bluuebunny/crossref_metadata_2025 huggingface dataset:
The Stimulus-Secretion Coupling of Glucose-Induced Insulin Release: IX. The Participation of the Beta Cell Web
Authors: Malaisse Willy J , Hager Diana L , Orci Lelio
Published: December 2014

The rat pancreatic beta cell is surrounded by an ectoplasmic band of microfilamentous material located just beneath the plasma membrane. This cell web extends into the core of microvillous processes. Alteration of such a microfilamentous network by cytochalasin B (10 μg./ml.) results in a shortening or disappearance of the microvillous processes, a prominent margination of secretory granules and a redistribution of the cell web with the appearance of large and heterogenous masses of granular material extending into the cytoplasm. These ultrastructural changes are associated with a reversible enhancement of insulin release induced by glucose, theophylline or sulfonylurea in isolated islets of Langerhans. However, cytochalasin B fails to affect the basal rate of insulin release observed, respectively, at low glucose or calcium concentrations or in the presence of deuterium oxide. Cytochalasin B does not significantly modify the stimulant action of glucose on calcium accumulation and insulin biosynthesis in the isolated islets. These findings suggest that the microfilamentous cell web plays an important role in the active process of insulin secretion by controlling the access of insulin-containing secretory granules to the cell membrane.
Proinsulin and C-Peptide in Blood
Authors: Rubenstein Arthur H , Block Marshall B , Starr Jerome , Melani Franco , Steiner Donald F
Published: December 2014

Proinsulin-like components (proinsulin and its intermediate forms, PLC) and C-peptide have been identified as secretory products of the pancreatic beta cells in addition to insulin. Because a specific human proinsulin antiserum is not yet available, serum PLC can be measured with an insulin or C-peptide antiserum and a human proinsulin standard after separation of insulin and C-peptide by gel filtration. Assay of unextracted serum with these two immunoassay systems measures total insulin immunoreactivity (insulin + PLC) and C-peptide immunoreactivity (C-peptide + PLC), respectively.

Fasting PLC in normal subjects ranged between 0.05 and 0.4 ng./ml. After oral glucose, PLC levels rose more slowly than insulin and peaked at a later time. In relation to insulin, the percentage PLC was high in the basal state and two to four hours after glucose. The serum PLC concentration has also been measured in a variety of disease states including obesity, acromegaly, myotonic dystrophy, uremia, myxedema and Cushing's syndrome. However, the most frequent and marked abnormality in its level has been found in patients with islet cell tumors.

Equimolar amounts of C-peptide and insulin were found in serum of subjects with a wide range of insulin values. Thus the C-peptide level can be used as an indicator of beta cell secretory function. This application is especially useful in diabetic patients who develop circulating insulin antibodies in response to exogenous bovine or porcine insulin therapy. Measurement of serum C-peptide and proinsulin in these subjects has shown varying degrees of beta cell failure as well as marked fluctuations in secretory capacity in individual patients with progression of their disease.

Preliminary results have indicated the immunological heterogeneity of other circulating peptide hormones and have shown that they may be synthesized and stored in a form different from the secreted molecule. The discovery of proinsulin has thus opened up new and exciting areas which may have wide application in endocrinology.
Streptozotocin-induced Diabetes Mellitus by Direct Pancreatic Infusion in Macaca Nemestrina
Authors: Howard Charles F
Published: December 2014

Diabetes mellitus has been induced in pigtail macaques (Macaca nemestrina) by the direct infusion of streptozotocin (19 to 21 mg./kg. body weight) to the pancreas.
Increase in Plasma Immunoreactive Insulin Following Administration of Insulin to the Gastrointestinal Tract of Rabbits
Authors: Shichiri Motoaki , Okada Akira , Karasaki Kenkichi , Kawamori Ryuzo , Shigeta Yukio , Abe Hiroshi
Published: December 2014

Changes in plasma insulin levels in response to enterai administration of insulin have been studied in rabbits.

Insulin, when administered to the stomach, did not cause hypoglycemia at doses up to 150 U./kg. When insulin at doses over 40 U./kg. was infused to the upper jejunum via an indwelling catheter, there was a slight but significant increase in plasma insulin levels, followed by a significant fall in blood glucose. A considerable increase in plasma insulin was observed when insulin at doses over 20 U./kg. was infused to the Thiry-Velia loop of the jejunum in which no pancreatic secretion entered. With a dose of 100 U./kg., the mean plasma insulin rose promptly to the peak of 241 μU./ml., followed by a severe hypoglycemia.

As judged by hypoglycemie and immunological responses, insulin can be absorbed from the intestine in a physiologically active form, but the fraction absorbed is relatively small.
Characteristics of Nonsuppressible Insulin-like Activity in Fasting Human Serum
Authors: Meade Robert C , Klitgaard Howard M , Holanders Egils
Published: December 2014

Insulin-like activity (ILA) and nonsuppressible insulinlike activity (NSILA) of fasting normal human serum have been studied following fractionation by cation resin chromatography, or extraction with acid-ethanol or ethanol. Studies of solubility, heat stability and immunosuppressibility suggest three different fractions, none of which is immunoassayable insulin. The total activity of the fractions was usually several times that of the original serum.

“Bound” NSILA, which binds to a cation resin column, appears to be a smaller molecule than “free insulin” NSILA found in the column effluent. Our studies suggest that the column effluent NSILA is converted to the smaller “bound” NSILA by acid-ethanol extraction. Although the column effluent NSILA is partially suppressible with guinea pig antiserum, only a trace amount of immunoassayable insulin was found in this fraction.
Nerve Conduction Defect in Galactose-fed Rats
Authors: Gabbay Kenneth H , Snider Joel J
Published: December 2014

Dulcitol accumulation associated with swelling occurs in the peripheral nerves of rats fed a 40 per cent galactose diet. These alterations are associated with a motor nerve conduction velocity defect which is reversible on withdrawal of galactose from the diet. These findings suggest that the accumulation of sugar alcohol plays an important role in the etiology of galactosemic neuropathy.
Spontaneous Diabetes Mellitus in Mystromys Albicaudatus: Repeated Glucose Values from 620 Animals
Authors: Stuhlman Robert A , Packer James T , Doyle Richard E
Published: December 2014

The serum glucose values of 1,423 blood samples from 620 Mystromys albicaudatus have been determined and defined as ortho glycemie or hyperglycemie. Analyses of variance tests and regression analyses of the data revealed a significant difference between orthoglycemic and hyperglycemie serum glucose means and indicated that serum glucose is not affected by sex, inbreeding, or age in these animals. However, within classifications of orthoglycemic and hyperglycemie, weight did affect serum glucose. Therefore, while obesity did not occur during this study, obese-hyperglycemia syndromes might be expected should the animals become overweight.

The data and their analyses are strongly indicative that spontaneous diabetes mellitus in M. albicaudatus, as related to hyperglycemie, is very similar to the disease in man.
Neutralization of the Biologic Activity of Human Serum Bound Insulin by Potent Insulin Antisera
Authors: Antoniades Harry N , Simon James D
Published: December 2014

The in vivo biologic activity of human serum bound insulin is significantly neutralized in vivo, in intact mice and rats, by undiluted guinea-pig insulin antisera (GPAIS). Significant neutralization of biologic activity on both muscle and adipose tissue glycogen synthesis was observed with the addition of GPAIS.

The present studies demonstrate that the concentration of insulin antisera is critical for the neutralization of in vivo biologic activity of bound insulin. In addition, the results suggest that bound insulin injected intraperitoneally into mice or rats may be modified in such a way to allow reactivity with insulin antisera, as judged by loss of biologic activity.
Drug-induced Hypoglycemia: A Review Based on 473 Cases
Authors: Seltzer Holbrooke S
Published: December 2014

Both recognition and prevention of drug-induced hypoglycemia require awareness of the clinical conditions favoring its occurrence and the drugs and drug combinations most likely to cause it. Restricted food intake, age, hepatic disease and renal disease are the main predisposing factors, individually and even more so in combination.

Everyone in general, and insulin-requiring diabetics in particular, should always eat carbohydrate whenever they drink alcohol.

Sulfonylurea hypoglycemia has been reported often in diabetics older than fifty years, with more cases treated with chlorpropamide being reported than cases treated with other sulfonylureas ; it should therefore be used warily in older patients, and only when they are under daily observation by family or friends. In elderly diabetics taking any sulfonylurea agent, warfarin should be used for anticoagulation instead of bishydroxycoumarin, indomethacin for arthritic pain instead of phenylbutazone, and another agent than sulfisoxazole for urinary tract infections. Also in elderly diabetics using sulfonylureas, therapeutic doses of salicylates, monoamine-oxidase inhibitors and probably pro-pranolol should be co-administered with caution, including frequent blood glucose monitoring as long as necessary. Finally, the danger of refractory hypoglycemia in the newborn .proscribes the mother's use of sulfonylureas during the last month of pregnancy.

Drug-induced hypoglycemia is now so relatively common that virtually every unconscious patient should be considered hypoglycemie until immediate estimation of the blood sugar level rules the condition in or out. If it is ruled in, the clinician should promptly start 10 per cent glucose by vein and plan to maintain it uninterruptedly for one or more days, with added hydrocortisone and glucagon if necessary, until persistent hyperglycemia guarantees that all drug effects have worn off.
Evaluation of Programmed Education Among Juvenile Diabetics and Their Families
Authors: Etzwiler Donnea D , Robb Jean R
Published: December 2014

Patient education and involvement is a vital part of quality medical care in chronic diseases, such as diabetes mellitus. In this study the acceptance and effectiveness of programmed machine instruction was evaluated. Young diabetics and their parents can be taught about the disease and its control using an automated technic. There was no objective evidence to indicate control of the disease was significantly improved over a brief period of three months. Patients and parents participating in this study expressed acceptance of programmed instruction as a valuable adjunct to the total education process but stated that this technic should not be the sole educational method employed.
Effects of Amino Acids, Epinephrine and Heparin upon the Radioimmunoassay of Insulin in Plasma
Authors: Feldman Jerome M , Quickel Kenneth E
Published: December 2014

Recent reports have indicated that substances such as arginine, leucine, epinephrine and heparin artifactually alter the radioimmunoassay measurement of insulin. To further evaluate this problem fifty-eight plasma samples were enriched with arginine, fifty-eight samples with leucine and 141 samples with epinephrine, and all were assayed for insulin by a double antibody radioimmunoassay technic. Addition of these substances resulted in no alteration in insulin measurements. Arginine, leucine and epinephrine did not alter the measurement of insulin in standard solutions of human insulin. Also, 114 pairs of heparinplasma and serum samples were assayed for insulin, but no significant differences were noted. Heparin also had no effect on the measurement of standard solutions of human insulin. It is concluded that radioimmunoassay is capable of specifically measuring insulin levels in the presence of arginine, leucine or epinephrine. It also appears that either plasma or serum are equally suitable for insulin determinations. Comparison of our data with published reports from other laboratories indicate that there are differences in the specificity of radioimmunoassay methods used in various laboratories, and each laboratory must validate its own radioimmunoassay procedure.
Increased Production of Fructose by the Brain in Dogs Made Diabetic by Alloxan and by Growth Hormone
Authors: Spinowitz Bruce S , Altszuler Norman
Published: December 2014

The cerebrospinal fluid (CSF) concentration of fructose is elevated in diabetes. In the alloxan-diabetic animal this elevation has been attributed to increased fructose production by the brain. The present study seeks to determine if the increased fructose production is due to hyperglycemia or insulin deficiency. C-14-fructose was injected into the CSF in anesthetized dogs, and from its rate of removal the turnover of CSF fructose was calculated. Since plasma fructose does not pass readily into CSF, the fructose flux reflects fructose production by brain.

In dogs made diabetic with growth hormone, which results in hyperglycemia and hyperinsulinism, CSF fructose levels and turnover rate are significantly elevated. Restoration of normoglycemia by a thirty-six hour fast returns CSF fructose levels to normal. Glucose infusion to elevate plasma glucose for four hours in normal dogs raises plasma fructose but not CSF fructose levels. Similarly, eliminating hyperglycemia for three hours in alloxan-diabetic dogs by insulin infusion decreases plasma fructose, but CSF fructose levels remain elevated. Daily insulin injections do restore CSF fructose to normal.

It appears that increased fructose production by the brain in diabetes depends on hyperglycemia and the underlying metabolic processes for this require a number of hours to develop or be expressed.
Psychological Effects of a Special Summer Camp on Juvenile Diabetics
Authors: McCraw Ronald K , Travis Luther B
Published: December 2014

A group of children with diabetes mellitus were evaluated for self-esteem and manifest anxiety before and after attending a special summer camp. Both males and females showed significant increases in their self-esteem and decreases in manifest anxiety. In both areas, the girls showed a greater improvement than the boys but this was thought to be due partially to the lower initial self-esteem in the females.

A comparison was made between these children and a matched group of diabetic children who didnot attend camp. In this group, there was also an improvement in both variables on retesting. Theimprovements for the camp group were always greater than for the controls, but only in the case of female self-esteem was the difference statistically significant.
Dynamic Synthesis and Release of Insulin and Proinsulin from Perifused Islets
Authors: Sando Hiroyuki , Grodsky Gerold M
Published: December 2014

Insulin and proinsulin syntheses from leucine-H-3 were studied in glucose-stimulated perifused rat islets, with particular attention being placed on the contribution of de novo synthesis to the characteristic second phase of insulin release. At fifty to sixty minutes, when the second phase had reached approximately steady state, most of the islet radioactivity was still in the proinsulin fraction; newly synthesized insulin during this interval represented less than 0.5 per cent of the total insulin secreted. By 110 to 120 minutes, this value had increased, but to less than 17.5 per cent. The half time of conversion of proinsulin to insulin was approximately sixty minutes. At either fifty to sixty or 110 to 120 minutes, proinsulin was less than 5 per cent of the total hormone secreted. The ratio of specific activities for secreted to islet insulin was less than unity at sixty minutes and exceeded unity at 120 minutes; the comparable ratios for proinsulin were somewhat above unity at both times. Results suggest newly synthesized insulin is not responsible for the second phase of insulin release. In addition, storage of insulin is nonhomogeneous with preferential release of the older nonlabeled hormone occurring during the first hour of glucose stimulation.
Effect of Acetyl Choline on the Secretion of Glucagon and Insulin from the Isolated, Perfused Canine Pancreas
Authors: Iversen Johan
Published: December 2014

During perfusions with glucose concentrations of 25 and 150 mg./100 ml., the effect of infusions of acetyl choline on glucagon and insulin release was investigated in five perfusion experiments. Acetyl choline at concentrations of 10 to 100 μM. stimulated release of glucagon both at the low glucose strength as well as at the high concentration, which in itself inhibits basal glucagon release. Glucagon was released in a monophasic pattern, resembling the release pattern found after catecholamines and contrasting with the biphasic pattern obtained after stimulation with gastrointestinal hormones and amino acids, as previously reported from our laboratory.

Acetyl choline always stimulated release of insulin in a biphasic pattern, at the high glucose concentration, while no consistent effect was obtained at the low glucose concentration. At the termination of the acetyl choline infusions, a rebound increase in insulin was observed during perfusion with both low and high glucose concentrations.

Infusion of atropine at a concentration of 25 μM. completely abolished the stimulatory effect of acetyl choline on both glucagon and insulin release.

The results suggest that the parasympathetic nervous system may play a direct role in the control mechanism of the release of the pancreatic hormones during food ingestion.
Increased Intrahematic Glycolysis in Vitro: A New Abnormality in Prediabetes and Chemical Diabetes
Authors: Castillo-Olivares J , Guijo J , Pallardo L F
Published: December 2014

Glucose uptake by human blood cells was measured under appropriate conditions in blood samples during a standard oral glucose tolerance test in three groups: control, prediabetics (offspring of conjugal diabetics) and diabetic subjects. Glucose uptake was expressed as micromoles of glucose disappearance per gram of hemoglobin per hour of incubation. The significance of results, compared to fasting values, was studied for each group. Controls had lower values at every postchallenge point, but a significant difference occurred only at 120 mins. (p<0.05). On the contrary, all postchallenge values in both experimental groups were higher than corresponding fasting levels. In prediabetics these differences were significant at 60 and 120 mins. (p<0.025) and at 180 mins. (p<0.01). In chemical diabetes these differences were significant at 30 mins. (p<0.05) and at 60, 120 and 180 mins. (p<0.005). The increments produced in prediabetes and chemical diabetes were also compared to the decrements produced in controls. Highly significant differences were found: for prediabetes, p<0.005 at60 and 120 mins., and p<0.025 at 180 mins.; for chemical diabetes, p<0.05 at 30 mins. and p<0.005 at 60, 120 and 180 mins.
Lipolytic Effects of High Concentrations of Insulin on Isolated Fat Cells: Enhancement of the Response to Lipolytic Hormones
Authors: Lavis Victor R , Williams Robert H
Published: December 2014

When isolated rat fat cells were incubated with epinephrine or adrenocorticotropin, release of glycerol and nonesterified fatty acids was greater in the presence of 40 ng. per milliliter of insulin than with 2 ng. per milliliter of insulin. Enhanced lipolysis with the higher dose of insulin occurred in the absence of added carbohydrate, did not involve re-esterification of fatty acids, could not be attributed to the presence of glucagon, and was abolished by incubation with anti-insulin gamma globulin or by prior trypsinization of fat cells. Insulin did not augment lipolysis induced by theophylline or added cyclic 3′,5′-adenosine monophosphate (cyclic AMP).

In the presence of 5.5 μM. epinephrine, the initial rate of lipolysis was decreased by insulin in the amount of 2 ng. per milliliter but not by the higher dose, 40 ng. per milliliter. The ability of fat cells to continue accelerated lipolysis was prolonged by 40 ng. per milliliter of insulin, compared with epinephrine alone.

Cycloheximide, and probably puromycin, partially inhibited enhancement of lipolysis by insulin, 40 ng. per milliliter, in the presence of 5.5 μM. epinephrine. This effect of cycloheximide first appeared 120 minutes after exposure of cells to the drug. Responses to epinephrine alone and to 2 ng. per milliliter of insulin were not affected by these drugs.

These results imply that insulin can enhance the lipolytic activity of hormonal stimulators of adenylate cyclase by actions which at least in part require protein synthesis. Indirect evidence suggests that cyclic AMP mediates the lipolytic effects of insulin.
Factors in the Pathogenesis of Experimental Nonketotic and Ketoacidotic Diabetic Stupor
Authors: Joffe B I , Seftel H C , Goldberg R , As M Van , Krut L , Bersohn I
Published: December 2014

In an attempt to elucidate some of the factors responsible for the absence of significant ketosis in hyperosmolar nonketotic diabetic stupor, an experimental model was created in rats. This involved the intravenous administration of alloxan (40 mg. per kilogram) to produce moderate hyperglycemia, followed by daily hydrocortisone injections and dextrose feeding. For comparison, ketoacidotic diabetic rats and various control situations were also studied.

The biochemical profiles of the nonketotic and ketoacidotic diabetic rats resembled those of their clinical counterparts, although some discrepancies were apparent. Attention was. directed at measuring plasma free fatty acid (FFA) and ketone body levels, as well as hepatic glycogen and portal and peripheral plasma immunoreactive insulin (IRI) concentrations in the diabetic and control groups. The hyperosmolar nonketotic diabetic rats were characterized by: a mean plasma FFA level intermediate between that of the controls and that of the ketotics; modest rises in 3-hydroxybutyrate and acetoacetate; and a striking elevation in hepatic glycogen concentration. In addition, their mean portal IRI value resembled that of the control animals (both significantly greater than ketotics) but their mean peripheral plasma IRI value was similar to that of the ketotics (both significantly lower than controls).

It is suggested that the absence of severe ketosis in the hyperosmolar nonketotic diabetic rats was, at least in part, due to the ability of their glycogen-rich, ‘insulinized’ livers to metabolize incoming FFA largely along nonketogenic pathways. The relevance of these findings to the clinical situation is briefly considered.
Beta Cell Replication in Rat Pancreatic Monolayer Cultures: Effects of Glucose, Tolbutamide, Glucocorticoid, Growth Hormone and Glucagon
Authors: Chick William L
Published: December 2014

Rat pancreatic monolayer cultures were utilized to study the effects of glucose, tolbutamide, dexamethasone phosphate, bovine growth hormone and porcine glucagon on beta cell replication. Cultures were established in medium 199 (glucose concentration 1 mg. per milliliter) containing 10 per cent fetal bovine serum. They were subsequently incubated for two consecutive two day intervals in this same control medium or in media containing the test agents. Cultures were then labeled with 3-H-thymidine and reincubated in control medium for two days to permit beta cell regranulation, thus facilitating staining. Replication was estimated by determining the frequency of labeling of aldehydethionin positive (AT+) cells in stained radioautographs. Both glucose (3 mg. per milliliter medium) and tolbutamide (100 μ. per milliliter) caused a three- to fourfoldincrease in labeling compared to controls (14 labeled AT+ cells per 500 AT+ cells). In -contrast, dexamethasone (10 μ. per milliliter) produced a two-thirds decrease in labeling. Growth hormone (10 μ. per milliliter) and glucagon (10 μ per milliliter) produced no statistically significant effects. Alterations in labeling correlated with changes in the quantity of insulin released into the medium during each of the two day incubation intervals. Both glucose and tolbutamide increased insulin release; dexamethasone decreased insulin release, while growth hormone and glucagon produced no significant effects. These data suggest that agents which stimulate insulin release can trigger beta cell replication in vitro. In addition, since growth hormone, glucocorticoid and glucagon stimulate beta cell replication in vivo but not in vitro, this action in vivo may be mediated by effects on other tissues rather than by direct action on the beta cell.
Glucose- and Tolbutamide-Mediated Insulin Response after Preinfusion with Ethanol
Authors: Kuhl C , Andersen O
Published: December 2014

Intravenous glucose tolerance tests (1VGTT) were carried out in five normal subjects after ethanol preinfusion for one, two or four hours. Constant serum level of ethanol was maintained throughout the experiments. Control experiments were performed with saline. Basal levels of serum glucose and insulin were unaffected by ethanol. As regards glucose tolerance a nonsignificant rise in the glucose assimilation constant was seen. During IVGTT peak insulin concentration was unaffected by preinfusion with ethanol for one or two hours, but significantly elevated after four hours. The declining part of the insulin concentration curve was significantly elevated after one or four hours of preinfusion. The insulin increment per glucose increment (the insulinogenic index) rose with the duration of the preinfusion period and, compared to the control experiment, a twofold increment was seen after four hours. When tolbutamide (1 gram) was given intravenously to two of the subjects after preinfusion with ethanol for four hours, the subsequent insulin response followed the same pattern as seen in the four-hour-IVGTT experiment. As the potentiation increases with the duration of the preinfusion period, it might be explained by cummula-tive changes in the beta cell. However, a diminished hepatic degradation rate of insulin cannot be ruled out.
Increased Hepatic Gluconeogenesis without a Rise of Glucagon Secretion in Rats Fed a High Fat Diet
Authors: Eisenstein Albert B , Strack Inge , Steiner Alton
Published: December 2014

We have recently demonstrated that in rats fed a high protein, carbohydrate-free (HP) diet plasma glucagon and liver cyclic AMP are increased and as a result hepatic gluconeogenesis is stimulated. To determine whether increased protein intake or lack of dietary carbohydrate was responsible for these changes, the effects of a high fat, carbohydrate-free (HF) diet on plasma glucagon and insulin, liver cyclic AMP and hepatic gluconeogenesis were determined. Perfused livers of HF-fed rats showed greater conversion of alanine and pyruvate into carbohydrate than did control liver, although the rates were less than in HP-liver. Despite elevated gluconeogenesis in liver of HF-rats, plasma glucagon and insulin and liver cyclic AMP were normal. These findings demonstrate that some mechanism other than a rise in the level of glucagon is responsible for stimulating carbohydrate synthesis. We have postulated that acetyl CoA, which is formed in large amounts as a result of accelerated fatty acid oxidation, promotes gluconeogenesis in HF-fed rats. The observation that plasma glucagon is elevated in HP-fed but not in HF-fed rats demonstrates that protein intake and not carbohydrate restriction stimulates glucagon secretion since both diets are carbohydrate-free. Despite the lack of dietary carbohydrate, plasma glucose of HF-fed rats was normal and liver glycogen was about half that of controls. When HF animals were starved for twenty-four hours, mobilization of carbohydrate stores was diminished indicating that glucose utilization is reduced as a result of fat feeding.
Renin, Angiotensin, and Norepinephrine in Alloxan Diabetes
Authors: Christlieb A R
Published: December 2014

The renin-angiotensin system and catecholamines were evaluated in short term alloxan diabetic rats which were either “severely diabetic” (polyuric with serum glucose > 450 mg. per 100 ml.) or “mildly diabetic” (normouric with serum glucose <450 mg. per 100 ml.). Plasma renin activity (PRA), renal renin activity (RRA), and the amount of angiotensin II producing an acute 10 mm Hg increase in blood pressure were all significantly decreased in the diabetic rats with this decrease correlating inversely with the severity of the diabetes. Insulin treatment of these rats resulted in partial normalization of angiotensin II responsiveness, PRA, and blood urea nitrogen. Injection of alloxan directly into the left renal artery did not decrease RRA. Protection of the left kidney during systemic alloxan injection did not prevent the decrease in renal renin activity. Streptozotocin-treated diabetic rats had increased vascular responsiveness to injected angiotensin II. Norepinephrine sensitivity (amount producing a 10 mm Hg increase in blood pressure) and norepinephrine stores (blood pressure response to tyramine) were normal in both alloxan- and streptozotocin-treated rats.

Blood volume as related to lean body mass was elevated in the severely diabetic rats thus suggesting one possible mechanism for the decrease in the renin-angiotensin system.

These results suggest that (1) norepinephrine responsiveness and norepinephrine stores are normal, and (2) there is suppression of RRA leading to decreased PRA and increased vascular reactivity to angiotensin II in the acutely diabetic alloxan-treated rat. Further, these abnormalities appear to be related to the degree of diabetes as assessed by serum glucose and twenty-four hour urine volume.
Morbidity and Mortality in Diabetics In the Framingham Population: Sixteen Year Follow-up Study
Authors: Garcia Mariano J , McNamara Patricia M , Gordon Tavia , Kannell William B
Published: December 2014

In a sixteen year follow-up study in Framingham, it was found that diabetics in general show an increased morbidity and mortality from all cardiovascular causes. Insulin-treated diabetic women showed the greatest relative mortality from coronary heart disease. Diabetics were found to have higher lipid values, more hypertension and more obesity, even prior to diagnosis. When all the associated risk factors, individually or together, were taken into consideration their presence could not entirely explain the increase in cardiovascular morbidity and mortality experienced by the diabetic. An as yet unknown factor appears to be present in diabetics that could be responsible for much of the higher incidence of cardiovascular complications in diabetics.
Insulinotrophic Drugs: Effect on Intestinal Absorption of Sugar
Authors: Botros M , Selim R , Ghoneim Kh , Ghareeb A , Wahba N
Published: December 2014

The effect of some insulinotrophic drugs on the transport of sugar was investigated in fasted, narcotized rats by continuous perfusion of cannulated long intestinal loops with galactose solution (18 mM.) circulated by air lift. Three consecutive perfusions (fifty minutes each) were performed in each rat, the drug being given in the second perfusion only. The rate of galactose disappearance was expressed as per cent of that in the first perfusion in the same rat.

Tolbutamide (50 mg./l kg. weight), glycodiazine (50 mg./l kg. weight), glisoxepid (BAY 4231, 2 mg./l kg. weight) and glibenclamide (0.25 mg./l kg. weight) were found to increase the rate of galactose disappearance in the second perfusion by 21 per cent, 5 per cent, 12 per cent and 25 per cent, respectively, and in the third perfusion by 21 per cent, 26 per cent, 32 per cent and 21 per cent, respectively, as compared to the rate in the corresponding perfusion of a control group. This increase was significant (P values < 0.05) with all drugs in the second and third perfusions with the exception of glisoxepid in the second perfusion. These results are discussed in relation to the action of insulin and the effect of diabetes on intestinal absorption of sugars.
Effect of Adrenalectomy on Adipose Tissue and Liver in Rats with Acute Insulin Deficiency
Authors: Linder Cecilio , Migliorini Renato H
Published: December 2014

Effects of adrenalectomy on adipose tissue and liver lipogenesis were studied in rats with acute insulin deficiency induced either by interrupting insulin administration to previously treated alloxan-diabetic rats or by almost completely removing pancreatic tissue in a convenient two-stage procedure. The adrenals were removed at the time insulin deficiency was induced and the effects of excision were determined within the next twenty-four hours. Adrenalectomy prevented the marked reduction in incorporation of 14-C from glucose and acetate into fatty acids, as well as the decrease in carbon dioxide production from hexose, in vitro, which rapidly ensue in adipose tissue from alloxan-diabetic rats following insulin withdrawal. In the same conditions, adrenal removal did not affect the metabolism of U-14-C-glucose by liver slices, but a small increase in liver fatty acid synthesis from acetate was observed during one of the experimental intervals. In similarly designed experiments, adrenalectomy increased the recovery of 14-C from acetate, administered in vivo, from fatty acids of the carcass and liver of alloxan-diabetic animals. The effects of adrenalectomy on the metabolism of U-14-C-glucose by adipose tissue from pancreatectomized rats were similar to those observed in alloxandiabetic rats although less marked. Again, adrenal removal did not affect glucose metabolism by liver slices from pancreatectomized rats, but improved liver lipogenesis from acetate. The present results, compared with others in the literature, suggest that the effects of adrenal excision are fully manifested only if the glands are removed before the metabolic changes induced by diabetes in adipose tissue are well established.
Insulin Degradation: IX. On the Presence of Glutathione-insulin Transhydrogenase in Human Leukocytes
Authors: Chandler Michael L , Varandani Partab T
Published: December 2014

The occurrence of insulin-degrading activity in the components of human blood has been studied. Leukocytes have been found to contain such activity. On the basis of activation by reduced glutathione, complete inhibition by N-ethyl-maleimide, kinetic studies, and reaction with antibody to purified human liver glutathione-insulin transhydrogenase (GIT), it is concluded that the insulin-degrading activity present in leukocytes is, in fact, GIT. The data indicate that erythrocytes contain a very small amount of insulin-degrading activity; this activity is probably associated with the cell membrane. Preliminary studies in normal human volunteers indicate that there are apparent differences between individuals in the leukocyte GIT content. No evidence was found for any consistent changes in leukocyte GIT content during the course of a glucose tolerance test.
Observations on Lipolysis in Ketosis-resistant Growth-onset Diabetes
Authors: Hagroo Abdul A , Verma Narendra P S , Datta P , Ajmani Narinder K , Vaishnava Hari
Published: December 2014

This study was undertaken to determine the mechanism of ketosis resistance, which is often observed among patients with growth-onset diabetes in the tropics. Lipolysis was tested in vivo in the ketosis-resistant patients with growth-onset diabetes by determining: (1) Plasma immunoreactive insulin (IRI), blood glucose, and serum free fatty acid (FFA) concentrations during tests with epinephrine, phentolamine and epinephrine, and propranolol and epinephrine in twenty-five patients; and (2) blood ketone bodies during epinephrine and propranolol and epinephrine tests in fifteen patients. The findings were compared with results obtained in a similar number of ketosis-prone subjects with growth-onset diabetes and twenty-two normal controls.

The mean fasting plasma IRI levels were significantly lower in the ketosis-resistant diabetics than in the normal subjects, although the fasting blood glucose levels were three and one-half times greater in these diabetics than in the controls. There was no significant change in the glucose and IRI levels during the three tests. Fasting serum FFA levels were significantly lower in the ketosis-resistant than those in the ketosis-prone diabetics. No detectable serum FFA response was observed in the ketosisresistant patients during any of the three tests. Blood ketone levels were comparable with the values obtained in the normal controls, but were significantly lower than those in the ketosisprone patients. Blood ketones also did not change significantly during epinephrine and propranolol with epinephrine tests in the ketosis-resistant patients.

These results are interpreted to indicate that the mobilization of FFA from the adipose tissue is inadequate in the growth-onset diabetics who are ketosis resistant. The tailure is attributed to insensitivity of the adrenergic receptor sites and/or unresponsiveness of the adenyl cyclase-cyclic AMP-lipase system in the adipose tissue of these young diabetics. The absence of ketonemia in these diabetics is attributable to an insufficient delivery of the substrate (FFA) from the adipose tissue to the liver.
Factors Affecting the Secretion of Insulin and Glucagon by the Rat Fetus
Authors: Girard Jean R , Kervran Alain , Soufflet Elizabeth , Assan Roger
Published: December 2014

Insulin (IRI) and glucagon (IRG) increased in the plasma of the rat fetus from 18½ to 20½ days of gestation and decreased on day 21½. The demonstrated failure of insulin and glucagon to cross the placenta of the rat allowed the conclusion that fetal rat pancreas secreted IRI and IRG in the plasma of the fetus at the end of gestation. Fetal hyperglycemia induced by perfusing pregnant rats with glucose for one hour produced a marked increase in fetal plasma IRI but did not modify plasma IRG. Fetal hypoglycemia induced by perfusing pregnant rats with insulin for one hour produced a fall in fetal plasma IRI but no rise in fetal plasma IRG. Chronic fetal hypoglycemia produced by fasting pregnant rats for ninety-six hours or by intrauterine growth retardation of fetuses increased fetal plasma IRG and decreased fetal plasma IRI. Norepinephrine injection in term rat fetus increased plasma IRG and decreased plasma IRI. Acetylcholine injection increased both plasma IRI and IRG, whereas serotonin remained without effect. These data suggest that IRI and IRG secretion by the fetal rat pancreas is controlled by both the blood glucose level and autonomic nervous system activity. Lower blood glucose levels and higher plasma IRI and IRG levels in pregnant than nonpregnant rats are also reported.
Homeostasis of Body Weight in a Diabetes Clinic Population
Authors: Goodner Charles J , Ogilvie James T
Published: December 2014

Body weights, blood glucose concentration, and therapeutic and clinical data were summarized by computer for each patient visit to our diabetes clinic between 1965 and 1970. Homeostasis of body weight was examined by plotting regression of body weight on time for patients making five or more visits to the clinic during the study period. A similar analysis was made of blood glucose values. Data from 131 patients treated with oral agents or by dietary regulation alone and forty-one patients treated with insulin were analyzed. Precision of regulation was assessed by calculating the coefficient of variation of body weight while the trend of body weight was assessed by calculating the slope of the linear regression equation relating body weight and time.

In both treatment groups the individual slopes for body weight clustered closely around zero and the mean slopes did not differ significantly from zero. The coefficient of variation of body weight was also small, averaging 4.6 and 3.7 per cent of body weight in the oral agent and insulin treatment groups respectively. In contrast, blood glucose fluctuated widely in the two groups. Mean slopes for glucose versus time did not differ significantly from zero, however.

The remarkable stability of body weight in this diabetic population despite widely varying modes of therapy, glucose concentrations, and degrees of body adiposity suggests that signals controlling long-term feeding behavior are either not related to these variables or, more likely, are multiple and sufficiently redundant to permit adaptation to perturbations of several metabolic variables.
Effects of Hypoglycemic Sulfonamides on Glucagon and Insulin Secretion in Ducks and Dogs
Authors: Kajinuma Hiroshi , Kuzuya Takeshi , Ide Takehiko
Published: December 2014

Infusions of tolbutamide (1 mg./kg. min.), glibenclamide (2.5 μg./kg. min.), or glymidine Na (1 mg./kg. min.) in ducks produced a prompt fall in plasma immunoreactive glucagon (IRG), a prompt rise in plasma immunoreactive insulin (IRI) and a subsequent fall in plasma glucose. In dogs, the infusions of these three sulfonamide drugs also caused a rise in IRI and subsequent hypoglycemia, but no specific changes in IRG level in the pancreatic vein and the femoral artery. The infusion of glibenclamide (0.013 μg./kg. min.) into the pancreatic artery of a dog increased IRI secretion and produced a fall in plasma glucose but did not affect IRG level in the pancreatic vein. Carboxytolbutamide, which lacks hypoglycemic activity, failed to influence IRG and IRI in ducks.

The results suggest that the hypoglycemic effect of sulfonamide drugs is mediated by insulin release and, in ducks but not in dogs, by suppression of glucagon secretion. The cause of this species difference is unknown, but the present results and additional data suggest that ducks may be much more dependent than dogs on glucagon for carbohydrate metabolism.
Insulin Action on the Cultured Human Fibroblast: Glucose Uptake, Protein Synthesis, RNA Synthesis
Authors: Fujimoto Wilfred Y , Williams Robert H
Published: December 2014

After cultured human fibroblasts had been maintained in a serum-free medium for twenty-four hours, a biologic effect of physiologic concentrations of insulin was demonstrated. Insulin at physiologic concentrations (0.1 mil./ml.) stimulated glucose uptake and uridine incorporation into RNA by cultured human fibroblasts. Incorporation of leucine into protein was a less sensitive index of insulin action. Fetal fibroblasts were more sensitive than adult fibroblasts to the insulin effect on RNA metabolism. This may be in part the reason for the faster growth rate of fetal fibroblasts.
Abnormalities of Myocardial Depolarization in Overt, Subclinical and Prediabetes: A Vectorcardiographic Study
Authors: Riff Emmanuel R , Riff Kenneth M
Published: December 2014

Vectorcardiograms were performed on fifteen diabetic patients, and all were found to have either the vectorcardiographic criteria for myocardial infarction or “bites.”

Twenty adults with normal fasting blood sugars and not known to be diabetics were found to have bites; eleven (55 per cent) had an abnormal glucose tolerance test; four of the remaining nine were tested further and three (75 per cent) had an abnormal cortisone glucose tolerance test.

Four apparently normal children, age four to twelve, from two families were studied. In both families, the mother had insulindependent diabetes and the father had subclinical diabetes. All four children had vectorcardiographic abnormalities.

This pilot study indicates that if the vectorcardiographic criteria for myocardial damage are correct, then it exists at an earlier stage in diabetes than has previously been recognized. Alternatively, if a morphologic abnormality cannot be demonstrated then a physiologic explanation must be advanced to account for these vectorcardiographic abnormalities.
Islet Cell Changes in the Rat Following Injection of Homogenized Islets
Authors: Heydinger David K , Lacy Paul E
Published: December 2014

The effect of repeated subcutaneous injections of homogenized rat islets on the morphology of the pancreas of the injected animals was determined. Male Wistar rats were injected with fifty homogenized islets every two weeks and were killed in groups of two to three over a twelve-month period beginning two months after the first injection of islets. The chronic injection of islet homogenates produced fibrosis of the islets in the injected animals with marked distortion of the architecture of the islets and the deposition of hemosiderin in the peri-insular tissue. In a few instances, lymphocytic infiltration was observed in the peri-insular area. The cause of this unusual islet lesion was presumably due to an antigen-antibody reaction in the islets. None of the injected animals developed either hyperglycemia or glycosuria.
Decrease and Inhibition of Liver Glycogen Phosphorylase After Fructose: An Experimental Model for the Study of Hereditary Fructose Intolerance
Authors: Thurston Jean Holowach , Jones Elizabeth M , Hauhart Richard E
Published: December 2014

Inhibition of liver phosphorylase may play an important role in the fructose-induced hypoglycemia of hereditary fructose intolerance. This report is an in vivo study of the effects of fructose on selected metabolic intermediates and on phosphorylase activity in the liyers of young mice. Phosphorylase activity in liver homogenate was measured in the direction of glycogen breakdown. The Km for Pi was 1.12 mM and the Ki for fructose-1-phosphate was 1.19 mM. This finding is particularly relevant since twenty minutes after fructose injection (30 mmoles per kilogram intraperitoneally) liver Pi was reduced 50 per cent, p < 0.001 and fructose-1-phosphate was increased fifty fold, p < 0.001. Liver glucose was unchanged.

In controls, activity of phosphorylase was dependent on the state of the animals: 2.43 ± 0.31 μ/moles/gm. min−1 in anesthetized mice, 9.55 ± 0.55 in excited animals. Under these same conditions phosphorylase activity in fructose-injected littermates was reduced 40 to 80 per cent (mean 48 per cent, p = 0.002). At the concentrations of Pi and fructose-1-phosphate found in liver after fructose, phosphorylase activity in vitro was inhibited 88 per cent (p < 0.001). In vivo the activity of liver phosphorylase is apparently reduced by two mechanisms, a conversion to the inactive form and an inhibition of the remaining active enzyme by reduced Pi and elevated fructose-1-phosphate levels. We have postulated that de novo synthesis of glucose from fructose in normal animals could mask any hypoglycemia which might result from reduced liver phosphorylase activity.

The in vivo effect of glucose injection on liver phosphorylase was also studied. At high levels of enzyme activity, glucose reduced phosphorylase activity by 43 per cent, p = 0.012; at low levels of enzyme activity, glucose had no effect.