bluuebunny/crossref_metadata_2025 huggingface dataset:
24-Hour Studies of the Effects of Somatostatin on the Levels of Plasma Growth Hormone, Glucagon, and Glucose in Normal Subjects and Juvenile Diabetics
Authors: Christensen S E , Hansen Aa P , Weeke J , Lundbaek K
Published: September 2013

Somatostatin was infused in various doses into normal subjects and juvenile diabetics for a 24-hour period preceded by a 24-hour control period and followed by another three-hour control period. Saline was infused during the first control period. Meals were served during the two 24-hour periods. Blood samples were taken hourly.

Five normal males received a total dose of 4 mg. somatostatin. Four male diabetics received 2 mg., four received 4 mg., and four 6 mg. In the diabetics, somatostatin suppressed plasma growth hormone, glucagon, and glucose throughout the infusion. All parameters rebounded at cessation of infusion. In the normals, somatostatin suppressed plasma growth hormone, glucagon, and insulin but increased plasma glucose.

It is concluded that the plasma glucose suppression in the diabetics is mainly due to the suppression of the diabetogenk hormones growth hormone and glucagon. A minor effect of decreased and/or delayed absorption of carbohydrates cannot be excluded in these experiments. The elevated plasma glucose levels in normals must be due to the suppressive effects of somatostatin on insulin secretion.
Effect of Glucose on the Glucagon Response to L-dopa in Normal and Diabetic Subjects
Authors: Klimeš Iwar , Vigaš Milan , Jurčovičová Jana , Repčeková Daniela , Kolesár Pavel
Published: September 2013

The effect of an oral dose of 1 gm. L-dopa either without or after a concomitant oral administration of 100 gm. glucose on the plasma level of pancreatic glucagon, plasma immunoreactive insulin (IRI), and plasma growth hormone (GH) was assessed in eight normal and 10 insulin-treated diabetic subjects. In the normal group the stimulatory effect of L-dopa on pancreatic glucagon release was reconfirmed. Moreover, in the diabetics essentially the same plasma glucagon increase after drug administration was found, such a response being inhibited in both groups by glucose.

The increase of plasma GH after L-dopa in both healthy persons and diabetics and the inhibition of this response by glucose in healthy subjects was reconfirmed. Furthermore, the same effect of exogenous glucose on the L-dopa-induced GH release was observed in diabetics.

It may be concluded that glucagon may play a pathogenetic role in the worsening of parkinsonian diabetic patients during the treatment with L-dopa and that diabetic hyperglycemie per se seems to be insufficient for an inhibition of the release of both glucagon and GH after L-dopa.
Effect of Insulin Therapy on the Profiles of Plasma Immunoreactive Glucagon in Juvenile-type and Adult-type Diabetics
Authors: Raskin Philip , Unger Roger H
Published: September 2013

To determine if the abnormal A-cell function of human diabetes can be corrected by insulin therapy, 10 patients with juvenile-type and 10 with adult-onset types of diabetes were aggressively treated with insulin for up to 10 days. Glucose, immunoreactive glucagon (IRG), and, where possible, insulin were measured in plasma specimens obtained at two-hour intervals for periods of up to 10 days. These patients were compared with nine nondiabetics who were studied similarly.

During a two-day “uncontrolled” period, marked hyperglycemie, glycosurie, and elevated IRG concentrations were present in both groups of diabetic patients. “Improved control” was achieved in the juvenile-type diabetic group with an average insulin dose of 115 ± 24 U. per day. Such therapy significantly reduced the mean plasma glucose (p < 0.001) and IRG (p < 0.05) concentrations when compared with the “uncontrolled” period, but both remained above (p < 0.05) the values seen in the nondiabetk subjects.

“Improved control” was achieved in the maturity-onset group of patients with an average insulin dose of 160 ± 24 U. per day. This dose was associated with a mean plasma-insulin value of 106 ± 26 μU. per milliliter, significantly greater (p < 0.05) than that of the nondiabetk: group. Mean plasma glucose (p < 0.001) and IRG (p < 0.02) concentrations were reduced significantly as compared with the “uncontrolled” period; the mean IRG level was the same as that of the nondiabetics, but the mean plasma glucose levels remained significantly greater (p < 0.001) than in the nondiabetics.

The results indicate that aggressive administration of insulin by conventional means does significantly reduce the average IRG level in juvenile-type and adult-type diabetics. However, despite the large doses of insulin and unphysiologically high concentrations of circulating insulin in the juvenile-diabetic group, IRG remained significantly above that of the nondiabetics. In the adult-onset group, although it was reduced to normal, the IRG level can be viewed as above normal relative to the persistent hyperglycemie and hyperinsulinemia.
Phosphate Metabolism and Glucose-initiated Efflux of Phosphate Ions in Islets of Fetal Pancreas
Authors: Asplund Kjell , Freinkel Norbert
Published: September 2013

Elsewhere we have proposed that the rapid transient efflux of 32P orthophosphate that occurs when prelabeled pancreatic islets are exposed to nutrient secretagogues (the “phosphate flush”) reflects one of the earliest steps in islet stimulus-secretion coupling. We have now shown that the “phosphate flush” is much smaller with islets from fetal rats 21½ days old. This could be attributed to decreased cellular stores of radioactivity, especially inorganic orthophosphate (32P), at the onset of stimulation, which may have been due, in part, to the diminished ability of fetal islets to retain the radiophosphorus accumulated during the labeling period. Certain other differences in phosphate metabolism were also observed. With prelabeled islets from adult rats, exposure to 3.0 mg. per milliliter glucose effected acute increases in the tissue content of AT32P and GT32P. Comparable stimulation of prelabeled fetal islets with 3.0 mg. per milliliter glucose did not elicit detectable changes in the labeling of ATP or GTP. The findings indicate that selected aspects of phosphate metabolism may be immature in fetal islets and, perhaps, implicated in their obtunded secretion of insulin in response to stimulation with glucose.
Glucose Tolerance in Viral Hepatitis: A Study of Twenty Patients During the Acute Phase and After Recovery
Authors: Chupin Maurice , Charbonnel Bernard , Bodic Louis Le , Grolleau Jean-Yves , Chupin Françoise , Guillon Jean
Published: September 2013

Twenty patients with viral hepatitis were investigated during the acute phase and after recovery in order to study their glucose tolerance. During hepatitis, three tests were performed: oral and intravenous glucose tolerance tests and tolbutamide test, with measurements of glucose, insulin, free fatty acids, trigiycerides, growth hormone, and cortisol. After recovery, a control oral glucose tolerance test was performed. All these results were compared with those of healthy controls.

During the acute phase, both oral and intravenous glucose tolerance tests showed two groups of patients: nine with normal glucose tolerance but significant hyperinsulinism, and 11 with glucose intolerance but a delayed and not increased insulin response. Tolbutamide test was always normal, without any difference between these two groups.

Free fatty acids (FFA) were increased only in the glucose-intolerant group; there was a significant negative correlation between basal FFA and the K values. Trigiycerides were increased in the two groups, but were higher in the normal glucose-tolerant one. Growth hormone and cortisol were increased only when the K value was very low.

All these parameters returned to normal in all the patients after their recovery.

Clinical features, hepatic tests, and HLA typing were similar in the two groups, with no significant differences. A comparative group of patients with mild and nonhepatic infections did not show any abnormalities.

This study suggests there is a transitory insulin-resistant state during viral hepatitis, which can be due to an increase in FFA concentrations. Glucose intolerance occurs in half of the cases, possibly as a consequence of an additional β-cell impairment.
Interactions of Obesity and Glucose-stimulated Insulin Secretion in Familial Hypertriglyceridemia
Authors: Maruhama Yoshisuke , Abe Ryuzo , Okuguchi Fuminobu , Oikawa Shinichi , Ohneda Akira , Goto Yoshio
Published: September 2013

Plasma lipids and lipoproteins, glucose tolerance, plasma insulin response to glucose load, and liver function were examined in 81 relatives of 12 index cases with primary endogenous hypertriglyceridemia, hyperinsulinemia, and hepatic steatosis, as well as in 90 nonrelatives, including the spouses, as controls. Insulin hypersecretion (with or without glucose intolerance), endogenous hypertriglyceridemia, and abnormal liver function suggesting hepatic steatosis were shown to exist in the relatives mostly in combined fashion. Correlation analysis and stepwise multiple regression analysis revealed that the combined disorder developed on the basis of obesity. The incidence of diabetes mellitus was significantly high in the relatives (14.8 per cent) as compared with the normal Japanese population (3.5 per cent).

Although the vertical transmission of the combined disorder was noted in almost all pedigrees, the frequency distribution analysis of insulin response, glucose tolerance, and plasma triglyceride showed the histograms of these variables similarly skewed to the right as compared with those in the controls, with no apparent bimodality.

In view of the hitherto suggested role of insulin in triglyceride metabolism, it is concluded that hyperinsulinemia coupled with obesity seems to be the basic trait of this form of familial hypertriglyceridemia and hepatic steatosis, though the mode of transmission remains to be elucidated.
Diabetes Screening Using a Quantitative Urine Glucose Method
Authors: Davidson John K , Reuben David , Sternberg James C , Ryan William T
Published: September 2013

Sensitivity and specificity of three methods (random urine glucose (RUG) > 25 mg. per deciliter; positive Clinitest; and random plasma glucose (RPG) > 140, > 120, and > 100 mg. per deciliter) for detecting the unknown diabetic were compared. In 1,952 screenees, RUG of 96.7 per cent was 3 to 25 mg. per deciliter (normoglucosuria), RUG of 2.0 per cent was 26 to 100 mg. per deciliter (moderate hyperglucosuria), and of 1.3 per cent was > 100 mg. per deciliter (marked hyperglucosuria). Twenty-five randomly selected from each of the first two groups and 18 from the third group had a glucose tolerance test (GTT); seven in the third group had fasting plasma glucose tests > 150 mg. per deciliter. GTTs were evaluated by United States Public Health Service (USPHS), Fajans-Conn (F-C), and summation (S) criteria, and tested screenees divided into nondiabetic (ND) and diabetic (DM). NDs with RUG > 25 mg. per deciliter were false positive screens: renal hyperglucosurics (RHG) if GTT urine glucose ≥ 80 mg. per deciliter, nonrenal hyperglucosurics (NRHG) if GTT urine glucose ≤ 25 mg. per deciliter. The prevalence of DM was 1.24 per cent (USPHS), 1.37 per cent (F-C), and 1.45 per cent (S). The prevalence of false positives (USPHS) was 2.04 per cent (1.19 per cent RHG and 0.85 per cent NRHG). In the normoglucosuria group, 100 per cent who had a GTT were true negatives. In the moderate hyperglucosuria group, 16 per cent (USPHS) were true positives, 84 per cent false positives (44 per cent RHG, 40 per cent NRHG). In the marked hyperglucosuria group, 72 per cent (USPHS) were true positives, 28 per cent false positives (24 per cent RHG and 4 per cent NRHG). By Clinitest, 23 per cent of the DMs (USPHS) were false negatives, and 1.8 per cent in the normoglucosuria group were false positives. Nine per cent of the DMs were false negatives by RPG > 140, and 4.5 per cent were false negatives by RPG > 120.

RUG > 25 mg. per deciliter was as sensitive as the GTT in detecting unknown DMs but was less specific. Random normoglucosuric screenees are unlikely to have diabetes; about 40 per cent of random hyperglucosuric screenees have diabetes.
Obesity, Hyperinsulinemia, and Portal Blood Flow: A Theoretic Study of the Effects of Increased Portal Blood Flow Upon Fasting Peripheral Insulin Concentrations
Authors: Bucolo Richard J
Published: September 2013

A mathematical model of steady state insulin metabolism was developed to predict the effects of blood flow changes upon fasting arterial insulin concentration. In addition to blood flows to major organs and tissues, the model includes representations for insulin feedback regulation of hepatic insulin clearance and pancreatic insulin secretion. Within the range of insulin sensitivities assumed for hepatic and pancreatic feedback regulation and the range of initial insulin secretion rates employed, the model predicts that the fasting arterial insulin concentration rises by up to 20 μU. per milliliter as portal blood flow increases. The necessary elevations in portal blood flow lie well inside the range of increased total hepatic blood flow observed in obese subjects. The results of this study suggest that a significant portion of the elevation in fasting insulin concentrations seen in obesity may be the result of increased portal blood flow and that other clinical observations and metabolic changes that accompany obesity may also be related to altered portal flow.
A Pharmacologic Profile of McN-3495 [N-(1-methyl-2-pyrrolidinylidene)-N' -phenyl-1-pyrrolidinecarboximidamide], A New, Orally Effective Hypoglycemic Agent
Authors: Tutwiler Gene F , Kirsch Thomas , Bridi Gary
Published: September 2013

McN-3495, a new compound unrelated structurally to the sulfonylureas or phenformin, has been found to produce a hypoglycemic effect in nondiabetic rats, dogs, mice, and monkeys. The minimum effective dose of McN-3495 that lowers fasting blood glucose and improves glucose tolerance was found to be about 2.5 to 5 mg. per kilogram, per os, except in fasted monkeys, in which a tenfold greater potency was observed. When McN-3495 was given repeatedly for three to five days, no tolerance to the hypoglycemic activity occurred and no changes in other biochemical parameters were observed. In addition to being three to four times more potent than tolbutamide, McN-3495 also differs from the sulfonylureas in lowering blood glucose concentrations of streptozotocin-diabetic rats and db/db mice, and, moreover, oral administration to normal fasted dogs did not produce the characteristic rise in insulin concentrations observed with tolbutamide. Furthermore, unlike the biguanides, McN-3495 can lower dog and rat fasting blood glucose concentrations and can improve glucose tolerance whether the glucose is administered orally or parenterally. However, McN-3495, as phenformin, fails to work in totally depancreatized dogs.
Comparison of McN-3495 [N-(1-methyl-2-pyrrolidinylidene-N' -phenyl-1-pyrrolidinecarboximidamide], A New, Orally Effective, Hypoglycemic Agent, with the Biguanides
Authors: Tutwiler Gene F , Bridi Gary
Published: September 2013

McN-3495 [chemical name: N-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-1-pyrrolidinecarboximidamide], a new, oral, effective hypoglycemic agent that is structurally distinct from the biguanides, has been shown to be mechanistically distinct from the biguanides and to lack comparable side effects in animals. The biguanides (phenformin, buformin, metformin), which were active when glucose was given orally to fasted rats and dogs, failed to lower fasting blood glucose or improve glucose tolerance when the glucose was administered parenterally, thus suggesting that biguanides inhibit intestinal glucose absorption. McN-3495, however, lowered the fasting concentrations of glucose and increased glucose disappearance whether the glucose was administered orally or parenterally. Furthermore, intestinal glucose transport, measured by use of the everted sac technique, was inhibited after oral pretreatment of rats with buformin and phenformin but not with McN-3495. However, both phenformin and McN-3495 inhibited glucose transport when added directly in vitro, although McN-3495 did so at higher concentrations. The reasons for the differing actions of McN-3495 and the biguanides on intestinal transport in vivo and in vitro are discussed. New models for biguanide-induced lactacidemia using normal and streptozotocin-diabetic rats were developed. In addition, a number of the gastrointestinal side effects of phenformin use were observed in animal experiments. McN-3495, at doses above projected therapeutic doses, however, did not produce lactacidemia or comparable gastrointestinal side effects. Thus, McN-3495 is a novel oral hypoglycemic agent, probably safer than phenformin, that could provide better control of blood glucose in diabetic patients.
The Diabetogenic Activity of Fragments of Human Growth Hormone in Obese (ob/ob) Mice
Authors: Reagan Charles R
Published: September 2013

The genetically obese (ob/ob) mouse was used to investigate the effects of highly purified human growth hormone (hGH), reduced and S-carbamidomethylated hGH (RCAM-hGH), plasmin-digested RCAM-hGH (PD-RCAM-hGH), and peptide fragments isolated from the plasmin digests of RCAM-hGH on fasting blood glucose concentration and glucose tolerance. Mice treated for three days with hGH exhibited both increased fasting blood glucose concentrations and aggravated intolerance to administered glucose. Similar changes in the fasting blood glucose concentration and glucose tolerance were observed after treatment of mice with RCAM-hGH and PD-RCAM-hGH. Moreover, two noncovalent complexes of peptides of RCAM-hGH, one consisting of residues 1-134 bound to 141-191 (Dal) and the other consisting of almost equal amounts of 1-134 and 42-134 bound to 141-191 (Dc2), appeared to retain the full activity of the native hormone in that they increased fasting blood glucose concentrations and aggravated glucose intolerance in the ob/ob mice. A peptide consisting of residues 95-134 of RCAM-hGH appeared to retain some diabetogenic activity, while a peptide consisting of residues 20-41 was devoid of activity. Tolerance tests performed six hours after a single injection of either hGH or fraction Dal indicated that this time interval was not sufficient to elicit the diabetogenic response. Thus, these studies indicate that neither intact disulfide bridges nor intact primary amino acid sequence of the hGH molecule are required for the expression of its diabetogenic activity.
Chemical Diabetes in Childhood: Integrated Concentrations of Glucose, Insulin, and Growth Hormone
Authors: Winter Robert J , Plotnick Leslie P , Thompson Robert G
Published: September 2013

Children and adolescents with varying degrees of glucose intolerance were studied with constant, blood withdrawal methods, and concentrations of glucose, insulin, and growth hormone were evaluated during a normal twenty-four-hour routine. Integrated concentrations of glucose and insulin in children with chemical diabetes were normal despite abnormal oral glucose–tolerance tests. All but two insulin–dependent diabetics had elevated integrated concentrations of growth hormone, as did some but not all chemical diabetics. Three of four mildly ketoacidotic individuals with newly diagnosed diabetes, who were studied before insulin therapy, had normal growth hormone–integrated concentrations. These data differentiate pharmacologic and physiologic assessments of carbohydrate homeostasis, and they support the concept that elevated growth hormone concentrations may not be a direct result of poor diabetic control.
Juvenile-onset Diabetes: HLA-A, -B, -C, and -DR Alloantigens
Authors: Solow H , Hidalgo R , Singal D P
Published: September 2013

We studied the distribution of HLA-A, -B, and -C antigens in 94 juvenile-onset diabetic patients and of HLA-DR antigens in 62 of these patients. The frequencies for HLA-B15, -B40, and -Cw3 were significantly increased in the patient group as compared with the control group. With respect to the B-cell specificities, DRw4 was significantly increased in the patients. Analysis of the data to detect the possible presence of primary and secondary associations between HLA alleles and diabetogenic gene(s) indicated that DRw4 possessed a primary association with the diabetogenic gene(s). As a result, B15, B40, and Cw3 possessed secondary associations.
Somatostatin and Pancreatic Polypeptide Secretion: Effects of Glucagon, Insulin, and Arginine
Authors: Weir G C , Samols E , Loo S , Patel Y C , Gabbay K H
Published: September 2013

The isolated perfused canine pancreas with duodenal exclusion was used to examine islet hormone output in response to arginine and exogenous glucagon and insulin. Exogenous glucagon (100 ng/ml) stimulated insulin and somatostatin secretion, which occurred in a biphasic pattern. The insulin response to glucagon was markedly enhanced by increased perfusate glucose, unlike the somatostatin response, which was little affected. The insulin and somatostatin responses were seen between 15 and 45 s after the glucagon stimulus. Pancreatic polypeptide secretion was uninfluenced by exogenous glucagon.

Biphasic release of glucagon, somatostatin, and pancreatic polypeptide was evoked by 10 mM arginine, the responses first being apparent within less than 30 s. Exogenous insulin (50 mU/ml) infused for 10 min had no statistically significant effect on glucagon, somatostatin, or pancreatic polypeptide secretion. This study suggests that these four islet hormones may all be involved in the dynamic mechanisms of nutrient metabolism. In addition, potential intra-islet paracrine effects are identified.
Pharmacogenetics of Tolbutamide Metabolism in Humans
Authors: Scott Joanne , Poffenbarger Phillip L
Published: September 2013

This study was designed to focus on the genetic control of tolbutamide disposition in humans and to provide insight into the potential for high accrued blood levels in individuals receiving fixed dosage regimens. Tolbutamide was administered intravenously to 42 nondiabetic subjects, eight of their relatives, and to five sets of twins. A ninefold variation in the rate of tolbutamide disappearance from plasma (Kd) was found. This variation was characterized by a trimodal frequency distribution, suggestive of monogenic inheritance and consistent with pedigree analysis, indicating autosomal transmission of rapid and slow inactivation of tolbutamide. A heritability value of 0.995 for Kd indicated little influence of environmental factors on variation of this rate.

Interindividual differences in the binding of 35S-tolbutamide to serum proteins were also assessed. No correlation was found between tolbutamide serum protein binding affinity and Kd. Analysis of the metabolites of tolbutamide in urine samples provided evidence for the microsomal oxidation of the drug to hydroxytolbutamide as the primary site of genetic control.

In conclusion, this study provides evidence for monogenic control of tolbutamide metabolism in man. The results suggest that fixed dosage regimens of this drug, as were prescribed in the controversial University Group Diabetes Program study, might lead to higher accrued blood levels in slow inactivators.
Effects of Calcium, Lanthanum, and Bicarbonate Ion on Epinephrine Modification of Insulin Release In Vitro
Authors: Lorenz R , Sharp R , Burr I M
Published: September 2013

The role of calcium flux in mediating epinephrine modification of insulin release was investigated by using lanthanum, an inhibitor of calcium flux, in the in vitro perifusion system. Lanthanum inhibits insulin secretion stimulated by glucose and by acetylcholine to basal levels. Epinephrine and lanthanum have additive effects in inhibiting insulin secretion to glucose stimulation. The effect of epinephrine prestimulation on insulin secretion to subsequent glucose challenge varies markedly, depending on the presence or absence of bicarbonate ion: epinephrine priming is reversed inthe absence of bicarbonate, an effect possibly related to reduced calcium uptake. In the presence of bicarbonate, lanthanum blocks the priming effect of epinephrine on insulin secretion. The data further support the postulated role of calcium in adrenergic effects on beta cell function.
Studies of Cultured Human Fibroblasts in Diabetes Mellitus: Changes in Heparan Sulfate
Authors: Silbert Cynthia K , Kleinman Hynda K
Published: September 2013

The incorporation of [35S]sulfate into glycosaminoglycans was studied in cultures of normal and diabetic skin fibroblasts. Heparan sulfate was determined by column chromatography after enzymatic degradation of chondroitin sulfates and dermatan sulfate by chondroitinase ABC. Cultured skin fibroblasts from both insulin-dependent and noninsulin-dependent diabetics were found to have increased proportions of heparan sulfate in the media relative to the other sulfated glycosaminoglycans.
Reduction in Portal Vein Blood Flow by Somatostatin
Authors: Jaspan Jonathan , Polonsky Kenneth , Lewis Michael , Rahim Moossa A
Published: September 2013

Intravenous somatostatin boluses produced striking diminution in portal vein blood flow in dogs (maximally 40–55%). This effect was of rapid onset, without observable changes in hepatic artery flow, systemic blood pressure, pulse or central venous pressure. The duration of action was short, but could be sustained by continuous intravenous infusion. These observations are consistent with an endocrine role of somatostatin in the regulation of nutrient balance.
Nutrition and Somatomedin. VIM. The “Somatomedin Inhibitor” in Diabetic Rat Serum is a General Inhibitor of Growing Cartilage
Authors: Phillips Lawrence S , Vassilopoulou-Sellin Rena , Reichard Larry A
Published: September 2013

Serum somatomedin activity appears to reflect the presence of both somatomedins and “somatomedin inhibitor,” a factor(s) that blunts cartilage stimulation by somatomedins. Although poor growth in uncontrolled diabetes is associated with an increase in inhibitor, suggesting a possible physiologic role, little is known of the interactions between this factor and somatomedins. We examined such interactions by measuring the effects of serum from normal rats (NRS, enriched in somatomedins) and serum from streptozo-tocin-diabetic rats (DRS, enriched in inhibitor) on costal cartilage from hypophysectomized rats. A 48-h exposure of cartilage to NRS resulted in an uptake of sulfate and uridine 125 ± 36% and 59 ± 14% (m ± SEM) above buffer levels, respectively, but addition of DRS to NRS produced sulfate and uridine uptake of 66 ± 3% and 95 ± 2% below buffer, respectively, indicating that chondroitin sulfate and RNA synthesis were both affected. Significant inhibition of uridine uptake (an early cartilage process) occurred as little as 4 h after exposure to DRS, while inhibition of sulfate uptake (a later process) was not found until 20 h. The decrease in isotope uptake following 24 h of exposure to DRS persisted over the next 24 h despite transfer of cartilage to fresh DRS-free medium and addition of NRS during the second 24-h period. When cartilage was incubated with a fixed concentration of DRS and increasing concentrations of NRS, Lineweaver-Burk analysis of both sulfate and uridine uptake indicated that NRS/DRS interactions were noncompetitive.

These results indicate that the inhibitory factor in DRS affects different cartilage processes, produces profound, long-lasting decreases in cartilage activity, and has noncompetitive interactions with somatomedins in NRS. We conclude that somatomedin inhibitor in the serum of diabetic rats is a general inhibitor of growing cartilage that not only blocks stimulation by somatomedins, but also inhibits cartilage metabolism directly.
Genetic Susceptibility to Diabetes Mellitus: the Distribution of Properdin Factor B (Bf) and Glyoxalase (GLO) Phenotypes
Authors: Kirk R L , Theophilus Jaya , Whitehouse S , Court J , Zimmet P
Published: September 2013

The distribution of phenotypes controlled by two loci on chromosome 6 has been studied in a series of 239 patients with type 1 (insulin-dependent) and 297 patients with type 2 (non-insulin-dependent) diabetes mellitus. At the properdin factor B (Bf) locus there is a significant increase in the frequency of the Bfs1 and BfF1 alleles for type 1 patients, and the combined increase in frequency of Bfs1 and BfF1 in those patients is highly significant. The relative risk for F1 is 6.2 and for F1 and S1 combined is 5.3. These results confirm the association with F1 reported recently by Raum and co-workers in Boston. The two rare alleles Bfs1 and BfF1 are in significant negative disequilibrium with HLA B8.

For the glyoxalase (GLO) locus there is a slight but nonsignificant increase in the frequency of the GLO2 allele, but a significant disturbance in the distribution of the GLO phenotypes for type 2 patients. These results for the GLO alleles may be due to stratification in our series of type 2 patients. Further studies are in progress to test this hypothesis.
Studies of Insulin Binding in Children Using Human Erythrocytes in Small Amounts of Blood
Authors: Kappy Michael S , Plotnick Leslie
Published: September 2013

We have demonstrated specific insulin binding by the erythrocytes (RBCs) of children.

Complete binding studies were done using as little as 5 ml of blood.

The receptors exhibited competition-inhibition curves and nonlinear Scatchard plots similar to those reported for insulin target tissues, such as the hepatocyte and the adipocyte.

Compared with those from adults, the RBCs from children had significantly greater numbers of insulin receptors per cell (P < 0.05). The total insulin bound by the RBCs from both children and adults, however, was not different over the physiologic range of insulin concentrations. Cord blood RBCs showed greater numbers of receptors per cell than did those from either children or adults; however, the affinity for insulin was similar in both groups. The total amount of insulin bound by cord blood was significantly greater than that in either children (P < 0.01) or adults (P < 0.05) over the physiologic range of insulin concentrations.

The method used to measure insulin binding by erythrocytes had relatively little intra- and interassay variability, and there was little diurnal variation in binding. Storage of heparinized blood at 4°C for 24-36h had no effect on insulin binding by the RBCs. We conclude that the measurement of insulin binding by RBCs from small volumes of blood may be particularly useful in the study of infants and children with disorders of carbohydrate metabolism to elucidate the role, if any, of abnormal receptor function in their condition.
Chronic Hyperinsulinemia in the Fetal Rhesus Monkey: Effects on Hepatic Enzymes Active in Lipogenesis and Carbohydrate Metabolism
Authors: McCormick Kenneth L , Susa John B , Widness John A , Singer Don B , Adamsons Karlis , Schwartz Robert
Published: September 2013

Hyperinsulinemia was produced in fetal rhesus monkeys for 21 days in the last third of gestation by subcutaneous pork insulin injected at 19 U a day. Plasma insulin concentrations in treated fetuses (N = 4) were 3525 μU/ml compared with controls' (N = 6) 51 μ/ml. There was no difference in paired pre- and post-treatment fetal plasma glucose concentration. Activity of the hepatic enzymes that promote glucose utilization (glucokinase and hexokinase) and glycolysis (phos-phofructokinase, pyruvate kinase, and pyruvate dehy-drogenase) was unaffected. Similarly, glycogen metabolism enzymes (active and inactive synthase and phosphorylase) were unaltered. Two gluconeogenic enzymes (PEPCK and glucose-6-phosphatase) were diminished in the treated group compared with controls. Fetal hyperinsulinemia enhanced lipogenic and NADPH-producing enzyme activities, as evidenced by a twofold increase in fatty acid synthase and in citrate cleavage enzyme activity. Malic enzyme was absent. Hyperinsulinemia with euglycemia (1) increases the activity of enzymes that participate in lipogenesis, (2) decreases some of those controlling gluconeogenesis, and (3) has no effect on the enzymes of glycolysis.
Gamma-Aminobutyric Acid in Peripheral Tissue, with Emphasis on the Endocrine Pancreas: Presence in Two Species and Reduction by Streptozotocin
Authors: Gerber Joseph C , Hare Theodore A
Published: September 2013

A screen of selected peripheral organs of the rat found that γ-aminobutyric acid (GABA) is generally present outside the central nervous system, and, of those organs examined, GABA was present at the highest concentration in the pancreas (∼40 pmol/mg wet wt). Furthermore, this putative inhibitory neurotransmitter was found to be present at even higher levels in islets of Langerhans tissue isolated from rat pancreas (190 pmol/mg). Administration of streptozotocin, a selective β-cell toxin, decreased pancreatic GABA levels significantly, but had no or only small effects on the GABA content of other organs. Normal teleost (catfish) Brockmann body contains about the same level of GABA as normal rat islet tissue.
Glucose Intolerance and Aging: Evidence for Tissue Insensitivity to Insulin
Authors: DeFronzo Ralph A
Published: September 2013

The relative contributions of impaired insulin secretion and of impaired tissue sensitivity to insulin to the glucose intolerance of aging were examined in 84 healthy volunteers, ranging in age from 21 to 84 yr, employing the hyperglycemie and euglycemic insulin clamp techniques, respectively.

HYPERGLYCEMIC CLAMP. The blood glucose concentration was acutely raised and was maintained at 125 mg/dl above basal levels for 2 h. Since the glucose concentration was held constant, the glucose infusion rate was an index of glucose metabolism (M). In young subjects, M averaged 9.48 ± 0.40 mg/kg · min compared with 6.48 ± 0.28 in old subjects (P < 0.001). When all subjects were considered together, a progressive age-related decline in M was observed (r = –0.665, P < 0.001). The plasma insulin response (I) was biphasic, with an early burst within the first 6 min, followed by a phase of gradually increasing insulin concentration. No difference in either the early or late phases of insulin secretion was observed between young and old subjects. Consequently, the M/l (×100) ratio, an index of tissue sensitivity to endogenous insulin, decreased from 14.90 ± 1.01 to 10.98 ± 0.81 mg/kg min per μU/ml (P < 0.005).

EUGLYCEMIC INSULIN CLAMP. The plasma insulin concentration was acutely raised and was maintained at about 100 μU/ml above basal levels by a primed continuous infusion of insulin. The blood glucose concentration was held constant at the basal level by a variable glucose infusion. M/I (×100), again, was a measure of tissue sensitivity to insulin (exogenous) and was decreased in old (4.95 ± 0.31 mg/kg · min per μU/ml) versus young (6.95 ± 0.45) subjects (P < 0.001). Hepatic glucose production was measured with tritiated glucose during the euglycemic clamp study; it declined similarly in young (to 0.13 ± 0.05 mg/kg · min) and old (to 0.09 ± 0.03 mg · min) subjects.

In conclusion, under the present experimental conditions, employing intravenous glucose and/or insulin, impaired tissue sensitivity to insulin is the primary factor responsible for the decrease in glucose tolerance observed with advancing age. Since hepatic glucose production is normally suppressed by insulin in old subjects, the site of insulin resistance must reside in peripheral tissues. Beta cell response to glucose, as determined by the hyperglycemie clamp technique, cannot account for the age-related decline in M.
Factors from Fibroblasts Promote Pancreatic Islet B Cell Survival in Tissue Culture
Authors: Rabinovitch Alexander , Russell Thomas , Mintz Daniel H
Published: September 2013

A possible role for fibroblasts in promoting the survival and function of islet B cells in tissue culture was examined by the addition of fibroblasts from a mouse embryo cell line (3T3-L2) to islet cell monolayer cultures prepared from newborn rat pancreases. Co-culture of islet cells with fibroblasts significantly increased the recovery of insulin in medium and cells after 7 days of culture in medium supplemented with 10% serum, and prevented the deterioration of islet cells cultured in serum-free medium. Similarly, serum-free medium, conditioned by cultures of either 3T3-L2 fibroblasts or fibroblasts freshly isolated from newborn rat pancreases, maintained the release and content of insulin in islet cell monolayer cultures at levels four- to eightfold higher than in control serum-free medium. Serum-free, fibroblast-conditioned medium also enhanced the survival of intact islets maintained in free-floating culture for 28 days. The active factor(s) in fibroblast-conditioned medium has a high molecular weight and is heat-stable. We conclude that fibroblastic cells produce a macromolecular factor(s) capable of enhancing the survival of functional islet B cells in tissue culture.
Comparison of a Colorimetric Assay for Glycosylated Hemoglobin with Ion-exchange Chromatography
Authors: Pecoraro Roger E , Graf Ronald J , Halter Jeffrey B , Beiter Howard , Porte Daniel
Published: September 2013

Because levels of glycosylated hemoglobin (GHb) are increased in diabetes and reflect the previous metabolic control, clinicians and clinical investigators are finding increasing applications for measurements of GHb in diabetic patients. We report the characterization of a colorimetrie assay procedure for GHb and compare its performance with that of a commonly used assay by ion-exchange chromatography. Although results of GHb determination by both methods correlate highly (r = 0.943, P < 0.001), the two procedures estimate different glycosylated fractions. The colorimetrie procedure is nonstoichiometric, requiring careful standardization of assay conditions, including the concentration of total hemoglobin in the assayed aliquot, to achieve precision and permit comparison of results. We characterized the effect of storage of hemolysates or packed erythrocytes on the subsequent determination of GHb by both methods. Determinations of GHb by the colorimetrie method, but not by column chromatography, are reproducible on hemoly-sates or packed erythrocytes stored frozen for at least 5 mo. A unique advantage of the colorimetrie procedure is the capability to estimate GHb levels when variant hemoglobins, including fetal and sickle hemoglobins, are present.
Mononeuropathy in Diabetes Mellitus
Authors: Fraser D M , Campbell I W , Ewing D J , Clarke B F
Published: September 2013

Fifty-one diabetic patients with mononeuropathy were studied to examine possible etiological factors, to determine the relationship with other diabetic complications, and to correlate with the presence and severity of background peripheral and autonomic neuropathy. The median, ulnar, and lateral popliteal nerves were most commonly affected and cranial neuropathy was relatively uncommon. When bilateral involvement of the same nerve was excluded, multiple mononeuropathies were found in only five patients. Median and ulnar mononeuropathy were gradual in onset and affected the dominant limb whereas other types of mononeuropathies were acute In onset with no predilection for either side. No consistent relationship was shown between the onset of mononeuropathy and age, sex, diabetic treatment, duration of diabetes, diabetic control, or other diabetic complications. In particular, there was no significant background peripheral and autonomic neuropathy, as assessed clinically and by objective tests, in almost one-half of the patients studied. It is concluded that diabetic mononeuropathy may occur independently of peripheral and autonomic neuropathy. It is possible, however, that a minimal degree of background damage, known to be present in all diabetic patients, may render them more susceptible than the general population to the various factors causing mononeuropathy.
The Insulin Receptor and Insulin of the Atlantic Hagfish: Extraordinary Conservation of Binding Specificity and Negative Cooperativity in the Most Primitive Vertebrate
Authors: Muggeo M , Van Obberghen E , Kahn C R , Roth J , Ginsberg B H , De Meyts P , Emdin S O , Falkmer S
Published: September 2013

The North Atlantic hagfish, a cyclostome that is representative of the most primitive vertebrates still alive, diverged from the other vertebrates about 500 million years ago. Hagfish insulin, which differs from porcine insulin in 18 (38%) of its amino acids, had a potency of 5-10% that of porcine insulin in stimulating glucose oxidation and deoxyglucose transport in rat adipocytes and was 5-10% as potent as porcine insulin in binding to insulin receptors on rat adipocytes and human (IM-9) lymphocytes. Like all other naturally occurring insulins, hagfish insulin accelerated the dissociation of 125I-porcine insulin from insulin receptors and the degree of the acceleration was related to its occupancy of the receptor. The insulin receptor of the hagfish erythrocyte showed the time, temperature, and pH dependence of binding and the negative cooperativity that are characteristic of all other insulin receptors. That the negative cooperativity is fully conserved in such an ancient insulin and receptor suggests that it is an important functional feature of this hormone-receptor system.

The hagfish receptor showed the same absolute affinity and rank order of preference for insulins and insulin analogues (chicken > pork > proinsulin > guinea pig > desoctapeptide) found with other receptors of less primitive vertebrates, which supports the conclusion that the receptor for insulin is functionally better conserved evolutionary than the hormone. However, uniquely, hagfish insulin was more potent in binding to hagfish receptors than to mammalianreceptors; with all other species of insulins studied, the affinity of the hormone for homologous receptor was the same as for receptors of heterologous species.
Theophylline: Potentiation of Arginine-induced Somatostatin Release from the Isolated Rat Pancreas
Authors: Goto Yasuo , Seino Yutaka , Taminato Tomohiko , Kadowaki Seizo , Chiba Tsutomu , Note Shinya , Imura Hiroo
Published: September 2013

Somatostatin's release from the isolated rat pancreas was studied using a perfusion technique. Arginine at a concentration of 19 mM produced a biphasic increase in somatostatin release from the perfused rat pancreas. Both first and second phases of somatostatin's increase are significantly higher in the presence of 1 mM theophylline than in the absence of the drug. These results indicate the possible inclusion of the adenylate cyclase-cyclic AMP system in the regulatory mechanism of rat pancreatic somatostatin secretion.
Splanchnic Metabolism of Alanine in Intact Man: Effects of Somatostatin and Somatostatin Plus Insulin
Authors: Rabin David , Mueller G L , Lacy W W , Liljenquist J E
Published: September 2013

We examined splanchnic metabolism of alanine in 15 normal males under three sets of conditions: infusion of saline (control studies); infusion of somatostatin (SRIF) (bihormonal deficiency of insulin and glucagon); and infusion of somatostatin plus insulin (selective glucagon deficiency). Net splanchnic alanine uptake (NSAU) remained stable over 2 h during infusion of saline. Infusion of SRIF was associated with a fall in estimated hepatic plasma flow (EHPF) whether or not insulin was infused concomitantly. With SRIF only, arterio-hepatic venous alanine differences increased such that NSAU remained stable over 2 h, despite the fall in EHPF. In contrast, with selective glucagon deficiency, NSAU fell significantly after 2 h, an effect consequent on a fall in EHPF and a delayed fall in arterio-hepatic venous (A-HV) alanine differences. Our studies are compatible with a role for basal glucagon in maintenance of splanchnic extraction of alanine in normal man. However, the SRIF-initiated fall in EHPF may exert an infjuence on A-HV alanine differences independent of changes in pancreatic hormone secretion.
Lipoproteins in the Plasma and Hepatic Perfusates of the Zucker Fatty Rat
Authors: Witztum Joseph L , Schonfeld Gustav
Published: September 2013

The Zucker fatty rat develops marked hyperlipidemia characterized by elevations in all lipoproteins. The compositions of these lipoproteins are altered. The purpose of our study was to determine the hepatic contribution to the alterations seen in plasma.

Zucker fatty rats and lean controls were fed ad libitum. Fatties gained more weight than leans. Levels of lipids were determined chemically, and apoproteins A(ApoA)-I and B(ApoB) by radioimmunoassay (RIA). Very low density lipoproteins (VLDL) (d < 1.006) and VLDL density subfractions were isolated by ultracentrifugation. VLDL size and density distributions were assessed by column chromatography and ultracentrifugation, respectively. Compositions were studied by isoelectric focusing (IEF) and polyacrylamide gel electrophoresis. Livers from fatty and lean controls were perfused in vitro and whole perfusates and perfusate VLDL were studied as for plasma.

Triglyceride (TG) increased ∼10-fold in fatty plasma, cholesterol (Choi) twofold, and ApoA-I fourfold, but ApoB was ∼40% lower. The VLDL of fatties were larger, TG-enriched, and less dense. Although total VLDL-protein was elevated, the proportion of the VLDL-protein that was ApoB and ARP was low. Therefore, VLDL-protein was enriched with ApoC. ApoB and ApoE contents of VLDL subclasses varied directly with particle density, while ApoC varied inversely. Changes in ApoC subspecies were also noted. For any given VLDL subfraction, fatty VLDL had less ApoB and ApoE and more ApoC than the corresponding VLDL subfraction in the lean controls.

Compared with livers of lean, the livers of fatty rats secreted VLDL that were larger, TG-enriched, and less dense. Here, too, VLDL-protein was higher because of relative increases in non-ApoB proteins. ApoB and ApoE content varied directly with particle density in VLDL subfraction of the perfusates, while ApoC varied inversely; for any given VLDL subfraction, fatty VLDL had less ApoE and more ApoC than analogous fractions in lean controls, though levels of ApoB were similar. As in plasma, the distribution of the ApoC subspecies differed in the perfusate VLDL of fatty and lean animals. Thus, the hepatic secretion of altered VLDL could explain many of the changes seen in the VLDL of plasma. However, differences remained between perfusate and plasma VLDL, which may be due to alterations introduced by intravascular catabolism and/or by lipoproteins secreted from the gut.

Although plasma ApoA-I levels were fourfold higher in fatty, the hepatic secretion of ApoA-I was similar in the fatty and lean rats. The contribution of the liver to plasma pools of A-I was calculated as 34.8% in lean and 10.7% in fatty. These data are consistent with the concept that the gut, not the liver, is the major contributor to plasma ApoA-I.