bluuebunny/crossref_metadata_2025 huggingface dataset:
Placental Glycogen Metabolism in Diabetes Mellitus
Authors: Gabbe Steven G , Demers Laurence M , Greep Roy O , Villee Claude A
Published: December 2014

Carbohydrate metabolism may be markedly altered in the pregnant patient with diabetes mellitus. How such changes in maternal physiology affect the placenta, a tissue of fetal origin, has been studied by measuring glycogen synthetase, glycogen phosphorylase, and glycogen concentrations in fresh term placental tissue from eight normal women delivered vaginally, eight normal patients delivered by repeat cesarean section, and fifteen patients with diabetes mellitus. Placental weights were also determined.

Placentas of normal patients, whether delivered vaginally or by cesarean section, were extremely similar in all parameters studied. In contrast, the glycogen concentration in placentas from diabetic patients was significantly elevated (p < .001) although glycogenesis appeared limited by decreased levels (p < .01) of synthetase I. Phosphorylase a activity was increased significantly (p < .025) in placental tissue of diabetic patients as was total phosphorylase (p < .05). Placental weight was decreased in patients with retini-tis proliferans.

These placental enzyme differences noted between the normal and diabetic patient suggest that insulin may play an important role in controlling glycogen metabolism in the human placenta. In diabetes mellitus, increased glycogen concentrations of the placenta may be due to prolonged hyperglycemia throughout gestation and that the elevated term placental glycogen may be responsible for the observed suppressed synthetase I formation and the stimulated phosphorylase a activity found in the diabetic term placenta.
Ultrastructural Study of Alterations in Beta Cells of Pancreatic Islets from Cyproheptadine-Treated Rats
Authors: Longnecker Daniel S , Wold John S , Fischer Lawrence J
Published: December 2014

Pancreatic islet β-cells undergo structural changes in rats which are given daily 45 mg./kg. oral doses of cyproheptadine. The ultrastructural features of this lesion were studied after 1, 2, 4, 7, and 14 days of treatment. There was progressive degranulation of β-cells which was largely complete at two days, although a few granules were still evident at fourteen days. The rough endoplasmic reticulum underwent sequential changes of cisternal dilation, vesiculation, vesicle fusion, and vacuole formation. No normal appearing rough endoplasmic reticulum remained in β-cells of seven- and fourteen-day-treated rats. Ribosomes were lost from much of the surface of the vacuoles and vesicles which appeared to be derived from rough endoplasmic reticulum in these cells. Other cytoplasmic organelles of β-cells retained generally normal structure. Autophagy and necrosis were absent. Alteration in the glucose tolerance test was observed after two daily doses of cyproheptadine. Alpha and delta cells of islets and acinar cells appeared to be unaffected.
Effect of Insulin on Protein Synthesis
Authors: Manchester Keith L
Published: December 2014

The mechanism by which insulin controls protein metabolism is not fully understood. Insulin stimulates protein synthesis; it also enhances transport of some amino acids, but the latter action does not appear to be sufficient explanation of the increase in synthesis. The various actions seem to be independent of effects on glucose metabolism. In diabetic muscle there are fewer than normal polysomes, and insulin rapidly enhances attachment of monomers to messenger-RNA. Insulin also increases the effectiveness of cell sap in catalyzing protein synthesis by ribosomal systems. The way in which the hormone may affect either initiation or peptide synthesis is not known.

Experiments are reported bearing on whether availability of amino acids could be a mechanism by which effects of insulin are mediated. Activity of liver and muscle soluble fractions declines on fasting and, for the latter tissue, possibly also on a low protein diet. Sap from fasting animals allows a much smaller response of isolated ribosomes to added amino acids. Availability of glutamate in amino acid mixtures may be of special importance. However, insulin can influence the activity of the sap fraction of diaphragm muscle during incubation without the presence of amino acids in the medium. Understanding of what mechanisms are involved will depend on resolution of the critical sap factors.
Amino Acid Sequences of Insulins
Authors: Smith Leslie F
Published: December 2014

The amino acid sequences of insulins determined to date are summarized. Guinea pig, coypu and rat insulins are discussed in particular.
Amino Acid Sequences of Proinsulins and Intermediates
Authors: Chance Ronald E
Published: December 2014

Comparison of the amino acid sequences of human, porcine and bovine proinsulins reveals a high degree of variance within the respective connecting peptide segments. This is particularly reflected by species-specific guinea pig antisera which indicate that the proinsulin antigenic determinants are contained within the connecting peptides. In porcine proinsulin, the major antigenic determinant appears to be a hydrophobic region within the 41–54 amino acid sequence. Collectively, proinsulin and proinsulin-related intermediates may account for 3 to 6 per cent of the protein in commercial insulin preparations, which explains most of the heterogeneity observed by the sensitive polyacrylamide disc-gel electrophoresis technic. Theoretically, many of these intermediates may be formed from proinsulin by the combined actions of trypsin and carboxypeptidase B or by enzymes of similar specificity; this implies that such enzymes comprise the conversion system in the beta cells. On the basis of structure-activity studies with these unique insulin analogs, the connecting peptide probably interferes with insulininsulin antibody interactions, and a free NH2-terminal glycine on the A chain is needed for full biological activity.
Molecular Basis of Insulin Action: Contributions of Chemical Modifications and Synthetic Approaches
Authors: Zahn Helmut , Brandenburg Dietrich , Gattner Hans-Gregor
Published: December 2014

Current methods used in the preparation of modified insulins for investigating structure-activity relations are briefly discussed. Several chemical degradation and semisynthetic procedures are outlined which were used in the authors' laboratory for the preparation of molecularly homogeneous insulin analogs and derivatives. Des-PheB1 insulin was obtained through selective Edman degradation of insulin, Arg-GlyAl insulin was synthesized by elongation of A-chain S-sulfonate, and this was followed by combination of Arg-GlyA1 chain with natural B chain S-sulfonate. The preparation of [p-iodo-PheB1] insulin was accomplished by removal and replacement of PheB1. Monoacetyl insulins, substituted at GlyA1 or LysB29, respectively, were obtained via partial acetylation of insulin as well as by acetylation of the separate chains. The five compounds could be crystallized in the presence of zinc.

Two insulin derivatives with split A7-B7 disulfide bond, [di(S-carboxymethylcysteine)A7,B7] insulin and [di(S-sulfocysteine)A7,B7] insulin, were obtained through selective electrolytical reduction or partial sulfitolysis.

Some biological and immunological properties of these and seven other modified insulins are presented. The N-terminus of the A chain is highly sensitive to chemical alterations, with the biological activity decreasing in the following order: substitution > removal of the NH2 group > removal of Gly > removal of Gly and lie. The deletion of PheB1 causes no activity loss; the A7-B7 bond can be cleaved and full or at least partial activity be retained.

In view of the scope and limitations of both semisynthetic and synthetic methods, both approaches will be required in future work to prepare potentially important analogs based upon predictions from the three-dimensional structure of insulin as determined by x-ray analysis.
Synthesis of Polypeptides Related to Porcine Proinsulin
Authors: Yanaihara Noboru , Hashimoto Tadashi , Yanaihara Chizuko , Sakagami Masanori , Sakura Naoki
Published: December 2014

Syntheses are described of eleven protected peptide fragments which cover the entire sequence of porcine proinsulin and of two partially protected polypeptides which correspond to the 17–84 and 15–84 amino acid sequences, respectively, of porcine proinsulin.

The amino acid sequences of the two partially protected polypeptides are illustrated in the text. In these peptides, the sulfhydryl group of cysteine is protected with the ethylcarbamyl function, and the s-amino group of lysine is blocked with the formyl function. The partially protected octahexacontapeptide I cross-reacted with anti-synthetic porcine connecting peptide antisera to the same extent as did the porcine proinsulin or the synthetic connecting peptide. Heptacontapeptide II cross-reacted with antisera to porcine proinsulin and slightly with antisera to porcine insulin.
On the Biosynthesis, Intracellular Transport and Mechanism of Conversion of Proinsulin to Insulin and C-Peptide
Authors: Kemmler Wolfgang , Peterson James D , Rubenstein Arthur H , Steiner Donald F
Published: December 2014

The detailed mechanism of the enzymic transformation of proinsulin has not yet been elucidated, but it appears to be a complex process requiring the participation of several proteolytic activities. A useful model system is described in which ordinary pancreatic trypsin arid carboxypeptidase B are shown to rapidly and quantitatively convert proinsulin to insulin. This reaction is accompanied by the liberation of the C-peptide and four basic amino acids. Studies on the biosynthesis and conversion of proinsulin in isolated islets of Langerhans suggest that the conversion to insulin begins in the Golgi apparatus and continues within newly formed secretory granules. Evidence bearing on this conclusion is summarized, and experiments are described that demonstrate conversion of proinsulin to insulin in a crude secretory granule fraction prepared from islets of Langerhans. Lysates of this subcellular fraction have been shown to contain low levels of trypsin-like activity. With lightly trypsin-treated proinsulin labeled with [3H]-arginine in the regions of specific cleavage as a substrate, a carboxypeptidase B-like activity has also been detected. Further studies will be required to elucidate the nature of these enzymes and their possible relationship to the pancreatic acinar trypsins and carboxypeptidases. Structural studies on C-peptides from several mammalian species are briefly discussed. Comparisons of these amino acid sequences indicate that considerably greater interspecies variation occurs in this region of the molecule. Extension of these comparative studies of C-peptide structure should shed light on the role of this region in facilitating the correct folding of the proinsulin polypeptide chain, and these also may disclose new aspects of insulin evolution.
Nutrient Regulation of Insulin Secretion in Human Subjects
Authors: Kipnis David M
Published: December 2014

Of all the known secretogogues, glucose is the only one that produces a biphasic secretory response (an early, rapid release of insulin followed by a long, sustained release) and is the only metabolite that stimulates both insulin secretion and biosynthesis at physiologic concentrations. The initial phase is a major determinant of the rate at which the organism utilizes glucose.

An enteric receptor system in man recognizes whether glucose is being ingested or given parenterally. Dynamics of insulin secretion following oral glucose differ markedly from those following parenteral administration. It is suggested that the excessive plasma insulin levels in some maturityonset diabetics during an oral GTT are related primarily to the enteric receptor system and to a delayed release of insulin. Normally, glucose is extracted by the liver due to the early release of insulin. A delay in the release of insulin by maturity-onset diabetics permits glucose to escape hepatic extraction. Thus, the glycemic stimulus is much greater. Known enteric secretogogues enhance the secretory effect of the elevated plasma glucose. Hypoglycemia may develop.

A critical level of glucose is needed to demonstrate the enhancement of insulin secretion by glucagon in children. Intravenous glucagon failed to elicit insulin release when plasma glucose was below 50 mg. per 100 ml.

It is suggested that the genetically determined defect in diabetes mellitus involves the glucoreceptor mechanism. The inability to perceive a glucose signal accounts for the hypoinsulinemic response observed in prediabetic subjects. The insulin-resistant characteristic of the obese state is a secondary adaptation to the hyperinsulinemia produced by excessive carbohydrate intake. It may represent an adaptive mechanism whereby the individual who eats excessive carbohydrate is protected from intermittent hypoglycemia.
Streptozotocin-induced Diabetes and Islet Cell Alterations in Rabbits
Authors: Lazarus Sydney S , Shapiro Stanley H
Published: December 2014

Rabbits are demonstrated to be susceptible to the dia-betogenic and B cell cytotoxic effects of streptozotocin. A single intravenous dose of 300 mg./kg. results in more marked and consistent B cell lesions than 150 or 75 mg./kg. but with greater lethal toxicity after eighteen hours. Animals surviving forty-eight hours or longer show marked hyperglycemie. Although serially progressive B cell alterations are noted both by light and electron microscopy, they are not uniform in any one pancreas or at any one time. Some B cells show necrobiosis with nuclear pyknosis within two hours after drug administration. However, most B cell nuclei show early aggregation of chromatin, rarefaction of interchromatinic material with nuclear enlargement and loss of typical nucleoli. This is followed by nuclear pyknosis with shrinkage and compression of content and eventual loss of chromatin with karyorrhexis by eighteen to twenty-four hours. Cytoplasmic changes at two to four hours include proliferation of ergastoplasm and ribosomes, the appearance of electronlucent regions of hyaloplasm at the secretory pole and mitochondrial swelling. Later there is dilatation of cisternae of endoplasmic reticulum, the appearance of electron dense intramitochondrial matrical aggregates and the breakdown of intercellular membranes. B cell granules persist until the cells begin to disintegrate. Streptozotocin was also found to induce necrobiosis in occasional A cells but no effect could be detected on D cells.
Release of Clearing Factor Lipase (Lipoprotein Lipase) in Vivo and from Isolated Perfused Hearts of Alloxan Diabetic Rats
Authors: Aktin E , Meng H C
Published: December 2014

The release of clearing factor lipase (CFL) into the blood stream after heparin injection and from hearts during perfusion with a heparin-containing fluid was studied using normal and alloxan diabetic rats. In addition, the effect of alloxan diabetes on heart tissue lipase activity and the “repletion” of this enzyme in previous “depleted” animals by pre-injection of heparin were also investigated. The results show that the plasma CFL activity after an injection of a standard dose of heparin and that of the medium incubated with heart slices or homogenates in the presence of heparin was significantly decreased in alloxan diabetic rats. CFL release from isolated perfused hearts of alloxan diabetic rats was comparable to that from hearts of normal animals during the short perfusion period of five to ten minutes. However, the enzyme release from hearts of alloxan diabetic rats was considerably decreased during prolonged perfusion. Addition of insulin and glucose to the fluid perfusing hearts of diabetic animals did not correct the defect. Insulin treatment restored the CFL activity in plasma, heart slices, homogenates, and perfusates to normal levels. The CFL release into the blood stream or from perfused hearts of rats previously treated with heparin was decreased when rats were given a second injection of this agent or when rats were killed and hearts were perfused less than two hours after the first heparin administration. This decrease was more marked in diabetic than in normal rats. The “repletion” of CFL in hearts of normal rats was completed in three hours with an overshoot four hours after heparin injection. The CFL release from perfused hearts of diabetic rats remained at a low, depleted level even eight hours after heparin administration. The heart tissue lipase activity in rats with heparin pretreatment was also decreased; this decrease was more marked in diabetic than in normal animals. The “repletion” of tissue lipase was also much slower in diabetic rats. Omission of heparin in the incubation medium of heart slices and the perfusion fluid markedly decreased the lipase release especially that from the perfused heart; the decrease was very slight in the incubation medium of heart homogenates. Tissue and perfusate lipase were inhibited by sodium chloride and protamine.
Immunohistopathology of Diabetic Glomerulosclerosis
Authors: Westberg N Gunnar , Michael Alfred F
Published: December 2014

The cause and nature of the lesions in small blood vessels in diabetes mellitus is still unknown. Immunological mechanisms possibly related to reactions between insulin and antibodies to insulin, or damage caused by transudation of serum proteins, have been proposed by several investigators. To study these factors, we have examined by immunofluorescence thirty-seven samples of diabetic kidney tissue, showing varying degrees of pathology from normal to end-stage. A thin linear staining of the glomerular basement membrane was seen in about half the cases for IgG and IgM, including four tissues with normal or only slightly abnormal histology, and less frequently for fibrin, β1C, albumin and ceruloplasmin. Heterologous complement did not bind in vitro to the basement membrane. Eluted IgG from the isolated glomeruli and sera from anephric diabetic patients did not react with normal glomeruli in indirect immunofluorescence. Fluorescent insulin did not bind to diabetic basement membrane and antibodies to insulin did so only exceptionally. The results are interpreted as showing that the serum proteins are found in the basement membrane as a result of nonimmunological mechanisms, possibly as a result of alteration in the glomerular basement membrane or mesan-gial dysfunction.
Fatty Acid Oxidation, Oxidative Phosphorylation and Ultrastructure of Mitochondria in the Diabetic Rat Liver: Hepatic Factors in Diabetic Ketosis
Authors: Harano Yutaka , DePalma Ralph G , Lavine Lawrence , Miller Max
Published: December 2014

Oxidative phosphorylation, maximum rate of palmitate xidation and ultrastructure of mitochondria (MT) were tudied in livers of ketotic, nonketotic and insulin-treated liabetic rats. Significant changes in oxidative phosphorylaion were found only in ketotic diabetes. Respiratory control atios were decreased for all of the substrates studied and vere primarily due to increased state 4 respiration with lalmitylcarnitine and 2-oxoglutarate, and lowered state 3 espiration in the case of succinate. ADP/O ratio was only partially lowered with 2-step oxidation of 2-oxoglutarate. The naximum rate of palmitate oxidation to acetoacetate was ncreased 90 per cent in MT of rats with ketotic diabetes ind 50 per cent in MT from animals with nonketotic diabetes. Accompanying these changes were ultrastructural alteritions of MT. The average size of MT in the diabetic rat liver was 50 per cent larger in cut sections. MT within hepacocytes in ketotic diabetes were distorted, enlarged, and had irregular shapes and contours. Cristae tended to be deranged; when isolated, crescentic MT were predominant, In the insulin-treated diabetic rats, these functional and morphological changes were not observed. The results imply that in diabetic ketosis, increased availability of free fatty acid(s) (FFA) in hepatocytes together with increased capacity of mitochondrial FA oxidation produces more acetyl CoA which in turn results in an overproduction of ketone bodies. Since a significant increase in state 4 respiration of MT isolation from ketotic diabetic rats was observed, FA oxidation may proceed independently of ADP availability because of “loose” coupling of respiration to phosphorylation.
The Glycemic Response to Arginine in Man
Authors: Felig Philip , Marliss Errol
Published: December 2014

To determine the mechanism of the glycemic response to administration of arginine in man, incorporation of arginine-U-C-14 into blood glucose was investigated in postabsorptive subjects given an intravenous infusion of 30 gm. of Larginine monochloride containing 50 μCi of L-arginine-UC-14. As expected, a prompt increase in blood glucose and serum insulin levels was observed. However, whereas the maximal increment in blood glucose of 15 to 22 mg./100 ml. occurred within twenty to thirty minutes of initiation of the infusion, recovery of arginine-C-14 in blood glucose was not detectable until after thirty to fifty minutes, reaching peak levels at 120 min. In subjects given only the tracer dose of arginine-C-14 in whom serum insulin concentration remained at postabsorptive levels, incorporation of C-14 into blood glucose was detectable within ten minutes.

It is concluded that the glycemic effect of arginine cannot be explained on the basis of gluconeogenesis from this amino acid. The insulinogenic action of arginine may contribute to the delay in incorporation of this amino acid into glucose.
Connective Tissue Macromolecular Changes in Rats with Experimentally Induced Diabetes and Hyperinsulinism
Authors: Berenson Gerald S , Radhakrishnamurthy B , Dalferes Edward R , Ruiz Harold , Srinivasan Sathanur R , Plavidal Ferdinand , Brickman Fred
Published: December 2014

A study of connective tissue components from skin of rats with induced diabetes and hyperinsulinism was performed. Diabetes was induced in rats by a single injection of streptozotocin (50 to 75 mg./kg. body weight) and hyperinsulinism by daily injection of NPH insulin (½ to 2½ U.). Serum was analyzed for protein-bound carbohydrates and free sugars. A decrease in serum protein-bound sugars was observed in the diabetic animals. These slightly increased in hyperinsulin state. Acid mucopolysaccharides (MPS), glycoproteins (GP) and collagen were isolated from skin of experimental animals and compared with the controls. The contents of total MPS and GP decreased in diabetic skin; these increased in hyperinsulin state, similar to that observed in human diabetes. Diabetic rat skin had more soluble collagen, while less soluble collagen was observed in hyperinsulin state. It is suggested from these observations that insulin is a driving force toward the synthesis and accumulation of these compounds in connective tissue in experimental hyperinsulinism and, perhaps, in human diabetes with prolonged insulin treatment.
Effect of Ammonium Chloride Acidosis on the Oral Glucose Tolerance and Insulin Sensitivity of Normal Rats
Authors: Frost Philip , Reaven Gerald M
Published: December 2014

Moderate systemic acidosis (pH 6.97-7.20) was produced in rats by the oral administration of ammonium chloride. The rats were treated for two and one-half days, and during this period had free access to food. The effect of this degree of metabolic acidosis on glucose tolerance was studied by determining the plasma glucose response to an oral glucose load (3 gm./kg. body weight) and the effect of acidosis on insulin sensitivity was estimated by measuring in vitro glucose oxidation of isolated epididymal fat pads. It was not possible to demonstrate a significant effect of acidosis in either instance, and it is concluded that moderate acidosis in the absence of starvation, has a relatively modest effect on glucose tolerance and on adipose tissue responsiveness to insulin.
Hyperglycemia, Hypoglycemic Attacks, and Production of Anti-Insulin Antibodies Without Previous Known Immunization: Immunological and Functional Studies in a Patient
Authors: Følling I , Norman N
Published: December 2014

A forty-two-year-old man with hyperglycemia and pronounced reactive hypoglycemia after meals and oral glucose is reported. He produced anti-insulin antibodies without previous known immunization.

Labeled insulin, when mixed with the patient's serum, passed with the serum proteins on gel filtration, and was found among the 7S globulins on preparative ultracentrifugation, in the anodic γ-region on agar electrophoresis, and among the anodic γG-globulins on immunoelectrophoresis. The clearance of labeled insulin in vivo was very slow, and the glucose response to intravenous insulin was absent. The free binding capacity in serum was several thousand μU./ml. Acid splitting of the insulin—anti-insulin complexes revealed 7,000 μU./ml. or more of endogenous insulin, and antibodies which bound human and pig insulin better than bovine insulin. After oral glucose the patient's serum insulin increased by 2,300 μU./ml. Some new principles are introduced in the quantitative studies on serum insulin and antibodies. Theoretical restrictions on these and other quantitations are discussed.

The hyperglycemia may be explained by the antibodies binding secreted insulin, and the hypoglycemia by an insulin overshoot from maximally stimulated β-cells when saturation of the binding capacity was approached. Carbohydrate restriction prevented the hypoglycemic attacks. The cause of the antibody production and the properties of the antibodies are discussed.
Effects of Long-term Infusion of Glucagon on Carbohydrate Metabolism, Insulin and Growth Hormone Secretion in Patients with Congestive Heart Failure
Authors: Frey Harald M M , Falch Dagfinn , Forfang Kolbjørn , Norman Nils , Fremstad Dag
Published: December 2014

Glucagon was given by continuous intravenous infusion for ninety-six hours to eight patients with severe congestive heart failure. The dose was 4 or 2 mg. per hour. Results were similar in both groups and are presented together.

Mean fasting blood sugar increased significantly during infusion (from 87 to 103 mg./100 ml.). Mean fasting serum immunoreactive insulin (IRI) increased considerably (from 9.1 to 32.0 μU/ml.) and mean fasting serum immunoreactive growth hormone (HGH) increased from 2.8 to 11.9 ng./ml.

Intravenous glucose tolerance tests were performed before and during glucagon infusion. The glucose disappearance rate (K-value) declined significantly during the infusions (from a mean of 0.85 to 0.46), although serum IRI responses to the intravenous glucose were much higher than before. Serum HGH levels were not suppressed by the glucose and sometimes even showed a rise.

A carbohydrate-rich meal induced the same rises in blood sugar during glucagon infusion as before, but serum IRI responses were much higher during glucagon, and elevated serum HGH values were not normalized.

It is concluded that long-term infusion of pharmacological doses of glucagon to patients with cardiac insufficiency leads to a state of mild carbohydrate intolerance, characterized by some increase in fasting blood sugar and decrease in glucose disappearance rate, in spite of very considerable rises in serum IRI. This diabetes-like state may be accounted for by elevated levels of serum HGH, although other insulin-antagonistic factors may be involved.
Pancreatic Compartmentalization of Insulin: Evidence for Pituitary Control
Authors: Merimee Thomas J , Fineberg S Edwin
Published: December 2014

African pygmies who appear to be insensitive to the metabolic effects of human growth hormone (HGH) are insulinopenic after administration of either glucose or arginine. Contrary to our expectation, insulin responses in this group were normal after tolbutamide and glucagon. To clarify this observation, insulin secretion was studied in twenty-nine normal controls and six dwarfs with growth hormone deficiency.

After arginine and glucose, peak insulin responses in controls were, respectively, 90.4 ± 8.6 μU./ml. and 108.0 ± 12.0 μU./ml. In HGH deficient dwarfs, responses were 38.6 ± 6.0 μU./ml. and 40.0 ± 6.4 μU./ml. (p < .01). In controls as well as HGH deficient dwarfs, the mean maximal insulin responses to arginine and glucose were increased two- to fourfold by HGH treatment (5 nig. twice a day for five days). Similar results occurred after ingestion of mixed meals.

Both tolbutamide and glucagon caused normal insulin responses in the HGH deficient group. Mean maximal responses to tolbutamide were 69.4 ± 15.0 μU./ml. in controls and 61.6 ± 7.7 μU./ml. in HGH deficient dwarfs. Mean maximal responses to glucagon were 101.6 ± 19.4 μU./ml. and 102.0 ± 9.4 μU./ml., respectively. Unlike arginine and glucose, HGH had no effect upon insulin responses to either agent in controls.

The data support the division of pancreatic pools of insulin into two major groups: those dependent and those not dependent upon pituitary secretion of HGH.
A Method for the Determination of Plasma Insulin Antibodies and Its Application in Normal and Diabetic Subjects
Authors: Sebriakova M , Little J A
Published: December 2014

A practical, sensitive and specific method for the assay of antibodies to insulin in human plasma has been developed. This method involves competition for insulin antibody between a constant, trace amount of I-125-insulin and increasing concentrations of unlabeled insulin standard. The insulin standard is prepared from the soluble form of therapeutic insulin that the patient has been receiving. The quantity of antibody is calculated arbitrarily from the amount of unlabeled insulin required to displace 25 per cent of bound I-125-insulin from the antibody. The result is expressed as microunits of insulin antibody per milliliter of plasma. Since this is not the absolute amount of antibody present but does indicate a relative, quantitative immunologic response of each patient to the antigen, insulin, the result is referred to as an antibody index. The method has a precision of 20 per cent and sensitivity of 1 μU./ml. The coefficient of variation is significantly less at higher antibody indices: 8 per cent in the 1,001 to 80,000 range and 22 per cent in the 0.08 to 40 μU./ml. range.

Therapeutic subcutaneous doses of Lente or Sulphated insulin do not interfere with the antibody assay, whereas the interference from Regular insulin continues for several hours. The antibody index declines after withdrawal of insulin therapy and has a half-life of approximately eighteen days. There is no diurnal variation in antibody index. Three newborn infants of insulin-treated diabetic mothers were found to have insulin antibodies.
Gluconeogenesis in Renal Cortical Tubules: Effect of Phenformin
Authors: Gordon Edwin E , Hartog Maria de
Published: December 2014

Studies of gluconeogenesis were carried out with isolated tubules prepared from the renal cortex of fasted rats. A study of the metabolic characteristics of this preparation upon incubation at 37° revealed a sustained respiratory rate, a constancy of ATP levels, and a linear rate of gluconeogenesis. Virtually no glucose synthesis was observed unless appropriate substrates were added; succinate and α-ketoglutarate were the most effective precursors. The addition of phenformin to the suspension of isolated tubules led to a decline of O2 uptake and ATP content in the absence and in the presence of added substrate. In the presence of succinate, there was a close correlation between the ATP content and the rate of gluconeogenesis. The data indicate that the phenformin-induced inhibition of gluconeogenesis is secondary to limitation of ATP generation rather than a direct effect on the enzymatic sequence leading to new glucose formation or to limited availability of reducing equivalents.
Relationship Between the Basal Glucose Concentration Glucose Tolerance and Forearm Glucose Uptake in Maturity-onset Diabetes
Authors: Jackson R A , Perry Gillian , Rogers J , Advani Usha , Pilkington T R E
Published: December 2014

The relationship between the basal glucose concentration, glucose tolerance and peripheral glucose uptake has been studied in nonobese diabetic males not requiring insulin by determining forearm glucose uptake (FCU) during a 100 gm. oral glucose tolerance test (GTT) before and after carbohydrate restriction.

On a normal diet basal glucose concentrations were elevated and glucose tolerance was grossly impaired; the increment in FCU during the CTT (0 to 180 minutes) amounted to 52.8 mg./100 ml. forearm. After carbohydrate restriction basal glucose concentrations were reduced, the glucose tolerance curve was lowered and the increment in FCU rose to 76.5 mg./100 ml. forearm; glucose tolerance, however, expressed as the incremental area under the glucose tolerance curve (0 to 180 minutes), remained unchanged.

Serum insulin responses during the tests were low and uninfluenced by carbohydrate restriction. Blood lactate concentrations were increased by glucose loading before but not after carbohydrate restriction. FFA and β-hydroxybutyrate concentrations fell progressively after glucose loading while, conversely, acetoacetate concentrations were initially unchanged. During the GTT acetoacetate was taken up by the forearm while lactate and β-hydroxybutyrate were released.

In addition, the responses of three diabetics on a normal diet were compared with those of age-matched normal men; in each diabetic FGU was equal to or greater than that in the normal subjects, but nonetheless, the increment in glucose concentrations was several times greater.

The results suggest that in these patients with diabetes [1] the lowering of the glucose tolerance curve by carbohydrate restriction is not synonymous with an over-all improvement in tissue glucose disposal but is due primarily to a fall in the basal glucose concentration and [2] the impairment of glucose tolerance both before and after carbohydrate restriction is predominantly the result of a reduction in hepatic rather than peripheral glucose uptake.
Insulin Patterns in Equivocal Glucose Tolerance Tests (Chemical Diabetes)
Authors: Danowski T S , Khurana Ramesh C , Nolan Sean , Stephan Thorsten , Gegick Charles G , Chae Soo , Vidalon Carlos
Published: December 2014

Hyperinsulinemic patterns are a well recognized feature of equivocal glucose tolerances of the chemical diabetes type, i.e. those that are neither definitely nondiabetic nor clearly diabetic. A more complete characterization of such insulin responses is obtained when the data are expressed in terms of increments in insulin from the zero time point.

Thus, two patterns of insulin increments after oral glucose become evident when the equivocal zone of glucose tolerance is divided into lower and upper segments. Tests in the lower segment show normal increments at the halfhour point of the test; at one hour these tests show excessive increments which persist throughout the five hours of observation. On the other hand, tests in the upper zone show delays in the serum insulin rise at the half-hour point, followed by normal increments at one hour and excessive increments thereafter. The pattern is the same whether or not obesity is present.

It is suggested that tests in the equivocal zone of Glucose Tolerance Sum values be taken to be indicative of chemical diabetes. Tests with the Sum in the lower half of the equivocal zone could then represent chemical diabetes with mild intolerance stemming from insulin ineffectiveness, since insulin increments in this group are at or above the mean values recorded in nondiabetic controls. On the other hand, chemical diabetes with moderate glucose intolerance and Glucose Tolerance Sums in the upper half of the equivocal zone would be understood to result from a combination of an initial delay in the serum insulin rise followed by normal and then excessive increments in serum insulin with the latter two indicative of insulin ineffectiveness. However, insulin ineffectiveness may also be present at the time of the insulin delay.

High glucose:insulin ratios in tests indicative of chemical diabetes are almost always attributable to higher glucose increments with insulin increments normal or excessive compared to normal glucose tolerances. Deficient insulin increments contribute to the high ratios only at the half-hour point in tests with Glucose Tolerance Sums in the upper zone of equivocal glucose tolerances.
Thirty-two Fatal Cases of Severe Diabetic Ketoacidosis, Including a Case of Mucormycosis
Authors: Beigelman P M , Warner N E
Published: December 2014

There were thirty-two fatalities in 340 episodes of severe diabetic ketoacidosis occurring in 257 subjects during a three year period. Five patients expired within three hours of admission, before adequate therapy could be started. Causes of death were multiple and complex in certain patients— primary causes were classified as myocardial infarction in seven, pulmonary edema due to coronary arteriosclerosis in one, pneumonia or pneumonitis in eight, cerebrovascular accident in three, acute renal failure in two, gram-negative septicemia in two, acute pancreatitis in two, uncomplicated severe diabetic ketoacidosis in four, carcinoma of pancreas with metastases in one, hyperthyroidism (thyroid “storm”) in one, and mucormycosis in one. This patient expired despite correction of the ketoacidosis and a course of amphotericin B therapy. Insulin resistance, pyelonephritis, gangrene of the leg, diabetic intracapillary glomerulosclerosis, and hepatic cirrhosis also contributed to fatalities in this series of cases.
Insulins of Hystricomorph Rodents
Authors: Neville R W J , Weir Barbara J , Lazarus Norman R
Published: December 2014

The ability of a guinea pig antibeef/pork insulin serum to neutralize the endogenously secreted insulins of five species of hystricomorph rodents has been studied. Endogenous insulins of the tuco-tuco, casiragua and degu were apparently not neutralized, but endogenous insulins of the cuis and chinchilla did appear to be neutralized.
Alcohol Inhibition of Cyclic AMP-induced Insulin Release
Authors: Colwell A R , Feinzimer M , Cooper D , Zuckerman L
Published: December 2014

In order to define the role of alcohol in cAMP-induced insulin release, the two agents were infused into the pancreas or liver of normal dogs separately or in combination. Blood levels of insulin and glucose were measured in the portal vein. CAMP infusion in the pancreatic artery provoked a greater early insulin response than did a similar infusion into the portal vein when glycemic levels were comparable. The addition of alcohol suppressed insulin response to intrapancreatic cAMP. Alcohol in the absence of the stimulus failed to suppress insulin below basal levels. It is concluded that pancreatic alcohol directly inhibits cAMP-related insulin release and that this is the mechanism by which glucagon-induced insulin release is blunted by alcohol. Glucose-induced release, which is potentiated by intravenous alcohol, apparently involves another mechanism.
Regulation of Rat Hexokinase Isoenzymes: II. Effects of Growth Hormone and Dexamethasone
Authors: Bernstein Robert S , Kipnis David M
Published: December 2014

The effects of dexamethasone and growth hormone on hexokinase (HK) isoenzymes and glucose utilization were studied in adipose tissue from young rats. Dexamethasone (0.1 mg./kg. twice a day) caused hyperinsulinemia with normal blood glucose and marked diminution of adipose tissue HK-II after twenty-four and forty-eight hours. HK-I activity was reduced after twenty-four hours but normal after forty-eight hours. There was no change in HK four hours after a single injection of 0.2 mg./kg. Bovine growth hormone (1 mg. daily) had no effect after twenty-four hours, but increased HK-II after forty-eight hours. Plasma glucose and insulin remained unaltered by GH, and HK-I was also unchanged.

Isolated adipocytes showed the same changes as whole fat pads with dexamethasone, aging, fasting and refeeding; GH had no significant effect. HK-I activity under all circumstances was correlated with in vitro lipogenesis from glucose in the absence of insulin, but not with glucose oxidation. Both lipogenesis and oxidation in the presence of insulin (100 μU./1 ml.) werestrongly correlated with HK-II and glucose-6-phosphate dehydrogenase activįties. These results suggest that control of phosphorylation by HK-II may be a mechanism for mediating hormonal actions on insulin-stimulated glucose utilization.
Effect of Phenformin on the Exocrine Function of the Pancreas and on Insulin Secretion after Intraduodenal Infusion of HCL and Intravenous Injection of Secretin
Authors: Czyzyk Artur , Szadkowski Marian , Rogala Henryk , Lawecki January
Published: December 2014

The effect of phenformin on the exocrine function of the pancreas was studied in thirteen healthy subjects. Pancreatic exocrine secretion was stimulated by intraduodenal infusion of 100 ml. of a 0.1 N hydrochloric acid solution and, after fifty minutes, intravenous injection of 1 U. secretin per kilogram of body weight. At the same time serum insulin level was determined by a radioimmunologic method. In each subject the test was performed twice; the first test provided control values, and the second was preceded by treatment with phenformin. Administration of the antidiabetic biguanide markedly reduced the basal secretion rate and its amylase content and also inhibited the increase in secretion normally caused by either intraduodenal infusion of a HCI solution or injection of secretin. In these healthy subjects, intraduodenal infusion of a HCI solution produced a smaller increase in insulin secretion than did intravenous injection of secretin. Previous phenformin treatment largely eliminated the increase in insulinemia after intraduodenal infusion of a HCI solution, whereas it failed to affect the increase in insulinemia after secretin injection. The clinical significance of these observations is discussed.
The Course of Diabetic Retinopathy: A Longitudinal Study
Authors: Gerritzen F M
Published: December 2014

A prospective study was devoted to the spontaneous course of diabetic retinopathy. The retinas of 459 diabetics were photographed every two years for a total follow-up period, planned beforehand, of eight years.

For two-year intervals progression of retinopathy was found in 14 to 29 per cent, a stationary picture in 60 to 69 per-cent, and amelioration in 7 to 17 per cent of cases. For four-year intervals these percentages were 32 to 39, 47 to 57, and 10 to 12, for six-year intervals 39–50, 40–47, and 10–14, respectively. During the total eight-year period, 48 per cent progressed, 38 per cent remained stationary, and 14 per cent improved. When the patients in whom retinopathy developed during the investigation were included, the percentages changed numerically without altering the general trend. The influence of the dropout of patients on the results is emphasized.

The results are compared with the results of other prospective studies.
Modeling Blood Glucose and Insulin Kinetics in Normal, Diabetic and Obese Subjects
Authors: Segre G , Turco G L , Vercellone G
Published: December 2014

A two-compartment model (figure 1) and digital computer technics have been applied to the analysis of glucose and insulin control mechanisms in twenty-six normal, sixteen diabetic, and eight obese subjects. The system was perturbed by infusing glucose (0.5 gm./min. for about 300 minutes) into the three groups or by injecting glucose intravenously as an impulse of 0.33 gm./kg.; plasma insulin and glucose levels were determined and the model was solved by simultaneously fitting to it the experimental data for glucose and insulin, and the additional information gathered by determining the blood disappearance curve of intravenously injected C-14-glucose.

A discriminant analysis for two groups gave a statistically significant separation between normal and diabetic subjects (with infused or impulsive glucose) and between normal and obese subjects (with infused glucose) on the grounds of the seven parameters that characterize the model.

The prominent feature of the diabetics (in addition to the obvious hyperglycemia) was a decrease of λ21 (figure 1), a parameter which measures the insulin response to a glucose load. The prominent feature of the obese subjects was an increase of λ21 and a decrease of —λ21, a parameter which measures the glucose response to insulin. These dynamic characteristics are in agreement with present knowledge of the impairment of glucose and insulin control mechanisms in these pathologic states.
Proinsulin-Specific Antibodies in Human Sera
Authors: Kumar Dinesh , Miller Leona V
Published: December 2014

Sera from nine diabetic patients treated with commercial insulin contained antibodies which reacted to I-125-bovine proinsulin. These antibodies had two distinct components: anti-insulin antibodies which crossreacted with proinsulin, and antiproinsulin antibodies, which were specific to proinsulin and did not react with insulin (purified, single component). Proinsulin-specific antibodies were detectable by their binding to I-125-bovine proinsulin in sera adsorbed with insulin-phe-sepharose or in sera preincubated with excess insulin.

I-125-bovine pro insulin-reactive antibodies showed species specificity. They reacted weakly with porcine proinsulin and appeared to have no crossreactivity with porcine-C-peptide.

The data suggest that proinsulin-specific antibodies (a) may be induced by the contaminants present in commercial insulin; (b) do not inactivate exogenous insulin and therefore, would not influence directly the daily insulin requirements of diabetic individuals.
Metabolic Responses to Fasting and Ethanol Infusion in Obese, Diabetic Subjects: Relationship to Insulin Deficiency
Authors: Kalkhoff R K , Kim H-J
Published: December 2014

During total fasting, insulin regulates plasma glucose concentrations primarily by controlling hepatic glucose production rather than by influencing peripheral tissue glucose utilization. Administration of ethanol to individuals deprived of food lowers plasma glucose principally by suppressing hepatic gluconeogenesis. With these two observations in mind, an indirect study was made of insulin deficiency and disturbed hepatic carbohydrate metabolism with persistent hyperglycemia during total fasting in six severely diabetic obese women, matched in age and weight with six nondiabetic and six moderately diabetic, obese female subjects. The degree of abnormal hyperglycemia that distinguished the two diabetic groups from each other and from control patients during a seven day total fast were related to the degree of hypoinsulinemia. Plasma glucogenic amino acids, including alanine were significantly depressed in the severely diabetic patients throughout the fasting interval. Four hour intravenous infusions of ethanol after fasting lowered plasma glucose to the greatest extent in patients with severe diabetes and least in the nondiabetic obese. In all instances, ethanol infusion decreased plasma glucogenic amino acids. Differential sensitivities of plasma glucose responses to fasting and to ethanol administration in these patients suggest that hepatic glucose production is inappropriate in severely diabetic, obese subjects. The defect correlates with subnormal plasma glucogenic substrate concentrations, suggesting increased hepatic extraction and conversion to glucose. Hypoglycemic effects of ethanol may be induced, in part, by altered availability of plasma amino acid precursors.