69 mg/dl blood glucose) and hyperglucagonemic. Islets were atrophic, showing variable leukocytic infiltration. Although hyperinsulinemic at 2 mo, mutant males had only normal or below normal plasma insulin at 4 mo. Electron microscopic examination confirmed beta-cell necrosis and the appearance, in prenecrotic betacells, of numerous intracisternal type A (retrovirus) particles (IAP). In contrast, db/db females became increasingly obese with age but remained healthy, suffering no mortality at 6 mo. These mice were only transiently hyperglycemic and were able to sustain hyperinsulinemia. Light and electron microscopy revealed beta-cell hypertrophy that was not accompanied by increased numbers of IAP or by necrosis. Retrovirus induction therefore seemed a consequence rather than a cause of hyperglycemia.
Ovariectomy coupled with testosterone injection failed to induce severe diabetes in females; castration failed to moderate male diabetes. Instead, biweekly injections of 25 μg each of 17β-estradiol and progesterone effected complete diabetes remission in males. Experiments using cultured CBA/J islet cells did not support the hypothesis that ovarian steroids were directly protective at the beta-cell level. This study shows that db gene-induced pathogenesis is not restricted to mice with the H-2d haplotype, and that sex steroids are important modifiers of syndrome severity.
Prostacyclin Production by Isolated Adipocytes
Authors: Axelrod Lloyd , Levine Lawrence 
Published: September 2013

Isolated rat adipocytes produce prostacyclin (PGI2) in relatively large quantities during norepinephrine (NE)-induced lipolysis. The endogenous NE-induced production rate of PGI2, calculated from the NE-induced production rate of PGI2 observed in our studies (2.2 ng/106 cells/2 h) and from the number of fat cells in the normal organism, is 1.46 ng/kg/min for rats, 4.46 ng/kg/min for men, and 11.86 ng/kg/min for women. These rates are comparable to the exogenous PGI2 infusion rate that alters platelet aggregation and blood pressure in rats and humans. Exogenous PGI2 failed to modify the rate of NE-induced lipolysis. Inhibition of endogenous PGI2 production by indomethacin had no effect on the rate of NE-induced lipolysis when either a maximal or submaximal lipolytic concentration of NE was used.
PGI2 [rather than prostaglandin (PG) E2] may be the substance that accounts for the functional vasodilatation that accompanies hormone-induced lipolysis. PGI2 is produced in larger quantities than PGE2 during NE-induced lipolysis and is a more potent vasodilator than PGE2. Its instability can account for the inability of previous investigators to detect a vasodilator substance in the venous effluent of adipose tissue.
The production of PGI2 by adipocytes may be an important modulator of the regulation of vascular tone and platelet aggregation by catecholamines in the vascular bed of adipose tissue and perhaps other tissues. PGI2 produced by adipocytes, by virtue of its ability to cause vasodilatation and inhibit platelet aggregation, may contribute to the maintenance of luminal patency in the vascular bed of adipose tissue and possibly other tissues as well.
Cholesterol Metabolism in Diabetes Mellitus: The Role of Diet
Authors: Saudek Christopher D , Young Nancy L 
Published: September 2013

There is extensive evidence that cholesterol metabolism is abnormal in diabetes. Total plasma cholesterol is elevated, and more subtle indices of sterol homeostasis are also deranged.
Insulinization of the poorly controlled diabetic reduces fecal bile acid excretion. Fecal neutral sterol excretion increases compensatorily, at least when caloric intake is maintained during insulinization. Thus, net sterol balance is not changed by insulin treatment, again assuming the diet remains constant. Other workers have found decreased sterol synthesis after insulinization if calories are reduced. Using isotopically labeled squalene turnover as a reflection of cholesterol synthesis, insulin treatment increases the flux of squalene.
Pursuing diabetes' effect on cholesterol synthesis at a more basic level, we found that HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, is increased in small intestine, and decreased in liver by diabetes in rats eating ad libitum.
These changes in reductase activity are due to hyperphagia (increased caloric and/or cholesterol intake), not to insulin deficiency alone, since diabetic rats restricted to a normal food intake have normal reductase activity in liver and small intestine. It appears that increased input of dietary and newly synthesized cholesterol by the small intestine raises plasma cholesterol level and represses reductase activity in liver of chronically diabetic rats.
Experiments measuring the incorporation of tritiated water into cholesterol find that diabetes has a net suppressive effect on cholesterol synthesis, consistent with insulin's increasing squalene turnover, and consistent with the suppressed liver synthesis being quantitatively more significant than increased intestinal synthesis. When dietary cholesterol intake is included in the calculation, however, hyperphagia may tip the balance in favor of increased net cholesterol input (synthesis plus diet).
We hypothesize that diet plays a central role in the diabetic's cholesterol homeostasis. The hyperphagia of experimental diabetes increases net cholesterol intake and increased HMG-CoA reductase in a hypertrophic small intestine.
Long-term Study of Mortality and Vascular Complications in Juvenile-onset (Type I) Diabetes
Authors: Lestradet H , Papoz L , Hellouin De Menibus CL , Levavasseur F , Besse J , Billaud L , Battistelli F , Tric PH , Lestradet F 
Published: September 2013

A cohort of 372 insulin-dependent diabetic children, diagnosed between October 1949 and December 1960, were followed-up until December 1976 by the same team of physicians. At the time of diagnosis all patients were under 16 yr of age and were given standardized treatment which did not change from 1949 to 1976. The therapy consisted of daily insulin adjustment based on clinical assessment, the degree of physical activity, and the results of semi-quantitative urine tests for sugar and ketone bodies. These tests were systematically performed before breakfast, lunch, and dinner. Diet was normal, unmeasured, rich in carbohydrates (approximately 60%), and quantitatively unrestricted unless the patient was overweight. Rates for mortality and for the principal complications among this cohort were computed by the actuarial method. During the 26 yr of study, 26 deaths occurred, 16 of which were directly connected with diabetes.
After 16 yr of follow-up, rates of proteinuria and hypertension were 4% and 2.1% respectively. The incidence of retinopathy reached 27%, including 1.5% proliferative retinopathy. After 26 yr, the rates rose to 14% for proteinuria, 16% for hypertension, and 85% for retinopathy, including 18% in the proliferative phase.
Effects of Experimental Diabetes and Insulin on Cyclic AMP Phosphodiesterase and its Protein Activator in Rat Adipose Tissue
Authors: Solomon Solomon S , Palazzolo Marjorie , McPherson Janet , Smoake Al 
Published: September 2013

Streptozotocin-induced diabetes in the rat has been shown to decrease and insulin to increase the activity of cyclic AMP phosphodiesterase (PDE) in adipose tissue. Protein activator (PA), a substance of low molecular weight, is essential for full activity of some component phosphodiesterases. A significant decrease in protein activator level (60% of control) is found in the 13,000 × g boiled supernatant from streptozotocin-diabetic rat adipose tissue. When diabetic animals are treated with insulin 24 h following the induction of diabetes, protein activator is restored to 80% of the normal control level; when diabetic animals are immediately treated with insulin, the levels of protein activator are not reduced (98% of control). Hence, insulin is capable of reversing both the decrease in protein activator and phosphodiesterase activity seen with diabetes. When partially purified supernatant from diabetic animal fat is chromatographed on a DEAE Sephacel column, the untreated diabetics show inhibition, whereas insulin-treated diabetics show maximal stimulation of the low Km cyclic AMP phosphodiesterase. Protein activator and an inhibitor are readily separated when adipose tissue homogenate is centrifuged at 13,000 × g and the boiled supernatant is passed over a DEAE Sephacel column.
Diabetes is associated with a decrease in both cyclic AMP phosphodiesterase and protein activator activity, both of which are restored to normal by administration of insulin. We also report the presence of an inhibitor of activator, which is increased in streptozotocin diabetes. All of these components appear to play a role in the pathophysiology of diabetes.