bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of Insulin Secretion by Exogenous Insulin in Normal Man as Demonstrated by C-peptide Assay
Authors: Liljenquist John E , Horwitz David L , Jennings Anthony S , Chiasson Jean-Louis , Keller Ulrich , Rubenstein Arthur H
Published: September 2013

To investigate whether insulin exerts feedback regulation of its own secretion, paired studies were performed in normal men in two separate protocols. In the first protocol, four men were studied on two occasions. On one occasion, insulin was infused at 5 μU. per kilogram per minute for 120 minutes, achieving arterial insulin levels of 600 to 700 μU./ml. With use of a variable glucose infusion, the plasma glucose concentration was maintained at fasting levels for 60 minutes and then raised abruptly to 165 mg./dl. and was maintained at that level for the remaining 60 minutes. On a second occasion, the study was repeated except that saline was infused instead of insulin. The plasma glucose concentration remained at fasting levels until the last 60 minutes, when it was similarly raised to 165 mg./dl. and maintained at that level until the end of the study. Connecting peptide reactivity (CPR) was measured as an index of endogenous insulin secretion in the presence of exogenous insulin. During the initial 60 minutes of the study, with euglycemia maintained, there was a significant (46 per cent) decline (p < 0.01) in the levels of CPR in the insulin-treated subjects. At 60 minutes, when hyperglycemia was induced, CPR rose in both groups. The rise of CPR in the insulin-treated group, however, was significantlyless (p < 0.01) than in the saline control group.

To investigate whether insulin inhibition of insulin secretion during hyperglycemia would occur without prolonged insulin pretreatment, paired studies were performed in three additional men. In this protocol, insulin (5 mU. per kilogram per minute) or saline was infused for 70 minutes. Euglycemia was maintained for just 10 minutes. Thereafter, the plasma glucose concentration was. raised to 170 mg./dl. in both groups. This acute induction of hyperglycemia without prolonged insulin pretreatment resulted in similar increases in CPR in both insulin- and saline-treated groups.

From these data we conclude that (1) exogenous insulin administration, with maintenance of euglycemia, results in significant inhibition of basal insulin secretion; (2) the administration of exogenous insulin for 60 minutes before and for 60 minutes after the acute induction of hyperglycemia results in significant inhibition of glucose-stimulated insulin secretion; and (3) exogenous insulin administered for just 10 minutes before and during the acute induction of hyperglycemia, however, does not result in inhibition of the insulin response to the hyperglycemic stimulus.
Neurotensin Hyperglycemia: Evidence for Histamine Mediation and the Assessment of a Possible Physiologic Role
Authors: Nagai Katsuya , Frohman Lawrence A
Published: September 2013

The hyperglycemic and hyperglucagonemic effects of systemically administered neurotensin in rats were investigated to explore the possibility that they are mediated by histamine and to determine whether neurotensin might have a role in the mediation of the responses to central nervous system glucopenia. The hyperglycemic response to neurotensin was partially blocked by the histamine H-l receptor blockers, diphenhydramine and promethazine, and by the H-2 receptor blocker, cimetidine. The hyperglucagonemic response was completely blocked by diphenhydramine and promethazine and only partially blocked by cimetidine. The effects of histamine on glucose, glucagon, and insulin secretion were similar to those of neurotensin, and the inhibitory effects of both H-l and H-2 blockers were comparable. The stimulatory effect of histamine on insulin secretion observed after adrenal autotransplantation was also similar to that previously reported for neurotensin. Neither antineurotensin serum nor diphenhydramine, however, was effective in blocking the hyperglycemic and hyperglucagonemic responses to the central administration of 2-deoxyglucose. The results are consistent with a histamine mediation of the effects of exogenously administered neurotensin but do not support a proposed role for neurotensin or histamine in the mediation of the hyperglycemic and hyperglucagonemic responses to central glucopenia.
Heterogeneity in Diabetes Mellitus—Update, 1978: Evidence for Further Genetic Heterogeneity within Juvenile-onset Insulin-dependent Diabetes Mellitus
Authors: Rotter Jerome I , Rimoin David L
Published: September 2013

The concept that idiopathic diabetes mellitus is a genetically heterogeneous group of disorders has been established by twin and HLA studies that have permitted the separation of juvenile-onset and maturity-onset diabetes. The extent of the heterogeneity within the juvenile-onset and maturity-onset types is still in question. On the basis of recent inununologic and metabolic studies we believe that further heterogeneity can be demonstrated within the juvenile-onset diabetic group. We wish to hypothesize that there are at least two distinct forms of juvenile-onset diabetes, one associated with HLA B8 and the other with BW15. The B8 type is characterized by autoimmunity, microangiopathy, and a stronger association with the HLA D locus. The BW15 type is characterized by antibody response to exogenous insulin and a stronger association with the HLA C locus. Greater understanding of the pathogenesis, natural history, and genetics of diabetes mellitus will result as the full extent of genetic heterogeneity is elucidated.
The Positive Inotropic Action of Sulfonylureas: A Mechanism Independent of Cyclic Adenosine 3',5'-Monophosphate
Authors: Linden Joel , Brooker Gary
Published: September 2013

The effect of sulfonylureas on contractility in atria isolated from rabbits, rats, and guinea pigs was examined. Tolbutamide was most efficacious on rabbit preparations, and 1 mM tolbutamide increased tension development about 30 per cent above control. Tolbutamide did not elevate cyclic adenosine 3',5'-monophosphate (cyclic AMP) or increase the rate of spontaneously contracting rabbit, rat, or guinea pig preparations. Glibenclamide, which also increased tension development, was about 300 times as potent as tolbutamide, paralleling its potency relative to tolbutamide as an insulinotropic agent. Tolbutamide enhanced adenylate cyclase activity in homogenates of rabbit myocardium only at very high concentrations (1 to 10 mM), and this activation was attributable to a nonspecific detergent action. Glibenclamide, at concentrations as high as 100 μM, failed to activate adenylate cyclase. Three inotropic agents, thought to act by elevating myocardial cyclic AMP—norepinephrine, histamine, and the phosphodiesterase inhibitor l-methyl-3-isobutyl xanthine (MIX)—failed to increase tension developed when added after a maximally effective concentration of isoproterenol. However, both calcium ion and tolbutamide could increase systolic and diastolic tension when added to contracting atria after maximal isoproterenol. It is concluded that the inotropic action of sulfonylureas is not mediated by cyclic AMP and may result from an effect upon myocardial calcium metabolism.
Antiketogenic Action of Fructose in Man
Authors: Dietze Günther , Wicklmayr Matthias , Mehnert Hellmut
Published: September 2013

The effect of fructose infusion (10 gm. every five minutes as a bolus followed by 0.5 gm. per kilogram × hours) on arterial concentrations and hepatic balances of ketones was studied in four juvenile diabetics 24 hours after the withdrawal of insulin. Arterial and hepatic venous concentrations of β-hydroxybutyrate, acetoacetate, free fatty acids, fructose, and oxygen were measured. Hepatic blood flow was also determined.

At constant rates of splanchnic fructose extraction, an 82 per cent diminution of the arterial hepatic venous concentration difference of the ketones was observed but the arteriovenous difference of free fatty acis rose moderately. Since hepatic blood flow was only slightly increased (17 per cent) there was no doubt that total hepatic ketone body formation was reduced. The magnitude of this antiketogenic action became apparent from the continuous fall of the arterial ketone concentrations. Since splanchnic oxygen uptake rose 40 per cent, it is suggested that the antiketogenic effect of fructose was due not only to enhanced re-esterification but also to accelerated oxidation of free fatty acids.
Reproducibility and Comparative Analysis of Repeated Intravenous and Oral Glucose Tolerance Tests
Authors: Ganda O P , Day J L , Soeldner J S , Connon J J , Gleason R E
Published: September 2013

We have developed a methodology for measuring the reproducibility of the oral glucose tolerance test (OGTT) and the intravenous glucose tolerance test (IVGTT) in normal subjects and in offspring of conjugal diabetic parents.

Both groups of subjects revealed more striking correlations of several parameters of blood glucose and insulin secretion between two IVGTTs than between two OGTTs. Employing arbitrary criteria, we calculated a “reproducibility index” as a quantitative measure of blood glucose variability in each subject. No significant difference was found in the reproducibility of OGTT versus IVGTT, nor in normals versus the offspring. Only about 50 per cent of the tests in normals and in the offspring could be considered to be “reproducible.”

The offspring revealed greater correlations of several parameters, particularly insulin secretion, between the two IVGTTs and between the two OGTTs as compared with the normal group. However, the blood glucose variations tended to be considerably greater in the offspring from one to the other test.
The Acute Effect of Insulin on Capillary Endothelial Cells
Authors: Østerby R , Gundersen H J G , Christensen N J
Published: September 2013

A quantitative morphologic study of the capillary endothelium of striated muscle was performed in diabetic rats one hour after injection of insulin. Diabetic and nondiabetic rats injected with saline constituted the reference groups. In a randomized sample of capillary profiles, morphometric data on micropinocytotic vesicles (MPV) and on various capillary characteristics were collected.

The numeric density of MPV was higher in diabetic rats injected with insulin than in diabetic rats injected with saline (44.2 ± 8.5 versus 34.0 ± 4.5 MPV/μ2 endothelial cytoplasm (mean ± S.D.), 2p = 0.045), thereby approaching the control value of 48.0 ± 7.3, 2p = 0.51. The insulin-injected animals, furthermore, differed markedly from the diabetic reference group as regards the ratio of free-to-attached vesicles, since they showed a large increase in the numeric density of free MPV (1.40 ± 0.18 versus 1.00 ± 0.23/μ circumference, 2p = 0.015, control value 1.59 ± 0.20) and a small decrease in the density of attached MPV (0.19 ± 0.03 versus 0.23 ± 0.02/μ circumference, 2p = 0.022; controls: 0.15 ± 0.04). Both the height of the endothelial cytoplasm and the size of the MPV were similar in all groups.

These findings may be the morphologic counterpart of the clinically demonstrated decrease in plasma volume and in the intravascular pool of albumin in diabetic patients after insulin injection. The present results demonstrate that insulin has an acute effect on the endothelial cells, including a change in the kinetics of the vesicular transport pathway
Enhancement of the Mitochondrial Ca2+ Uptake Rate by Phenethylbiguanide and Other Organic Cations with Hypoglycemic Activity
Authors: Davidoff F , Bertolini D , D Haas
Published: September 2013

At concentrations below 50 μM, phenethylbiguanide enhanced the initial rate of enertized Ca2+ uptake into energized guinea pig liver mitochondria by as much as 45 per cent; Ca2+-stimulated O2 uptake increased in parallel. The biguanide concentration that enhanced Ca2+ uptake maximally was at least 15 times lower than that required for 50 per cent inhibition of respiration. Kinetic studies indicated that the enhanced rate of Ca2+ transport resulted from an increase in Vmax, while Km for Ca2+ was unaffected by the biguanide. Several other organic cations known to lower blood sugar in intact animals or to block the hepatic gluconeogenic response to glucagon also enhanced the mitochondrial Ca2+ uptake rate; three of these compounds did not inhibit respiration even at high concentrations. One organic cation, triethyltin, which is a potent respiratory inhibitor that does not affect blood sugar, had no effect on Ca2+ uptake. We concluded that enhancement of the mitochondrial Ca2+ uptake rate is related to the mechanism of therapeutic blood sugar lowering by these drugs, probably by impairing the gluconeogenic response of the liver to glucagon.
Insulinoma Resection Facilitated by the Artificial Endocrine Pancreas
Authors: Kudlow Jeffrey E , Albisser A Michael , Angel Aubie , langer Bernard , Yip Cecil C , Zinman Bernard , Stokes Elaine
Published: September 2013

The artificial endocrine pancreas was adapted to assist with the intraoperative localization of an insulin-secreting islet cell adenoma in a 23-year-old patient with a five-month history of hypoglycemic attacks. Glycemia was monitored in continuously withdrawn whole blood, and dextrose was infused to maintain euglycemia by an artificial endocrine pancreas with a closed loop that excluded its usual insulin delivery capability. The dextrose infusion rate was established in accordance with a control algorithm whose parameters were chosen to amplify changes in dextrose delivery rate for small alterations in the measured baseline glucose concentration. The dextrose infusion rate preoperatively was 155 mg. per minute and decreased to 100 mg. per minute with initiation of surgery. An area in the tail of the pancreas suspected of containing the insulinoma was excluded from the circulation by a noncrushing clamp. After 14 minutes the dextrose infusion progressively decreased to 27 mg. per minute reflecting a glycemic rise of 15 mg. per deciliter. These changes were taken to represent a fall in ambient insulin activity. This was subsequently confirmed directly by the demonstration of reduction in immunoreactive insulin and progressive increase in both plasma free fatty acid levels and postoperative glucose intolerance. Exclusion of the insulinoma from the circulation resulted also in a rapid decrease of circulating proinsulin concentration giving an estimated half-life of 25 minutes.
Virus-induced Diabetes Mellitus: XI. Replication of Coxsackie B3 Virus in Human Pancreatic Beta Cell Cultures
Authors: Yoon Ji-Won , Onodera Takashi , Jenson A Bennett , Notkins Abner Louis
Published: September 2013

The capacity of Coxsackie B3 virus to infect insulin-containing beta cells was studied in human pancreatic cell cultures. Antibody to Coxsackie B3 virus was labeled with fluorescein isothiocyanate, and antibody to insulin was labeled with rhodamine. By use of a double-label antibody technique, three populations of cells were identified: uninfected insulin-containing beta cells, which stained only with rhodamine-labeled anti-insulin antibody; Coxsackie-infected (noninsulin-containing) cells, which stained only with fluorescein-labeled anti-Coxsackie antibody; and Coxsackie-infected insulin-containing beta cells, which stained with both antibodies. Radioimmunoassay showed that intracellular immunoreactive insulin decreased rapidly beginning at 24 hours after infection, and the decrease in insulin roughly paralleled the increase in viral titer. It is concluded that, under in vitro conditions, human beta cells are susceptible to Coxsackie B3 virus.
The Regulation of Plasma Ketone Body Concentration by Counter-regulatory Hormones in Man: II. Effects of Growth Hormone in Diabetic Man
Authors: Schade David S , Eaton R Philip , Peake Glenn T
Published: September 2013

Growth hormone has classically been considered to be a diabetogenic hormone. However, in insulin-dependent diabetic man the mechanism of its ketogenic activity has not been resolved. Therefore, this study was designed to examine three aspects of growth hormone's ketogenic activity: first, whether growth hormone's ketogenic activity can be entirely accounted for by its lipolytic effect; second, whether growth hormone's ketogenic activity is rapid or delayed in onset; and third, whether growth hormone may exert ketogenic activity indirectly by altering the plasma concentration of other ketone body-regulatory hormones (i.e. insulin, glucagon, and cortisol). In order to obtain data relative to these three questions, growth hormone was administered to six insulin dependent, ketosis-prone diabetic subjects. Both acute and prolonged growth hormone exposure studies were performed in all subjects and compared with a control study. Plasma free-fatty-acid concentration was elevated in all studies by heparin administration to assess growth hormone's ketogenic activity independent of its lipolytic effect.

Our results suggest that, in insulin-dependent diabetic man, growth hormone exerts profound ketogenic activity that is delayed at least 60 minutes. Although this ketogenic activity may be a direct effect of the hormone, our results indicate that at least two indirect mechanisms may participate in raising plasma ketone body concentration. First, growth hormone may exert ketogenic activity indirectly by elevating plasma free-fatty-acid substrate concentration. Second, growth hormone administration results in a significant reduction in circulating plasma free–insulin concentration, an observation that has not been previously reported. Since the diabetics in this study were given a fixed dose of exogenous insulin, these results suggest that growth hormone alters either the absorption and/or degradation of injected insulin in diabetic man. This latter mechanism may account for our observation that growth hormone exerts ketogenic activity independent of its lipolytic effect.
Defect in Glucose Removal in Nonketotlc Diabetic Patients with Fasting Hyperglycemia
Authors: Davis Bonnie M , Bernstein Robert , Kolterman Orville , Olefsky Jerrold M , Reaven Gerald M
Published: September 2013

The present experiments were performed to determine the ability of insulin to stimulate glucose uptake in normal subjects as compared with nonobese patients with fasting hyperglycemia at similar steady state plasma glucose and insulin concentrations. The studies were carried out at two different steady state plasma glucose levels (approximately 250 and 350 mg/100ml), and, in both instances, patients with fasting hyperglycemia removed approximately one-half as much glucose from the plasma as did normal subjects. Since the plasma insulin levels were comparable in the two groups (approximately 100 μU/ml), these results demonstrate that patients with fasting hyperglycemia are more insulin resistant than are normal subjects. Furthermore, the differences in glucose removal were observed under conditions in which the plasma glucose levels in the normal and the diabetic groups were similar; therefore, the insulin resistance of patients with fasting hyperglycemia is independent of differences in plasma glucose pool size. Finally, glucose removal increased proportionately in both experimental.groups at the higher plasma glucose levels, suggesting that saturation of the glucose transport system does hot occur at these plasma glucose concentrations. These results further document the fact that nonobese patients with significant fasting hyperglycemia are less responsive than normal subjects to the acute action of insulin that stimulates glucose removal from plasma.
In Vitro Studies of the Substrates for Energy Production and the Effects of Insulin on Glucose Utilization in the Neural Components of Peripheral Nerve
Authors: Greene Douglas A , Winegrad Albert I
Published: September 2013

An “endoneurial” preparation from a rabbit tibial nerve fascicle was used to study the ability of peripheral nerve axons and Schwann cells to derive their composite energy requirements from glucose, D-β-hydroxybutyrate, or albumin-bound palmitate, and the effects of insulin in vitro on their composite glucose utilization. Samples incubated with 5 mM glucose for 2 h maintained a stable O2 uptake and P-creatine and ATP concentrations, and they exhibited a slight increase in P-creatine/creatine ratio (the electron microscopic appearance of the preparation was previously shown to be unaltered under these conditions). The rate of glucose oxidation required to account for the O2 uptake accounted for 61% of the glucose uptake. In samples incubated without substrate for 2 h, a marked fall in tissue glucose was associated with a 50% decrease in O2 uptake and with decreases in P-creatine, ATP, and in the P-creatine/creatine ratio. In medium lacking glucose but containing 5 mM DL-β-hydroxybutyrate, a stable rate of D-β-hydroxybutyrate uptake was observed, and acetoacetate production accounted for only a small fraction; significant decreases in O2 uptake or ATP were prevented, and, although P-creatine and the P-creatine/creatine ratio fell, they remained significantly higher than after incubation without substrate. An efficient blood-nerve barrier to albumin is known to exist. Medium containing albumin-bound palmitate with molar ratios of palmitate/albumin of 1 or 2 (highest FFA concentration, 1.32 meq/L) failed to prevent decreases in P-creatine, ATP, and in the P-creatine/creatine ratio during incubations without glucose; the associated O2 uptakes suggested that the tissue is susceptible to respiratory uncoupling and depression on exposure to albumin-bound palmitate as compared with non-neural tissue. Insulin (100 or 1000 μU/ml) had no detectable effects on glucose utilization in the endoneurial preparation during 2-h incubations with 5 mM glucose or (U-14C) glucose. In contrast, in epineurial tissue from rabbit sciatic nerve, insulin (100 μU/ml) increased (U-14C) glucose incorporation into CO2 and total lipid. The neural components of peripheral nerve are probably dependent on glucose as their major substrate for energy production and respiration under most physiologic conditions in which elevated plasma ketone body concentrations are absent; their composite glucose utilization is not subject to acute, direct regulation by insulin in concentrations that might reasonably be derived from plasma insulin of pancreatic origin.
Somatomedin Activity and Diabetic Control in Children with Insulin-Dependent Diabetes
Authors: Winter Robert J , Phillips Lawrence S , Klein Mordecai N , Traisman Howard S , Green Orville C
Published: September 2013

To test the hypothesis that somatomedin activity is influenced by diabetes and its metabolic regulation, the relationship between somatomedin activity and diabetic control as assessed by hemoglobin A1C was investigated in 40 children with insulin-dependent diabetes. An inverse correlation between hemoglobin A1c and serum somatomedin activity was statistically significant. The data suggest that abnormalities of linear growth, which can occur in children with poorly controlled diabetes, may involve abnormalities in net somatomedin activity.
Studies on Plasma Glucagon Concentration in Maturity-Onset Diabetics with Autonomic Neuropathy
Authors: Levitt N S , Vinik A I , Sive A A , Child P , Jackson W P U
Published: September 2013

The mean fasting plasma immunoreactive glucagon (IRG) concentration in 25 non-insulin-dependent, maturity-onset diabetics (MODs) was 15.4 ± 3.1 pmol/L, which was not significantly different from the 16.8 ± 2.4 pmol/L in 17 normal controls of similar age. However, in seven MODs with autonomic neuropathy (AN) the mean fasting IRG concentration of 44.7 ± 4.4 was significantly greater than the 17.4 ±1.3 pmol/L in 18 MODs without neuropathy and compared with controls. We, therefore, investigated IRG concentrations in five age-matched, non-insulin-dependent MODs with AN and five without it. Plasma IRG concentrations were measured in the basal state on three separate occasions and in response to insulin and to a mixed meal. Fasting or basal IRG concentrations were measured in the morning with and without a preceding 12-h insulin infusion to determine the effects of reduction in fasting plasma glucose concentrations and after 12 h of nasogastric aspiration to exclude continued stimulation caused by delayed gastric emptying. In the select group of Subjects the mean basal plasma IRG concentration was raised above the normal in diabetics with AN (49.4 ± 5.1) and was 16.2 ± 2.1 in diabetics without AN, which was within normal limits. Neither 12 h of insulin infusion (0.5–0.8 U/h) nor 12 h of nasogastric aspiration altered basal IRG concentrations in either group. The maximum incremental IRG response to acute insulin administration (0.2 U/kg) in diabetics with AN was 6.8 ± 3.9, which was significantly impaired compared with 24.9 ± 4.8 in nine MODs without AN and with 26.3 ± 6.7 in five normal controls. The maximum increment in IRG response to acute insulin administration in diabetics with AN rose significantly to 32.8 ± 12.9 after 12 h of insulin infusion. Although the maximum IRG responses to a mixed meal were higher in both diabetic groups than in the normal controls, there was a delayed initial rise and persistent elevation in diabetics with AN. We suggest that (1) basal IRG concentrations may be dependent on the integrity of the autonomic nervous system in MODs; (2) MODs without AN seem to have a normal response to insulin-induced hypoglycemia, whereas in MODs with AN the response is impaired and can be corrected by an adequate degree of both insulinization and reduction in fasting blood glucose concentration; and (3) the maximum IRG response to a mixed meal is exaggerated in all MODs and is not dependent on the integrity of the autonomic nervous system, although the pattern of response may be altered in the presence Of AN.
Plasma and Urine Carnitine in Diabetic Ketosis
Authors: Genuth Saul M , Hoppel Charles L
Published: September 2013

Cernitine is an essential factor in fatty acid oxidation and, hence, in ketoacid production. In plasma, therefore, free carnitine, short-chain acylcamitine, long-chain acylcarnitine, and total carnitine (sum of all three fractions) were determined in normal subjects, in diabetics with ketosis, and in diabetics in ketoacidosis. Short-chain acylcarnitine (mean ± SEM) was significantly higher in ketoacidotic diabetics (31.0 ± 4.0 μm) and ketotic diabetics (11.8 ± 1.2 μm) than in normals (5.8 ± 0.65); long-chain acylcarnitine was significantly higher in ketoacidotic diabetics (8.0 ±1.0 μm) than in ketotic diabetics (4.9 ± 0.39 μm) or normals (4.2 ± 0.22 μm); free carnitine was significantly lower in ketoacidotic diabetics (20.5 ± 3.3 μm) than in ketotic diabetics (31.8 ± 2.2 μm) or normals (36.5 ± 1.5 μm). Plasma short-chain acylcarnitine correlated positively with blood beta hydroxybutyrate in normals (r = 0.69, P < 0.001) but not in either diabetic group. However, the abnormal distribution in plasma of free carnitine and acylcarnitines in the diabetics was promptly returned toward normal, in parallel with blood beta hydroxybutyrate, by insulin treatment. The latter also resulted in a 70% reduction in 24-h urinary excretion of acylcarnitine. these data are consistent with a postulated role for carnitine in diabetic keto-genesis in man.
Genetic Selection for Diabetogenic Traits in Yucatan Miniature Swine
Authors: Phillips R W , Panepinto L M , Will D H
Published: September 2013

Yucatan miniature pigs have been selectively bred for reduced and increased glucose clearance during an intravenous glucose tolerance test. Pigs with low glucose clearance rates (low K) have been selected through the F-5 generation. They have a significantly reduced rate of glucose clearance and a blunted peripheral IRI increase in response to the challenge. Through the F-5 generation, heritability of glucose tolerance is estimated at 0.26. Sporadic fasting blood glucoses in excess of 100 mg/dl are seen in later generations of this group. High glucose clearance pigs (high K) have been selected through the F-4 generation. They have significantly increased rates of glucose clearance and a greater increase in peripheral IRI than the low K animals. The estimated heritability for high K through the F-4 generation is 0.31. No evidence of fasting hypo- or hyperglycemia has been seen in the high K animals.
Higher Levels of Erythrocyte Membrane Microviscosity in Diabetes
Authors: Baba Yasutada , Kai Motoaki , Kamada Tetsuro , Setoyama Shiro , Otsuji Shogo
Published: September 2013

Significantly higher levels of erythrocyte membrane microviscosity (MV) [η̅: 5.22 ± 0.17 (4.70–5.92), mean ± SD (range), poise, N = 67, P < 0.005] measured by fluorescence depolarization using 1,6-diphenyl-1,3,5-hexatriene as a fluorescent probe were found in diabetic patients when compared with normal controls [5.05 ± 0.15 (4.70–5.29), N = 22]. No significant differences in MV existed between males and females, nor was MV significantly correlated with diabetic age, duration of diabetes, plasma cholesterol, cholesterol/phospholipid ratios, and plasma lecithin :cholesterol acyltransferase activities. No significant difference in MV was observed between groups with or without diabetic retinopathy. There was, however, significantly higher MV [5.29 ± 0.19 (5.00–5.92), N = 20, P < 0.05] in the group with fasting blood glucose (FBG) > 140 mg/dl than that [5.19 ± 0.15 (4.70–5.46), N = 47] in the group with FBG < 140 mg/dl. The changes in erythrocyte membrane MV presented in this study appear to be related to the current metabolic control of diabetic patients and are considered to be one of the factors responsible for the reduced erythrocyte deformability in diabetes.
Tissue and Serum Somatostatin-like Immunoreactivity in Fed, 15-h-fasted, and 72-h-fasted Rats
Authors: Shapiro B , Berelowitz M , Pimstone B L , Kronheim S , Sheppard M
Published: September 2013

Somatostatin-like immunoreactivity (SLI) was measured in extracts of gastric antrum, colon, pancreas, and central nervous system, as well as in unextracted portal and inferior vena caval serum from fed, 15-h-fasted, and 72-h-fasted rats. No differences were found in SLI in the central nervous system of the three groups. However, striking variations were found in the gastrointestinal tract and pancreas; the antrum, colon, and pancreas of 15-h-fasted rats contained the least SLI, the content being significantly elevated in these three areas after feeding and after a 72-h fast. Portal serum levels were highest after feeding but lowest in 72-h-fasted rats, in spite of high intestinal and pancreatic SLI content in both. These tissue and serum differences suggest a physiologic role for SLI in nutrient homeostasis not only at tissue level, but also putatively as a hormone in the portal system.
Responses of Patients with Insulinomas to Stimulators and Inhibitors of Insulin Release That Have Been Linked with Cyclic Adenosine Monophosphate
Authors: Lins Per-Eric , Efendić Suad
Published: September 2013

The study comprises nine consecutive patients who had pancreatic beta-cell tumors and spontaneous hypoglycemia, seven of whom had verified, benign insulinomas and one a malignant insulinoma with metastases to the liver. The ninth patient, who refused surgery, was followed for three years without displaying any signs of malignancy. Among the patients with benign insulinomas, three showed exaggerated, two normal, and two unusual insulin responses to glucose. One such patient as well as the one with a malignant tumor did not respond to glucose. In general, the insulin responses to glucagon were similar to those to glucose. Somatostatin reduced basal insulin levels as well as the responses to glucose and glucagon only in subjects with normal or exaggerated responses to these agents. Einephrine behaved like somatostatin when insulin release was stimulated by glucose, but it was a weak inhibitor of the glucagon-stimulated response. The subject with the malignant insulinoma did not respond to either glucose or somatostatin. The remission of the disease, which followed streptozotocin treatment, was accompanied by restoration of the normal responsiveness to the above agents.

Glucagon stimulates insulin release by increasing the intracellular level of cyclic adenosine monophosphate (AMP). The effects of glucose, somatostatin, and epinephrine are supposed to be mediated, at least partially, by way of the adenylcyclase-cyclic AMP system. Therefore, the present data suggest that the variability of the beta-cell responsiveness to glucose and glucagon in patients with insulinoma reflects the responsiveness of the adenylcyclase-cyclic AMP system of the beta-cell tumor, which may be exaggerated, normal, or absent.
Effect of Fasting on the Release of Insulin and Somatostatin from Perifused Islets of Langerhans
Authors: Schauder Peter , McIntosh Christopher , Arends Jann , Frerichs Heiko
Published: September 2013

Release of somatostatin and insulin from perifused islets of fasted and control rats was compared. After a fasting period of 48 h glucose-induced insulin release but not somatostatin release was diminished. Islets from fasted rats released significantly more somatostatin in the presence of 3.3 mM glucose than islets from controls. Simultaneously, the somatostatin content of isolated islets from fasting rats was significantly decreased.

The results indicate that the low secretory activity of islet B cells in the fasting state is associated with a high secretory activity of islet D cells.
Maintenance of Basal Plasma Glucose and Insulin Concentrations in Maturity-Onset Diabetes
Authors: Holman R R , Turner R C
Published: September 2013

Normal and mildly diabetic subjects each have their own “set” of basal plasma glucose and insulin concentrations. Diabetic patients have raised basal plasma glucose, with low-normal basal plasma Cpeptide concentrations. Restoring normal glucose levels in mild diabetes by an insulin infusion further reduces the C-peptide concentration, but both the plasma glucose and the C-peptide return to their “set” level when the insulin is withdrawn. These results accord with the action of beta cells and liver in a negative feedback loop that maintains basal plasma glucose and insulin concentrations.
Localization of Occult Insulinoma by Super-Selective Pancreatic Venous Sampling for Insulin Assay through Percutaneous Transhepatic Catheterization
Authors: Millan Victor G , Urosa Claudio L , Molitch Mark E , Miller Harry , Jackson Ivor M D
Published: September 2013

Preoperative localization of insulinomas by arteriography is successful only 66% of the time. With small tumors, intraoperative localization is usually unsuccessful also. Because surgical morbidity and mortality are increased greatly when major, blind, pancreatic resections or reoperations are performed, additional preoperative localization procedures are needed. We now report the successful localization of an occult insulinoma by means of blood sampling for insulin radioimmunoassay, obtained by selective pancreatic vein sampling through percutaneous transhepatic catheterization.

Our patient had symptoms of fasting hypoglycemia for 11 months. Routine studies were normal and two fasting plasma glucose concentrations were 34 and 16 mg/dl to correspond with insulin values of 33 and 75 μU/ml. Celiac arteriography was normal. Percutaneous transhepatic portal and pancreatic venous catheterization revealed insulin concentrations (μU/ml) of between 23 and 36 in portal and splenic veins, 17 in the short, gastric vein, 17 in the dorsal pancreatic vein, 19 in the superior, mesenteric vein, and 61 and 288 in two pancreatic magna veins draining the tail. An insulinoma of 2 × 3 cm was resected from the tail. On the basis of our experience with this patient, it is clear that selective venous sampling may facilitate the localization of occult insulinomas at surgery and thereby avoid extensive, blind, pancreatic resections and the need for reoperation.
Insulin and Glucagon Secretion from Rat Islets Maintained in a Tissue Culture-Perifusion System
Authors: Gingerich Ronald L , Aronoff Stephen L , Kipnis David M , Lacy Paul E
Published: September 2013

A tissue culture-perifusion system is described that allows for long-term culture of pancreatic islets and study of the dynamics of islet hormone secretion. Islets cultured in this system demonstrate brisk, reproducible biphasic insulin and glucagon release. Glucose-stimulated insulin release is similar after 1 or 14 days in culture. Freshly isolated islets are relatively insensitive to somatostatin, requiring 100 ng/ml to suppress partially the glucose-induced insulin secretion. After 24 h of culture, the same islets demonstrate a marked increase in sensitivity to this hormone. Glucagon secretion from islets maintained in this system occurred in a predictable fashion to arginine stimulation and glucose inhibition.
Downregulation of Insulin Receptors in Obese Man
Authors: Wigand James P , Blackard William G
Published: September 2013

In an attempt to determine whether the decreased number of insulin's receptors in obesity is a result of downregulation of the receptors, diazoxide (5 mg/kg/d) was given to 10 obese subjects. Insulin's suppression by diazoxide in these 10 subjects resulted in a mild glucose intolerance and an increase in insulin's receptors in seven of the 10 subjects. The subjects could be divided into three groups by analyzing the Scatchard plots of their insulin receptor studies before and after diazoxide. Four subjects exhibited an increase in both high affinity and low. affinity receptors, three showed an increase only in high affinity receptors, and three failed to demonstrate any change in receptors in response to diazoxide. These studies support the concept that the decreased number of insulin's receptors observed in obesity is a result of the downregulation of the receptors and is not the primary, underlying cause of insulin resistance in obesity, although a contributory role cannot be ruled out.
Malformations in Infants of Diabetic Mothers Occur Before the Seventh Gestational Week: Implications for Treatment
Authors: Mills James L , Baker Lester , Goldman Allen S
Published: September 2013

In the present study we used a developmental morphologic approach to fix the latest time in development at which the malformations commonly reported in infants of diabetic mothers could occur. Developmental morphologic dating shows that the significantly more common congenital malformations in infants of diabetic mothers occur before the seventh week of gestation. This suggests that any therapeutic intervention aimed at decreasing the incidence of congenital malformations must be instituted during the critical early period.
Characteristics of Growth Hormone Secretion in Clinically Stable Diabetes
Authors: Merimee Thomas J , Fitzgerald Constance R , Gold Larry A , McCourt Jerome P
Published: September 2013

Although the secretion of growth hormone (GH) is widely accepted as being increased in diabetes mellitus, this conclusion appeared to us to be the result of bias in case selection. Newly diagnosed and hospitalized diabetics cannot be assumed as representative of the clinically stable diabetic state. In view of the postulated importance of growth hormone to the vascular complications of diabetes, we re-examined this problem in 58 clinically stable diabetics and 38 age-matched controls. GH was measured in serum samples collected hourly during a 24-h period of normal activity.

Control and clinically stable diabetic subjects of normal weight had similar mean serum GH concentrations for 24 h. In subjects of normal weight, values were 4.4 ± 0.6 ng/ml for women of the control group and 4.0 ± 0.8 ng/ml for diabetic women (P = NS) and values in men were 2.4 ± 0.3 ng/ml in controls and 2.1 ± 0.3 ng/ml in diabetic men (P = NS). Obese controls and obese diabetics had similar, but significantly lower values than nonobese subjects.

When hyperglycemia (125 mg to 175 mg/dl) was induced in 12 control subjects for 24 h, glycemia was obtained comparable to that seen in a select group of nine diabetics. Mean serum concentrations of GH were significantly less in the glucose-infused controls than in both euglycemic controls and diabetics.

These data do not support an absolute increase of circulating GH in stable diabetics; GH levels appear to be normal in this group but inappropriate for the level Of glycemia.
Severe Hyperglycemia: Effects of Rehydration on Endocrine Derangements and Blood Glucose Concentration
Authors: Waldhäusl W , Kleinberger G , Korn A , Dudczak R , Bratusch-Marrain P , Nowotny P
Published: September 2013

Diabetic ketoacidosis is associated with an excess secretion of counterregulatory hormones. The effect of rehydration on these endocrine derangements before insulin administration is unknown. Therefore, we measured the effect of rehydration with hypoosmolal fluid (220 mosmol/kg) on blood glucose (BG), immunoreactive insulin (IRI), immunoreactive C-peptide (IRCP), immunoreactive glucagon (IRG), human pancreatic polypeptide (hPP), growth hormone (GH), prolactin (PRL), cortisol, aldosterone, renin (PRC), epinephrine, norepinepnrine, and parathyroid hormone (PTH) in ketoacidotic diabetic patients [pH 7.03 ± 0.05 (SEM); n = 8] and in patients (n = 2) with nonketotic hyperglycemia (BG, 29.8 mmol/L and 46.8 mmol/L). The cumulative net fluid balance after rehydration was 4364 ± 690 ml. Basal insulin was inappropriately low, and IRCP was below the normal range (1.5 ± 0.5 ng/ml). Serum osmolality fell during hypoosmolal rehydration (n = 9) from 335 ± 11 to 315 ± 9 mosmol/kg. Rehydration with hypoosmolal fluid with bicarbonate added at a pH of less than 7.2 induced a fall in BG ranging from 6.1 mmol/L to 22.6 mmol/L, or of 16.7% to 79.8% of the initial BG level, as well as a decrease in plasma lactate and urinary glucose. These effects were paralleled by a decrease in IRG, cortisol, epinephrine, norepinephrine, aldosterone, and PRC. No fall in BG was seen in one patient whose dehydrated state was maintained by infusion of isotonic saline. Low dose insulin treatment was initiated in all patients immediately when no further fall in blood glucose levels was achieved.

We conclude that rehydration improves the metabolic situation in severe diabetic hyperglycemia and ketoacidosis by reducing (a) the availability of counterregulatory hormones and (b) peripheral insulin resistance on a cellular level. Thus, proper rehydration will support the beneficial action of simultaneous low dose insulin treatment in patients with severe hyperglycemia.
Control of Blood Glucose in Experimental Diabetes by Means of a Totally Implantable Insulin Infusion Device
Authors: Blackshear Perry J , Rohde Thomas D , Grotting James C , Dorman Frank D , Perkins Paul R , Varco Richard L , Buchwald Henry
Published: September 2013

Near-normal glucose tolerance tests in diabetic dogs were obtained during basal rate insulin infusions in restrained animals by use of extracorporeal infusion pumps and in conscious, unrestrained animals by means of implanted infusion pumps. Even better regulation of blood glucose in diabetic animals was obtained by the addition of predetermined pulses of insulin at higher flow rates than the basal flow rate, accomplished by use of a transcutaneously activated valve mechanism attached to the implanted infusion pump. We conclude that near-normal blood glucose concentrations can be maintained throughout the day in the dog by these means and that similar approaches, using implantable infusion pumps, in man may lead to better long-term control of diabetes than is currently available.
Insulin Resistance Caused by Massive Degradation of Subcutaneous Insulin
Authors: Paulsen Elsa P , Courtney John W , Duckworth William C
Published: September 2013

Severe resistance to subcutaneous insulin but sensitivity to intravenous insulin persisted for 15 months in a 17-year-old diabetic girl. Heat-labile insulin-degrading activity was present in the patient's ketotic sera and in the 100,000 g fraction (soluble fraction) of adipose tissue. Serum-degrading activity was not inhibited by N-ethylmaleimide. The soluble fraction also degraded glucagon and B chain but not growth hormone or myoglobin. It was inhibited by incubation with the patient's nonketotic sera, normal sera, or Trasylol. Glutathione-insulintranshydrogenase (GIT) activity was 66% of normal.

The biopsy of adipose tissue at remission showed a normal level of insulin- and glucagon-degrading activity. The activity was eluted from Sephadex G200 as a single peak and had properties consistent with those of the insulin-specific protease (ISP).

The increased degrading activity present during insulin resistance had properties not shared with ISP, suggesting the presence of an uncharacterized protease.
Cellular Mechanisms of Insulin Release: Effects of Retinol on Insulin Release and Islet Ultrastructure
Authors: Chertow Bruce S , Buschmann Robert J , Kaplan Robert L
Published: September 2013

In previous studies using perifused collagenase-isolated rat islets, retinol (vit A) inhibited glucose-induced Diphasic insulin release and glucose oxidation. To further evaluate vit A action and elucidate cellular mechanisms of insulin release, we tested the effects of vit A on glucose uptake by islets, on other stimuli of insulin release, and oh islet ultrastructure and the effects of calcium on vit A inhibition of insulin release. Vit A did hot inhibit 2-deoxy-D-glucose uptake into islets. Vit A inhibited second phase 9.7 and 13.9 mM glucoseinduced insulin release to 50%, 10 mM glyceraldehydeinduced release to 64%, and 20 mM leucine-induced release to 66% of control. First phase, release was unaffected. Kinetic analysis of the effects of vit A on glucose-induced release indicated a change in the Vmax but not in the Km, suggesting inhibition of a potentiator of insulin release by vit A. Calcium (4 mM) opposed vit A inhibition of glucose-induced release.

Ultrastructurally, vit A decreased the volume fraction of secretory granules to 90% of control, increased the volume fraction of material within the rough endoplasmic reticulum to 147% of control, and increased the outer and decreased the inner mitochondrial compartment volume fractions by 14%.

Our functional and ultrastructural findings, in all, suggest that vit A inhibitioh of second phase insulin release is not specific for glucose and may be mediated in part through impairment of mitochondrial function and intracellular glucose oxidation.
Studies on Dehydrogenases of the Glucuronate-Xylulose Cycle in the Livers of Diabetic Mice and Rats
Authors: Tulsiani Daulat Ram P , Touster Oscar
Published: September 2013

In view of reports that accessory pathways of glucose oxidation are enhanced in the diabetic state, we have determined the levels of key enzymes of the glucuronate-xylulose cycle in the livers of diabetic mice and rats. Genetically diabetic mice (db/db) were found to have increased levels of two NADP-linked enzymes of this cycle [NADP-xylitol dehydrogenase and NADP-L-hexonate dehydrogenase (aldehyde reductase II)], whereas other NAD- and NADP-linked dehydrogenase activities of the pathway were not changed. On the other hand, the livers of streptozotocin-diabetic mice and rats showed normal levels of all these enzymes. In the course of this study, evidence was obtained for the presence in db/db mouse liver of low molecular weight material inhibitory for glucose 6-phosphate dehydrogenase. The use of these animal models in diabetes research is briefly discussed.