bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenformin-induced Lactic Acidosis in Diabetic Patients
Authors: Assan Roger , Heuclin Christine , Girard Jean Raymond , LeMaire Francois , Attali Jean Raymond
Published: September 2013

Eighteen diabetic patients with lactic acidosis (L.A.) were analyzed for possible causal factors, metabolic changes, and efficacy of treatment. An antecedent phenformin therapy was performed in fifteen cases and was associated with renal insufficiency in ten cases and liver disease in eight cases. Tissular anoxia of primary hemodynamic or respiratory origin was absent in all cases. The severe metabolic acidosis (pH = 6.93 ± 0,03 ; HCO3¯ = 6 ± 1 mM ; PaCO2 = 18 ± 2 mm. Hg) and hyperlactatemia (14.2 ± 0.3 mM) were associated with high lactate/pyruvate ratio (70 ± 22). High alanine levels (up to 4.6 mM) were measured in some of these patients. High beta-hydroxybutyrate levels were sometimes measured (up to 7.6 mM), and substantial amounts of acetoacetate were also detected in twelve cases. Glucagon level was always increased (1,050 ± 240 pg./ml.), and insulin/glucagon ratio was low. Cortisol (49 ± 10 µg./100 ml.) and HGH (10.8 ± 2.6 ng./ml.) were also elevated. Increased plasma levels of phenformin were measured in five L.A. diabetic subjects (50 ± 5 µ./ml.) by comparison with other phenformin-treated diabetic subjects. The specificity of the assay was investigated, and phenformin metabolites were characterized by thin-layer chromatography. For the treatment of L.A., adjunction of dialysis and furosemide improved the efficacy of early and massive sodium bicarbonate infusion. It is suggested that accumulation of phenformin via renal insufficiency plays a determinant role in causing L.A. through an impairment of lactate metabolism in the liver. An accelerated epuration of the drug may be helpful. in therapy of L.A. Phenformin treatment should be avoided in case of renal and/or liver insufficiency.
Effects of Cyproheptadine on Insulin Secretion by Isolated Perifused Rat Isletss
Authors: Richardson Brian P , McDaniel Michael L , Lacy Paul E
Published: September 2013

The effects of cyproheptadine on basal and glucose-induced insulin release by isolated rat islets was studied by use of a perifusion system. A forty-five minute preincubation of islets with a medium containing both 34.3 µg./ml. (10-4 M) cyproheptadine and 1.0 mg./ml. glucose completely abolished the biphasic pattern of increased insulin secretion normally obtained after islets are stimulated with a medium containing 3.0 mg./ml. glucose. In another series of experiments, similar results were obtained when the cyproheptadine and 3.0 mg./ml. glucose were presented together. Here, however, the inhibition of the first phase of insulin secretion did not achieve statistical significance and some recovery of the islets' secretory capacity was observed late during the second phase. In studies designed to investigate the influence of cyproheptadine on basal insulin secretion, no obvious effect was observed. These results are discussed in relation to the species-specific alterations in pancreatic beta-cell morphology that have been reported in rats after the oral administration of cyproheptadine.
Factitial Panniculitis and Necrotizing Fasciitis in Juvenile Diabetes
Authors: Oh Changyul , Ginsberg-Fellner Fredda , Dolger Henry
Published: September 2013

A fifteen-year-old diabetic girl developed multiple inflammatory areas on the extremities and abdominal wall at the site of insulin injection. The bizarre clinical manifestations led to great difficulties in determining both its etiology and its treatment. However, three months after her initial hospitalization, we found that the lesions were probably secondary to self-injection with a chemical agent rather than a result of insulin allergy. If idiopathic recurrent dermal infection is observed, then factitial origin should be suspected.
Incorporation of 75Se-Selenomethionine into Human Apoproteins: I. Characterization of Specificity in Very-low-density and Low-density Lipoproteins
Authors: Eaton R Philip
Published: September 2013

Characterization of specificity of incorporation of 75Seselenomethionine into human apoproteins following in-vivo injection of the radioactive amino acid precursor is reported. Apoprotein fractionation was attained by serial ultracentrifugation, anhydrous partial delipidization, decyl sulfate solubilization with Sephadex G-150 gel filtration into polypeptide fractions, Sf-I, and Sf-II, for VLDL, and LDL subfractions. Similarity of the Sf-I fractions isolated from VLDL, LDL1 and LDL2 was defined by gel exclusion volume, disk-gel electrophoresis, immunodiffusion, and amino acid composition. Enrichment of the Sf-I fractions with75Se-SM in VLDL and LDL subfractions was observed, suggesting a possible use for this isotopic method for the investigation of apoprotein metabolism.
Norepinephrine, Epinephrine, and Dopamine Contents of the Cardiovascular System in Long-term Diabetics
Authors: Neubauer B , Christensen N J
Published: September 2013

Norepinephrine, epinephrine, and dopamine concentrations were studied in the cardiovascular system of postmortem material obtained from six long-term diabetics and six control subjects.

Norepinephrine concentration was considerably reduced in the cardiovascular system of the diabetic patients. The mean norepinephrine concentration in the apex of the heart, the radial artery, the posterior tibial artery, and the femoral artery in the diabetics averaged 6, 9, 12, and 20 per cent, respectively, of the corresponding mean values in the controls.

Epinephrine was present in the cardiovascular system in the controls but in small amounts in comparison with norepinephrine. There was no correlation between the epinephrine and the norepinephrine concentrations in the tissue. In the diabetics the epinephrine concentration in the heart and in the arteries did not differ from the values obtained in the controls.

The dopamine concentration averaged 11 per cent of the norepinephrine concentration in the cardiovascular system in the controls. There was a strong correlation between tissue concentrationsof dopamine and of norepinephrine. In the diabetics the dopamine concentration was reduced, but relatively less than that of norepinephrine, and constituted 53 per cent of the norepinephrine concentration.

It is suggested that the depletion of the norepinephrine stores in the heart in diabetic patients may in part be responsible for their reduced survival rate in acute myocardial infarction.
Growth Hormone Stimulating the Growth of Arterial Medial Cells in Vitro: Absence of Effect of Insulin
Authors: Ledet Thomas
Published: September 2013

Earlier studies have shown a stimulatory effect of diabetic serum on the growth of rabbit aortic medial cell cultures.

Growth media supplemented with normal serum with added insulin (50-2,000 μU./ml. serum) did not enhance the growth of the medial cell cultures. Control media containing serum from recent diabetics with low insulin concentration stimulated the growth (2p < 0.01).

Supplementation of normal serum with human growth hormone (final concentration 1-5 ng./ml. medium) resulted in a significant enhancement of growth (2p < 0.005). The growth-promoting effect of growth hormone was not detectable with lower concentrations (0.5 ng. and 0.1 ng./ml. medium).

The growth effect of the low concentration of growth hormone could not be augmented by increasing the concentration of glucose in the incubation medium.

Growth hormone in an amount of 1 ng./ml. medium increased both the number of 3H-thymidine-labeled cells as identified by autoradiography and the number of mitotic bodies (2p < 0.005 and 2 p < 0.025).

The present results demonstrate that the growth-stimulating factor(s) in diabetic human serum described earlier is not insulin but may well be growth hormone.
Reversal of Somatostatin Inhibition of Insulin and Glucagon Secretion
Authors: Bhathena S J , Perrino P V , Voyles N R , Smith S S , Wilkins S D , Coy D H , Schally A V , Recant L
Published: September 2013

These studies were designed to elucidate the mechanism of inhibitory action of somatostatin (SRIF) on glucagon (IRG) and insulin (IRI) secretion. Studies were carried out in the unrecirculated isolated rat pancreas perfusion with arginine 19.2 mM and glucose 5.5 mM as stimulus primarily for IRG but also IRI secretion. The effects of excess Ca++ (15.2 mEq./L.) and excess K+ (12.8 mEq./L.) on IRG, IRI, and the SRIF-inhibited pancreas were studied. Ca++ excess in five perfusions strikingly stimulated IRG secretion (+92 per cent) but only stabilized IRI secretion compared with control perfusions. K+ excess (in seven perfusions) markedly inhibited IRG secretion (–39 per cent) while stimulating IRI secretion (+16 per cent). Restoration of normal concentrations of K+ resulted in a rebound of IRG to levels 120 per cent that of controls. SRIF, at concentrations from 0.1–20 ng./ml., produced inhibition of both IRG and IRI. In 11 perfusions, with SRIF at 10 ng./ml., IRG decreased more than IRI (–75.2 per cent IRG and –46.9 per cent IRI). In five perfusions, addition of Ca++ (15.2 mEq./L.) 10 minutes after SRIF was started resulted in a reversal of IRG inhibition to 69.4 per cent and IRI to 73.2 per cent of the arginine controls. The reversal by Ca++ of SRIF effect on IRG was greater at higher concentrations of Ca++, suggesting some form of competition. In four perfusions, excess K+ reversed SRIF-induced IRI inhibition to 79.6 per cent that of controls but had no effect on IRG inhibition. Studies in vitro with isolated islets revealed that SRIF (2 μg./ml.) inhibited 45Ca uptake of islets as did epinephrine (10−5 M). It was concluded that SRIF-induced inhibition of hormone release appears related to an action on Ca++ uptake.
Treatment of Insulin-induced Lipoatrophy
Authors: Hulst S G Th
Published: September 2013

Twenty children with insulin-induced lipoatrophy were successfully treated by injecting the insulin into the lipoatrophic area. In 10 children insulin therapy was replaced by monocomponent insulins, while the other 10 children were treated with the insulins they previously used.

It is concluded that both monocomponent and less purified insulins are suitable for treating the complication of insulin therapy when the insulin is injected into the lipoatrophic area.
Intracellular Enzymes of Collagen Biosynthesis in Rat Kidney in Streptozotocin Diabetes
Authors: Risteli Juha , Koivisto Veikko A , Åkerblom Hans K , Kivirikko Kari I
Published: September 2013

The activities of the four enzymes catalyzing intracellular post-translational modifications of the collagen polypeptide chains were assayed in the kidneys of rats with streptozotocin diabetes. When the changes in the four enzyme activities were expressed per milligram of protein in the 15,000 × g supernatant of the kidney homogenates, there were no changes in any of the enzyme activities at four weeks and only slight increases in the prolyl and lysyl hydroxylase activities at 12 weeks after the induction of diabetes. When the changes were expressed as total enzyme activities per two kidneys, again no changes were found in any enzyme activity at four weeks, but at 12 weeks significant increases were found in all four enzyme activities, namely prolyl hydroxylase, lysyl hydroxylase, collagen galactosyltransferase, and collagen glucosyltransferase. The data would be consistent with an increased collagen synthesis in diabetic kidneys, but they do not support the hypothesis that there might be specific changes in some of these enzyme activities or in the level of certain posttranslational modifications of the collagen polypeptide chains in this disease.
The Lilly Lecture 1976: Insulin, Glucagon, and Somatostatin in Normal Physiology and Diabetes Mellitus
Authors: Felig Philip , Wahren John , Sherwin Robert , Hendler Rosa
Published: September 2013

Studies are reviewed in which the roles of insulin and glucagon in normal physiology and in diabetes are examined. In normal man, glucose ingestion is accompanied by a rise in insulin and fall in glucagon and is primarily disposed of in the liver, an organ sensitive to both hormones. However, infusions of glucagon in physiologic amounts indicate that insulin secretion rather than glucagon inhibition is the primary factor determining glucose disposal. Furthermore, minor elevations in blood glucose elicit increments in insulin concentration and inhibition of hepatic glucose output in the absence of changes in plasma glucagon. The primary physiologic role of glucagon is to prevent the hypoglycemia that would otherwise accompany noncarbohydrate (protein)-mediated insulin secretion. In diabetic as well as normal patients the stimulatory effect of glucagon on hepatic glucose production is evanescent. Increases in glucagon or changes in the I/G ratio can bring about deterioration in glucose tolerance or in diabetic control only so long as absolute insulin deficiency is present or pharmacologic elevations in glucagon are produced. After somatostatin administration, prolonged hypoinsulinemia in normal subjects is observed to result in fasting hyperglycemia in the absence of basal glucagon secretion. In diabetic patients the improvement in postprandial hyperglycemia produced by somatostatin can be accounted for by its inhibitory action on carbohydrate absorption in the gastrointestinal tract. It is concluded that insulin deficiency is the primary pathophysiologic disturbance in diabetes. While glocagon may worsen the consequences of insulin lack, it is neither sufficient nor necessary for the development of diabetes.
Community Screening for Diabetes by Blood Glucose Measurement: Results of a Five-year Experience
Authors: Genuth Saul M , Houser Harold B , Carter James R , Merkatz Irwin , Price J Wade , Schumacher O Peter , Wieland Ralph G
Published: September 2013

The Diabetes Association of greater Cleveland screened 307,000 individuals in the metropolitan area for diabetes with a 75-gm. oral load of carbohydrate. Of these subjects 12,600 (4.1 per cent) had a two-capillary blood glucose level of > 139 mg. per cent and were defined as positive. Seventy per cent of the positives were retested, and 65 per cent of these again had two-hour levels > 139 mg. per cent. Seventy-one per cent of the original screening values were between 104 and 199 mg. per cent. The rate of positivity on retesting increased with the original screening bracket reaching 90 per cent at an original screening level of 240 mg. per cent or higher. The frequency of positive retests also increased with age irrespective of whether the original screening level was < or > 200 mg. per cent. The implications of this large detection experience for conducting future mass surveys for diabetes are discussed.
Continuous Extracorporeal Monitoring of Animal Blood Using the Glucose Electrode
Authors: Layne E C , Schultz R D , Thomas L J , Slama G , Sayler D F , Bessman S P
Published: September 2013

A continuous extracorporeal monitoring system for blood glucose employing an electrochemical sensor is described. The sensor, about the size of a nickel, is rapid, is specific for glucose, generates its own power, and consists of two galvanic oxygen electrodes. Over one oxygen electrode is affixed a plastic matrix to which glucose oxidase is covalently bound; a blank matrix is over the other, which serves as a reference. Oxygen is consumed in the glucose-oxidase-containing matrix, decreasing the current from the underlying oxygen electrode. The current decrease is nonlinearly proportional to the glucose concentration.

The sensor is clamped between small blocks of plastic fitted with inlet and outlet nipples so that blood pumped from the animal passes over the two electrodes and thence to an automated chemical analysis for comparison. Blood is collected and anticoagulant added in a double-lumen catheter. Blood is withdrawn at the rate of 1 cc. per hour.

Results obtained by use of the system in rabbits are reported. The capacity of the system to continuously monitor changes in blood glucose produced by repeated glucose tolerances is shown in hypo-, normo-, and hyperglycemic animals. Some properties of the system and its calibration are discussed.
Insulin degradation: XVI. Evidence for the Sequential Degradative Pathway in Isolated Liver Cells
Authors: Varandani Partab T , Nafz Mary Ann
Published: September 2013

Isolated liver cells contain insulin-degrading activity. Examination by chromatography on Sephadex G-75 of the products formed from 125I-insulin (1 nM or 1 µM) upon incubation with suspensions of hepatocytes for various time periods showed that there is at first a transient accumulation of the intermediate product, A chain, which is further hydrolyzed by protease(s) to low-molecular-weight components. These results indicate that the sequential degradative pathway is operative, both at low and high concentrations of insulin, in isolated liver cells, i.e., the insulin is first split at the disulfide bonds by glutathione-insulin transhydrogenase (GIT) into A and B chains, followed by proteolysis of the resultant polypeptides, and that this system might be used for well-defined studies of factors controlling insulin metabolism.

The chelating agent ethylenediamine tetraacetic acid (EDTA) accelerated the accumulation of A chain (i.e., enhanced the activity of GIT), which is in keeping with its effect with purified GIT. In contrast to previous studies with tissue homogenates in which EDTA caused a marked inhibition of the proteolytic stage, EDTA had little or no effect with intact liver cells. Since EDTA does not appreciably penetrate the cell membrane, these data suggest that GIT activity either occurs on the cell surface or is readily available at the cell surface, whereas the proteolytic activity either occurs inside the cell or is inaccessible at the cell surface.
Isotransplantation of Organ-Cultured Neonatal Pancreas: Reversal of Alloxan Diabetes in the Rat
Authors: Hegre O D , Leonard R J , Schmitt R V , Lazarow A
Published: September 2013

Pancreases from neonatal rats four to 16 days postpartum were grown in organ culture for from two to nine days. Approximately 10-20 explants, each measuring 1 mm.3 (1 mg.), were grown on a single Millipore filter placed at the gas-liquid interface of a medium consisting of 50 per cent horse serum and 50 per cent chick embryo extract. Following organ culture, an estimated 9-20 mg. of cultured islet tissue were dissociated with collagenase and isotransplanted into the peritoneal cavity of alloxan-diabetic recipients.

In seven of eight recipients the diabetes was reversed between 11 and 53 days of posttransplantation. Animals receiving 12-16 mg. of cultured islet attained normoglycemia in 11-20 days; animals receiving 9-10 mg. of cultured islet tissue recovered between 45 and 53 days. These animals have remained symptom-free for over six months.

Biopsies of grafts taken from the peritoneal cavity following reversal of diabetes contained well-vascularized islets compared primarily of heavily granulated beta cells. Quantitative analysis of host pancreases by the linear scanning method (biopsied at one to two weeks and four to five months following reversal of the diabetes) demonstrated that the total beta-cell mass was 3 per cent and the total insulin content was 6 per cent of the normal values. Little or no evidence of regeneration of host beta cells was observed.

These studies show that a period of organ culture prior to isotransplantation does not impair the ability of islet tissue to reverse alloxan diabetes in the rat.
Virus-induced Diabetes Mellitus: IV. Genetic and Environmental Factors Influencing the Development of Diabetes After Infection with the M Variant of Encephalomyocarditis Virus
Authors: Ross Michael E , Onodera Takashi , Brown Kenneth S , Notkins Abner Louis
Published: September 2013

The M variant of encephalomyocarditis virus (EMC) infects pancreatic beta cells and causes the development of a diabetic syndrome in susceptible strains of mice. By examining four F1 crosses of susceptible and resistant strains of mice, we found that the development of diabetes after infection was inherited as a recessive trait. Analysis of the data from the F2 generation indicated that more than one gene was involved in the development of EMC-diabetes. The severity and frequency of abnormal glucose levels in EMC-infected animals was markedly influenced by environmental factors.
Inhibition of Insulin Release by Scorpion Toxin in Rat Pancreatic Islets
Authors: Johnson David G , Henry David P , Moss Jonathan , Williams Robert H
Published: September 2013

Toxin purified from venom of the scorpion Leiurus quinquestriatus was used to release the norepinephrine from adrenergic nerve terminals in isolated pancreatic islets perifused in vitro. Addition of toxin (10 µg./ml) to the perifusion medium caused a sixfold increase in release of norepinephrine in the presence or absence of 3 × 10-5M phenoxybenzamine. During 20 minutes of stimulation with toxin, the pancreatic islets released an average of 15 pg. of norepinephrine per islet, which represented 20 per cent of the normal content of norepinephrine in islets. Insulin secretory rates in response to either 1.0 or 3.0 mg./ml. glucose were inhibited similarly by scorpion toxin. Addition of phenoxybenzamine abolished the inhibition of insulin release caused by scorpion toxin. Phenoxybenzamine alone did not affect release of insulin. Neither the enhanced release of norepinephrine nor the decreased release of insulin was reversed by a 20-minute wash-out period after infusion of toxin. These results indicate that the sympathetic nerve terminals in the rat pancreatic islet contain considerable amounts of norepinephrine that can be released by scorpion toxin. The norepinephrine released from sympathetic nerve endings in the pancreatic islet can inhibit release of insulin through an alpha-adrenergic action that is blocked by phenoxybenzamine.
Some Considerations in the Preparation of Radioiodoinsulin for Radioimmunoassay and Receptor Assay
Authors: Schneider Bruce , Straus Eugene , Yalow Rosalyn S
Published: September 2013

125I-insulins, prepared by iodination with chloramine T in marked excess or by stepwise, stoichiometric addition of the oxidizing agent, were compared with respect both to their molecular distribution of iodine and to their suitability for use in a cultured lymphocyte receptor assay. Iodination of insulin in aqueous solution results in the same distribution of iodine atoms, independent of experimental method and dependent only on the average iodine number. This distribution can be calculated on the basis of a Monte Carlo simulation, For insulin iodinated at an average of 0.8 I atoms per molecule, approximately 50 per cent of the radioactivity is in other than monoiodoninsulin. Purification methods that separate on the basis of charge, such as starch-gel electrophoresis, are then required, to obtain monoiodoinsulin. More highly iodinated insulin do bind to the lymphocyte receptor, although, as in radioimmunoassay, the overiodinated species are less satisfactory for use as tracers. The shelf life of iodinated insulin appears to be related better to the average iodine content than to any other factor, presumably because of decay catastrophe. There is no evidence to suggest that exposure to chloramine T in marked excess for a few seconds is deleterious to insulin.
Phenformin-associated Metabolic Acidosis
Authors: Fulop Milford , Hoberman Hemry D
Published: September 2013

We report 18 consecutive phenformin-treated diabetic patients admitted to this Medical Service acutely ill with metabolic acidosis. Lactic acidosis was anticipated, and documented, in all. Also, however, though most of the patients had only weakly positive, or even negative, serum reactions with the nitroprusside reagent, all were found to have coexisting ketoacidosis, plasma 3-hydroxybutyrate averaging 7.1 mmol/L. ± 3.9 (S.D.). This finding suggest that treatment of these patients should include insulin, and often also glucose, because most do not have marked hyperglycemia and some have hypoglycemia.

The lactic acidosis in the nine patients who survivied was, on average, less severe than in the nine who died, but the difference was not statistically significant. Surivival correlated closely with the absence of shock on arrival.

Only eight patients had a identifiable acute illness other than the metabolic acidosis. The other 10 patients had no discernible cause for the acute illness apart from their treatment with phenoformin. This finding raises serious doubts about whether phenformin should be used to treat patients with diabetes.
Arginine-Stimulated Hyperglucagonemia in Diabetic Pima Indians
Authors: Aronoff Stephen L , Bennett Peter H , Rushforth Norman B , Miller Max , Unger Roger H
Published: September 2013

Groups of 27 nondiabetic Pima Indians, 34 nondiabetic Caucasians, and 12 diabetic Pima Indians with recent onset of their disease received an arginine infusion to determine if (1) nondiabetic Pima Indians and Caucasians had a similar glucagon response to arginine and (2) diabetic Pimas had excessive glucagon response to arginine as reported in other racial groups. The fasting glucagon levels in the three groups were not significantly different. During arginine monochloride infusion (5 mg./kg./minute for 40 minutes) the diabetic Pimas had glucagon levels significantly higher at 10 minutes and at all sampling points thereafter than the normo-glycemic Pimas. Plasma insulin levels also increased during the infusion but, notably, never differed significantly between these two groups. There was no significant difference in the glucagon levels at any sampling point between the nondiabetic Pimas and Caucasians. The differences in glucagon levels between the nondiabetic and diabetic Indians are similar to those differences reported between diabetic and nondiabetic subjects of other racial origins.
Altered Lysosomal Glycohydrolase Activities in Juvenile Diabetes Mellitus
Authors: Bomback Fredric M , Nakagawa Sachiko , Kumin Selma , Nitowsky Harold M
Published: September 2013

Studies have been carried out on activities of lysosomal β-N-acetylhexosaminidase (hex), β-galactosidase (β-gal), α-glucosidase (α-glu), and acid phosphatase (AP) in serum and urine from patients with juvenile diabetes and matched controls. There is a large increase in blood and urinary hex activity (the former presenting three distinct patterns of abnormality), a moderate increase in urinary β-gal, and a small increase in urinary α-glu activity, but no elevation of blood or urinary AP in the diabetics. Urinary α-glu activity in the diabetics shows striking inhibition by glucose, and this may reflect a similar phenomenon in vivo.

Although glycohydrolase activities are elevated in patients with no detectable microangiopathy, more striking changes may be observed in patients with severe small-vessel disease. These alterations may be associated with increased glycoprotein catabolism in the diabetic, an area in need of further studies in the human and experimental diabetic animal.
Ocular Palsies in Children with Diabetes Mellitus
Authors: Grunt Jerome A , Destro Robert L , Hamtil Lawrence W , Baska R Eugene
Published: September 2013

The findings in three children with ocular palsies are reported in this paper. Two had insulin-requiring diabetes and one demonstrated only an abnormal I.V. glucose tolerance test. In the first patient the condition resolved in four weeks; in the second it had not fully resolved after 21 months, and in the third patient surgery was required for correction after seven months. We suggest that any child who develops a sudden ocular palsy should be examined for diabetes mellitus.
Nitrogen Metabolism and Insulin Requirements in Obese Diabetic Adults on a Protein-Sparing Modified Fast
Authors: Bistrian Bruce R , Blackburn George L , Flatt Jean-Pierre , Sizer Jack , Scrimshaw Nevin S , Sherman Mindy
Published: September 2013

A protein-sparing modified fast (PSMF), which is a total fast modified by the intake of 1.2–1.4 gm. protein per kilogram ideal body weight (IBW), fluids ad libitum, and vitamin and mineral supplementation, allows effective control of carbohydrate metabolism and hunger. It reduces serum glucose and insulin concentrations in obese diabetic patients and increases free fatty acid and ketone body concentrations; ketonuria appears within 24–72 hours. When this fast was applied to seven obese adult-onset diabetics who were receiving 30–100 units of insulin per day, insulin could be discontinued after 0–19 days (mean, 6.5). In the three patients who had extensive nitrogen-balance studies, balance could be maintained chronically by 1.3 gm. protein per kilogram IBW, despite the gross caloric inadequacy of the diet. The PSMF was tolerated well in an outpatient setting after the initial insulin-withdrawal phase had occurred in the hospital. Significant improvements in blood pressure, lipid abnormalities, parameters of carbohydrate metabolism, and cardiorespiratory, symptoms were associated with weight loss and/or the PSMF. For diabetics with some endogenous insulin reserve, the PSMF offers significant advantages for weight reduction, including preservation of lean body mass (as reflected in nitrogen balance) and withdrawal of exogenous insulin.
Hyperlipoproteinemia in Streptozotocin-treated Rats
Authors: Bar-On Hanoch , Roheim Paul S , Eder Howard A
Published: September 2013

In order to study hyperlipidemia in diabetes mellitus, rats were made diabetic by administration of streptozotocin and the optimal conditions for production of severe and persistent hyperlipoprotenemia determined. Two groups of rats were compared: rats fed sucrose-rich diets and rats fed laboratory chow. The optimal dose of streptozotocin was 45 mg/kg body weight for the sucrose-fed rats. With this dose, plasma glucose reached a maximum of over 600 mg./100 ml., and plasma insulin was reduced by 60 per cent. Plasma triglycerides rose in the sucrose-fed rats to over 1,000 mg/100 ml. two days after the streptozotocin was given and then decreased to over 770 mg./100 ml. 12 days after treatment and then to 585 mg./100 ml. 10 weeks after induction of diabetes. With this dose, ketonuria did not occur nor did any of the animals die, as occurred with higher doses. In the chow-fed rats, plasma triglyceride levels were elevated with the induction of diabetes to levels of approximately 300 mg./100 ml.

The concentration of all the plasma lipoproteins increased with the induction of diabetes. The concentration of very-low density lipoprotein (VLDL) protein in the sucrose-fed diabetic increased fivefold, the low-density lipoprotein (LDL) protein increased, and especially striking was the increase in high-density lipoprotein (HDL) protein concentration, which became more pronounced with the duration of the diabetes. The diabetes produced by streptozotocin administration to sucrose-fed rats, thus, provides a useful model for the study of the hyperlipoproteinemia of diabetes.
Nutrition and Somatomedin: II. Serum Somatomedin Activity and Cartilage Growth Activity in Streptozotocin-diabetic Rats
Authors: Phillips Lawrence S , Young Harvey S
Published: September 2013

Since diabetes mellitus is a condition in which poor growth occurs despite elevation of plasma GH, we have attempted to determine if poor growth in diabetes, as in malnutrition, could be associated with a decrease in somatomedin activity. Young male rats were rendered diabetic with intravenous streptozotocin (STZ). The growth activity of their cartilage was estimated by 35SO4 incorporation in vitro, and somatomedin (SM) activity in their serum was determined by the stimulation of SO4 incorporation by cartilage from hypophysectomized rats or normal young pigs. Cartilage growth activity was significantly decreased 24 hours after STZ and fell to hypopituitary levels after 48 hours. The decreased growth activity could not be attributed to decreased cartilage responsiveness to SM, since incubation of diabetic cartilage with normal rat serum (normal SM) resulted in significant stimulation of cartilage SO4 incorporation. SM in diabetic serum decreased to hypopituitary levels 24 hours after STZ, and decreased further after 48 hours. The decrease in SM and cartilage growth activity was not prevented by the administration of high doses of bovine GH. The fall in bioassayable SM appeared to be due in part to the presence of an SM inhibitor in the diabetic serum, since addition of diabetic serum to normal serum decreased to measurable SM in the normal serum. Administration of insulin to diabetic rats 48 hours after STZ led to significant increases in SM and cartilage growth activity, and insulin therapy 24 hours after STZ prevented the decreases in SM and cartilage growth activity which occurred without insulin.

Thus, acute STZ-induced diabetes in rats was associated with a significant decrease in both serum SM and cartilage growth activity; these changes were not ameliorated by administration of GH, and insulin therapy could both prevent and reverse the fall in SM and cartilage growth activity. From these observations, we conclude that (1) that fall in somatomedin activity and cartilage growth activity associated with STZ-induced diabetes appears to be due to insulin deficiency and (2) growth failure in diabetes, as in malnutrition, may be due to decreased somatomedin activity.
Influence of Fixation and Morphometric Technics on Capillary Basement-membrane Thickening Prevalence Data in Diabetes
Authors: Williamson Joseph R , Rowold Edwin , Hoffman Phyllis , Kilo Charles
Published: September 2013

Muscle tissue obtained by needle biopsy from 20 diabetic subjects and from 20 age-matched control subjects was divided into two portions, one of which was fixed and processed by our routine procedure (primary glutaraldehyde fixation followed by osmium fixation and embedment in araldite) and the other was fixed initially in osmium tetroxide and embedded in maraglas, the procedure employed by Siperstein et al. Basement-membrane width of capillaries was measured by the 20-point method of Siperstein et al. and by the two-minimum-point technic developed in our own laboratory. Contrary to the experience of Siperstein et al., the prevalence of basement-membrane thickening in diabetic subjects based on mean width values and/or standard deviations in excess of 95 per cent tolerance intervals was highest (65 per cent) in minimum measurements of glutaraldehyde-fixed tissues and lowest (30 per cent) in osmium-fixed tissues (X2 = 4.9123, p < 0.05).

Internal discrepancies in the data of Siperstein et al. indicate that (1) their basement-membrane-width values derived from multiple measurements from control subjects are anomalous (low) and (2) the very high prevalence of basement-membrane thickening they reported in diabetic and in prediabetic subjects and considered as strong support for their conclusion that basement-membrane disease is independent of and precedes glucose intolerance is suspect.
Locating the Site(s) of Insulin Resistance in Patients with Nonketotic Diabetes Mellitus
Authors: Kimmerling George , Javorski W Curtis , Olefsky Jerrold M , Reaven Gerald M
Published: September 2013

Insulin resistance and the ability of insulin to inhibit hepatic glucose production and to increase efficiency of glucose uptake were determined in 24 nonobese individuals: eight subjects with normal oral glucose tolerance, eight patients with chemical diabetes, and eight nonketotic patients with fasting hyperglycemia (> 150 mg. per cent). Insulin resistance was estimated by measuring the steady-state plasma glucose response to a continuous infusion of insulin, glucose, epinephrine, and propranolol. This approach permits us to inhibit endogenous insulin release, attain comparable steady-state plasma levels of exogenous insulin, and use the height of the steady-state plasma glucose response as a direct estimate of insulin resistance. The ability of insu lin to inhibit hepatic glucose production and to increase efficiency of glucose uptake was calculated from the results of two studies in which a continuous infusion of 3H-2-glucose was used to measure glucose turnover rate. The first study was performed after an overnight fast, under conditions of basal insulin levels, while the second was conducted during the infusion of insulin, glucose, epinephrine, and propranolol. Hepatic glucose production is equal to glucose turnover rate during the basal study and is equal to glucose turnover rate minus the infusion rate of cold glucose during the second study. Glucose uptake in both studies is equal to glucose turnover rate minus urinary glucose loss, and the efficiency of glucose uptake is calculated by dividing glucose uptake by the plasma glucose pool size. The mean (± S. E.) steady-state plasma glucose response wasll3 ± 9 mg. per cent in normal subjects, 205 ± 14 mg. per cent in chemical diabetics, and 346 ± 30 mg. per cent in patients with fasting hyperglycemia. Thus, insulin resistance exists in nonketotic diabetes, and the greater the degree of glucose intolerance, the greater the insulin resistance. The resistance to the insulin infusion in patients with chemical diabetes seemed to be mainly a function of the inability of insulin to increase efficiency of glucose uptake, since insulin did retain its ability to inhibit glucose production (although not to normal levels). In contrast, the infusion of insulin neither inhibited hepatic glucose production nor increased efficiency of glucose uptake in patients with fasting hyperglycemia. Thus, the insulin resistance that exists in patients with nonketotic diabetes cannot be considered to be a global phenomenon. Significant differences exist in the responsiveness of various tissues to the two general aspects of insulin's action on glucose homeostasis, and these differences provide a physiologic basis for the variations in degree of over-all insulin resistance that are present in the three groups of subjects.
Insulin and Brain Metabolism: Absence of Direct Action of Insulin on K+ and Na+ Transport in Mouse Brain
Authors: Thurston Jean Holowach , Hauhart Richard E , Dirgo John A
Published: September 2013

This is a study of the effect of insulin on the transport of K+ and Na+ from the blood into the brains of normal mice. Despite profound reductions in plasma and brain glucose levels, reduction of plasma K+ concentration and progressive deterioration of neurologic function 30–120 minutes after insulin injection, in 20–22-day-old animals there was no increase in brain K+ and Na+ concentrations. In fact, at 120 minutes, when the brain water content increased 0.7 per cent, brain K+ concentration was significantly reduced, not elevated.

The effect of insulin on brain electrolyte and water content in adult mice was also studied. Although brain water increased 0.5 per cent at 120 minutes, there was no changes in brain Na+ or K+ concentrations at any time after insulin injection.

The data from mice do not support a role of insulin in electrolyte transport in brain.
Determination of Free and Total Insulin and C-Peptide in Insulin-treated Diabetics
Authors: Kuzuya Hideshi , Blix Petra M , Horwitz David L , Steiner Donald F , Rubenstein Arthur H
Published: September 2013

Serum levels of free and total insulin as well as total C-peptide immunoreactivity (C-peptide and proinsulin) and C-peptide were measured in insulin-treated diabetics with circulating insulin antibodies by the addition of polyethylene glycol (PEG) before and after acidification. PEG resulted in complete precipitation of insulin antibodies from serum and made it possible to measure free insulin in the supernatant. Incubation of serum at 37δ C. for two hours before addition of PEG resulted in values for free insulin that probably resembled the in-vivo levels most closely. The same method could also be used to remove proinsulin bound to circulating insulin antibodies and permitted the measurement of C-peptide in the supernatant.

Clinical studies using this approach indicate that combined measurements of serum free and total insulin and C-peptide provide information that is helpful in understanding the contribution of endogenous and exogenous insulin to the course and metabolic control of insulin-requiring diabetic patients.
The Effects of Fasting and Streptozotocin Diabetes on Hepatic Triglyceride Lipase Activity in the Rat
Authors: Elkeles R S , Hambley J
Published: September 2013

The activity of hepatic triglyceride lipase in the rat was reduced by fasting. Withdrawal of insulin from insulin-treated streptozotodn-diabetic rats resulted in a decrease in hepatic triglyceride lipase activity. The behavior of the enzyme in both situations was similar to that of adipose tissue lipoprotein lipase. It is concluded that hepatic triglyceride lipase, like adipose tissue lipoprotein lipase, is under hormonal regulation by insulin.
Genetic Influence of the Streptozotocin-induced Insulitis and Hyperglycemia
Authors: Rossini Aldo A , Appel Michael C , Williams R Michael , Like Arthur A
Published: September 2013

Multiple injections of subdiabetogenic doses of streptozotodn (SZ) to CD-I male mice produce a diabetic syndrome that includes a cell-mediated immune reaction against the pancreatic islet. The importance of the host genetic background in the pathogenesis of this model of diabetes was studied by comparing various inbred strains of mice. Of eight strains of mice studied, only C57BL/KsJ developed insulitis and hyperglycemie comparable to that observed in CD-I mice. In two mouse strains (DBA/2J and BALB/cJ) having an haplotype similar to the C57BL/KsJ, only mild insulitis and glucose intolerance were observed. These data suggest that major histocompatibility complex genes, as presently defined, cannot be the only determinant of the severity of hyperglycemia and insulitis in this model.
Psychiatric Status of Diabetic Youth Matched with a Control Group
Authors: Simonds John F
Published: September 2013

The psychiatric status of 40 diabetic youths in good control and 40 diabetic youths in poor control was compared with the psychiatric status of a matched nondiabetic control group selected from a family practice clinic. The numbers of youths with psychiatric diagnoses, interpersonal conflicts, and noninterpersonal conflicts were determined from a semistructured psychiatric interview done by the investigator. The good-control diabetic group had significantly fewer youths with both types of conflicts when compared with the control group and the poor-control diabetic group. However, psychiatric diagnoses were made with equal frequency in all three groups. Results of a parent questionnaire concerning a youth's behavior problems revealed significant differences only for two items—“anxiety” and “depression”—which were more frequent problems for diabetic youths in poor control. The good-control diabetic group seemed to be in the best mental health, and their families were less prone to divorce. Youths in poor diabetic control were not very different psychologically from the nondiabetic control group except for the parents' report of more frequent anxiety and depression. It was speculated that these youths were more anxious because of the progression of the diabetic condition, which became less predictable as the control worsened. The low per cent of psychiatric diagnoses in the investigator's groups was in contrast to other studies. The results of the study seemed to indicate that there was no need to worry about the negative emotional effects of a structured medical regimen for diabetes.
Insulin Responses in Equivocal and Definite Diabetes, with Special Reference to Subjects Who Had Mild Glucose Intolerance but Later Developed Definite Diabetes
Authors: Kosaka Kinori , Hagura Ryoko , Kuzuya Takeshi
Published: September 2013

Insulin secretory responses during the 100-gm. glucose tolerance test (GTT) were studied in subjects who had or had had glucose intolerance. Patients who had metabolic diseases other than diabetes were excluded. The ratio (ΔIRI/ΔBS) of increments of blood insulin to blood sugar 30 minutes after glucose load was used as the most sensitive index to detect the abnormality of early Insulin release In diabetes. In patients with definite diabetes (I.e., those whose fasting blood sugar values (FBS) were or had been higher than 140 mg./lOO ml. or who had diabetic retinopathy), ΔIRI/ΔBS ratios were almost invariably subnormal regardless of FBS levels and the types of glucose tolerance at the time of GTT. In the rest of the patients (equivocal diabetics), ΔIRI/ΔBS ratios were either normal or subnormal. The decrease in ΔIRI/ΔBS was a fairly stable characteristic of each individual; in 330 equivocal diabetics, only 28 cases (8.4 per cent) moved between high-and low-insulin-responder groups during the follow-up. In 39 patients who had equivocal diabetes at the initial examination but subsequently developed definite diabetes (20 who began to have FBS above 140 mg./lOO ml. and 19 who developed retinopathy), the insulin response were already subnormal at the initial GTT and remained low throughout the follow-up periods, although their glucose tolerance varied between normal, borderline, and diabetic types. Thus, definite diabetes occurred exclusively in the low-insulin-responder group among equivocal diabetics. The decrease in insulin response to glucose seems to be a more Inherent, specific, and stable feature of true diabetes than glucose intolerance, because it precedes the occurrence and persists after the remission of derangement of carbohydrate metabolism in definite diabetes.
The Roles of Insulin, Glucagon, and Free Fatty Acids in the Regulation of Ketogenesis in Dogs
Authors: Keller Ulrich , Chiasson Jean-Louis , Liljenquist John E , Cherrington Alan D , Jennings Anthony S , Crofford Oscar B
Published: September 2013

The roles of basal insulin, glucagon, and free fatty acids in the regulation of ketogenesis were studied in three-day-fasted anesthetized dogs. Four protocols were employed: (1) infusion of somatostatin, resulting in combined insulin and glucagon deficiency, (2) somatostatin and intraportal glucagon replacement (1 ng./kg./min.) to produce insulin deficiency, (3) somatostatin combined with intraportal insulin replacement (350 μU./kg./min.) to produce glucagon deficiency, and (4) saline controls. Simultaneous blood sampling from the femoral artery and portal and hepatic veins allowed determination of hepatic uptake or production of free fatty acids, glycerol, ketone bodies, and glucose. When combined deficiency of insulin and glucagon was produced, no significant effect on hepatic ketone production was noted (108 ± 6 per cent of mean basal), whereas the induction of selective Insulin deficiency (basal glucagon level maintained) resulted in a rise of net hepatic ketone production (185 ± 24 per cent of mean basal, P < 0.01). Isolated glucagon lack (basal insulin maintained) did not alter net hepatic ketone production.

To assess the effect of increased substrate supply on ketogenesis, all experiments included a period of acute elevation of free fatty adds (FFA), produced by infusion of Intralipld and heparin. FFA elevation in saline controls caused only a moderate stimulation of ketone production (149 ± 16 per cent of mean basal, P < 0.01) despite a threefold increase in FFA uptake. However, the combination of elevation of FFA and selective insulin deficiency (glucagon maintained) resulted in a greatly increased hepatic ketone production (357 ± 58 per cent of mean basal, P < 0.01 vs. controls), which was also significantly higher than during combined insulin and glucagon deficiency (P < 0.05). Lipolysis, as indicated by arterial glycerol levels, as well as hepatic FFA uptake was not affected by acute suppression of pancreatic hormone levels.

The study demonstrated that basal insulin plays an important role in repressing ketogenesis and that basal amounts of glucagon, while ineffective in the presence of insulin, exert a stimulatory effect on ketogenesis when insulin is deficient. Glucagon's stimulatory effect on ketogenesis was due to an effect in the liver rather than to an increase in lipolysis or in hepatic FFA uptake. Increasing FFA supply per se was associated with only limited stimulation of ketogenesis, whereas the combination of insulin deficiency, basal concentrations of glucagon, and increased FFA load produced a synergistic augmentation of hepatic ketone production.