bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Spontaneously Diabetic Wistar Rat: Metabolic and Morphologic Studies
Authors: Nakhooda A F , Like A A , Chappel C I , Murray F T , Marliss E B 
Published: September 2013

A new, spontaneously diabetic syndrome has been recognized in nonobese outbred Wistar rats of both sexes. The age at detection of first glycosuria has varied from 48 to 120 days, with a mean of 67 days. Eighteen rats have been studied, 14 untreated and four during and after cessation of insulin treatment. The affected animals have demonstrated a spectrum of severity, with hyperglycemia (252–732 mg./dl.), hypoinsulinemia (0–1 ng./ml.), and hyperketonemia. The severely ketotic rats, with total blood ketone body levels between 6 and 13 mM, showed rapid loss in weight and dehydration over one to six days. The moderately ketotic (1–5 mM) declined gradually in weight over 15 days, with marked polyuria and glycosuria. The stable rats, with ketonemia less than 1 mM, sustained their weights, polyuria, and glycosuria for longer than 40 days.
A relative or absolute increase in plasma immunoreactive glucagon and elevated levels of free fatty acids and branched-chain amino acids were observed in relation to the severity of the syndrome. Intraperitoneal arginine or tolbutamide elicited no insulin response, but the glucagon response to arginine was exaggerated. Pancreatic insulin content was markedly diminished and glucagon content was normal or moderately decreased. Light-microscopic examination of pancreases of ketotic animals at the end stage of the disease showed islets to be very small and rare, consisting virtually of non-β cells. In stable and earlier ketotic rats, the islets were small, with reduction in β-cell number and a striking inflammatory cell infiltration. Surviving β cells showed variable degranulation. This model of spontaneous diabetes in nonobese rats displays insulin deficiency, glucagon excess, and ketosis, with a dramatic inflammatory lesion during active β-cell destruction.
The Cyclic AMP Response to Glucagon: Comparison of Tissue and Plasma Cyclic AMP Levels in the Rabbit
Authors: Jerums G , Hardy K J , Eisman J A 
Published: September 2013

The effects of glucagon on tissue and plasma cyclic AMP levels have been investigated in rabbits anesthetized with urethane. Glucagon (2 nmole/kg.) caused at least a twofold increase in hepatic cyclic AMP, which reached a peak within two minutes and declined to basal values after 40 minutes. Plasma cyclic AMP also increased at least twofold, reaching a peak at 10 minutes and declining to basal values after 60 minutes. Glucagon (20 nmole/kg.) stimulated hepatic and plasma cyclic AMP in a manner indistinguishable from that observed at the lower dose. Hepatectomy abolished the plasma cyclic AMP responses to glucagon, and no significant stimulation of cyclic AMP concentration was noted in the heart, adipose tissue, small bowel, or kidney.
Cyclic AMP hydrolysis was estimated in blood taken before and after administration of glucagon. Glucagon (2 nmole/kg.) increased cyclic AMP hydrolysis slightly, but this was explained by the raised cyclic AMP levels. By contrast, cyclic AMP hydrolysis increased two-to-threefold in blood taken 20 and 40 minutes after glucagon (20 nmole/kg.). The higher dose of glucagon also stimulated cyclic AMP hydrolysis in crude liver homogenate, which could not be explained by increases in cyclic AMP concentration. The increase in cyclic AMP hydrolysis observed in blood and liver may partly explain the failure to show additional stimulation of hepatic and plasma cyclic AMP levels with the higher dose of glucagon.
Despite the changes in cyclic AMP hydrolysis, a highly significant correlation was observed in individual rabbits between the hepatic and plasma cyclic AMP responses to glucagon (2 and 20 nmole/kg.), when these were calculated as incremental areas above mean basal levels. It is suggested that measurement of plasma cyclic AMP levels after stimulation by glucagon may be an accurate index of the hepatic cyclic AMP response to glucagon in vivo.
Transient Stimulatory Effect of Sustained Hyperglucagonemia on Splanchnic Glucose Production in Normal and Diabetic Man
Authors: Bomboy J D , Lewis S B , Lacy W W , Sinclair-Smith B C , Liljenquist J E 
Published: September 2013

Insulin can modulate glucagon-stimulated hepatic glucose production and is considered to be the major factor acting in vivo to exert a counterregulatory action to glucagon. The insulindependent diabetic, therefore, might be especially vulnerable to enhanced hepatic glucose production promoted by glucagon. To investigate this hypothesis, low-dose glucagon infusions were administered to normal and diabetic men to compare the effects of glucagon on net splanchnic glucose production (NSGP). Four normal and three insulin-dependent, ketosis-prone, hyperglycemic diabetic men (insulin withheld for 24 hours) underwent brachialartery-hepatic-vein catheterization. Each received a 90-minute glucagon infusion at 5 ng./kg./min. Glucagon levels rose four-tofivefold in both groups, plateauing at 300–600 pg./ml. In the normals, NSGP rose from 92 ± 12 to 211 ± 31 mg./min. at 15 minutes and returned to basal levels by 45 minutes. Insulin measured in the hepatic vein rose from 19 ± 6 to 33 ± 11 /μU./ml., while plasma glucose rose 17 mg./dl. In the insulin-dependent diabetics, NSGP rose from 78 ± 24 to a peak of 221 ± 33 mg./min. at 30 minutes and then fell sharply to 113 ± 15 mg./min. at 60 minutes despite continuing hyperglucagonemia. Plasma glucose in the diabetics rose 21 mg./dl.
These data suggest a mechanism that acts to rapidly diminish glucagon-induced hepatic glucose production in diabetic man but does not appear to be mediated by increased insulin secretion.
Accumulation of Myocardial Triglycerides in Ketotic Diabetes: Evidence for Increased Biosynthesis
Authors: Murthy Veeraraghavan K , Shipp Joseph C 
Published: September 2013

The accumulation of triglycerides in the myocardium of nonketotic and overtly ketotic diabetic rats was studied. There was no increase in heart triglycerides of nonketotic rats taken off insulin treatment, although the rats exhibited several indices of diabetes. In nonketotic diabetic rats untreated with insulin, myocardial triglycerides repeatedly increased and declined to control levels.
In severely ketotic rats, heart triglycerides increased about threefold and did not decline with time. In order to understand the mechanism of increase in myocardial triglycerides in ketotic diabetes, the biosynthesis of triglycerides was studied with heart homogenates. The total esterification of sn-glycero-3-phosphate was unaltered, but the synthesis of diglycerides and triglycerides was increased in the myocardium of the ketotic rat. On treatment of the diabetic rats with insulin, the synthesis of di- and triglycerides in heart homogenates reverted to control values. Thus the results of the present study demonstrate that (1) a persistent increase in myocardial triglyceride content was observed only in the ketotic diabetic rat and (2) increased synthesis of triglycerides is a factor in its accumulation in the myocardium of the ketotic rat.
Studies on the Mechanism Underlying the Influence of Alanine Infusion on Glucose Dynamics in the Dog
Authors: Saccà L , Trimarco B , Perez G , Rengo F 
Published: September 2013

These experiments have been designed to study the influence of alanine infusion on glucose dynamics in the dog and to further elucidate the role of pancreatic hormones in the interaction of alanine with glucose homeostasis. The primed constant infusion of glucose-2-t was used in order to quanti ta te the rates of glucose production by the liver (Ra) and glucose utilization (Rd). In a first group of experiments, the intravenous infusion of alanine at the rate of 2 mg./kg./min. produced a moderate enhancement of plasma insulin (IRI), while pancreatic glucagon (IRG) increased more consistently. This different pattern of IRI and IRG response caused the insulin/glucagon molar ratio to decline progressively throughout the experiment. Both rates of glucose turnover increased significantly during alanine infusion. Since Ra rose more rapidly than Rd did initially, hyperglycemia developed. Later, glucose production slowly decreased and, in spite of the sustained hyperglucagonemia, reached levels very close to the baseline in the second part of the experiment. A significant direct correlation between Ra and IRG was found, while the changes in Ra correlated inversely with those in I/G molar ratio.
In a second group of experiments, alanine was infused at the same dose together with 0.4 /mg./kg./min. of cyclic somatostatin. In the First part of the infusion, IRG fell more than IRI did, so that I/G ratio increased. Later, IRI levels maintained at low values while IRG returned slowly to the baseline and consequently I/G ratio significantly decreased. Glucose production fell rapidly soon after the beginning of the infusion, and therefore hypoglycemia developed. Later, Ra increased progressively to levels above baseline and plasma glucose returned to the preinfusion levels. As in the first group of experiments, a significant direct correlation between Ra and IRG and an inverse correlation between the changes in Ra and I/G ratio were observed.
These experiments demonstrate that alanine infusion produces an acceleration of glucose turnover and that a clear interrelationship between the release of glucose by the liver and the mobilization of pancreatic hormones exists. Finally, the experiments with somatostatin indicate that hyperglucagonemia is one of the mechanisms underlying the stimulatory effect of alanine on glucose production.
Abnormalities in Proliferation and Protein Synthesis in Skin Fibroblast Cultures from Patients with Diabetes Mellitus
Authors: Rowe David W , Starman Barbra J , Fujimoto Wilfred Y , Williams Robert H 
Published: September 2013

Several aspects of in-vitro cell growth and protein synthesis were assessed in cultures of skinfibroblasts from subjects with juvenile-onset diabetes mellitus (JODM) or adult-onset diabetes mellitus (AODM) and from age-matched nondiabetic controls (C). Ibere was an inverse correlation between increasing age and both the log-phase doubling rate and saturation density at confluence in C fibroblasts. JODM and AODM cells had a reduction in both indices of cell population growth in comparison with age-matched c fibroblasts. Fibroblasts grown in the presence of 0.3 μM hydrocortisone were stimulated to grow more rapidly and to a greater saturation density. Stimulation of cell division by hydrocortisone accentuated the abnormalities in growth of JODM and AODM fibroblasts.
Total protein and collagen synthesis was measured when the fibroblasts had grown to confluency in medium with or without hydrocortisone. Hydrocortisone did not produce a significant change in total protein and collagen synthesis per cell by C fibroblasts. Fibroblasts from AODM had a 180 per cent increase in total protein and collagen synthesis in the presence of hydrocortisone. In contrast, total protein and collagen synthesis decreased 40 per cent in fibroblasts from JODM when grown in the hydrocortisone medium. These studies indicate that skin fibroblast cultures from patients with diabetes exhibit abnormalities in cell proliferation. Furthermore, hydrocortisone appears to unmask differences in protein synthesis that distinguish JODM and AODM fibroblasts in culture.
Glucose-induced Proinsulin Biosynthesis Role of Islet Cyclic AMP
Authors: Maldonato Aldo , Renold Albert E , Sharp Geoffrey W G , Cerasi Erol 
Published: September 2013

The effects of glucose on cAMP accumulation, insulin (IRI) release, and proinsulin synthesis were simultaneously measured in isolated rat islets. Proinsulin synthesis was assayed by measuring the incorporation of [3H] leudne into islet proteins reacting with Sepharose-bound anti-insulin gamma globulin. The accumulation of cAMP in islets and incubation medium was measured by the incorporation of [3H]-adenine into [3H] CAMP and purified by ion-exchange chromatography and barium sulfate precipitation. Glucose dose-response studies were performed in the absence and presence of 0.1 and 1.0 mM isobutylmethylxanthine (IBMX).
The IRI and cAMP responses to glucose demonstrated similar stimulation thresholds and Km values at all IBMX concentrations. With increasing amounts of IBMX, the Vmax was increased and the Km decreased for both responses. There was parallelism between IRI secretion and accumulation of [3H] CAMP in the medium, except at nonstimulatory glucose concentrations, where, especially in the presence of 1.0 mM IBMX, a marked stimulation of cAMP accumulation was accompanied by only modest IRI release.
Proinsulin biosynthesis showed a much greater sensitivity to glucose than the cAMP and IRI responses. The threshold for stimulation by glucose was around 1.4 mM, and the response already saturated at 7.0 mM. Except when 1.0 mM IBMX was present, no IRI or cAMP responses were registered in this glucose dose range. These findings indicate that IRI release and proinsulin synthesis have distinct glucose recognition mechanisms and that ghicoseinduced cAMP stimulation does not mediate the effect of the hexose on hormone synthesis in the islet cell.
When islet cAMP was elevated with IBMX, a decrease in the Km of the proinsulin response to glucose was observed, while the Vmax of the reaction was only slightly modified. This suggests that the level of cAMP in the islet may modulate the sensitivity of the B-cell for the effect of glucose on insulin biosynthesis and thus provide a mechanism for the regulation of insulin biosynthesis by such factors as gut hormones and glucagon under in-vivo conditions.
Acute Renal Failure Following Intravenous Use of Radiographic Contrast Dyes in Patients with Diabetes Mellitus
Authors: Kamdar Anjana , Weidmann Peter , Makoff Dwight L , Massry Shaul G 
Published: September 2013

Acute renal failure following roentgenologic procedures employing intravenous administration of contrast media was observed in seven diabetic patients over an 18-month period. All had longstanding diabetes mellitus complicated by retinopathy and cardiovascular disease; six had mild impairment in renal function before x-ray studies. The renal failure occurred within 48 hours of the procedure and was of the oliguric type in six of the patients. Renal function returned toward the prestudy levels within four weeks.
None of the patients required dialysis. Combined analysis of our data and those of 31 cases reported in the literature suggest that certain factors in diabetic patients make them prone to develop dye-induced acute renal failure: These include old age; long duration of diabetes; preëxisting impaired renal function; the presence of diabetic complications such as retinopathy, neuropathy, and cardiovascular disease; and dehydration. All diabetic patients should be monitored closely after a radio-contrast study to detect the development of acute renal failure so that appropriate management can be instituted early in the course of the disease.
Carbohydrate and Lipid Oxidation in Normal and Diabetic Subjects
Authors: Felber J P , Magnenat G , Castheélaz M , Geser C A , Müller-Hess R , Kalbermatten N de , Ebiner J R , Curchod B , Pittet Ph , Jéquier E 
Published: September 2013

Carbohydrate and lipid oxidation was measured in normal and diabetic human beings by means of continuous indirect calori metry in the course of a 100-gm. oral glucose tolerance test.
After the glucose load, the carbohydrate (CHO) oxidation rate of 10 control subjects gradually rose, from 30 to 180 minutes, during the decline of plasma glucose and immunoreactive insulin (IRI). The lipid oxidation rate decreased during the same period.
Diabetics were divided into two groups. In a group of six nonobese maturity-onset diabetics with a slight IRI response to glucose load and a fall in plasma free fatty acid (FFA) levels, the CHO oxidation rate was found to be of the same order of magnitude as in normal subjects, but this occurred at a high plasma concentration of glucose. The lipid oxidation rate decreased as in normal subjects.
Conversely, in a group of four juvenile-type diabetics with no IRI response to glucose load and no fall in FFA levels, the CHO oxidation rate was markedly diminished and the lipid oxidation rate presented only a slight fall after glucose load.
In the group of maturity-onset diabetics, a slight insulin secretion seemed to be sufficient to prevent lipolysis and to allow normal rates of lipid and CHO oxidation in response to glucose load. On the other hand, in the group of juvenile-type diabetics, the lack of endogenous insulin secretion seemed to be responsible for increased lipolysis, leading to decreased responses of lipid and CHO oxidation to glucose load.
The Roles of Insulin and Glucagon in the Regulation of Gluconeogenesis in the Postabsorptive Dog
Authors: Jennings A S , Cherrington A D , Liljenquist J E , Keller U , Lacy W W , Chiasson J L 
Published: September 2013

The aim of the present study was to determine the role of insulin and glucagon in the regulation of basal gluconeogenesis in overnight-fasted anesthetized dogs. A deficiency of either or both pancreatic hormones was achieved by infusing somatostatin (1 μg./kg./min.), a potent inhibitor of both insulin and glucagon secretion, alone or in combination with intraportal replacement infusions of either pancreatic hormone. Infusion of somatostatin alone caused the arterial levels of insulin and glucagon to drop rapidly by 72±6 per cent and 81±8 per cent, respectively. Intraportal infusions of insulin and glucagon at rates of 400 μU./kg./min. and 1 ng./kg./min., respectively, resulted in the maintenance of the basal levels of each hormone. Gluconeogenesis was assessed by measuring both the splanchnic extraction of alanine and the conversion of 141C-alanine into l4C-glucose.
Isolated glucagon deficiency (basal insulin level maintained) resulted in a 44±9 per cent (P &lt;0.05) decrease in the conversion rate of alanine into glucose. Isolated insulin deficiency (basal glucagon level maintained) resulted in a 74±7 per cent (P &lt;0.01) increase in the conversion rate of alanine into glucose. Somatostatin had no effect on alanine conversion into glucose when the changes in the pancreatic hormone levels that it normally induces were prevented by simultaneous intraportal infusion of both insulin and glucagon. A deficiency of either hormone for up to 60 minutes failed to alter the splanchnic extraction rate of alanine.
In conclusion, in the overnight-fasted anesthetized dog, (1) basal glucagon plays a significant role in the stimulation of gluconeogenesis from alanine, (2) basal insulin exerts a potent inhibitory effect on the rate of conversion of alanine into glucose, with the result that glucagon's gluconeogenic potential is markedly enhanced during insulin deficiency, and (3) somatostatin has no acute effects on gluconeogenesis from alanine other than those it induces through perturbation of pancreatic hormone secretion. This study indicates that the opposing actions of the two pancreatic hormones are important for the fine regulation of gluconeogenesis.
The Immunogenicity of Different Insulins in Several Animal Species
Authors: Neubauer Horst Paul , Schöne Hans Hermann 
Published: September 2013

The immunologie properties of homologous and heterologous insulins have been investigated. Pigs, dogs, cows, sheep, goats, rabbits, guinea pigs, and rats were immunized with different hormone preparations alone or in combination with complete Freund adjuvant. The results obtained provide convincing evidence that in pigs homologous insulin cannot produce specific antibodies, whereas heterologous insulin can. Because the insulins of dogs and pigs have identical amino acid sequences, no antigenicity of porcine insulin in dogs could be observed either.
In cattle, sheep, and goats, not only heterologous but also homologous insulins stimulated antibody production. Sheep and goats proved to be excellent reactor animals.
Most of the small laboratory animals developed specific antibodies against insulin after hyperimmunization. In rabbits, not only the groups injected with nonchromatographed bovine insulin but also those hyperimmunized with single-component bovine insulin responded with a high serum level of specific antibodies. The data suggest that highly purified insulin preparations have not less antigenic activity than nonchromatographed insulin. Immunologically, des-Phe-B1-insulin acted exactly like the original hormone.
Histologie examination of the pancreases of 45 pigs, 22 of which had high antibody titers, did not reveal insulitis. The results of the present paper point out that the production of specific antibodies is essentially a question of species specificity.
C-peptide and Insulin in Liver Disease
Authors: Johnston Desmond G , Alberti K George M M , Wright Ralph , Smith-Laing Gray , Stewart Alison M , Sherlock Sheila , Faber Ole , Binder Christian 
Published: September 2013

The liver is the primary organ of insulin clearance; thus, hyperinsulinism in peripheral blood may result from diminished insulin degradation rather than hypersecution. Proinsulin is cleaved in the pancreatic β-cell to insulin and C-peptide, which are released into the circulation in equimolar quantities. Unlike insulin, C-peptide is not degraded by liver, and in liver disease the peripheral C-peptide concentration is a better index of insulin secretion than is peripheral insulin concentration.
Fasting plasma insulin concentration was raised in 21 cirrhotic patients (0.13 ± 0.02 vs. 0.06 ± 0.01 nmol per liter) despite normal fasting blood glucose concentrations. C-peptide concentrations and, therefore, insulin secretion did not differ from controls', and the C-peptide:insulin ratio was decreased in cirrhotic subjects (4.0 ± 0.5 vs 7.0 ± 1.1). After oral glucose, hyperinsulinemic cirrhotic subjects had similar C-peptide concentrations to those of cirrhotics with a normal insulin response in whom glucose values were similar. Hyperinsulinism (both fasting and after glucose) appears to result from diminished insulin degradation, therefore.
To distinguish the roles of liver damage and of portal-systemic shunting, similar studies were performed in patients with ostensibly normal liver function but long-standing portal venous block. Despite mild hyperglycemia, hyperinsulinism was not found in these subjects, either fasting or after oral glucose. The fasting C-peptide:insulin ratio was normal, and only after stimulation of insulin secretion by glucose was a mild impairment of insulin degradation seen.
The hyperinsulinism of hepatic cirrhosis is due to impaired insulin degradation; this is more likely to result from liver damage per se than from portal-systemic shunting.
Beta-cell Function in Children with Diabetes
Authors: Ludvigsson J , Heding L G 
Published: September 2013

Although it is generally believed that insulin secretion is minimal or absent in juvenile-onset diabetes, we have found appreciable levels of C-peptide at the time of onset in 12 patients, 4 to 16 years old (9.3 ± 4.2). Ten of them had ketonuria but none severe ketoacidosis. All entered a remission period. Most of the patients had near normal C-peptide levels during the remission, and their beta cells had the capacity to respond to a breakfast stimulation with increased insulin secretion.
C-peptide and proinsulin were also determined in 98 juvenile diabetics with age at onset of 1 to 16 years (6.8 ± 3.9) and a duration of diabetes between two and 17 years (6.7 ± 3.4). Many were found to have persisting beta-cell function, which seems to be of importance for ensuring stability in metabolic control. Although little is known about factors that may slow or reverse the process leading to beta-cell failure, our results suggest that early detection and intensive treatment of diabetes before severe metabolic disturbances have occurred may help preserve beta-cell function.