bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperosmolar Nature of Diabetic Coma
Authors: Fulop Milford , Rosenblatt Andrew , Kreitzer Stephen M , Gerstenhaber Brett
Published: September 2013

Stupor in patients with nonketotic hyperglycemia has been ascribed to hyperosmolarity, but the cause of depressed consciousness in patients with ketoacidosis has been puzzling. In this study, blood pH, serum glucose and sodium concentrations, and serum osmolality were measured in eighty-five consecutive episodes of diabetic ketoacidosis and forty-seven of nonketotic hyperglycemia. In the acidotic patients, as in those with nonketotic hyperglycemia, stupor closely paralleled hyperosmolarity and not the severity of acidemia. Indeed, the mean elevations of serum osmolarity were almost the same in the ketotic and in the nonketotic patients who were deeply obtunded.

It seems likely that depression of consciousness in patients with severely uncontrolled diabetes mellitus, if not due to a nonmetabolic disorder, such as acute stroke, is attributable to hyperosmolarity, whether or not ketoacidosis is present.
Plasma Immunoreactive Insulin (IRI) and Immunoreactive Glucagon (IRG) After Evisceration with and Without a Functional Liver
Authors: Penhos J C , Ezequiel M , Lepp A , Ramey E R
Published: September 2013

Fed male Wistar rats were eviscerated by two procedures. The first group of eviscerated rats were left with a nonfunctional liver in situ while the second group were eviscerated by a newer technic, developed in this laboratory, that preserves liver function.7 The animals were maintained on a regimen of saline and antibiotic treatment, and abdominal aortic blood was drawn at intervals up to seventy-two hours postoperatively from animals with a functional liver and up to six hours postoperatively in those with nonfunctional liver status. Blood concentrations of glucose, immunoreactive insulin, and immunoreactive glucagon were measured. Our results indicate that even with a functional liver, totally pancreatectomized eviscerated rats maintained normal amounts of plasma IRI and IRG for more than twenty-four hours. IRI and IRG were measurable even at forty-eight hours postoperatively. At the same time, these animals developed abnormally high blood glucose levels, which were sustained despite the presence of “normal” IRI in plasma. It had been suggested that the presence of measurable IRI and IRG in the classically prepared eviscerated animal was due to a deficit liver destruction of these substances. To the contrary, our data suggest that even with a functional liver, the eviscerated preparation maintains a circulating level of insulin and glucagon-like materials forty-eight hours after the known sources of such substances are removed. The physiologic meaning of immunoassay results following pancreatectomy are thus difficult to interpret.
Arginine-stimulated Acute Phase of Insulin and Glucagon Secretion: I. In Normal Man
Authors: Palmer Jerry P , Walter Robert M , Ensinck John W
Published: September 2013

To document and characterize the immediate phase of glucagon secretion as detected in peripheral blood in man, we have given pulses of L-arginine (0.1 gm. to 10.0 gm.) intravenously over twenty to thirty seconds to twenty-three healthy young men. Peak glucagon and insulin levels averaging four and five times basal levels respectively were reached two to five minutes after arginine administration and had returned to baseline levels by fifteen to thirty minutes. Computing the area above basal for the initial ten minutes after arginine stimulation established a dose-response relationship for the acute phases of glucagon and insulin secretion. A maximal glucagon response was elicited by doses of arginine of 5.0 gm. or greater, whereas for insulin, the plateau was reached at 2.5 gm. of arginine. Sequential 5.0-gm. pulses of arginine administered every thirty minutes showed that there was no augmentation or attenuation of the timing, magnitude (area 0-10 minutes) or absolute peak values reached for either the glucagon or insulin responses. The effect of induced hyperglycemia on the acute phase of insulin and glucagon secretion was assessed by administering the arginine during marked elevation of ambient glucose concentration achieved by the intravenous administration of glucose. This resulted in marked suppression of the acute glucagon response and dramatic accentuation of the insulin response.
Effect of Physical Exercise on Secretion of Growth Hormone, Glucagon, and Cortisol in Obese and Diabetic Children
Authors: Garlaschi Cristina , Natale Berardo di , Guercio Maria Josè del , Caccamo Anna , Gargantini Luigi , Chiumello Giuseppe
Published: September 2013

The effect of muscular exertion of moderate intensity on blood sugar (BS), plasma levels of growth hormone (GH), glucagon, and cortisol (F) has been studied in endocrinologically normal children with short stature and compared with children with clinical diabetes mellitus and obese children with normal and diminished carbohydrate tolerance.

In diabetic children, physical exertion induces a rise in plasma GH levels comparable to that in controls; in obese children with normal or with diminished glucose tolerance, the rise is considerably smaller.

Physical exertion caused no change in F levels in the groups tested, although basal level in the obese children was significantly higher than in the controls. Basal glucagon levels were similar in all groups and showed no change on physical exertion.

The behavior of GH and glucagon in diabetic children was comparable to that in the controls even where blood sugar level was high.
Alcoholic Ketosis
Authors: Fulop Milford , Hoberman Henry D
Published: September 2013

Twenty-four chronic alcohol abusers hospitalized during a twenty-seven-month period were suspected of having “alcoholic ketoacidosis” because they had ketonuria or ketonemia with little or no glucosuria. Twenty-one had moderate or severe ketosis, with plasma 3-hydroxybutyrate of 5.2 to 22.5 mmol/L. Fifteen of this group were not diabetic, while six were later found to have mild postprandial hyperglycemia without glycosuria. Three patients who had continued to drink until shortly before admission, though at first suspected of having alcoholic ketosis, were found to have predominant lactic acidosis, with minor elevations of plasma 3-hydroxybutyrate.

In contrast to previously reported patients with “alcoholic ketoacidosis,” severe acidemia was uncommon in this series. Indeed, seven patients were alkalemic, because of coexisting respiratory or metabolic alkalosis.

Most patients had eaten poorly for several days (and usually longer) and had allegedly decreased their alcohol intake during that period. That history, and the usual rapid clearing of ketosis simply by treatment with solutions of glucose and NaCl, suggested that acute starvation was an important factor in the pathogenesis of this disorder.

Four patients were treated with insulin and four with NaHCO3 solutions. In retrospect, the need for either of these treatments was not clear. Two of the twenty-four patients died, one from circulatory failure secondary to hemorrhage and the other from pulmonary edema, but no patient died because of ketoacidosis per se.
The Inexhaustible Beta Cell
Authors: Vinik A I , Kalk W J , Botha J L , Jackson W P U , Blake K C H
Published: September 2013

Repeated intensive pancreatic beta-cell stimulation was carried out in 42 subjects, comprising 22 normal controls, 10 mild to “severe” maturity-onset diabetics, and 10 chronic pancreatitis patients. Each subject received 75 gm. oral glucose twice and 1 mg. glucagon plus 0.5 gm. tolbutamide intravenously three times at short intervals. Each of the three combined stimuli caused almost equivalent marked spikes of insulin release in all experimental groups. The total calculated output of insulin was equivalent to the total daily insulin output in normal subjects. Pancreatitics and those with severe diabetes (fasting blood sugar greater than 120 mg./100 ml.) had qualitatively similar but a quantitatively smaller response. Those with mild diabetes were similar to the normal subjects but had an exaggerated response to the second oral glucose dose, suggesting overactivity of the enteroinsular axis. Despite the inordinate insulin levels, hypoglycemia did not occur.
Plasma Glucagon and the Insulin:Glucagon Ratio in Gestational Diabetes
Authors: Kuhl C , Hoist J J
Published: September 2013

The influence of pregnancy on serum glucose, serum insulin, and plasma glucagon concentrations was studied in eight normal women and 14 nonobese gestational diabetics. Each normal individual was subjected to an oral glucose tolerance test in midpregnancy, and all subjects were investigated late in pregnancy and again four to six weeks postpartum. As compared with the postpartum values, fasting glucose concentration decreased during gestation in the normals and increased in the gestational diabetics, but the changes were small and insignificant. In contrast, fasting insulin concentration increased equally and significantly in pregnancy in both groups. Likewise, the glucagon concentration was enhanced in the fasting state in both groups in pregnancy. However, the molar insulin-to-glucagon ratio was significantly elevated in both normals and gestational diabetics. In late pregnancy the magnitude of the insulin response to oral glucose (i.e., the incremental insulin area above fasting baseline) was equally and significantly enhanced in the normals and the gestational diabetics. However, when the insulin response during the first 60 minutes of the OGTT was expressed per unit of glucose stimulus (i.e., the Δinsulin/Δglucose ratio) a significantly higher mean response was found in the normal pregnants than in the gestational diabetics. In pregnancy and postpartum, plasma glucagon always decreased to levels significantly below fasting levels after glucose ingestion. In normal midpregnancy the degree of suppression of glucagon was close to that of postpartum, whereas an exaggerated and prolonged suppression was found in late pregnancy in the normals as well as the gestational diabetics. These findings indicate that plasma glucagon and serum insulin concentrations are profoundly influenced by pregnancy. As the changes, however, lead to an increased insulin-to-glucagon ratio, the diabetogenicity of pregnancy is not explained by this relationship.
Incorporation of 75Se-Selenomethionine into Human Apoproteins: II. Characterization of Metabolism of Very-low-density and Low-density Lipoproteins in Vivo and in Vitro
Authors: Eaton R Philip , Crespin Stephen , Kipnis David M
Published: September 2013

This investigation is designed to explore the potential role of apoVLDL as a precursor of a polypeptide component of human LDL. Attention was directed to the chromatography-defined Sf-I polypeptide fraction of apoVLDL, which has been previously shown to be immunologically and chemically indistinguishable from the major component of apoLDL1–3. In VLDL isolated from blood drawn within two hours following 75Se-SM injection, the Sf-I polypeptide fraction of apoVLDL was highly enriched with isotope, providing an appropriate preparation for in-vitro tracer studies. Conversion of 75Se-VLDL to 75Se-LDL occurred in vitro in the presence of normal plasma at 37° C., and this conversion was augmented by post-heparin plasma. No conversion to HDL lipoproteins could be detected. Injection of heparin in vivo resulted in acute reciprocal changes in the radioactivity contained within serum apoVLDL and apoLDL. These findings suggest that a component of the Sf-I polypeptide fraction of apoVLDL can be metabolized into the apoprotein of LDL in man. Thus, the biochemical and immunologic similarities between the Sf-I fractions of apoVLDL and apoLDL may result from a physiologic “precursor-product” relationship between the apoprotein moieties of these two lipoprotein species. A method for further investigation of the metabolism of human apoprotein is suggested.
Fetal Pancreas Transplantation for Reversal of Streptozotocin-induced Diabetes in Rats
Authors: Brown Josiah , Clark William R , Molnar I G , Mullen S
Published: September 2013

Streptozotocin-induced diabetes in rats was completely reversed by transplantation of syngeneic fetal pancreases placed beneath the kidney capsule. To accomplish complete reversal of diabetes, four or more pancreases were necessary; three resulted in partial reversal, and two produced a slight but significant effect in some recipients. Removal of the transplants resulted in the prompt return of diabetes. The islets of Langerhans in the transplants functioned homeostatically; this was indicated by regular normal blood glucose values, in addition to normal findings in blood IRI response and glucose disappearance rate after glucose injection. Disappearance of exocrine elements, with only ducts and fibrous tissue remaining, resulted in a pure endocrine organ. The advantages of this technic, such as ease of accessibility for placement, observation, and removal, are of great importance for possible application to humans.
Potentiation of Glucose-induced Insulin Release by Glucose in the Isolated Pancreas of Fed and Fasted Rats
Authors: Efendić Suad , Cerasi Erol , Luft Rolf , Gladnikoff Gils
Published: September 2013

Glucose, apart from its acute insulin-releasing effect, exerts a time-dependent potentiating action on subsequent stimulations of the pancreas.1 The influence of a 24-hour starvation on these two actions of glucose was studied with the completely isolated, perfused rat pancreas preparation.

Starvation had no effect on the time kinetics of the insulin response, but the magnitudes of the early and late insulin-secretion phases were reduced to similar extents. It was demonstrated by using a wide glucose concentration range that the maximal insulin response is not significantly modified by starvation. In contrast, both the threshold of stimulation by and the Km for glucose were higher in the pancrease from fasted rats. Thus, starvation reduces the sensitivity of the islet for the insulin-releasing action of glucose.

When the stimulatory concentrations of glucose were preceded for 40 minutes by the perfusion of 8.3 mM instead of the basal, 4.4 mM glucose, insulin secretion from the pancreas of fed animals was not modified. In contrast, raising the glucose concentration of the equilibrium period to 8.3 mM potentiated markedly the insulin response to subsequent stimulations in the pancreas from fasted rats. This potentiation expressed itself as increase in the maximal response: the Km for glucose was not reduced. Thus a 40-minute pretreatment with 8.3 mM glucose does not correct the diminished sensitivity induced by a 24-hour starvation.

It is concluded that in starvation (1) the sensitivity for glucose of the mechanisms that initiate insulin release is diminished; (2) the sensitivity of the pancreas for the potentiation-inducing action of glucose is augumented. (3) In both respects, the insulin response of fasted rats is similar to that of mildly diabetic subjects. These and other findings3 suggest that the effect of glucose in initiation of insulin release and on generation of a state of potentiation in the islet are mediated by different mechanisms.
Plasma Renin Activity and Hypertension in Diabetes Mellitus
Authors: Christlieb A Richard , Kaldany Antoine , D'Elia John A
Published: September 2013

Plasma renin activity (PRA) was determined in 48 patients with diabetes mellitus in sodium balance on a 10-20 mEq. Na diet. Nine were normotensive (group I), 11 were hypertensive without diabetic nephropathy (group II), and 28 had hypertension and nephropathy (group III). Results were compared with those in 16 normal subjects and 49 nondiabetic patients with essential hypertension in similar Na balance. Mean supine PRA did not differ significantly among groups I and II, normal subjects, and patients with essential hypertension. Group III diabetics had a supine PRA of 2.4 ± 0.4 ng./ml./hr. ( ± S.E.M.), significantly lower than the other diabetic groups (P < 0.005) and normal subjects (P < 0.05). Upright PRA was 12.8 ± 2.2 in group I diabetics, similar to that in normal subjects (13.3 ± 2.3), and 8.1 ± 1.4 in group II diabetics, similar to that in essential hypertensives (6.8 ± 0.8). In group III diabetics, upright PRA was 4.0 ± 0.5, significantly lower than that in any other group. These results suggest that (1) PRA is normal in normotensive diabetics, (2) upright PRA in diabetics with hypertension but no nephropathy is similar to that in essential hypertension, and (3) patients with diabetes, hypertension, and nephropathy have “low renin hypertension,” explaining the virtual absence of malignant hypertension in this group. Although the major mechanism for this low PRA may be volume expansion, indicating the need for potent diuretics, other mechanisms include hyalinization of the afferent arteriole, decreased cathecholamine stimulation of renin release, and inadequate conversion of prorenin to renin.
Renal Wastage of Insulin in Children with Diabetes Mellitus
Authors: Malone John I , Root Allen W
Published: September 2013

In normal human beings the percentage of serum insulin excreted in the urine is constant over a wide range of values. The quantity of immunoreactive insulin found in the urine is believed to reflect the level of free insulin in the serum. Immunoreactive insulin was measured in the urine of nondiabetic children and diabetic children receiving exogenous insulin. Children with diabetes mellitus excreted greater amounts of immunoreactive insulin (18.5±8 μU./mg. creatinine) than did nondiabetic children (11.9±5 μU./mg. creatinine). This difference was statistically significant (p < 0.0005). Children with “poor glycemic control” excreted a greater portion of their administered insulin dose than did those with “good control.” The renal wastage of insulin correlated (r=0.94) with the duration of insulin treatment but not with the quantity administered. Antibody binding of serum insulin may explain in part these observations, but an acquired defect in the renal tubular reabsorption of insulin may also exist. Modifications in the management of diabetes that reduce the renal wastage of insulin may improve the metabolic stability of children with “poor diabetic control.”
Current Concepts of Somatomedin and Other Biologically Related Growth Factors
Authors: Chochinov Ronald H , Daughaday William H
Published: September 2013

Since the discovery 20 years ago that the growth-promoting effects of somatotropin are mediated through a serum factor(s), research in this area has rapidly expanded. It is the purpose of this review to bring this area of scientific endeavor into perspective.

The first part of this review will deal with aspects of total serum somatomedin activity and its biologic actions and measurements in health and disease. The last part of this review will summarize some of the physical and biologic characteristics of the recently purified “somatomedin-like” substances: somatomedin A, B, and C, NSILA-S (nonsuppressible insulin-like activity-soluble in acid ethanol) and MSA (multiplication-stimulating activity).
Measurement and Partial Characterization of Immunoreactive Glucagon in Gastrointestinal Tissues of Dogs
Authors: Morita Soichiro , Doi Kunihiro , Yip Cecil C , Vranic Mladen
Published: September 2013

We have reported previously that increasing amounts of immunoreactive glucagon (IRG), measured by four specific antisera, appeared in plasma of depancreatized insulin-deficient dogs. It was therefore concluded that pancreatectomy was not accompanied by glucagon deficiency in the dog, but instead excessive amounts of extrapancreatic IRG could contribute to the diabetic syndrome. In order to locate the source of extrapancreatic glucagon, tissue extracts were assayed with anti-glucagon sera 30-K and K-44, which cross-react minimally with crude gut extracts. IRG was detected in all gastrointestinal tissues and in the salivary glands, but not in extracts of liver, kidney, brain, heart atrium, and adenohypophysis. Immunologic dilution curves of extracts from all gastrointestinal tissues were parallel to those of the pure pancreatic glucagon standard, and both antisera (30-K and K-44) measured the same concentrations. The highest concentration of gastrointestinal IRG was found in the fundus and corpus of the stomach. Presence of IRG in gastrointestinal tissues of depancreatized dogs indicates that gastrointestinal cells can not only secrete but also store large amounts of IRG.

Extracts of mucosa of stomach fundus were further purified by gel filtration on Biogel P-30 columns. The immunoreactivity in the eluate was assayed by 30-K and a strongly crossreacting antibody, K-4023. One pooled fraction corresponding to marker pancreatic glucagon in its elution volume was found to contain the largest amount of IRG and the highest specific immunoreactivity (IRG/protein concentration). This fraction showed also the highest activity in a glucagon-receptor assay system. Disc gel electrophoresis in the presence of urea resolved this fraction into three immunoreactive components, one of which was identical to pancreatic glucagon in its electrophoretic mobility. It appears, therefore, that mucosa of the upper stomach in the dog contains a polypeptide similar to pancreatic glucagon.

We conclude that (a) hyperglucagonemia in the dog can result from excessive secretion of IRG not only by the pancreatic α cells but also by cells of the gastrointestinal tract; (b) the highest IRG concentration was found in fundus and corpus of the stomach and lower concentrations throughout the gastrointestinal tract; (c) the IRG component in the stomach displayed immunologic and physical properties similar to pancreatic glucagon.
Metabolic and Morphologic Studies in Intraportal-Islet-Transplanted Rats
Authors: Pipeleers-Marichal Miriam A , Pipeleers Daniel G , Cutler John , Lacy Paul E , Kipnis David M
Published: September 2013

The intraportal injection of 350 to 1,000 isolated islets into streptozotocin-diabetic rats immediately normalized (∼ 24 hours) fasting plasma glucose and insulin levels. Polyuria, polydipsia, and hyperglucagonemia disappeared more gradually over a 2-to-12-week period—the time required for normalization varying with the severity of the diabetes and the number of islets transplanted. In long-term islet-transplanted rats (> five months), the hepatic insulin and glucagon reserves averaged 50 per cent and 25 per cent, respectively, of the corresponding normal pancreatic hormone content. Glucagon was increased slightly in the pancreas of streptozotocin-diabetic rats and decreased considerably in transplanted animals. However, total pancreatic glucagon (i.e. pancreatic and hepatic reserves) in transplanted animals was the same as the pancreatic content of normal control rats, indicating the presence of feedback control mechanism(s) in the regulation of pancreatic glucagon reserves. Long-term transplanted islets demonstrated well-granulated A-, B-, and D-cell movement out of the vascular space and the formation of narrow intercellular spaces and junctional complexes with surrounding hepatocytes.
Infant Human Pancreas: A Potential Source of Islet Tissue for Transplantation
Authors: Sutherland David E R , Matas Arthur J , Steffes Michael W , Najarian John S
Published: September 2013

Twelve pancreases from human infants one year old or less were analyzed for tissue insulin and amylase content before and after dispersal of pancreatic fragments by mincing and collagenase digestion. Tissue insulin and amylase content provide an index of pancreatic islet mass and exocrine digestive enzyme content, respectively. The results were compared with similar anaylses performed on juvenile and adult human pancreases before and after islet isolation and on intact and dispersed neonatal rat and adult rat pancreas. Infant human pancreas has an average tissue insulin concentration of 1,128 μg./gm. of tissue and a total insulin content of 1,718 μg/pancreas, as against values of 140 μg./gm. of tissue and 7,209 μg./pancreas for adult human pancreas. Average tissue amylase concentration is 0.24 mg./gm. of tissue in infant human pancreas and 3.0 mg./gm. of tissue in adult human pancreas. The insulin/amylase ratio in infant pancreas is 4,800, as against 46 in the adult pancreas. Neonatal rat pancreas, which can be dissociated and transplanted without separation of islet and exocrine components, has a similarly high tissue insulin and low tissue amylase content when compared with adult rat pancreases. Infant human pancreas has a total islet mass 24 per cent that of an adult human pancreas, and neonatal rat pancreas has a total islet mass 11 per cent of that of an adult rat pancreas. One neonatal rat pancreas prepared by minimal collagenase digestion can cure diabetes when transplanted via the portal vein to a rat. Following dispersal of infant human pancreas by collagenase digestion, the islet content and the insulin/amylase ratio of the recovered tissue equals or exceeds that which usually can be isolated from adult cadaver pancreases. Infant human pancreas is a rich source of islet tissue that is relatively uncontaminated by exocrine digestive enzymes. After dispersal, infant human pancreas may be ideal for transplantation to selected diabetic patients.
The Insulin Receptor: Its Role in Insulin Resistance of Obesity and Diabetes
Authors: Olefsky Jerrold M
Published: September 2013

In recent years, techniques have become available to study the interaction between insulin and its cellular receptors. This has led to an explosion of information concerning the status of insulin receptors in normal and abnormal physiologic states. Obesity and nonketotic diabetes are two common abnormal states in which insulin resistance exists, and the purpose of this review is to summarize current knowledge concerning the cellular mechanisms of insulin resistance in these conditions, with specific emphasis on insulin receptors and how they may relate to the pathogenesis of resistance to insulin action.
Subpopulations of Peripheral Lymphocytes in Juvenile Diabetes
Authors: Hann Suhung , Kaye Robert , Falkner Bonita
Published: September 2013

Subpopulations of peripheral lymphocytes were studied in 26 children with insulin-treated juvenile diabetes and in 27 control children of comparable age. T-lymphocytes were quantitated by spontaneous rosette-formation with sheep erythrocytes and B-lymphocytes by indirect immunofluorescence with the use of monovalent, fluorescein-labeled rabbit antiserum specific to the heavy chains of human IgG IgM, or IgA. No significant quantitative difference in subpopulations of the peripheral lymphocytes, T-cells, and B-cells with IgG, IgA, or IgM markers found between children with juvenile diabetes and the control group, although the B-lymphocytes with IgG or IgA markers tended to be higher and those with IgM markers lower in the diabetic than in the control group.
Florid Diabetic Retinopathy and its Response to Treatment by Photocoagulation or Pituitary Ablation
Authors: Kohner Eva M , Hamilton A M , Joplin G F , Fraser T R
Published: September 2013

A group of 34 patients with florid diabetic retinopathy are reported. Nine of these had at least one eye untreated and of these only two maintained vision at one year—the others were blind. Ten patients had 11 florid eyes treated by photocoagulation. At one year six were blind and five had good vision. At two years only three could still see. Of 20 pituitary-ablated patients with 29 florid eyes, only three were blind at one year. Even at five years, 12 of 17 eyes could see and only two patients were blind. The one- and two-year visual acuities were significantly better in the pituitary ablated eyes than in the untreated and photocoagulated ones (p = 0.01 – 0.03). It is suggested that for this rare form of retinopathy pituitary ablation remains the treatment of choice if vision is to be maintained.
Metabolism of Forearm Tissues in Man: Studies with Glucagon
Authors: Pozefsky Thomas , Tancredi Robert G , Moxley Richard T , Dupre John , Tobin Jordan D
Published: September 2013

The role of glucagon in regulating peripheral tissue metabolism in man was assessed in the present studies. To do this, glucagon was infused for two hours into the brachial artery to produce a high but physiologic increment in the glucagon content of arterial blood supplying ipsilateral tissues. Metabolic effects on muscle and on subcutaneous adipose tissue plus skin were sought in seven overnight-fasting subjects and seven subjects starved briefly (60 hours).

In the overnight-fasted group the infusion increased bassl glucagon concentration by 1,216 pg./ml. but was without effect on forearm tissue metabolism of glucose, lactate, glycerol, or amino acids. Starvation significantly reduced basal insulin (11.0 to 7.4 μU./ml.) and increased endogenous glucagon (116 to 134 pg./ml.). Basally, there was substantial ketone utilization and a decrease in glucose consumption by both muscle and subcutaneous adipose tissue plus skin. The glucagon infusion increased basal glucagon by 784 pg./ml. Muscle balances of glucose, lactate, acetoacetate, amino acids, and glycerol were unaffected. The metabolism of glucose, lactate, acetoacetate, glycerol, and free fatty acids by subcutaneous adipose tissue plus skin was also unchanged. It is concluded that physiologic increments of glucagon lasting two hours are without effect on forearm tissues in overnight-fasted and briefly starved man.
Peripheral T-lymphocytes in Juvenile-onset Diabetics (JOD) and in Maternity-onset Diabetics (MOD)
Authors: Cattaneo R , Saibene V , Pozza G
Published: September 2013

The percentage and absolute number per mm.3 of peripheral T-lymphocytes were determined in 11 juvenile-onset diabetics (JOD), in 21 maturity-onset diabetics (MOD), and in 18 normal subjects (NS). The percentage was significantly lower in JOD (38.1) than in MOD (57.2) and NS (56.5). The absolute T-lymphocytes number per mm.3 was significantly lower in JOD (833) than in NS (1,260); this was also true for JOD as against MOD (1,026), even if the difference was not statistically significant. No difference was found between MOD and NS, or between MOD on oral therapy and on insulin treatment. The decrease of peripheral T-lymphocytes in JOD was not related to associated illness or drugs. The data presented suggest the possibility of an altered cell-mediated immunity in juvenile-onset diabetics.
Cyclic Nucleotides in Pancreatic Islets: Tolbutamide- and Arginine-induced Insulin Release
Authors: Charles M Arthur , Lawecki January , Steiner Alton L , Grodsky Gerold M
Published: September 2013

With the use of isolated rat islet perfusion, levels of the islet cyclic adenosine 3′ ,5′-monophosphate (cAMP) were compared with dynamic insulin secretion induced by tolbutamide and arginine. Tolbutamide elevated islet cAMP rapidly and augmented both glucose-induced islet cAMP levels and insulin secretion; arginine, however, did not elevate islet cAMP but did enhance glucose-induced insulin secretion. Since the latter result could have been modulated by cyclic guanosine 3′,5′-monophosphate, this cyclic nucleotide was also measured and found to remain unchanged during stimulation of insulin secretion by arginine and a combination or arginine and glucose.

Thus, the action of tolbutamide appears to be modulated in part by cAMP, whereas arginine appears to augment insulin secretion independently of cyclic nucleotides.
Assessment of Peripheral Vascular Disease in Patients With Diabetes: Two Case Studies
Authors: Rhodes Buck A , Bader Pearl , Stolz Kathleen , White Robert I , Siegel Michael E
Published: September 2013

This report proposes that perfusion scanning in combination with arteriography be included in the diagnostic work-up of the diabetic patient who, because of peripheral vascular complications, is a candidate for surgery. Two cases are reported which illustrate the extremes of the findings: abnormal arteriogram-normal scan indicating large-vessel disease without significant small-vessel involvement. It is suggested that these patients are candidates for vascular reconstruction. The other extreme is the normal arteriogram-abnormal scan indicating small-vessels disease without significant large-vessel involvement. It is apparent that these patients are not candidates for vascular reconstruction.
Structural Studies of Insulin and Insulin Derivatives Using Various Immunologic Indicators and Antibody Populations
Authors: Arquilla Edward R , Dorio Raymond J , Brugman Thomas M
Published: September 2013

These studies suggest that the immunologic indicator in the radioimmune assay, 125I-iodoinsulin, selects antibody populations from within the antiserum that interact with determinants distant from the solvent surface on the insulin molecule to which iodine is substituted. Evidence is presented that the connecting peptide of proinsulin is in close proximity to regions on the solvent surface of the A-chain of insulin that include the tyrosyl residues at A-14 and A-19.

A marked immunologic cross-reaction between derivatives of insulin with perturbations in the regions of tyrosyl A-14 and A-19 was noted in the radioimmune assay employing desalanine-(B-30)-desasparagine-(A-21)-insulin antiserum. This observation is consistent with the presence of a restricted population of antibodies in such antisera that is directed toward immunologic determinants in or near the insulin dimer site.

The apparent immunologic activity of insulin derivatives depends on which antibody populations from the antiserum pool can react with the immunologic indicatory employed on the one hand and on the composition of antibodies in that antiserum on the other. These studies indicate that the specificity of antibody populations in a given antiserum can be identified and their levels quantitated with several assay systems, each employing one of a variety of indicators.
Diabetes Mellitus in the Guinea Pig
Authors: Lang Max C , Munger Bryce L
Published: September 2013

Spontaneous diabetes mellitus has been documented in a colony of guinea pigs. The contagious nature of the disease has been verified, but the nature of the infectious agent is not known. Animals from the original colony or animals exposed to the colony with normal glucose tolerance tests (GTT) became diabetic, as evidenced by elevated one- and four-hour GTT values, and in most cases have significant glycosuria. The severity of pathologic changes in the pancreatic islets parallel, in general, the severity of the clinical symptoms (glycosuria and abnormal GTT). Those animals with severe glycosuria and elevated FBS as well as one- and four-hour GTT values had the most pronounced degranulation and most prominent cytoplasmic inclusions in islet B cells. The severity of scarring in the islets can be correlated with the duration of the overt diabetic state. The other clinical parameters of note were elevated serum triglycerides, normal serum but elevated aortic cholesterol, and absence of ketonemia or ketonuria. The reproductive capacity of diabetic females was compromised. While the clinical manifestations are mild or variable, the presence of significant islet pathology is reminiscent of human juvenile diabetes mellitus. These findings lend support to the concept that infectious and/or immune mechanisms could be operative in the etiology and pathogenesis of human diabetes mellitus.
Further Studies on the Metabolism of D-Glucose Anomers in Pancreatic Islets
Authors: Idahl Lars-Åke , Rahemtulla Firoz , Sehlin Janove , Täljedal Inge-Bert
Published: September 2013

The α and β anomers of commercially available D-(5-3H) glucose were separated by miniaturized Hudson-Dale procedures based on precipitation with acetic acid. Reflectometric measurements of the reactivity with matrix-bound glucose oxidase showed that the preparations were about 90 per cent pure with respect to anomeric composition. Nonradioactive anomers separated by the same procedures were analyzed by optic polarimetry and gas chromatography. The preparations were about 90 per cent pure with respect to anomeric composition and produced no peaks but D-glucose on trimethylsilylation and chromatography. Microdissected pancreatic islets of noninbred ob/ob-mice exhibited a linear production of 3H2O for three to nine minutes when incubated with 6 mM α-D-(5-3H) glucose, β-D-(5-3H) glucose, or D-(5-3H) glucose in anomeric equilibrium; the three glucose preparations did not differ in their rate of conversion to 3H2O. The rate of 3H2O production increased with glucose concentration (3–21 mM) during incubations for three minutes and, again, there was no evidence for the metabolic activity's being dependent on the anomeric composition of the labeled sugar. When microdissected islets were perifused without glucose and suddenly exposed to 5–6 mM α-D-glucose or β-D-glucose, the concentration of glucose-6-phosphate rose within five minutes and did not differ significantly between experiments with α-D-glucose and β-D-glucose. In the same perifusion experiments, only α-D-glucose caused a pronounced stimulation of insulin secretion, the difference from β-D-glucose being significant. The results indicate that the recognition of glucose as an insulin secretagogue does not only involve metabolism by glucose-6-phosphate. The possible roles of the sorbitol pathway and of hypothetical regulatory sites for the glucose molecule (“receptors”) are briefly discussed.
Effect of Multiple Daily Insulin Injections on the Course of Diabetic Retinopathy
Authors: Job Didier , Eschwege Eveline , Guyot-Argenton Claudine , Aubry Jean-Pierre , Tchobroutsky Georges
Published: September 2013

Forty-two diabetic patients on insulin once a day in the early stage of diabetic retinopathy were randomly assigned to one of two kinds of insulin regimen, i.e., single or multiple daily injections. Retinal changes were quantitatively estimated by counting the microaneurysms (MAs) observed on fluorescein angiograms at the posterior pole of the more diseased eye. Baseline characteristics of the two groups were not significantly different. These included duration of diabetes, age at diagnosis, daily dose of insulin, amount of urinary sugar excreted in 24 hours, fasting blood sugar (FBS), and number of MAs. During the follow-up (mean duration of three years) the mean yearly progression in the number of MAs was significantly less in the multiple-than in the single-injection groups: 1.8 ± 0.7 versus 7.2 ± 1.9 (p < 0.01; nonparametric test: p < 0.02). Final values were, respectively, MAs: 15.2 ± 4.9; 33.0 ± 7.9; glycosuria (gm./24 hrs): 20.6 ± 2.5; 27.5 ± 4.3; FBS (mg./100 ml.): 154 ± 15; 195 ± 11. P values comparing the two groups were <0.02, <0.02, and <0.05.

Thus, in this clinical trial, made under routine treatment conditions, the use of divided daily insulin injections was effective in improving diabetic control and delaying retinal changes.
Human Maternal and Fetal Serum Insulin and Growth Hormone (HGH) Response to Glucose and Leucine
Authors: Grasso S , Palumbo G , Messina A , Mazzarino C. , Reitano G.
Published: September 2013

Maternal and fetal serum insulin and HGH responses to glucose, leucine, and glucose plus leucine were examined by infusions to pregnant women at term immediately before cesarean section. Leucine (15 gm.) with glucose (50 gm.) administered for 30 minutes to the mothers stimulates markedly maternal and fetal insulin secretion while infusion of glucose (50 gm.) causes a lower insulin response. When infusing glucose alone we noted that the duration rather than the degree of hyperglycemia determined the fetal insulin response. In fact, when glucose is given to the mother for 60 minutes the fetal insulin response is higher than when the same dose is infused for 30 minutes. Maternal infusion of leucine (15 gm.) for 30 minutes elicits only a very slight increase of insulin secretion in the mother and no change in the fetus. None of the infusions causes any alteration whatsoever in either maternal or fetal HGH secretion.
Retinopathy in Pima Indians: Relationships to Glucose Level, Duration of Diabetes, Age at Diagnosis of Diabetes, and Age at Examination in a Population with a High Prevalence of Diabetes Mellitus
Authors: Dorf Arthur , Ballintine Elmer J , Bennett Peter H , Miller Max
Published: September 2013

The occurrence of retinopathy and its relationship to diabetes in 1,640 Pima Indians age 15 and over has been determined. Eighteen per cent of those with two-hour postload plasma glucose levels of equal to or greater than 200 mg./dl. had some evidence of retinopathy. Of those with retinopathy and diabetes, 7 per cent were found to have proliferative or neovascular changes, the remainder having microaneurysms and/or exudates. The frequency of retinopathy increased from 3 per cent among newly diagnosed diabetics to 47 per cent among those with diabetes of 10 or more years duration. No relationship was found with sex, age at diagnosis of diabetes, or age at time of examination when duration of diabetes was taken into account. The occurrence of retinopathy was confined largely to those who fell into the second or hyperglycemic component of the frequency distribution of plasma glucose levels in the population, indicating the significance of the bimodal glucose tolerance frequency distribution.
Diabetes Mellitus: Incidence, Prevalence, Survivorship, and Causes of Death in Rochester, Minnesota, 1945–1970
Authors: Palumbo P J , Elveback Lila R , Chu Chu-Pin , Connolly Daniel C , Kurland Leonard T
Published: September 2013

The incidence and prevalence of diabetes mellitus in residents of Rochester, Minnesota, for 25 years (1945 to 1970) were determined from available medical records. The over-all incidence rate for diabetes is 133 new cases per 100,000 population per year (age-adjusted to 1970 U.S. white population). The rate increased with age for both men and women and was higher among men over 30 years of age. The average annual incidence rates per five-year period for juvenile-onset diabetes mellitus were low and variable and showed little change. Polyuria, polydipsia, glycosuria, lean habitus, loss of weight, and high levels of fasting hyperglycemia at initial diagnosis occurred more frequently in younger than in older patients.

The peak incidence in 1960 through 1964 and the decrease in the following five years may be a reflection of the introduction of the AutoAnalyzer method for blood glucose in 1958. The average annual incidence rates for 1955 through 1959 and 1965 through 1969 were essentially the same. The over-all prevalence for diabetes mellitus is 1.6 per cent, with a higher rate among men than among women over 40 years of age; among school children the rate is 0.1 per cent. Survivorship in the diabetic population is lower than that in the general population. The leading cause of death was coronary heart disease, the death rate from it being higher than for the general population.
Virus-induced Pancreatic Disease by Venezuelan Encephalitis Virus: Alterations in Glucose Tolerance and Insulin Release
Authors: Rayfield Elliot J , Gorelkin Leo , Curnow Randall T , Jahrling Peter B
Published: September 2013

Viral infections have been implicated in the induction of diabetes mellitus in man and laboratory animals. Since virus-specific immunofluorescence (FA) is detectable in hamster pancreas during the acute phase of Venezuelan encephalitis (VE), experiments were designed to correlate pathologic and virologic events with metabolic studies in VE-infected hamsters. Golden Syrian hamsters were inoculated s.c. in groups of four to 12 with 100,000 plaque-forming units (PFU) of the vaccine strain (TC-83) of VE or 1,000 PFU of the virulent Trinidad strain of VE. Ultrastructurally, during Trinidad infection, mature virions were associated with the cell surfaces and within pancreatic beta cells in contrast to absence of virus-related changes in TC-83-infected hamsters. Virus-specific-FA was noted in islet cells and acinar cells of Trinidad-infected hamsters. VE growth curves demonstrated viral replication in pancreas with both strains. Although ultrastructural and FA changes were much more prominent in Trinidad-infected hamsters in contrast to TC-83-infected hamsters during the first few days of illness, the rapid lethality of the Trinidad-infected group necessitated performing all metabolic studies in TC-83-strain-infected hamsters. Accordingly, for the metabolic studies, glucose tolerance tests (GTT) using 2 mg. or 5 gm./kg. glucose i.p. were performed in groups of hamsters acutely infected two days earlier with the TC-83 vaccine strain and in 24-day and 90-day convalescent hamsters after TC-83 vaccine strain. Samples were obtained for glucose and immunoreactive insulin (IRI) determinations. Glucose intolerance occurred in hamsters in each of the infected groups given 5 gm./kg. glucose except for the 90-day convalescent TC-83 group. Severely decreased IRI responses occurred in the 24-day and 90-day convalescent TC-83 hamsters following both 2- and 5-gm./kg. glucose. Pancreatic IRI content in 24-day convalescent TC-83 hamsters was within normal limits, suggesting a defect in IRI release from the beta cells at this stage of convalescence.
Incorporation of 75Se-Selenomethionine into Human Apoproteins: III. Kinetic Behavior of Isotopically Labeled Plasma Apoprotein in Man
Authors: Eaton R Philip , Crespin Stephen , Kipnis David M
Published: September 2013

The metabolism of lipoprotein-apoprotein was examined in four subjects with normal lipid metabolism and in one subject with type II hyperlipemia by means of isotopic tracer methodology. Studies were performed after intravenous injection of a radioactive amino acid precursor for apoprotein synthesis (75Se-selenomethionine), in both the basal state and following the acute injection of intravenous heparin. Computer technics were used to evaluate a series of multicompartmental models, and a general model is proposed that yields optimum fitting of experimental data for serum free amino acid precursor, very-low-density lipoprotein-apoprotein (VLDapoprotein), and low-density lipoprotein-apoprotein (LDLapoprotein) in man.

The analysis demonstrates that approximately half of the transport of 75Se-apoVLDL from the plasma VLDL pool is converted to 75Se-apoLDL. The acute injection of heparin in two normal subjects results in a two-and-a-half-fold increase in this rate of conversion of 75Se-apoVLDL to 75Se-apoLDL. 75Se-apoLDL is metabolized by rapid transport into a recycling extravascular pool and by irreversible catabolism. The fractional rate of recycling is large relative to the fractional rate of catabolism of apoLDL (3.7:1.0), suggesting extravascular recycling as a potential site of regulation of the plasma concentration of apoLDL. In a patient with type II hyperlipemia, the extravascular recycling pathway is reduced and is not corrected with D-thyroxine therapy. However, this therapy did reduce conversion of apoVLDL to apoLDL in this type II patient.

The kinetic data support the validity of the compartmental model in simulating both normal and pathologic apoprotein metabolism and that perturbation of physiology seen with heparin injection and D-thyroxine therapy. These data support a quantitative role of apoVLDL as a precursor of apoLDL and identify an important recycling pathway of apoLDL metabolism in addition to that of catabolism.
Comparison of Peripheral and Portal Routes of Insulin Infusion by a Computer-controlled Insulin Infusion System (Artificial Endocrine Pancreas)
Authors: Botz C K , Leibel B S , Zingg W , Gander R E , Albisser A M
Published: September 2013

This study was undertaken to determine the different consequences of portal and peripheral routes of insulin administration by the artificial endocrine pancreas. Intraportal glucose was infused (10 mg./min./kg. for 60 minutes) in anesthetized normal and pancreatectomized dogs while blood glucose concentrations were monitored continuously. During computer-controlled insulin administration normal glucose tolerance was restored by both portal and peripheral routes of insulin delivery. There were also no significant differences in (1) glycemic patterns, (2) insulin infusion patterns, (3) peripheral IRI levels, and (4) total insulin requirements between the two routes. It is apparent that the peripheral route, which is more readily accessible than the portal route, may be an appropriate infusion site for an implantable or portable prosthesis for controlling blood glucose concentration.