bluuebunny/crossref_metadata_2025 huggingface dataset:
Determination of the Glycosylated Hemoglobins (Hb AI) with a New Microcolumn Procedure: Suitability of the Technique for Assessing the Clinical Management of Diabetes Mellitus
Authors: Abraham E C , Huff T A , Cope N D , Wilson J B , Bransome E D , Huisman T H J
Published: September 2013

Fifty-seven children who attended a diabetes camp were divided into five groups on the basis of retrospective evaluation of the management of their diabetes mellitus over the previous three or more months. Shortly after their arrival at camp, fasting blood samples were obtained for the measurement of glucose and the quantitation of Hb AI and for hemoglobin typing. Samples were obtained from 12 normal (nondiabetic) camp personnel at the same time. The Hb AI components were measured by the “macrocolumn” procedure of Trivelli et al., by the colorimetric procedure of Flukinger and Winterhalter, and by a new microcolumn procedure employing columns and reagents provided by Isolab, Inc. As might be expected from a number of previous reports by other investigators, there was no significant correlation of the percentage of Hb AI with single fasting blood sugar values. Hb AI tended to decrease as the management of diabetes became more adequate according to clinical ratings. Comparison of the Hb AI (Hb AIa+b+c) determinations showed an acceptable correlation of percentages obtained by the relatively laborious macrocolumn procedure and the more facile microcolumn procedure, indicating that the latter would be clinically useful. Values of Hb AIc obtained by the colorimetric procedure, which has been proposed as a procedure suitable for the clinical laboratory, did not correlate well with Hb AIc values determined by the macrocolumn technique, nor did these show as good an inverse relationship to the ratings of the management of diabetes.
Effect of Verapamil on Insulin Response to Alcohol Hypoglycemia in Patients with Primary Hyperparathyroidism
Authors: Röjdmark Sven
Published: September 2013

In hypercalcemic patients with primary hyperparathyroidism who were fasted over a prolonged period, alcohol ingestion induced a significant fall in glucose whereas insulin remained unchanged. The hypercalcemic patients thereby differed from normocalcemic subjects, who showed a significant decline in both glucose and insulin when alcohol was ingested after a prolonged period of fasting. An increased uptake of calcium into the β-cells appears to have been a prerequisite for the occurrence of an unchanged insulin secretion during alcohol hypoglycemia in hypercalcemic patients, since a calcium-blocking agent, verapamil, infused intravenously during and after alcohol ingestion, brought about a normalization of the insulin response to alcohol hypoglycemia in such patients.
The Regulation of Plasma Ketone Body Concentration by Counter-Regulatory Hormones in Man: III. Effects of Norepinephrine in Normal Man
Authors: Schade David S , Philip Eaton R
Published: September 2013

We examined the mechanism of norepinephrine's ketogenic activity in normal man. The contribution of norepinephrine's lipolytic activity to the subsequent ketosis was assessed by comparing the degree of ketosis attained during hormone infusion and the degree of ketosis observed after heparin-induced free fatty acid substrate generation. In addition, we examined the effect of norepinephrine infusion on the plasma concentration of other stress hormones (glucagon, cortisol, and growth hormone) with the experimental protocol.

The results obtained during norepinephrine infusion into normal man demonstrated that norepinephrine's lipolytic activity was not the principal determinant of its ketogenic activity. In fact, less than 50% of norepinephrine's ketogenic activity could be attributed to the rise in plasma free fatty acid concentration. Furthermore, the ketosis that resulted from plasma norepinephrine elevation may have been a direct hormonal effect at the liver or may have been secondary to the norepinephrine-induced elevation of glucagon and/or suppression of insulin.

Our results emphasize the important role that endogenous insulin secretion plays on modulating the ketogenic effects of the stress hormones. Thus, norepinephrine, which suppresses plasma insulin secretion, is markedly ketogenic compared with the normal ketogenic response to glucagon, in spite of the fact that both of these stress hormones may activate ketogenesis via cyclic AMP formation. In conclusion, this study, in concert with a previous study in diabetic man, firmly established norepinephrine as a major ketogenic hormone in man.
Changes in Glucagon Levels After Four to Five Weeks of Glucoregulation by Portable Insulin Infusion Pumps
Authors: Raskin Philip , Angel Pietri , Unger Roger
Published: September 2013

Near-normal glucoregulation was maintained in five patients with juvenile-onset diabetes mellitus for 4–5 wk with a preprogrammed, continuous, subcutaneous insulin infusion using a portable battery-powered infusion pump. This form of therapy significantly lowered immunoreactive glucagon (IRG) levels below those observed while on conventional insulin treatment at several times during the 24-h profile. The maximum IRG levels were also reduced in all five subjects. Thus, a flexible system of insulin delivery, as is provided by certain open-loop pump systems, can overcome inappropriate glucagon secretion that occurs with conventional insulin therapy.
Patient-controlled Portable Insulin Infusion Pump in Diabetics
Authors: Bojsen Jørgen , Deckert Torsten , Kølendorf Klaus , Lørup Birthe
Published: September 2013

Ten patients with unstable insulin-dependent diabetes mellitus, mean duration 17.5 yr, all treated with highly purified porcine NPH insulin twice daily, were placed on highly purified porcine regular insulin subcutaneously four times daily for 2 days. Thereafter a preplanned intravenous insulin infusion was given for 54 h. Insulin in an amount corresponding to 24-h insulin requirement was infused by a portable infusion pump. Immediately before the main meals the prandial infusion program was released by the patients by pushing a button. Capillary blood glucose was taken every 30 min during the day and every 2 h during the night. Endogenous insulin secretion was calculated by measuring the C-peptide response after 1 mg of glucagon intravenously. Insulin antibodies were measured in all patients.

Insulin antibody concentration was low in most cases, and only one patient reacted to glucagon by a significant but low rise of C-peptide. After an equilibration period of 5 h, mean blood glucose (MBG) was in the physiologic range in 6 of 10 patients during the infusion period. MGB in the 10 diabetics averaged 5.5 ±1.0 mmol/L (mean ± SD) compared with 4.4 ± 0.4 mmol/L in nondiabetic controls. The mean amplitude of glycemic excursions (MAGE) was 4.1 ±1.4 mmol/L (mean ± SD) against 1.8 ± 0.6 mmol/L in control subjects. MBG, MAGE, and glucosuria were significantly reduced on the infusion days compared with the days on subcutaneous insulin.

It is concluded that near-normal blood glucose fluctuations can be obtained in unstable diabetics by a preplanned prandial insulin infusion program activated by diabetic patients themselves.
The Effects of Different Conditions of Organ Culture on the Survival of the Mouse Pancreas
Authors: Chase H Peter , Ocrant Ian , Talmage David W
Published: September 2013

The effects of different conditions of organ culture on the viability of murine pancreatic tissues and, particularly, of pancreatic islets, was assessed by morphologic and histochemical analyses. High oxygen tension (1300 mm Hg), found previously to allow successful allogeneic thyroid transplantation, was toxic to pancreatic tissue. Low temperature (22°C) was associated with better islet preservation than high temperature (37°C). Hydrocortisone did not reduce the survival of pancreatic islets and did appear to preserve the acinar components. Fetal and neonatal pancreas responded similarly to the various organ culture conditions. These results have potential importance in guiding future transplantation experiments.
Insulin-potentiating Action of a Synthetic Amino-terminal Fragment of Human Growth Hormone (hGH 1-15) in Streptozotocin-diabetic Rats
Authors: Ng Frank M , Bornstein Joseph
Published: September 2013

The hypoglycemie activity of the synthetic peptide fragment of human growth hormone, hGH 1–15, is insulin dependent, although it does not alter the circulating levels of plasma insulin in normal and diabetic rats. In severe diabetes induced by streptozotocin, the peptide had no effect on the basal levels of blood glucose, but enhanced insulin sensitivity during intravenous insulin tolerance tests in 16-h-fasted rats. Radioreceptor binding studies show increased binding of insulin by hepatic plasma membranes prepared from rats pretreated with hGH 1–15. These results suggest that the biologic action of the peptide is, at least in part, on insulin receptors of plasma membranes.
Gastric Inhibitory Polypeptide Enhanced Lipoprotein Lipase Activity in Cultured Preadipocytes
Authors: Eckel Robert H , Fujimoto Wilfred Y , Brunzell John D
Published: September 2013

Fat feeding stimulated the release of gastric inhibitory polypeptide (GIP) without concomitant insulin secretion. Since antilipolytic effects of GIP have been demonstrated and the uptake of triglyceride fatty acid by adipose tissue postprandially is a process reciprocally regulated with lipolysis, a stimulatory role of GIP on adipose tissue lipoprotein lipase activity may be present. After cultured preadipocytes were incubated for 2 h with GIP, the release of lipoprotein lipase activity into the culture medium and the total cellular activity present in acetone-ether powders of cells were measured. GIP stimulated significant increases in the lipoprotein lipase activity released into the culture medium and in cells. A dose response relationship was strongest for the effect of GIP on the enzyme activity in extracts of acetone-ether powders of the cells. The increased lipoprotein lipase activity produced by GIP could provide a mechanism for clearance of chylomicron triglyceride after feeding in man.
Kinetics of Native Insulin in Diabetic, Obese, and Aged Men
Authors: McGuire Elizabeth Ann , Tobin Jordan D , Berman Mones , Andres Reubin
Published: September 2013

The kinetics of unlabeled porcine insulin were studied in 69 nondiabetic male subjects aged 18–83 yr with obesity indexes of 0.93–1.51 and in 12 maturity-onset diabetics age 46–78 yr with obesity indexes of 0.95–1.56 by using the euglycemic clamp technique. Analysis of the insulin kinetic data by using a mathematical model permitted the determination, for each individual, of steady state distribution masses and degradation rate constants. The individuals were grouped to allow comparison of the results on the basis of age, obesity index, or diabetes. The responses over a period of 120 mm to an infusion and wash out of insulin show some transient as well as steady state differences with age, obesity, or diabetes. Analysis of these data by use of compartmental models leads to the conclusion that in the steady state the ratio of insulin in extravascular spaces to that in plasma (T/P) is decreased in the moderately obese group (26%) and in the diabetic group (17%) but increased in the older group (13%) when each is compared with the appropriate control. Since extravascular insulin includes both insulin bound to receptors and insulin in the interstitial fluid, the observed changes in the extravascular to plasma mass ratio most likely reflect changes in in vivo binding to receptors, although the magnitude of the change would be modified somewhat by changes in the size of the interstitial spaces relative to plasma. In addition, the rate of entry of new insulin into plasma (BSDR) was increased in the diabetic population (45%; P <0.02) as well as in the moderately obese group (27%) but was decreased somewhat in the older group (11%).

The following general conclusions can be drawn from the results: The pattern of parameter changes seen with obesity is similar to that seen with maturity-onset diabetes. The decrease in T/P seen with obesity and with maturity-onset diabetes cannot be accounted for solely by changes in fasting plasma insulin levels in these populations. The pattern of changes seen in the older subjects is opposite that seen in the maturity-onset diabetics, which suggests that diabetes is a perturbation distinct from the normal aging process. Finally, the changes in the metabolism of insulin are not large, making it unlikely that they are the sole cause of the major alterations in glucose tolerance seen with aging, obesity, or diabetes.
Influence of Arginine on Splanchnic Glucose Metabolism in Man
Authors: Bratusch-Marrain P , Björkman O , Hagenfeldt L , Waldhäusl W , Wahren J
Published: September 2013

To examine the mechanism of the arginine-induced rise in blood glucose concentration, splanchnic glucose output (SGO) and precursor uptake were studied during i.v. infusion of arginine (30 g/30 min) with and without somatostatin infusion (500 μg/h, 90 min) in postabsorptive and in 60-h fasted healthy subjects. The hepatic venous catheter technique was employed.

In the postabsorptive state, arginine infusion was accompanied by an eightfold and a fivefold increment, respectively, in the hepatic venous concentration of insulin and glucagon; SGO doubled and blood glucose increased by 30%. After cessation of arginine infusion, SGO and blood glucose returned to basal levels within 30 min.

When both arginine and somatostatin were administered, glucagon rose threefold, whereas the insulin response was abolished. And while the rise in SGO during arginine infusion and its subsequent decline were uninfluenced by the simultaneous infusion of somatostatin, the rise in blood glucose was more pronounced and the glucose concentration remained elevated longer than in control studies without somatostatin. Splanchnic uptake of glucogenic precursors was uninfluenced by arginine infusion, with or without simultaneous somatostatin administration.

In the 60-h fasted group, arginine infusion was accompanied by a minimal increase in insulin but a fivefold elevation of the glucagon level. Combined arginine and somatostatin infusion did not boost insulin significantly but the glucagon level rose threefold above the basal value. Basal SGO was 55% lower than in the postabsorptive state, and it rose in response to arginine administration (+50%) as well as during combined arginine and somatostatin infusion (+80%). No significant change in splanchnic uptake of glucogenic precursors was observed during arginine infusion with or without somatostatin administration.

We conclude that (1) arginine infusion is accompanied by a rise in SGO and blood glucose due to arginine-induced stimulation of glucagon secretion, (2) the rise in SGO is caused primarily by glucagon-stimulated hepatic glycogenolysis, and (3) combined somatostatin and arginine administration is accompanied by a more marked rise in blood glucose due to hypoinsulinemia and reduced peripheral glucose Utilization.
Syngeneic Transplantation of Fetal Rat Pancreas: III. Effect of Insulin Treatment on the Growth and Differentiation of the Pancreatic Implants After Reversal of Diabetes
Authors: McEvoy Robert C , Hegre Orion D
Published: September 2013

Eight 18-day fetal pancreases were transplanted to syngeneic alloxan diabetic male rats. Some of the recipients were treated with insulin for a 7-day period immediately after transplant. By previously published clinical criteria, three groups of recipients could be identified after reversal of diabetes by the transplanted tissue: insulin-treated rapid reversal; insulin-treated slow reversal; and control (not treated with insulin). Five animals in each group were sacrificed after glucose tolerance testing for morphologic and hormonal analysis of the transplanted tissue. The insulin-, glucagon-, and somatostatin-positive islet cell masses of the fetal pancreatic implants were quantitated.

There was a correlation between the beta cell mass of of the implants and the glucose tolerance exhibited by the host animals. The rapid response insulin-treated recipients had significantly greater implant beta cell mass and insulin content compared with the other groups. There was no difference in implant alpha cell mass among the groups, but the insulin-treated implants had a significantly greater glucagon content. The delta cell mass of insulin-treated rapid response was less than that of the other two groups.

The results are discussed in relation to previously reported morphometric analysis 15 days after transplantation. The relationships of transplanted beta cell mass, beta cell differentiation, transplant site, and cell-to-cell interactions within the transplanted islet to the control of glucose homeostasis are also discussed.
Effects of Streptozotocin-induced Diabetes on Insulin Binding, Glucose Transport, and Intracellular Glucose Metabolism in Isolated Rat Adipocytes
Authors: Kobayashi Masashi , Olefsky Jerrold M
Published: September 2013

Insulin receptors and various aspects of glucose metabolism were studied in isolated adipocytes from insulin-deficient streptozotocin (STZ)-treated diabetic rats. Severe diabetes was induced by high dose (55 mg/kg) STZ administration and mild diabetes was induced by low dose (40 mg/kg) STZ treatment. The high dose STZ group (morning plasma glucose level of 511 ± 32 mg/dl) became markedly catabolic and gained weight at a rate of only 0.6 ± 0.9 g/day as compared with 6.7 ± 0.8 g/day for controls. The low dose STZ group gained weight at a near normal rate (5.8 ± 0.7 g/day) despite modest hyperglycemia (morning plasma glucose 214 ± 36 ng/100 ml) and hypoinsulinemia. Insulin binding to receptors was increased 25% in the low dose group due to greater receptor capacity with no change in affinity and was increased 105% in the high dose group due to enhanced receptor affinity and capacity. Glucose transport activity was decreased in adipocytes from the diabetic animals, and, in addition, all aspects of intracellular glucose metabolism studied were depressed. These effects were greatest in the high dose group. In summary, (a) in severely diabetic, catabolic animals, insulin binding to receptors is increased due to enhanced receptor capacity and affinity; in mildly diabetic rats only receptor capacity is increased; (b) glucose transport activity and intracellular pathways of glucose metabolism are impaired in insulin-deficient diabetic animals, most likely due to hypoinsulinemia; and (c) the cellular insulin resistance of insulin-deficient diabetes is due to multiple defects in effector systems distal to the insulin receptor.
Control of Gastric Glucagon Secretion in the Acutely Pancreatectomized Rat
Authors: Marre M , Bobbioni E , Suarez M , Reach G , Dubois M P , Assan R
Published: September 2013

Glucagon immunoreactivity (IRG) was measured in portal plasma from control and pancreatectomized rats and in arterial plasma from eviscerated rats with a functional liver. Portal IRG was 0.41 ± 0.02 ng/ml in control rats and 0.22 ± 0.01 in pancreatectomized rats. After evisceration, values of 0.08 ± 0.01 ng/ml were found (unextracted plasma, antiserum 30 K). Acid-ethanol plasma extracts demonstrated lower values, but a similar stepwise decrease was observed after pancreatectomy, then gastrectomy. Rat gastric extracts contained a low concentration of IRG (approximately 1/1200 the C-terminal IRG concentration of the corresponding pancreas). No IRG-positive cells were detected by immunofluorescence in the gastric mucosa.

In the pancreatectomized rats, portal IRG remained stable for 75 min in the absence of further manipulation. From IRG concentrations and hepatic blood flow estimation in both control and pancreatectomized rats, the contribution of the stomach to portal IRG in the basal state could be estimated as 20% of the total. Gastric IRG release was increased by acute hypoglycemia (peak value 0.75 ± 0.18 ng/ml; N = 10; P < 0.01) and by 2-deoxyglucose infusion (0.45 ± 0.15 ng/ml; N = 4; P < 0.05). Administration of glucose + insulin induced a decrease in portal IRG (0.13 ± 0.01 ng/ml; N = 4; P < 0.001). Vagal stimulation and arginine infusion induced a rise in portal IRG: 0.84 ± 0.27 ng/ml (N = 10; P < 0.05) and 0.31 ± 0.03 ng/ml (N = 9; P < 0.01), respectively, while portal insulin remained low or undetectable (0-18 μu/ml). A rise in blood glucose accompanied the increase of plasma IRG. A concomitant insulin-induced hypoglycemia (36 ± 5 mg/dl) strongly potentiated the effects of both arginine infusion (1.46 ± 0.47 ng/ml; N = 6; P / 0.005) and vagal stimulation (1.39 ± 0.47 ng/ml; N = 4; P < 0.005).Higher IRG values were observed after pancreatectomy in alloxan-diabetic rats: 0.36 ± 0.02 ng/ml (N = 3; P < 0.001).

We conclude therefore that: (a) the rat stomach contributes to the release of IRG in blood but to a limited extent, (b) the factors controlling this release appear very similar to those controlling pancreatic A cells; and (c) gastric IRG may be hyperglycemic in the rat.
Radioimmunoassay of Glibenclamide
Authors: Kawashima Koichiro , Kuzuya Takeshi , Matsuda Ayako
Published: September 2013

A specific, sensitive, and simple radioimmunoassay was developed for the oral hypoglycemic drug glibenclamide, N-4-[2-(5-chloro-2-methoxy-benzamide)- ethyl]-benzenesulfonyl-N'-cyclohexylurea. Antiserum against glibenclamide was obtained from rabbits immunized with an antigen prepared by conjugating the diazonium salt of N-(p-amino-benzamidoethyl)- benzenesulfonyl-N'-cyclohexylurea to bovine serum albumin through the diazocoupling. [3H]glibenclamide was used as a tracer. Dextran-coated charcoal was used to separate bound and free [3H]glibenclamide in the reaction mixture. The radioimmunoassay is able to determine as little as 25 pg of glibenclamide directly in plasma without the need for extraction. The antiserum used for the assay was highly specific for glibenclamide, and did not cross-react with two known major metabolites of glibenclamide. Comparable values of glibenclamide in dog plasma were obtained by radioimmunoassay and liquid chromatography. Plasma concentrations of glibenclamide in diabetic patients on glibenclamide treatment can be determined by radioimmunoassay, and the method has been applied to the routine assay of clinical samples. This radioimmunoassay seems to be useful for monitoring plasma glibenclamide concentrations.
Methyl 2-Tetradecylglycidate, An Orally Effective Hypoglycemic Agent that Inhibits Long Chain Fatty Acid Oxidation Selectively
Authors: Tutwiler Gene F , Mohrbacher Richard , Ho Winston
Published: September 2013

The oral hypoglycemic agents methyl 2-tetradecylglycidate (McN-3716) and 2-tetradecylglycidic acid (McN-3802), synthesized in an effort to design a specific inhibitor of long-chain free fatty acid (FFA) oxidation, were tested for their effects on rat hemidiaphragm oxidation of various substrates to CO2. When added in vitro, both compounds were more potent (100-1000 times) in inhibiting long-chain FFA oxidation than either a-bromopalmitic or 4-pentenoic acid. When fasting normal or diabetic rats were pretreated with McN-3716, the ability of the diaphragms to oxidize palmitate-1-l4C to 14CO2 incubated in vitro was also diminished. Closely related nonhypoglycemic analogs of McN-3716 failed to inhibit oxidation. The failure of McN-3716 to inhibit the oxidation by diaphragm of short-chain fatty acids, palmitoyl camitine, glucose, glycolytic intermediates, β-hydroxybutyrate, succinate, or citrate when added in vitro or after treatment of rats suggests that glycolysis, the tricarboxylic acid cycle, and the intramitochondrial β-oxidation of fatty acids were not inhibited. While depressing FFA oxidation, McN-3716 increased the ability of hemidiaphragms from normal and diabetic rats to oxidize glucose-14C to 14CO2. This supports an intimate relationship between FFA oxidation and glucose utilization in hemidiaphragm. The locus of this stimulation appears to be the glycolytic pathway. The earliest onset for the impairment of diaphragm muscle FFA oxidation and the rise of plasma FFA after treatment of fasting rats with McN-3716 preceded the stimulation of hemidiaphragm glucose oxidation and the lowering of plasma glucose and tissue glycogen stores. These results suggest that the carbohydrate changes are secondary to the inhibition of FFA oxidation.
Circulating Glucagon Antibodies in Children Who Have Insulin-dependent Diabetes Mellitus: Clinical Significance and Characterization
Authors: Villalpando Salvador , Drash Allan
Published: September 2013

A substance present in the sera of diabetic children that interferes with the radioimmunoassay for glucagon was found in six of 66 children who were participating in an inpatient study of diabetic control. Detailed studies documented unequivocally that this glucagonbinding substance is a specific antibody to glucagon and is located in the immunoglobulins. In a survey of diabetic children in the outpatient diabetes clinic and in a diabetes summer camp, antibodies to glucagon were found in about 12% of those evaluated. However, no children who had had diabetes for less than three years were found to have antibodies, and there appeared to be an increase with increasing duration of disease of up to greater than 20% at eight years' duration. The presence of glucagon antibodies may be of pathologic significance in that the patients have a greater tendency to develop hypoglycemia than do diabetic children without glucagon antibodies.
Factors Related to Diabetes Mellitus in Puerto Rican Men
Authors: Cruz-Vidal Mercedes , Costas Raúl , García-Palmieri Mario R , Sorlie Paul D , Hertzmark Ellen
Published: September 2013

Urban-rural comparisons of the prevalence of diabetes were made in a cohort of 2567 rural and 6190 urban participants aged 45 to 64, in the Puerto Rico Heart Health Program. The prevalence of diabetes in the urban population was more than double that in the rural. Consistent with this, blood glucose concentrations were significantly higher in urban than in rural populations.

The prevalence of diabetes increased with age and relative weight. It was associated with elevations of serum cholesterol, blood pressure, and fasting serum triglycerides. A positive family history was found more commonly in diabetics than in nondiabetics. If there was a history in both a sibling and a parent, there was at least a threefold increased prevalence over those with no family history.

The reason for the higher prevalence of diabetes in the urban than in the rural area is elusive. In obese men, the urban and rural prevalence rates are the same, but, among relatively lean men, the prevalence in the urban area is twice that of the rural men.
Fatty Acid Desaturation in Experimental Diabetes Mellitus
Authors: Eck M Gareth , Wynn James O , Carter William J , Faas Fred H
Published: September 2013

Microsomal fatty acid desaturation is defective in streptozotocin-induced experimental diabetes. This defect is correctable by insulin treatment. The electron transport chain needed for microsomal fatty acid desaturation was studied in liver microsomes of streptozotocin diabetic rats, and the defect was localized to the terminal desaturase enzyme. Cytochrome b5 levels were elevated in the face of decreased fatty acid desaturation and returned to normal after 48 h of insulin treatment; 2 U of regular insulin every 6 h for 24 h repaired the fatty acid desaturation defect, while 0.5 U failed to correct the defect. Both the δ6 and δ9 desaturase defects (linoleic acid and stearoyl-CoA desaturation) required similar amounts of insulin and periods of time for correction, although these are different enzymes. This is consistent with the desaturation defect being due to a protein synthetic effect. Diabetic rats treated twice daily with injections of 4 U of NPH insulin showed a “per” repair of their desaturase defect by 48 h: δ9 desaturase activity increased eight times over control activity, while δ6 desaturase activity increased two and one-half times over control activity. This, together with the fact that δ6 desaturase activity in diabetes (64% of control) is altered less than is δ9 desaturase activity (22% of control), indicates that δ6 desaturase enzyme activity is less responsive to insulin than is δ9 desaturase enzyme activity. The physiologic significance of altered fatty acid desaturation in diabetes mellitus is unknown.
Is Juvenile Diabetes Determined by a Single Gene Closely Linked to HLA?
Authors: Suarez Brian , Hodge Susan E , Reich Theodore
Published: September 2013

The transmission behavior of insulin-dependent juvenile diabetes mellitus (JDM) has been studied with respect to its frequency in the relatives of JDM probands and its possible linkage to the HLA complex. Mathematical analysis shows that under a single locus hypothesis a very restricted range of incidence rates is possible in the full siblings of probands once the concordance rate in monozygotic (MZ) twins is specified. Specifically, for a given population prevalence of the disease, high concordance rates in MZ twins require high incidence rates in siblings, and low rates require low incidence rates, if a single locus model is to be valid. Moreover, if these rates do conform to a single locus model, then they give additional information about possible linkage between the purported JDM susceptibility gene and the HLA complex. By using observations on the identity by descent scores at the HLA locus of sibling pairs, both of whom are affected with JDM, it is shown that tight linkage of a disease susceptibility locus is possible only when the MZ twin and sibling incidence rates are low, whereas high rates support loose linkage. If the single locus model is rejected, then an alternative hypothesis, involving epistasis between a JDM susceptibility locus and genes in (or close to) the HLA complex can be suggested as a mechanism whereby JDM would appear to be linked to HLA within families while maintaining an association with HLA at the population level.
Blood Glucose Regulates the Effects of Insulin and Counterregulatory Hormones on Glucose Production In Vivo
Authors: Saccà Luigi , Cryer Philip E , Sherwin Robert S
Published: September 2013

Continuous, low dose, insulin infusion in conscious dogs produced moderate hypoglycemia but only a transient fall in glucose production that rose towards preinfusion levels 20 to 30 min before any detectable increase in plasma counterregulatory hormones. Addition of epinephrine or glucagon to the insulin infusion prevented the fall in glucose production throughout the experiment but only partially diminished the hypoglycemic response. When hypoglycemia was prevented by a variable glucose infusion, neither epinephrine nor glucagon was able to counteract the suppressive effect of insulin on glucose output. These findings suggest that a fall in blood glucose per se may reverse insulin-induced inhibition of glucose production independent of a rise in counterregulatory hormones and that the insulin antagonist effect of counterregulatory hormones is modulated, at least in part, by blood glucose concentration.
HLA-D–related (DRw) Antigens in Juvenile Diabetes Mellitus
Authors: Farid Nadir R , Sampson Laura , Noel Petra , Barnard John M , Davis Albert J , Hillman Donald A
Published: September 2013

We studied the distribution of HLA-D–related (DRw) antigens in 40 patients with juvenile diabetes mellitus (JDM) and 79 matched controls. We found that DRw2 was significantly decreased in the JDM group, suggesting a protective effect of the antigen and that the decrease observed in B7 was secondary. HLA-DRw3 and HLA-DRw4 were increased in the diabetic group, and, as with B8/B15, these two antigen predisposed to the disease additively. The susceptibility for JDM was found to be more strongly related to HLA-DRw3 than to B8. On the other hand, B15 rather than DRw4 showed the stronger association with JDM. Moreover, we found that this second diabetogenic gene is associated primarily with B15 and only secondarily with Cw3, which is in linkage disequilibrium with B15. This study further emphasizes the immunogenetic heterogeneity of JDM.
The Mechanism of Zinc Uptake in Isolated Islets of Langerhans
Authors: Ludvigsen Carl , McDaniel Michael , Lacy Paul E
Published: September 2013

The uptake of zinc65 (Zn) was determined in isolated pancreatic islets employing a dual isotope procedure with sucrose as an extracellular marker. Islets slowly accumulated Zn over long periods of time (24 h or longer) reaching three to five times the extracellular concentration by 70 min and a 30-fold differential over extracellular concentration by 24 h. Zn uptake at low concentrations (0.5–7 μM) demonstrated saturation kinetics with the Km and Vmax, 1.5 nM and 11.1 Fmol/islet/min, respectively. At higher Zn concentrations (10–3000 μM), a linear relationship between initial rates of uptake and Zn concentration was observed. Zn at a low concentration (2 μM) was countertransported by 2 mM ZnCI2 pretreatment and inhibited by the presence of cadmium (2–20 μM). Countertransportation and cadmium inhibition of Zn uptake was not found at a higher Zn concentration (44 μM). Zn uptake at either 2 or 44 μM was not inhibited by pretreatment and presence of 300 μM dinitrophenol. Lowering of temperature from 37 °C to 20 °C and 4 °C depressed Zn uptake at 44 μM by 65% and 82%, respectively. However, at 2 μM Zn, the uptake was equivalent at 20 °C and 37 °C and showed a decrease of 70% at 4 °C. Zn uptake at either 44 or 2 μM in short (1–70 min) or long (1–24 h) studies was unaffected by concentrations of glucose that stimulated insulin secretion.

The results present the evidence that a facilitated mechanism of Zn transport predominates at low Zn concentrations and a diffusion mechanism of entry predominates at higher Zn concentrations.
Use of Reflected Green Light for Specific Identification of Islets in Vitro After Collagenase Isolation
Authors: Finke Edward H , Lacy Paul E , Ono Junko
Published: September 2013

A simple technique is described that permits specific identification in vitro of isolated islets as contrasted with small lymph nodes.
Ethnic Variability in the Plasma Insulin Response to Oral Glucose in Polynesian and Micronesian Subjects
Authors: Zimmet P , Whitehouse S , Kiss J
Published: September 2013

The pattern of insulin response to oral glucose over a wide range of glucose tolerance has been studied in two separate ethnic groups—Polynesians and Micronesians. Fasting insulin concentrations were relatively unchanged over the entire range of glucose tolerance in both populations, irrespective of whether comparable lean or obese samples of both groups were studied. The patterns of 2-h plasma insulins were similar over the whole range of glucose tolerance in Polynesians and Micronesians. However, in the comparisons of all subjects, or lean or obese groups of these populations, the plasma insulin concentrations of the Micronesians were both consistently and significantly higher. As the data analysis was arranged to take into account groups with identical 2-h plasma glucose concentrations and comparable degrees of obesity, the differences cannot be attributed to differences in the glucose levels or in obesity. In the presence of similar fasting insulin concentrations, these findings imply an ethnic variability in the pancreatic beta-cell response to oral glucose.
Capillary Basal Laminar Thickness in Diabetic Human Myocardium
Authors: Fischer Vernon W , Barner Hendrick B , Leskiw M Lisa
Published: September 2013

Biopsied myocardial tissue was obtained from 24 patients electing coronary arterial bypass surgery who were divided into three groups: chemical diabetics (CD) with normal fasting blood sugar levels and incidentally encountered elevated glucose levels after sugar loading; overt diabetics (OD) requiring insulin treatment; and euglycemic, nondiabetic patients (ND) serving as a control group. Specimens from the left anterior apical segment of the heart were processed for ultrastructural examination, with special emphasis on determining capillary basal laminar thickness with the aid of morphometric techniques.

Results of this study indicate that (1) a statistically significant increase in basal laminar thickness is evident in myocardial tissue of OD patients; (2) incipient alterations in laminar width are demonstrable in the CD group; (3) the predominant morphologic abnormalities, which we have examined in the parenchymal tissue of the biopsied hearts, namely myocardial hypertrophy and interstitial fibrosis, are present to a comparable degree in all three groups of patients; and (4) the average thickness of basal laminae around myocardial capillaries tends to be narrower compared with measurements reported in other tissue compartments.
Effect of a High Carbohydrate Diet on Insulin Binding to Adipocytes and on Insulin Action in vivo in Man
Authors: Kolterman O G , Greenfield M , Reaven G M , Saekow M , Olefsky J M
Published: September 2013

We studied the effects of short-term (5 days) and long-term (2 wk) high carbohydrate (75%) feedings on insulin binding to isolated adipocytes and insulin sensitivity in vivo in normal subjects. Ingestion of the high carbohydrate diet led to daylong hyperinsulinemia in both short- and long-term groups. Insulin binding to isolated adipocytes was decreased in both groups; in the short-term groups this decrease in insulin binding was caused by a decrease in the receptor affinity, whereas in the long-term group it was caused by a decrease in receptor number. On the other hand, despite this decrease in insulin binding, total in vivo insulin sensitivity was markedly improved in both groups. In conclusion, (1) the short-term adaptive response of the insulin receptor is a decrease in binding affinity whereas the long-term response is a decrease in receptor number, (2) sustained and chronic hyperinsulinemia can lead to a decrease in the number of cellular insulin receptors, (3) high carbohydrate diets lead to a general increase in insulin's ability to promote glucose removal from plasma, and (4) the paradox of enhanced insulin sensitivity in the face of decreased insulin binding can be explained if high carbohydrate diets also lead to an increase in the activity of steps in glucose metabolism distal to the insulin receptor.
Insulin Binding and Degradation by Muscles from Streptozotocin-diabetic Rats
Authors: Duckworth William C , Gifford Dan , Kitabchi Abbas E , Runyan Keith , Solomo Solomon S
Published: September 2013

Insulin degradation by muscle was examined in normal, streptozotocin-induced diabetic rats, and diabetic rats treated with insulin. Insulin degradation by the 100,000 × g supernatant fractions was identical in all three groups, but insulin metabolism by the intact epitrochlaris muscle was significantly increased in diabetic animals. Insulin treatment of the diabetic animals partially restored the activity toward normal. Specific binding of 125I-insulin to the intact muscles was also increased in the diabetic animals. Streptozotocin diabetes, therefore, increased the binding and degradation of insulin by intact muscle but did not alter the insulin degradation by the total soluble intracellular degradative activity.
Opposite Effects of Insulin and Glucagon in Acute Hormonal Control of Hepatic Lipogenesis
Authors: Beynen A C , Vaartjes W J , Geelen M J H
Published: September 2013

Conditions for the isolation of rat hepatocytes that are responsive to insulin with regard to fatty acid synthesis were explored. Cells prepared according to the procedure of Ingebretsen and Wagle require the presence of fetal calf serum for insulin expression. Cells isolated by the Seglen method are the preparation of choice, since they respond to insulin in a simple, well-defined medium and, moreover, show much higher basal rates of fatty acid synthesis. In the latter cells isolated from fed male rats, the rate of fatty acid synthesis, as determined by tritium incorporation from [3H]H2O at 37°C, is enhanced within 30 min after addition of insulin to the incubation medium; with glucagon, it is depressed. In the presence of insulin, the cellular content of malonyl coenzyme A is noticeably increased, whereas the concentrations of pyruvate, lactate, and citrate are not markedly affected. Glucagon, on the other hand, decreases the concentrations of all four intermediates. The activity of acetyl-CoA carboxylase is stimulated and depressed after addition of insulin and glucagon, respectively. In all conditions tested, the activity of acetyl-CoA carboxylase correlates with the rate of fatty acid synthesis, which in turn correlates with the cellular level of malonyl-CoA.
Acetylsalicylic Acid Restores Acute Insulin Response Reduced by Furosemide in Man
Authors: Giugliano Dario , Torella Roberto , Sgambato Saverio , D'Onofrio Felice
Published: September 2013

Prostaglandin E (PGE) infusion in normal man inhibits the acute insulin response to glucose. In order to determine whether endogenously released PGE might also inhibit insulin secretion, glucose-stimulated insulin responses were investigated in normal volunteers after furosemide (40 mg i.v.), a stimulator of endogenous PGE synthesis. Acute insulin response to glucose (20 g i.v.) was significantly reduced by furosemide (response before furosemide: 36 ± 5 μU/ml; after furosemide: 26 ± 5 μU/ml, m ± SE, mean change 3−10 min, N = 8, P < 0.01), whereas glucose disappearance rates were not modified after furosemide, Infusion of lysine acetylsalicylate (LAS), ah inhibitor of endogenous PGE synthesis, completely reversed the inhibitory effect of furosemide on insulin secretion and also augmented acute insulin response to glucose (response before furosemide + LAS: 41 ± 6 μU/ml; during furosemide + LAS: 50 ± 7 μU/ml, N = 10, P < 0.02). This effect was associated with an increase in glucose disappearance rates (P < 0.05).

These findings demonstrate that (1) furosemide inhibits glucose-induced acute insulin responses and (2) LAS completely reverses the inhibitory effect of furosemide and also accelerates glucose disposal. It is suggested that furosemide acts via the release of endogenous PGEs, which are known to inhibit insulin responses in man.
Effects of Glucose on Insulin Release and on Intermediary Metabolism of Isolated Perifused Pancreatic Islets from Fed and Fasted Rats
Authors: Trus Michael , Warner Howard , Matschinsky Franz
Published: September 2013

We examined the relationship between glucose-induced insulin release and the intermediary metabolism of islets from fed and fasted rats. Isolated islets were perifused and insulin release measured in the effluent. At various times after switching islets from 2.4 to 8.6 or 14.5 mM glucose or from 2.4 to 14.5 and back to 2.4 mM glucose, islets were quickly frozen, freeze dried, and subsequently analyzed for tissue content of glucose-6-P, fructose-1,6-P2 plus triose-P, P1, ATP, ADP, 5'-AMP, NADH, NADPH, total NAD, and total NADP using enzymatic fluorometric procedures. When islets from fed rats were exposed to high glucose, there were concomitant increases of insulin release and islet content of glucose-6-P, fructose-1,6-P2 plus triose-P, NADH, and NADPH. During stimulation P1 and 5'-AMP content fell markedly. The total adenine nucleotide content remained constant. Similar secretory and metabolic changes occurred when 1.5 mM P1 was added to the perifusion fluid. When glucose-stimulated islets were switched back to low glucose for 10 min, all substances but fructose-1,6-P2 plus triose-P, 5'-AMP, NADPH, and possibly ATP returned to the prestimulatory level. Starvation of rats for 3 days blocked the secretory response to 8.6 mM glucose. Fructose-1,6-P2 plus triose-P rose but it did not attain the level existing in islets from fed rats. The ratios (ATP)/(5'-AMP) and (ATP)/(P1,)(ADP) increased to the values observed in glucose-stimulated islets of fed rats.

The metabolic changes in islets from fed rats exposed to high glucose are consistent with an activation of glycolysis occurring concomitantly with stimulated rates of insulin release. This occurs despite the decrease of important activators of glycolysis—P1 and 5'-AMP. The enhanced glycolysis possibly results from P-fructokinase activation by increased fructose-6-P levels. Activation of glycolysis with 8.6 mM glucose was not as pronounced in islets from starved rats. Despite the different secretory response of islets from fed and fasted rats, the changes of phosphorylation state in the islets, in particular, P1, and 5'-AMP levels, were similar.
Insulin Degradation by Mononuclear Cells
Authors: Powers Alvin C , Solomon Solomon S , Duckworth William C
Published: September 2013

Mononuclear cells from peripheral blood possess insulin receptors that are altered in number or binding affinity in certain metabolic diseases as obesity. The monocyte, and not the lymphocyte, is the cell with the capacity to specifically bind insulin. Furthermore, this binding appears to mirror the receptor status on such insulin target tissues as liver, muscle, and fat. Since liver, muscle, and fat also degrade insulin, mononuclear cells from the blood of normal volunteers were examined for insulin-degrading activity. Intact cells were incubated with 125I-insulin and the amount of degraded insulin was measured by the trichloroacetic acid-precipitation technique. Insulin-degrading activity increased when the number of cells and the time of incubation were increased. Total insulin binding behaved in a similar fashion. Very little degradation was seen at 4° or 15°. The Km for insulin-degrading activity was 7.03 × 10−8 M. Homogenized mononuclear cells degraded two to five times more insulin than did intact cells and also demonstrated cell concentration, time, and temperature dependence for degradation. The Km of degradation for homogenized mononuclear cells was 2.2 × 108 M. Subcellular fractionation revealed significant degrading activity in the 100,000 × g supernatant, but little activity in the 100,000 × g pellet. A purified lymphocyte preparation did not bind insulin and contained little insulin-degrading activity.