bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma Glucose and Insulin Responses to Orally Administered Simple and Complex Carbohydrates
Authors: Crapo Phyllis A , Reaven Gerald , Olefsky Jerrold
Published: September 2013

We have studied the effects of glucose, sucrose, and various starches on postprandial plasma glucose and insulin responses in 19 subjects. All carbohydrate loads were calculated to contain 50 gm. of glucose, and the response to each carbohydrate was tested twice: when given alone in a drink or when given in combination with other nutrients as a meal. The data demonstrate: (1) Glucose and sucrose elicited similar plasma glucose response curves, but sucrose elicited a somewhat greater (20 per cent) plasma insulin response. (2) Raw starch ingestion resulted in a 44 per cent lower glucose response and a 35–65 per cent lower insulin response than did either glucose or sucrose ingestion. (3) When carbohydrate was given as a meal the plasma glucose responses were 40–60 per cent lower than when the same carbohydrate was given as a drink, while the insulin responses were generally similar, and (4) when different cooked starches were compared, the plasma glucose and insulin responses to rice were significantly lower (50 per cent) than to potato. In conclusion, the size of the carbohydrate molecule appears to influence the postprandial glucose and insulin responses such that more complex carbohydrates (starches) elicit lower responses. This effect may be related to differences in digestion rather than to differences in absorption.
Pharmacokinetic Evaluation of Dosing Regimens for Insulin in Diabetic Ketoacidosis
Authors: Hayton W L , Grisafe J A
Published: September 2013

A pharmacokinetic model of the insulin-glucose system was used to examine the effectiveness of insulin administered by a variety of routes and regimens for diabetic ketoacidosis. The blood plasma concentration of glucose was set at 1,000 mg. per dl., and the effects of the following insulin regimens on the glucose plasma level were compared: low dose (90mU. per kg. per hr.) administered by hourly intramuscular injection, constant-rate infusion, hourly intravenous bolus, constant-rate infusion with intravenous loading dose, and high dose (2 U. per kg.) with half given as an intravenous bolus and the remainder administered subcutaneously. Computer simulations showed that the high-dose regimen reduced the plasma glucose concentration rapidly to a hypoglycemic level (< 34 mg. per dl. at three hours postadministration). The low-dose regimens reduced the plasma glucose level more slowly than did the high-dose regimen. Differences among the low-dose regimens were noted. The initial decline of the plasma glucose level was relatively slow with both the intramuscular and constant-rate infusion regimens. An additional problem with the intramuscular regimen was the accumulation of insulin at sites of administration. This accumulation could make judgment of the appropriate time to discontinue insulin difficult. Both the hourly intravenous bolus and the constant-rate infusion with loading-dose regimens caused a prompt decline in the plasma glucose level. Their potential for causing hypoglycemia was low provided insulin was discontinued when the plasma glucose level reached 180 mg. per dl.
Evaluation of Diabetes Patient-education Programs
Authors: Graber Alan L , Christman Barbara G , Alogna Maria T , Davidson John K
Published: September 2013

Patient education is generally regarded as an essential component of the clinical management of diabetes. However, analysis of the role of patient education in diabetes control has been limited. Formal patient teaching programs at several medical centers range in operation from merely providing knowledge about diabetes to integrating patient education into the chronic health care system. Improvements in knowledge about diabetes have been demonstrated with patients who have been given questionnaires before and after instruction, but changes in diabetes control and other clinical parameters have not necessarily followed. In those cases in which patient education has been a part of a comprehensive improvement in the entire clinical management of diabetes, significant decreases in rates of hospitalization and acute complications have occurred. Guidelines for future evaluations are discussed.
Differences Between Insulin Degradation by Soluble Fractions and Insulin Clearance by Perfused Livers of Normal, Protein-depleted, and Starved Rats
Authors: Sacks H , Pimstone B , Waligora K , Peires L , Weinkove E , Saunders S
Published: September 2013

The activity of an insulin-degrading enzyme in soluble fractions of liver homogenate (“insulinase”) was compared with clearance of immunoreactive insulin (IRI) by cyclically perfused livers from normal, protein-depleted, and starved rats. Insulin disappearance from normal liver perfusates followed first-order kinetics, and clearances remained unchanged at levels between 1 and 5 nM insulin but fell at Insulin levels above 10 nM. At saturating concentrations (0.13 μM), the maximal rate of insulin removal was 12.5 pmol/mln./gm. wet liver, whereas the maximal degrading velocity of the “insulinase” fraction was 6.0 nmol/min./gm. wet liver. Furthermore, insulin clearance by the intact liver was not influenced by many substances affecting the “insulinase” system. Proinsulin (0.83 μM) acted as a competitive inhibitor, and glucagon, somatostatin, oxytocin, casein (all 1 to 6 μM), and Trasylol (2,000 K.I.U./ml.) inhibited “insulinase” noncompetitively. N-ethylmaleimide (1 mM) inhibited “insulinase” 100 per cent and partly delayed insulin removal from perfusates either because of concomitant reductions in oxygen consumption or because of incomplete titration of either accessible groups at active sites of insulin-degrading enzymes or cofactors.

When results were corrected for liver DNA, protein-depleted and starved rats, respectively, showed 80 per cent and 56 per cent of control “insulinase” activities (p < 0.005 and p < 0.005), but their intact livers cleared physiologic concentrations of insulin at similar.rates to those of controls. These differences, coupled with the lower saturability and probable higher affinity of the insulin removal process by the intact liver and the lack of inhibition of this process by “insulinase” inhibitors, suggest that the plasma membrane of the structurally preserved liver cell plays a physiologic role in the regulation of the rate of insulin catabolism either by degrading insulin itself or by limiting insulin delivery to degrading systems in the intracellular compartment.
Cyclic Nucleotide Phosphodiesterase: Insulin Activation Detected in Adipose Tissue by Gel Electrophoresis
Authors: Solomon Solomon S , Palazzolo Marjorie , King Lloyd E
Published: September 2013

In rat adipose tissue, insulin (100 μU./ml.) increases the activity of cyclic AMP (but not cyclic GMP) phosphodiesterase (PDE). Radioisotopic assay, auto radiography, and histochemical stains demonstrated that cyclic nucleotide PDE activity is associated with multiple bands of protein separable by polyacrylamide gel electrophoresis. The insulin activation of cyclic AMP PDE, however, was limited to a single band corresponding to the “low” Km enzyme specific for cyclic AMP; insulin had no effect on the “high” Km enzyme or on PDE bands with activity directed toward cyclic GMP. These data support the concept that insulin may modulate the activity of at least one of the cyclic AMP phosphodiesterases.
Effects of Exogenous Hyperglucagonemia in Insulin-treated Diabetics
Authors: Raskin Philip , Unger Roger H
Published: September 2013

This study was designed to determine if hyperglucagonemia approximating that believed to be present in the portal vein of poorly controlled diabetics can exert metabollcally deleterious effects in insulin-treated diabetics. Three juvenile-type diabetics and one maturity-onset-type patient were given glucagon intravenously at a dose of 6 ng./kg./min. for 24 hours while receiving a continuous infusion of Insulin. This raised their plasma IRG levels from an average of 122 ± 15 pg./ml. on the control day to 594 ± 60 pg./ml. Mean plasma glucose concentration, measured at two-hour intervals around the clock, averaged 200 ± 20 mg./dl. on the control day and increased significantly in all four patients to 293 ± 18 mg./dl. (p < 0.05) during glucagon administration; fasting glucose rose from 138 ± 10 mg./dl. to 201 ± 17 (p < 0.05). Glucose excretion rose significantly from the control value of 36 ± 14 gm. per 24 hours to 152 ± 19 gm. per 24 hours (p < 0.05). The excretion of both urea nitrogen and ketones also increased significantly (p < 0.05) during glucagon administration. The three juvenile-diabetic patients also received a glucagon infusion at a rate of only 3 ng./kg./min., and in each evidence of deterioration in metabolic control was observed. In every experiment, termination of the glucagon infusion was followed by a recession in the metabolic abnormalities.

These data indicate that exogenous hyperglucagonemia of the magnitude believed to be present in the portai vein of uncontrolled diabetics can cause metabolic deterioration in diabetics receiving continuous insulin treatment.
Pancreatic Beta Cell Toxicity by Streptozotocin Anomers
Authors: Rossini A A , Like A A , Dulin W E , Cahill G F
Published: September 2013

D-glucose in the pyranose (ring) form exists as two anomers. The α-anomer is more effective than the β-anomer in promoting insulin secretion, suppressing that of glucagon, and protecting β-cells against alloxan toxicity. Streptozotocin (SZ), a beta cell toxin, is composed of a cytotoxk moiety, 1-methyl 1-nitrosourea, attached to carbon-2 of glucose and exists as either of rwo anomers in the pyranose form. In 24-hour-fasted male rats, predominantly α-or predominantly β-SZ was injected intravenously and plasma glucose levels were obtained 48 hours later. The α-anomer produced significantly greater β-cell necrosis at doses of 30, 35, and 40 mg./ kg. body weight. At higher doses, no differences between the α and βanomers were observed. 3-O-Methyl glucose (3-OMG) protected against both SZ anomers; however, the α-SZ remained more toxic. Larger doses of glucose protected against the lower doses of SZ and, under such conditions, the individual glucose anomers appeared equally potent. Finally, mannitol at comparable molar concentrations was ineffective in protecting against the SZ toxkity.

This study suggests that streptozotocin's beta cell toxicity is mediated through recognition by the beta cell. In addition, 3-OMG and, to a lesser but significant extent, glucose were shown to protect against the streptozotocin toxkity, whereas mannitol did not.
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.
Lack of Glucagon Response to Hypoglycemia in Diabetic Autonomic Neuropathy
Authors: Maker Thomas D , Tanenberg Robert J , Greenberg Beryl Z , Hoffman James E , Doe Richard P , Goetz Frederick C
Published: September 2013

Glucagon response to insulin hypoglycemia was tested in diabetics with autonomic neuropathy (N=9), diabetics without neuropathy (N=8), and normals (N=9). With similar levels of hypoglycemia, growth hormone and plasma cortisol increased in all groups. The glucagon response in normals (121 ± 19 vs. 308 ± 30 pg./ml., mean ± S. E. M. of baseline vs. hypoglycemia peak) was significantly less in nonneuropathic diabetics than in normals (128 ± 13 vs. 209 ± 30) and absent in neuropathic diabetics (128 ± 23 vs. 115 ± 20). Arginine stimulation produced a glucagon response in the neuropathic diabetics (106 ± 16 vs. 523 ± 103). The data indicate that the capacity to release glucagon during hypoglycemia is lost in diabetic neuropathy while glucagon responsiveness to arginine is retained. Neuropathy in diabetes may contribute to metabolic instability.
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.
Decreased Rat Hepatic Guanylate Cyclase Activity in Streptozotocin-induced Diabetes Mellitus
Authors: Vesely David L , Castro Albert , Levey Gerald S
Published: September 2013

Guanylate cyclase is found in virtually all cells, but its physiologic role and the effect of hormones on its activity have not been clarified. Hepatic soluble guanylate cyclase activity (37,000 g supernatant) in rats with diabetes-mellitus-like syndrome induced by streptozotocin, 65 mg./kg. i.V., was 140 ± 8 pmoles accumulated/mg. protein/10 min. (n = 13 rats) as against 279 ± 16 pmoles accumulated/mg. protein/10 min. (n = 12 rats) in normal rats. The average blood sugar for the 12 normal rats was 100 ± 4 mg./100 ml. and 546 ± 32 mg./100 ml. for 13 diabetic rats. The decreased soluble hepatic guanylate cyclase activity in diabetic rats was completely restored to normal with 10 U. regular insulin, i.p. The maximum increase in guanylate cyclase activity was observed as early as five minutes and as late as two hours after insulin administration. Insulin restoration of guanylate cyclase was dose-related over a range of 1 U. to 10 U., i.p. Hepatic cyclic GMP levels in vivo paralleled in-vitro guanylate cyclase activity, being 29 ± 0.4 pmoles/gm. wet weight in normals, 17 ± 0.4 pmoles/gm. wet weight in streptozotocin-diabetic rats, and 38 ± 0.4 pmoles/gm. wet weight two hours after the injection of 10 U. regular insulin. We conclude that rat hepatic guanylate cyclase is decreased in streptozotocin-induced diabetes and that insulin modulates this enzyme. The administration of exogenous insulin in normal animals did not further augment hepatic guanylate cyclase activity.
Hypersecretion of Gastric Inhibitory Polypeptide Following Oral Glucose in Diabetes Mellitus
Authors: Ross S A , Brown J C , Dupré J
Published: September 2013

Gastric inhibitory polypeptide (GIP) is insulinotropic and is released after ingestion of glucose in normal man. Changes in plasma immunoreactive gastric inhibitory polypeptide (IRGIP) were therefore studied during a 50-gm. oral glucose tolerance test in 10 normal subjects and 20 subjects with maturity-onset diabetes mellitus. The diabetics were nonobese and treated by diet alone; they exhibited exaggerated increments of plasma IRGIP in association with delayed and diminished peak increases in plasma immunoreactive insulin, suggesting relative failure of the beta-cell response to GIP. The diabetic subjects also showed a paradoxk rise in mean plasma immunoreactive glucagon, with a peak coinciding with that of plasma IRGIP. It is suggested that the defective beta-cell response may lead to diminished feedback inhibition of GIP secretion by insulin in diabetes mellitus and that the glucagonotropic action of GIP may be expressed under these conditions.
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.
The Effect of Insulin on Vascular Reactivity to Norepinephrine
Authors: Alexander William D , Oake R J
Published: September 2013

The effect of insulin on the vasoconstrictor response to norepinephrine of the resistance bed of the isolated perfused rat tail has been studied. Insulin produced a significant attenuation of this response in concentrations of both 120 mU./ml. and 150 /μU./ml. It is suggested that this effect may be relevant to the hypotensive action of insulin observed in diabetics.
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.
Secretion of Insulin in a Perifusion System and Conversion of Proinsulin to Insulin by Pancreatic Islets from Hyperglycemic Rats
Authors: Kanti Jain , Logothetopoulos J
Published: September 2013

The secretory pattern of insulin and the rate of conversion of proinsulin to insulin were studied in isolated pancreatic islets from normoglycemic (buffer-infused for 24 hours) and hyperglycemie (glucose-infused for 24 hours) rats. The profiles of insulin secretion obtained during one hour of perifusion were markedly different in the two groups. The rate of insulin secretion by islets from the hyperglycemie rats was initially very high but progressively declined during the late period of the perifusion. The reverse pattern was found with the islets from buffer-infused rats. For the estimation of the rate of proinsulin to insulin conversion, islets were pulse-labeled with L-[4,5-3H]-leucine for 15 minutes and “chase”-incubated for 30 and 60 minutes. Labeled rat proinsulins and rat insulins in the medium and in the islet extracts were separated by a validated SDS-urea electrophoretic acrylamide procedure following immunoprecipitation. The conversion rate was estimated from the radioactivity in the insulin band, expressed as a per cent of the radioactivity in the proinsulin + insulin bands. Islets from hyperglycemie rats converted newly synthesized proinsulin to insulin at significantly higher rates than did control islets.
In-vitro Observations on Isolated Adipose Tissue Cells from Hyperobese Subjects
Authors: Burns Thomas W , Terry Boyd E , Langley Paul E , Robison G Alan
Published: September 2013

Isolated adipose tissue cells were prepared from subcutaneous samples obtained from nine morbidly obese subjects weighing from 187 to 306 per cent of ideal body weight. The responsiveness of these adipocytes to a number of test substances was determined by measuring cellular cyclic AMP concentration at one-half hour and glycerol release at four hours. Theophylline (10−3 M) and epinephrine (10−5 M) stimulated Upolysis; theophylline stimulated an increase in cyclic AMP, while epinephrine failed to prompt a significant change in the nucleotide. Neither the αblocker, phen tolamine (10−5 M), nor the β blocker, propranolol (3 × 10−5 M), affected lipolysis or cyclic AMP; when these agents were incubated in combination with epinephrine, changes occurred indicative of the presence of both α and β adrenergic receptor sites. Insulin significantly reduced both basal and stimulated lipolysis but failed to affect cyclic AMP. With minor exceptions, adipocytes from hyperobese. Subjects behaved similarly to cells from unselected donors; at the concentration used, there was no evidence of resistance to insulin.
Normalization of Glycemia in Diabetics During Meals with Insulin and Glucagon Delivery by the Artificial Pancreas
Authors: Marliss Errol B , Murray Frederick T , Stokes Elaine F , Zinman Bernard , Nakhooda Azima F , Denoga Araceli , Leibel Bernard S , Albisser A Michael
Published: September 2013

An extracorporeal “closed-loop” system has been employed to maintain glycemia in the normal range during consumption of meals in nine insulin-treated diabetics. This artificial pancreas system incorporated continuous blopd glucose monitoring (0.05 ml. per minute, delay time 90 seconds), a computer programed to respond to glycemia, and a hormone delivery system. Intravenous insulin delivery rates were determined by control parameters responsive to both glucose concentration and its rate of change. Because insulin-dependent diabetics often defend themselves poorly against hypoglycemie (in some cases due to inadequate glucagon responses), the instrument was also programed for exogenous glucagon delivery. A priori selection of ideal parameters for insulin and glucagon delivery for each individual is not yet possible. Con sequently, when the parameters were used for the first time on each subject, they were varied over a reasonable range. This approach resulted in a corresponding variety of glycemie responses, the average of which characterized a set of initial parameters that is generally applicable. Appropriate control parameters are presented that successfully prevented hypoglycemie. Glucagon delivery directly related to glycemia appeared sufficient for this purpose, thus obviating the need for dextrose administration. This system provides a technique for complete normalization of blood glucose concentration in the types of diabetics tested, during both fed and interprandial periods. It has yielded insights essential to the development of more sophisticated future devices.
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.
Relationship of Microvascular Disease in Diabetes to Metabolic Control
Authors: Engerman Ronald , Bloodworth J M B , Nelson Susan
Published: September 2013

Dogs were made alioxan-diabetic and randomly distributed into either of two prospective treatment groups. In one group it was intended that the metabolic signs of diabetes be controlled poorly, and commercial insulin was administered in doses inadequate to prevent chronic, severe hyperglycemie and glucosuria. In the other group it was intended that the metabolic disorder be well controlled, and the animals received food and commercial insulin twice daily such that the hyperglycemie and glucosuria became mild or infrequent. Experimental improvement of the carbohydrate disorder was accompanied by amelioration of hyperUpemia and other clinical signs of deficient insulin activity. By 60 months of diabetes, retinal capillary aneurysms, pericyte ghosts, obliterated vessels, and other microvascular abnormalities typical of diabetes were apparent In each animal of the poor-control group. Better control was found to reduce significantly the incidence and severity of microvascular lesions. The data suggest that the mechanism responsible for diabetic retinopathy is initiated as a result of deficient insulin activity and that the development of the microvascular complications of diabetes are preventable and may be inhibited by careful control of the metabolic disorder.
Pancreatic Perinuclear Inclusions in Diabetes Mellitus and Other Diseases
Authors: Greider Marie H , Lacy Paul E , Kissane John M , Rieders Elaine , Thomas Gene
Published: September 2013

Unusual perinuclear inclusions in pancreatic duct cells were observed by electron microscopy in 23 diabetic pancreases, in nine pancreases with islet hyperplasia, and in 10 of 27 pancreases without islet pathology. The origin and significance of the perinuclear inclusions could not be determined, but it is suggested that they may be of viral origin or may represent a cellular response to an unknown stimulus.
Immunoreactive Glucagon Levels in Obese-hyperglycemic (ob/ob) Mice
Authors: Dubuc P U , Mobley P W , Mahler R J , Ensinck J W
Published: September 2013

A series of studies examined the effects of various experimental manipulations on the glucose, immunoreactive insulin (IRI), and immunoreactive glucagon (IRG) levels of eight-week old ob/ob mice and their lean littermates. The levels of serum glucose, IRI, and IRG of ob/ob mice were significantly higher than those of the lean mice in the basal state and remained higher throughout an 18-hour period of fasting. Both groups responded to food deprivation with reduced glucose and IRI concentrations, but the IRG levels of obese mice were reduced by fasting while those of lean mice were marginally elevated. The IRG levels of both phenotypes were reduced to a similar degree by glucose administration, and the serum glucose and IRI responses of the two groups were proportional to their preinjection levels. Arginine treatment increased the IRG and IRI of both groups. Arginine also lowered the glucose levels of lean mice, but, notably, it did not affect the serum glucose of ob/ob mice. The simultaneous administration of arginine and insulin to lean mice potentiated the hyperglucagonemia and hypoglycemia that followed arginine alone, but in ob/ob mice combined treatment increased the glucose concentrations while not affecting IRG. These data indicate that ob/ob mice have several abnormalities in their metabolic-endocrine responses to both food deprivation and to stimulation with metabolically active agents. However, from the present results we could not determine a specific disturbance of IRI or IRG regulation that could account for the persistence of their hyperglucagonemia, hyperinsulinemia, or hyperglycemia.
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 <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 <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.