bluuebunny/crossref_metadata_2025 huggingface dataset:
Studies on the Nature and Mode of Action of the Insulin-sensitive Glucoregulator Receptor in the Central Nervous System
Authors: Szabo Olga , Szabo Andrew J
Published: September 2013

In vivo studies were undertaken in rats to provide evidence for the neural nature, tentative localization and mode of excitation of the insulin-sensitive central nervous system (CNS) glucoregulator center.

In rats under light barbiturate anesthesia minute amounts of insulin injected into the carotid artery resulted in an immediate decrease of the systemic blood sugar. This hypoglycemic action of regional insulinization of the CNS was lost when the animals were subjected to prolonged, deep barbiturate narcosis.

Competitive inhibition of glucose utilization in the CNS region by intracarotid administration of 2-deoxy-D-glucose did not block the systemic hypoglycemic effect of subsequent intracarotid insulin injection. Chronic endogenous hyperinsulinemia produced by daily growth hormone treatment resulted in an insensitivity of the CNS glucoregulator center to exogenous insulin. The ratio of the quantity of the injected insulin and the pre-existent plasma insulin concentration showed direct correlation with the systemic hypoglycemic response that followed intracarotid injection.

Present data support the hypothesis that the insulin-sensitive glucoregulator center located in the area supplied by the carotid artery is neural in nature, because of its inhibition by barbiturate anesthesia. The data are compatible with the working hypothesis that the center is located in the hypothalamus, since light cortical barbiturate anesthesia did not, but deep anesthesia did have an inhibitory effect on it.

Marked interference by chronic hyperinsulinemia suggests that the receptor center estimates the metabolic status of the animal through means related to physicochemical binding of insulin to specific receptors. However, since our attempt to inhibit glucose utilization in the CNS was without effect on the activity of the center, it appears that the signal for the glucoregulatory impulse is not insulin facilitation of glucose utilization in the receptor area, but another parameter of insulin action.
Hyperinsulinemia and Hypoinsulinemia: Insulin Responses to Oral Carbohydrate Over a Wide Spectrum of Glucose Tolerance
Authors: Savage Peter J , Dippe Stephen E , Bennett Peter H , Gorden Phillip , Roth Jesse , Rushforth Norman B , Miller Max
Published: September 2013

Oral glucose tolerance tests using a 75 gm. carbohydrate load were performed on 396 Pirna Indians. Subjects were divided into groups on the basis of two-hour plasma glucose levels and the patterns of insulin response examined. Two-hour insulin levels were highest in the group with two-hour plasma glucose levels between 140–169 mg./100 ml. and then fell progressively until levels above 400 mg./100 ml. were reached. Half and one-hour insulin levels showed little change in the groups with two-hour glucose levels up to 170 mg./100 ml., but at higher glucose levels these insulin levels also progressively diminished. Fasting insulin levels were relatively unchanged over the entire range of glucose tolerance. Obesity was the most important factor influencing the fasting insulin levels. Glucose level was the major determinant of post-load insulin responses, but these were also significantly influenced by obesity. No effect of age or sex on insulin levels was demonstrated.

Comparison with other published data indicates that different interpretations of insulin response in subjects with “mild diabetes” have resulted from comparisons of groups with different degrees of glucose intolerance.
Differential Effects of Alpha- and Beta-D-Glucose on Insulin and Glucagon Secretion from the Isolated Perfused Rat Pancreas
Authors: Matschinsky Franz M , Pagliara Anthony S , Hover Barbara A , Raymond Morey W , Stillings Susan N
Published: September 2013

The efficacy of α and β-D-glucose in causing insulin release and suppressing glucagon release from the isolated perfused rat pancreas was tested. In order to allow simultaneous assessment of the glucose effect on both α and β-cells, the pancreas was continually perfused with a physiological amino acid mixture (10 mM) which provokes glucagonvsecretion and also stimulates the β-cells, provided glucose is present. Under these conditions the α-anomer of D-glucose at 3 and 6 mM proved significantly more potent than the β-anomer in inducing insulin release and in inhibiting glucagon secretion. These data lend further support to the concept that α-cells and β-cells contain glucoreceptors controlling glucagon and insulin secretion and show that certain physicochemical properties of these receptors are alike in both types of cells.
Insulin Biosynthesis in Isolated Pancreatic Islets of Fetal and Newborn Rats
Authors: Heinze E , Schatz H , Nierle C , Pfeiffer E F
Published: September 2013

The effect of glucose and glucose plus glucagon on the incorporation of H3-L-leucine into proinsulin and insulin was examined in isolated islets of twenty-one-day old fetal and five- and ten-day old newborn rats. Maximal stimulation of (pro-) insulin biosynthesis was achieved with 100 mg. per cent of glucose in isolated islets of twenty-one-day old fetal rats. No additional effect was observed with 300 mg. per cent of glucose. On the other hand, in islets of five- and ten-day old newborn rats the incorporation of H3-L-leucine into proinsulin and insulin was gradually augmented by glucose up to concentrations of 300 mg. per cent. Addition of glucagon to the various glucose concentrations only enhanced the synthesis of insulin in ten-day old newborn islets, whereas it had no effect on the islets of the younger age groups. The results show a different pattern of insulin biosyntheses in fetal and newborn islets, which may be related to the varied plasma glucose concentrations of the perinatal period.
Prevalence of Concurrent Diabetes Mellitus and Idiopathic Facial Paralysis (Bell's Palsy)
Authors: Adour Kedar K , Wingerd John , Doty Howard E
Published: September 2013

Diabetes mellitus was present in 11.4 per cent of 684 patients with Bell's palsy, in 28.4 per cent of the sixty-seven with recurrent or bilateral palsy, and in 16.8 per cent of the 440 with palsy who were thirty years or older. Diabetes was present in only 3.8 per cent of 27,399 persons thirty years or older who had never had Bell's palsy and who underwent multiphasic health testing. These figures clearly indicate that diabetes is more common among patients with Bell's palsy than among persons who have never had that disease; and that the risk of Bell's palsy is increased in patients with diabetes. The diabetic patient is more prone than the nondiabetic person to nerve degeneration, and this tendency to nerve degeneration is not age-related. Although 10 per cent of our patients with Bell's palsy and known diabetes were younger than thirty-nine years, we now advise screening for blood sugar elevation only for patients who are forty years or older, or who have recurrent or bilateral facial paralysis.
Plasma and Cerebrospinal Fluid Amino Acid Levels in Diabetic Ketoacidosis Before and After Corrective Therapy
Authors: Aoki Thomas T , Assal Jean Ph , Manzano Francisco M , Kozak George P , Cahill George F
Published: September 2013

To evaluate the effect of insulin-saline-bicarbonate therapy on amino acid metabolism in diabetic ketoacidosis, arterial and venous blood samples as well as cerebrospinal fluid (CSF) were obtained from six patients before and after initiation of corrective therapy. Levels of CSF glutamine were decreased while alanine, α-amino-n-butyrate, valine, isoleucine and leucine were increased significantly compared to a control group composed of six normal, postabsorptive adults free of any neurologic disease. Following therapy, CSF levels of alanine, α-amino-n-butyrate, valine, isoleucine, and leucine declined while glutamine levels did not change.

Admission arterial plasma levels of the glycogenic amino acids were lower than normal while the branched-chain amino acids were elevated. Plasma alanine and glutamine arterio-venous (A-V) differences across forearm tissue were larger. After four hours of corrective therapy, arterial plasma levels of most of the amino acids had declined sharply and A-V differences for glutamine and alanine were markedly reduced (p <.O25 and p <.O1, paired t, respectively). Coincident with the decrease in A-V amino acid differences, plasma glucagon and free fatty acid levels declined significantly. These data suggest that the effect exerted by insulinsaline-bicarbonate therapy on amino acid metabolism is manifested by diminished A-V plasma alanine and glutamine differences across forearm tissue. Thus, the role played by the splanchnic bed both before and following corrective measures may be secondary to substrate availability.
Influence of Oral Glucose Ingestion on Splanchnic Glucose and Gluconeogenic Substrate Metabolism in Man
Authors: Felig Philip , Wahren John , Hendler Rosa
Published: September 2013

To evaluate the role of splanchnic and peripheral tissues in the disposal of an oral glucose load, splanchnic exchange of glucose, lactate, pyruvate, glycerol and amino acids was determined in ten healthy subjects in the basal state and for three hours following the oral ingestion of 100 gm. of glucose.

Following glucose ingestion, splanchnic glucose output rose rapidly, reaching values two to three times the basal rate at fifteen minutes and returning to baseline by ninety minutes. A secondary rise in splanchnic glucose output occurred at 150 minutes and coincided with a secondary increment in arterial glucose. Total splanchnic glucose output over three hours was 40 ± 3 gm., representing a total increase of only 15 ± 3 gm. above basal splanchnic glucose output. The peak rise in blood glucose was directly proportional to the increase in splanchnic glucose output.

Arterial concentrations of alanine, lactate and pyruvate rose by 15, 65 and 80 per cent, respectively, following oral glucose. These arterial elevations were preceded by a 75–100 per cent inhibition of splanchnic uptake of alanine and lactate; in the case of pyruvate there was a reversal from a net uptake in the basal state to a significant net splanchnic output after glucose ingestion. Arterial glycerol fell by 50 per cent and was accompanied by a comparable fall in splanchnic uptake.

It is concluded that in normal, postabsorptive man, (a) the major portion of a 100 gm. oral glucose load is retained within the splanchnic bed; (b) only 15 per cent of the ingested glucose is available for disposal by peripheral tissues as increased (abovebasal) glucose utilization; (c) the height and shape of the oral glucose tolerance curve are largely determined by the rate and pattern of splanchnic glucose escape; (d) glucose-induced hyperlactatemia, hyperpyruvicemia and hyperalaninemia are due at least in part, to altered splanchnic exchange of these substrates.
Pregnancy in a Juvenile Diabetic After Renal Transplantation (Class T Diabetes Mellitus)
Authors: Tagatz George E , Arnold Neil I , Goetz Frederick C , Najarian John S , Simmons Richard L
Published: September 2013

The successful outcome of a pregnancy in a juvenile diabetic after renal transplantation is reported. It is proposed that class T be added to the classification of pregnancies complicated by diabetes mellitus. Pregnancy prevention should be considered until significant longevity can be demonstrated in diabetics receiving renal transplants.
Modulation of Fatty Acid Metabolism by Glucagon in Man: I. Effects in Normal Subjects
Authors: Schaded David S , Philip Eaton R
Published: September 2013

This investigation was designed to examine the contribution of glucagon to the regulation of free fatty acid (FFA) metabolism in man. The acute effects of exogenous glucagon upon the concentration of plasma FFA and its metabolities: acetoacetic acid (AcAc), beta hydroxybutyric acid (BOH), and triglyceride (TG) were assessed in five normal male subjects. The threshold of response was determined by administering intravenous glucagon in a graded dose-response fashion, and assessing the magnitude of change in FFA and its metabolities.

A prompt rise in FFA concentration occurred after glucagon injection, and was associated with a synchronous elevation in both Ac Ac and BOH concentration in the plasma. The rise in FFA concentration was maximal with the glucagon dosage of 0.5 μg./kg. with no greater FFA response seen at higher hormone dosage. In contrast, the rise in plasma ketones was linearly related to the dosage of glucagon but not to the corresponding rise in FFA concentration. The behavior of plasma triglyceride concentration following glucagon challenge also contrasted with the linear rise in ketone concentration. At the lowest dosage of glucagon, TG concentration rose transiently, while at the highest two dosages the concentration of TG was reduced. The transitional dosage of hormone at which no change in TG concentration was observed was approximately 0.5 μg./kg. Comparing our in vivo data with the conclusions reached from published liver perfusion studies, it can be suggested that in the dosages employed, glucagon acutely elevates plasma FFA concentration and modulates their metabolism by augmenting conversion to AcAc and BOH while tending to reduce conversion to TG in man.
Modulation of Fatty Acid Metabolism by Glucagon in Man: II. Effects in Insulin-deficient Diabetics
Authors: Schade David S , Philip Eaton R
Published: September 2013

The potential role of glucagon in the pathogenesis of diabetic ketogenesis was examined by intravenous glucagon administration (1.0 μg/kg. body weight) in five insulin-deficient diabetic subjects. The metabolic response was defined by examining the changes in the plasma concentration of insulin, glucose, free fatty acids (FFA), triglycerides, betahydroxybutyrate, and acetoacetate in comparison to those changes occurring in five nondiabetic control subjects tested under identical experimental conditions.

Our results demonstrate that in the absence of endogenous insulin secretion, exogenous glucagon administration results in an enhanced ketonemia independent of the rise of FFA substrate. This augmented ketogenic response to glucagon in diabetic subjects was not reflected in the dynamics of glucose regulation, with similar changes in blood glucose concentration occurring in both diabetic and nondiabetic populations.

These data demonstrate that glucagon may potentiate ketonemia in insulin-deficient diabetics, although the mechanism mediating this augmentation is not defined. Since the rise in FFA substrate was indistinguishable in the diabetic as compared to the control group, increased hepatic conversion of FFA substrate into ketone bodies is suggested.
Special Topics in Diabetes: Evolving Role of Glucagon in Human Diabetes Mellitus
Authors: Philip Eaton R
Published: September 2013

Insulin has been available for the treatment of diabetes mellitus for more than fifty years, yet many puzzling clinical phenomena remain unexplained. Examination of plasma insulin concentration by radioimmunoassay has repeatedly demonstrated a divergence between the absolute concentration of plasma insulin and the simultaneous concentration of glucose. This apparent discrepancy is well documented in patients with “prediabetes” and is commonly recognized in emergent diabetic ketoacidosis. In these situations, plasma insulin levels may actually be elevated but are seemingly ineffective in reducing blood glucose concentration. The concept of “resistance” to the action of insulin has been aptly applied to such clinical situations, but the pathophysiology of the phenomenon remains obscure.
Antigenicity of “Monocomponent” Pork Insulin in Diabetic Subjects
Authors: Yue D K , Turtle J R
Published: September 2013

“Single-peak,” “single-component,” and “monocomponent” insulins have been produced in an attempt to eliminate insulin antigenicity. Recently “single-peak insulin” has been shown to be antigenic. From animal experiments and preliminary human studies it has been claimed that monocomponent (MC) insulin is nonantigenic or only negligibly so. In this study the antigenicity of MC insulin was determined in two groups of diabetic patients. In group 1, seven patients treated with insulin for the first time were given MC insulin for seven to fifteen months. Four of the seven patients developed significant IgG insulin antibodies after four to ten months. In one patient the IgG insulin antibody concentration was high (8.51 mU./ml.). In two patients IgG proinsulin-specific antibodies were detected. In group 2, fourteen patients with unstable diabetes, insulin allergy, or resistance were changed from conventional to MC insulin. Treatment with MC insulin did not decrease insulin requirement or improve diabetic control when assayed by the M factor. After seven to eleven months of therapy there was no significant fall in insulin antibodies except in two patients in whom corticosteroids had been administered simultaneously.

These results differ significantly from those previously reported and could be interpreted as suggesting that insulin itself is antigenic. When the purity of the MC insulin was determined, significant contaminants could be demonstrated in all of ten separate batches of MC insulin. Gel chromatography, polyacrylamide gel electrophoresis, and proinsulin radioimmunoassay were used to identify the presence of nonconvertible insulin dimer, proinsulin, and monodesamido insulin in antigenically significant concentrations.

The generation of IgG insulin antibodies in MC-insulin-treated patients cannot be interpreted as a true indication that insulin itself is antigenic. The problem of insulin antigenicity has not been resolved and will not be until a highly purified insulin is available. Unfortunately, the MC insulins do not meet these requirements.
Effect of Glucose and Anti-insulin Serum on Insulin Released from Adult Rat Isolated Islets of Langerhans in Long-term Organ Culture (Fourteen Days)
Authors: Turcot-Lemay Lucile , Lacy Paul E
Published: September 2013

Isolated islets of Langerhans from adult male rats were cultured in media containing either basal (1 gm./ml.) or high glucose (3 mg./ml.), and the media were changed every two days for fourteen days. The insulin released in each medium was measured by a back-titration radioimmunoassay. Insulin secretion was fairly constant in the basal glucose medium and a consistent three-to-sevenfold increase was observed in the alternated or continuous presence of high glucose. Addition of an excess of anti-insulin serum did not change significantly the basal or stimulated release of insulin. The electron microscopic appearance of the islets after fourteen days of incubation showed well-preserved islets both with or without antiinsulin serum. Anti-insulin serum did not alter the ultrastructural aspects of the islets in either basal or high glucose media.
Renal Substrate Exchange in Human Diabetes Mellitus
Authors: Wahren John , Felig Philip
Published: September 2013

Renal substrate exchange was examined in five male patients with insulin-dependent diabetes mellitus of several years' duration. Insulin was withheld for twenty-four hours prior to the study. A renal vein was catheterized from the femoral vein, and PAHclearance was employed for the determination of effective renal blood flow.

None of the patients was in ketoacidosis, but all were moderately hyperglycemic in the fasting state (16.8±1.5 mmol/L.) (225-384 mg./100 ml.). Nevertheless, no net release of glucose from the kidney was detectable. Instead, there was a significant net renal uptake of glucose (320±80 μmol/min.). In addition, there was a significant net uptake of glycerol and a net release of pyruvate. Renal amino acid exchange was similar to that reported for healthy subjects: glutamine, glycine, proline, and citrulline were taken up and serine, alanine, cystine, tyrosine, and threonine were released by the kidney.

It is concluded that (a) in nonketoacidotic diabetics there is no net production of glucose by the kidney; (b) renal amino acid exchange in diabetics is similar to that of healthy individuals; and (c) the kidney is not an important gluconeogenic organ in human diabetes.
Dietary-fiber Hypothesis of the Etiology of Diabetes Mellitus
Authors: Trowell H C
Published: September 2013

A hypothesis has been proposed that dietary fiber-depleted starchy foods are conducive to the development of diabetes mellitus in susceptible human genotypes.
Glucagon Response to Arginine after Treatment of Diabetes Mellitus
Authors: Ohneda Akira , Ishii Shoji , Horigome Ken , Yamagata Shoichi
Published: September 2013

To investigate the aminogenic glucagon response in diabetes mellitus, arginine infusion tests were carried out on twenty-four diabetic patients before and after treatment. Eleven healthy men served as a control group. Plasma glucagon was measured by radioimmunoassay using an antiserum, G21, specific for pancreatic glucagon. Out of twenty-four patients, five were treated with diet alone, eight with sulfonylurea, and eleven with insulin.

In all these diabetic groups, the glucose tolerance improved after treatment for diabetes mellitus, while the insulin response to the glucose did not show any remarkable change. The fasting levels of the plasma glucagon did not differ from that of the normal subjects both before and after treatment. Hyperresponsfveness of the plasma glucagon to arginine infusion was observed in all diabetic groups, in comparison with that of the normal controls. The exaggerated response of the plasma glucagon to arginine was lowered following appropriate treatment in each diabetic group. However, as far as the changes in glucagon area during the arginine test are concerned, the aminogenic hyperresponsiveness of the plasma glucagon was reduced prominently in the diabetic group treated with sulfonylurea. The relationship between the response of glucose and plasma insulin and between glucose and glucagon to arginine was investigated, and the importance of the changes in the insulin:glucagon ratio was emphasized. Moreover, the possibility that long-term administration of a sulfonylurea may reduce an exaggerated glucagon response to arginine was discussed.
Age-adjusted Analysis of Insulin Responses During Normal and Abnormal Glucose Tolerance Tests in Children and Adolescents
Authors: Rosenbloom Arlan L , Wheeler Lawrence , Bianchi Raymond , Chin Frank T , Tiwary Chandra M , Grgic Ante
Published: September 2013

This report analyzes age-specific glucose (PG) and immunoassayable insulin (IRI) responses during oral glucose tolerance testing (OGTT) and examines test results in children and adolescents with OGTT abnormality using the age-appropriate control data. Controls' (n = 93) and patients' (n = 63) results were compared on the basis of statural age (SA) at the time of testing. Control tests (n = 101) showed significant positive correlation of fasting and fourhour postingestion PG with SA (p <0.001), but mean area under the PG curves did not vary between the SA groups (I—18-69 months, 11—70-131 months, III—132+ months). The absence of differences at other sampling times permits uniform diagnostic criteria for this age group. IRI was positively correlated with SA at aU testing times, and mean levels differed significantly between each SA group at every sampling time; the mean areas under the IRI curve also differed significantly between SA groups as did the mean ratios of IRI area to PG area (group I—0.2639 ± 0.0175 S.E.M., groupII—0.3864 ± 0.0235, group III—0.6262 ± 0.0491).

Patient tests (n = 110) were separated into normal (N), borderline (B), and chemical-diabetic (C) for each SA group. IRI means were above control data for each test type in each SA group at all sampling times; one fourth of these differences were significant. IRI responses also increased within each SA group from N to B to C tests. Mean IRI areas and IRI area to PG area mean ratios were higher than in controls, and this difference was greatest with the most abnormal (C) test type in each SA group.

A subgroup of three patients who had low IRI responses from the outset and developed overt diabetes in one to three years was excluded from the analysis. In contrast to apparent relative insulin inefficiency with normal maturation and with chemical diabetes, they had exceptional responsiveness to their low IRI levels. Variable involvement of alpha as well as beta cells in the pathophysiology of diabetes is suggested as one explanation for these paradoxic observations. Changing receptor affinity might also be implicated.
Plasma Renin Activity in Juvenile Diabetes Mellitus and Effect of Diazoxide
Authors: Gossain Ved V , Werk Emile E , Sholiton Leon J , Srivastava Laxmi , Knowles Harvey C
Published: September 2013

Low plasma renin activity (PRA) has been reported in patients with long-term diabetes mellitus complicated by hypertension and nephropathy. We have assayed PRA in twelve normal subjects and in eight age- and sex-matched juvenile diabetics of greater than twelve years' duration without hypertension and nephropathy under control conditions and following stimulation with diazoxide. During control conditions PRA did not decrease with time in the diabetics as it did in the normals. Following diazoxide infusion, PRA increased in both groups, and although the levels were often higher in diabetics than in normals, the mean differences were not statistically significant. The findings are consistent with the suggestion that PRA is normal or possibly elevated in clinically uncomplicated insulin-dependent diabetes mellitus and decreases with establishment of hypertension and nephropathy.
Studies on Growth Hormone Secretion: VII. Effects of Somatostatin on Plasma GH, Insulin, and Glucagon in Sheep
Authors: Bryce David , Yeh Mary , Funderburk Cullie , Todd Herbert , Hertelendy Frank
Published: September 2013

To determine whether synthetic somatostatin originally isolated from sheep hypothalamus can inhibit hormone secretion in the same species, we measured plasma levels of GH, insulin, glucagon, and glucose of normal sheep under a variety of experimental conditions in the presence and absence of somatostatin infusion. An oral dose of 2.5 mg./kg. 3,5-dimethypyrazole increase plasma GH from 10.9 to 376.9 ng. per milliliter, which was suppressed by 50 per cent and 80 per cent with 0.5 and 1 mg. synthetic cyclic somatostatin, respectively. Linear somatostatin (0.5 mg.) was without effect in two animals tested. Propionate (0.5 mmole per kilogram) and arginine (10 gm.) induced a rise in plasma insulin and GH, and glucagon was effectively blocked by cyclic somatostatin (0.5 mg.). Similarly, somatostatin inhibited glucose, and glucagon provoked GH and insulin secretory responses without affecting glucose or FFA levels. Somatostatin had no effect on the disappearance of injected glucagon. Finally, addition of somatostatin to incubation media prevented PGE promoted GH release, and suppressed cyclic AMP accumulation, although to a lesser extent, in sheep anterior pituitary pieces. In view of the large amounts required to suppress stimulated hormone release and the general lack of specificity of somatostatin, it is suggested that this peptide may have a functional role only in the release of hormones of the pituitary, where it could occur in relatively high local concentrations. Its inhibition of extrapituitary hormone secretion may be purely a pharmacologic effect that, nevertheless, suggests an interference with a step common to the secretory process of hormones.
Immunoreactive Glucagon Responses to Intravenous Tolbutamide in Chronic Pancreatitis
Authors: Kalk W J , Vinik A I , Paul M , Keller P , Jackson W P U
Published: September 2013

The effects of tolbutamide infusion (1 gm. over forty minutes) on plasma pancreatic glucagon-like immunoreactivity (PGLI), serum insulin, and blood glucose were studied in six patients with chronic pancreatitis and six matched controls.asal PGLI levels were significantly higher in the patients, despite higher fasting glucose concentrations. Tolbutamide infusion had no significant effect on mean PGLI levels in controls but was associated with significant elevation in pancreatitis patients, despite higher circulating glucose levels in the latter. The data suggest that chronic calcific pancreatitis patients hypersecrete immunoreactive glucagon, possibly from a nonpancreatic source and that this immunocreactive material may be stimulated by sulfonylureas.
Marked Hyperthermia as a Manifestation of Hypoglycemia in Long-standing Diabetes Mellitus
Authors: Chochinov Ronald , Daughaday William H
Published: September 2013

Hyperthermia has recently been recognized as a manifestation of hypoglycemia. We describe two episodes of hypoglycemia associated with nausea, vomiting, chills, and impaired consciousness which were followed by marked hyperthermia. We suggest that the hyperthermia may result from excessive reaction to preceding hypothermia caused by the hypoglycemia. We would like to alert the clinician to the possibility of a previous, severe hypoglycemic episode in any diabetic patient with hyperthermia and coma.
Increased Hemoglobin AIc in Diabetic Mice
Authors: Koenig Ronald J , Araujo Diana C , Cerami Anthony
Published: September 2013

The minor hemoglobins AIa, AIb, and AIc were studied in mice with either genetic or chemically induced diabetes. Hemoglobin AIc was elevated approximately twofold in all the phenotypically diabetic mice studied (C57BL/KsJ-db/db, C57BL/KsJ-ob/ob, C57BL7/6J-db/db, and alloxan- and streptozotocin-treated mice). Elevation of the hemoglobin Ale in C57BL/6J-db/db mice was of short duration, reflecting the transitory diabetes characteristic of these mice. The degree of increase of hemoglobin AIclevels was unrelated to severity of hyperglycemia, duration of diabetes, age of mouse, or body weight. It is not-known what factor(s) dictates the steady-state concentration of hemoglobin AIc.
Relationship of Serum Glucose Concentration to Changes in Refraction
Authors: Gwinup Grant , Villarreal Arnold
Published: September 2013

The effect of chronic changes in serum glucose concentration on refraction was studied by increasing the dose of insulin or chlorpropamide in 10 diabetic patients who initially had relatively high glucose concentrations. In every case when serum glucose concentration was reduced the vision became less myopic or more hyperopic.

To assess acute changes, 10 diabetics (including four with aphakic eyes) were given an intravenous injection of glucose. In patients with intact lenses the vision became more myopic or less hyperopic following the administration of glucose, but in the aphakic eyes hyperopia increased.

It is concluded from both the acute and chronic studies that higher levels of serum glucose concentration produce myopia and lower levels produce hyperopia. Furthermore, these changes are related to changes in the optical properties of the crystalline lens.
A Nonsuppressible Increase of Glucagon Secretion by Isolated Islets of High-protein-fed Rats
Authors: Eisenstein Albert B
Published: September 2013

We recently demonstrated increased plasma glucagon but normal insulin in rats fed a high-protein, carbohydrate-free (HP) diet; however, other investigators have reported that both plasma glucagon and insulin are increased after protein feeding. For this reason, we have investigated the effects of an HP diet on pancreatic secretion of insulin and glucagon. Male rats were fed an HP or control diet for one, three, or five days, and, at the end of the feeding period, blood was taken for glucose, insulin, and glucagon determinations. Additional animals fed the HP and control diets for up to. 10 days were sacrificed, the pancreases removed, and islets of Langerhans isolated. Islets were incubated for 30 minutes in media with glucose concentration of 1.7, 8.3, 16.7, or 33.4 mM. Insulin and glucagon secreted into the media were determined by radioimmunoassay.

Plasma insulin was markedly reduced after one day of HP feeding but gradually returned to normal by the fifth day. Plasma glucagon was not altered on day 1 but was significantly increased after three days of HP feeding. The I/G molar ratio, which declined precipitously on day 1, increased thereafter but, as shown previously, remained at a level that promotes gluconeogenesis for up to 10 days.

Insulin secretion by isolated islets of control and HP rats increased more than 10-fold as medium glucose was raised from 1.7 to 16.7 mM. There was no difference in insulin release by the two groups of islets. Glucagon secretion by HP islets at low medium glucose remained normal during the first five days; however, beginning on day 3 there was gradual loss of the suppressive effect of high medium glucose on glucagon secretion. After one week of HP feeding, glucagon secretion at low medium glucose was doubled and there was complete lack of suppression of the elevated hormone production by high medium glucose. The alterations of alpha-cell function induced by HP feeding are similar to those found in human and experimental diabetes.
Gastric Inhibitory Polypeptide (GIP) in Maturity-onset Diabetes Mellitus
Authors: Crockett Samuel E , Mazzaferri Ernest L , Cataland Samuel
Published: September 2013

Serum GIP, insulin, and glucose concentrations were determined during a standard oral glucose tolerance test in 80 individuals, 45 of whom were normal and 35 of whom had adult-onset diabetes mellitus according to USPHS criteria. As a group, the diabetics had fasting hyperglycemia (219 ± 17 mg./dl.) and, in response to glucose, displayed a peak serum glucose of 373 ± 23 mg./dl. and sustained hyperglycemia (315 ± 24 mg./dl.) at 180 minutes. There were no statistically significant differences in absolute serum insulin levels between the two groups. However, insulin secretion was delayed, IRI increments were smaller, and the IRI concentrations were inappropriately low for the simultaneous serum glucose concentrations in the diabetics at every time interval tested. Mean fasting serum GIP was 335 ± 30 pg./ml. in the diabetics as against 262 ± 15 pg./ml. in normal individuals (p < 0.025). After the ingestion of glucose, diabetics had significantly higher (p < 0.001) mean serum GIP levels between five and 120 minutes. By 180 minutes, serum GIP levels remained above fasting in both groups, but the diabetics had higher than normal serum concentrations (p < 0.05). Peak serum GIP concentrations, which occurred at 30 minutes in both groups, were 1,376 ± 106 and 806 ± 75 pg./ml. in the diabetics and normals, respectively (p < 0.001). Total integrated serum GIP was also greater in diabetics than normals (140,852 ± 14,208 vs. 64,602 ± 8,719 pg.-min./ml.−1, p < 0.001). The higher serum GIP concentrations observed following glucose ingestion in diabetics could not be attributed to obesity or age. We conclude that both fasting and glucose-stimulated GIP concentrations are higher than normal in obese adult-onset diabetics. The significance of this observation is uncertain. However, since our current understanding suggests the GIP may be an important enteric signal for the release of insulin in man, and because GIP has been shown to stimulate the release of immunoreactive glucagon, GIP may play a role in the pathogenesis of diabetes mellitus.
Effects of Acute Insulin Withdrawal and Administration on Plasma Glucagon Responses to Intravenous Arginine in Insulin-dependent Diabetic Subjects
Authors: Gerich John E , Lorenzi Mara , Tsalikian Eva , Bohannon Nancy V , Schneider Victor , Karam John H , Forsham Peter H
Published: September 2013

To assess further the role of insulin in the abnormal alpha-cell dysfunction found in human diabetes mellitus, the effects of acute insulin withdrawal and administration on plasma glucagon responses to intravenous arginine were studied in eight insulin-dependent diabetic subjects. Arginine infusions (30 gm. over 30 minutes) were performed during and at one and four hours after discontinuation of a 14-hour insulin infusion (1.5 U. per hour), which had rendered the subjects euglycemic, and on another occasion before and one and four hours into a five-hour infusion of insulin (1.5 U. per hour). During the last hour of the 14-hour infusion, glucagon responses to arginine (area under the curve, nanograms per milliliter per minute) were similar to those found in normal subjects (10.3 ± 0.8 vs. 9.0 ± 0.8, respectively). After discontinuation of the insulin infusions, glucagon responses increased progressively (p < 0.01) to values (16.8 ± 1.2) that exceeded those of normal subjects by four hours (p < 0.01). These were similar to results found in the same subjects studied when their diabetes was in < optimal control (14.9 ± 1.3). Infusion of insulin under these conditions progressively decreased glucagon responses to arginine to values (9.6 ± 0.8; p < 0.01) that, at four hours, were similar to those of normal subjects and to values found at the end of the 14-hour infusion of insulin in the same diabetic individuals.

These results demonstrate a rapid effect of insulin on glucagon responses to arginine and suggest that the abnormal responses seen in diabetes mellitus are the immediate result of insulin deficiency. Since abnormal glucagon responses to glucose in diabetes are not as readily corrected by insulin, the mechanisms underlying the abnormal responses to these two stimuli may differ.
Impaired Plasma Insulin Response to Arginine in Hyperthyroidism: Important Role of the Rise of Blood Glucose in the Second Phase of Insulin Release Induced by Arginine
Authors: Imura Hiroo , Seino Yutaka , Ikeda Masaki , Taminato Tomohiko , Miyamoto Yoshikatsu , Goto Yasuo
Published: September 2013

Intravenous infusion of 30 gm. of L-arginine over a period of 45 minutes elicited a biphasic insulin response and a moderate blood glucose rise in normal subjects. In patients with hyperthyroidism, both insulin peaks, especially the second one, were low, with virtual absence of the blood glucose response. A single intravenous injection of 4 gm. of arginine provoked similar uniphasic plasma insulin responses in both normal subjects and hyperthyroid patients. Pretreatment with either glucose or xylitol almost completely restored the biphasic insulin response to arginine in patients with hyperthyroidism, whereas pretreatment with aminophylline only partially improved the insulin response. Combined administration of a small amount of glucose (2.25 mg./kg./min.) with arginine also restored the normal second-phase insulin release, with blood glucose rises similar to those in normal subjects given arginine alone. It is concluded that the plasma insulin response to arginine is impaired, especially in its second phase, in patients with hyperthyroidism due to the absence of a blood glucose rise. The second phase of arginine-induced insulin release seems more dependent on glucose than the first phase.
Luteinizing Release Hormone Tests in Impotent Diabetic Males
Authors: Wright A D , London D R , Holder G , Williams J W , Rudd B T
Published: September 2013

Assessment of pituitary-gonadal function was made in impotent diabetic males using luteinizing hormone-release hormone tests. Serum testosterone, sex-hormone-binding globulin capacity, and basal and incremental gonadotrophin concentrations in the impotent diabetics were similar to those in control diabetics, suggesting a primary neurologic rather than an endocrine defect as the cause of the impotence.
Effect of Environmental Temperature on Glucose-induced Insulin Response in the Newborn Rat
Authors: Kervran Alain , Gilbert Marc , Girard Jean R , Assan Roger , Jost Alfred
Published: September 2013

Blood glucose and plasma insulin and glucagon concentrations were determined in full-term rats delivered by cesarean section and exposed to 37° C. or 24° C. environmental temperature during the first hours of extrauterine life.

When newborn rats were maintained at thermal neutrality (37° C.), a transient period of hypoglycemia of two hours occurred, associated with a rapid fall in plasma insulin and a rise in plasma glucagon concentrations. During cold exposure (24° C.), the blood glucose level remained stable over the four hours studied; the decrease of plasma insulin was sluggish while the rise of plasma glucagon was unchanged.

In newborn rats maintained at 37° C., an intraperitoneal glucose load one hour after delivery produced a marked rise in blood glucose and plasma insulin concentrations one hour later. The distribution of experimental points suggested a sigmoidal dose-response curve. By contrast in newborn rats kept at room temperature (24° C.) the same glucose load did not induce any increase in plasma insulin in spite of hyperglycemia. However, phentolamine resulted in pronounced plasma insulin rise in hypothermic newborns in response to glucose administration. From these observations it is concluded that the in-vivo unresponsiveness of the beta cells to glucose at birth, reported by others, is mainly due to the experimental conditions.
Acute- and Late-Phase Insulin Secretion and Glucose Tolerance in Mild Alloxan Diabetes in Dogs
Authors: Pupo Armando A , Ursich Milani J M , Iamaguchi Emi , Vasconcellos Francisco G
Published: September 2013

The acute and late phases of insulin secretion were studied in mongrel dogs before and after the induction of mild alloxan diabetes. Fasting glucose and insulin levels were unchanged from pretreatment values. The alloxan-diabetic dogs had significantly decreased early-phase insulin responses to glucose pulses (0.5 gm./kg.) and slower plasma glucose disappearance rates. In contrast, these mildly diabetic dogs achieved comparable insulin levels and higher glucose levels during a four-hour 40 mg./min. glucose infusion than pre-alloxan control values. Similar findings in human congenital mild diabetes have been interpreted as beta cell insensitivity or impedance to efficiency of plasma glucose uptake. The present observations in alloxan-induced mild diabetes in dogs suggest that reduced early-phase secretion and intact later phase of insulin secretion are not dependent on genetic determinants and may be induced in a model of acquired diabetes.
Growth Hormone Levels in Diabetes: Correlation with the Clinical Control of the Disease
Authors: Vigneri R , Squatrito S , Pezzino V , Filetti S , Branca S , Polosa P
Published: September 2013

We carried out contemporaneous daytime blood sugar and growth hormone (HGH) determinations in eight juvenile and six middle-aged diabetics under both poor and good metabolic control. A continuous blood sampling technic was used. The following results were obtained:

1. HGH values in poorly controlled diabetics were higher and more fluctuating than in normals of a corresponding age.

2. After good control was reached, a significant HGH decrease was observed in all patients but one. In this condition HGH levels were normalized in middle-aged diabetics but not in juvenile ones. In the latter group HGH values, even if decreased, were persistently higher than in controls of the same age.

3. No difference was observed between newly diagnosed diabetics and patients known to have had diabetes for some years.

Our data support the suggestion that HGH abnormalities in diabetes are a consequence of the metabolic disturbance.
Tumor Hypoglycemia: Deficient Splanchnic Glucose Output and Deficient Glucagon Secretion
Authors: Silbert Cynthia K , Rossini Aldo A , Ghazvinian Sasan , Widrich Warren C , Marks Leon J , Sawin Clark T
Published: September 2013

Fasting hypoglycemia occurred in a patient with a histologically benign mesothelioma; the serum insulin was low (2-4 µU./ml.), as was the glucose utilization rate. Splanchnic glucose output was markedly decreased on direct measurement (21 mg./min.; normal: 108-180 mg./min.). Splanchnic uptake of gluconeogenic substrates plasma glucagon was low normal during hypoglycemia and responded poorly to oral and intravenous alanine. The nonsuppressible insulin-like (NSILA-s) and somatomedin-like activities of the serum were not elevated, and the tumor did not release insulin-like activity on incubation nor did it contain somatostatin. The marked decrease in splanchnic glucose output was the principal cause of hypoglycemia, was associated with an apparent decrease in glycogenolysis, and was at least partly due to deficient glucagon secretion. The relationship of the tumor to these defects is unclear. The tumor may have secreted an unknown insulin-like material affecting primarily the liver and/or pancreatic alpha cell. The approach used here may serve as a paradigm for the analysis of hypoglycemia not caused by excessive insulin.
Glucose Tolerance and Insulin Release, A Mathematical Approach: I. Assay of the Beta-cell Response After Oral Glucose Loading
Authors: Sluiter W J , Erkelens D W , Reitsma W D , Doorenbos H
Published: September 2013

From txshe dose-response relations between glucose and insulin after oral glucose loading, a reproducible parameter for beta-cell response was deduced. The main advantage of this parameter —corrected insulin response, defined as CIR = I · 100/G(G–70)— lies in it independence from the initial or reached glucose level.
Insulin Receptors in Cultured Human Fibroblasts
Authors: Rechler Matthew M , Podskalny Judith M
Published: September 2013

In order to study human insulin resistance, we have first characterized the interaction of insulin with specific insulin receptors in cultures of normal human fibroblasts. 125I-insulin bound rapidly to human fibroblasts in suspension at 15°, achieving steady state between one and three hours. Insulin was not degraded during the binding assays. In competitive binding experiments, 2 ng/ml. (3.3 × 10−10 M) of unlabeled insulin reduced 125I-insulin binding by 50 per cent. Insulin analogues competed for binding in proportion to their biologic potencies. A curvilinear Scatchard plot was obtained, suggesting the existence of negatively cooperative site-site interactions among the insulin receptors. This was confirmed directly by studies of the dissociation kinetics. The high affinity, specificity, and negative cooperativity of the fibroblast insulin receptor closely resembles the properties of other human insulin receptors. The cultuted human fibroblast should prove a useful tissue for the study of insulin-resistant states in man.
Actions of Insulin-Potentiating Peptides on Glycogen Synthesis
Authors: Ng Frank M , Larner Joseph
Published: September 2013

The action of urinary and synthetic AcG (acceleratory factor from growth hormone) peptides was studied in vitro and in vivo. Both peptides were inactive alone and active only in the presence of insulin to enhance glucose uptake, glycogen synthesis, and glycogen synthase conversion to the active I form in vitro and in vivo. Responses were dependent on both peptide and insulin concentrations in a dose-dependent manner. No response was obtained with glucose alone, but the presence of glucose did enhance the response of insulin alone or insulin in the presence of peptide. It is concluded that both AcG peptides enhance either the effective concentration or the activity of insulin at its site of action.