bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Fasting on Gluconeogenesis from Alanine in Nondiabetic Man
Authors: Chiasson J L , Atkinson R L , Cherrington A D , Keller U , Sinclair-Smith B C , Lacy W W , Liljenquist J E 
Published: September 2013

The present study was designed to determine the effect of fasting on gluconeogenesis from alanine. This process was measured by combining the infusion of l4C-alanine with the A-V difference technique. Normal subjects were studied after 12 and 48 h of fasting and obese subjects were studied after 18 days of therapeutic starvation. After a 12-h fast the hepatic venous 14C-alanine specific activity was 34% lower than the arterial 14C-alanine specific activity, which was consistent with a dynamic exchange of alanine between the intestine and the plasma and with a net release of unlabeled alanine by the intestine. Under these conditions the net splanchnic alanine uptake (106 μmol/min) would underestimate the actual hepatic extraction of alanine, which could be estimated as at least 147 μmol/min. After 48 h and 18 days of fasting, the 14C-alanine specific activity equaled that in the arterial plasma, indicating cessation of intestinal release of alanine into the portal circulation. Under these circumstances, net splanchnic alanine uptake would equal net hepatic alanine extraction. Thus, actual hepatic alanine ëxtraction rates at 48 h and 18 days of fasting were 134 and 94 μmol/min, respectively.
In the face of a decreasing hepatic alanine extraction with fasting, gluconeogenesis from alanine increased by 100% (from 41 to 82 μmol/min) after 48 h of fasting. After 18 days of starvation 51 /μmol/min of alanine was converted to glucose, a rate still 25% higher than after a 12-h fast.
We concluded: (a) fasting is associated with a gradual decrease in hepatic alanine extraction; (b) however, gluconeogenesis from alanine is increased after 48 h and 18 days of fasting due to a more efficient intrahepatic conversion of alanine to glucose.
Persistence of Ketosis Despite Suppression of Lipolysis by 16, 16-Dimethylprostaglandin E2 in Experimental Diabetic Ketoacidosis in Rats
Authors: Axelrod Lloyd , Slowman Sally D , Lloyd-Jones Peter , Martin Donald B 
Published: September 2013

We studied the effect of suppression of lipolysis on ketogenesis in rats with established diabetic ketoacidosis (DKA) using 16, 16-dimethylprostaglandin E2 (DMPGE2) as an antilipolytic agent.
DMPGE2 produced a dose-related reduction in plasma free fatty acid (FFA) levels and a reduction in plasma glycerol levels after an intravenous injection of up to 2 μg/kg body weight in animals with streptozotocin-induced DKA. In contrast, doses of PGE2 varying from 2 to 500 μg/kg body weight intravenously failed to suppress lipolysis and some doses were lipolytic. In nondiabetic rats, DMPGE2 produced a fall in the FFA and glycerol levels and a concomitant reduction in the plasma ketone levels.
When DMPGE2, 2 μg/kg body weight, was administered intravenously every 30 min for 4 h to rats with DKA, the plasm FFA level fell from 2.86 ± 0.36 meq/L at time 0 to 0.78 ± 0.07 meq/L at 4 h; the final value was lower than that found in fed, nondiabetic, nonketotic rats studied under the same conditions. However, the plasma ketone levels remained elevated in response to DMPGE2 (8.36 ± 0.46 mM at time 0; 7.19 ± 0.17 mM at 4 h). In contrast, insulin produced a rapid and marked fall in both the FFA and the ketone levels in comparable animals.
When DMPGE2 was administered together with insulin to rats with DKA, the plasma FFA level fell to the same low level achieved with insulin alone. Nevertheless, DMPGE2 impaired the effect of insulin on the total plasma ketone level. When both agents were given concurrently, the total plasma ketone level fell from 10.26 ± 0.99 mM at time 0 to 5.32 ± 1.67 mM at 4 h; with insulin alone, the total plasma ketone level fell from 8.47 ± 0.84 mM at time 0 to 0.78 ± 0.23 mM at 4 h. DMPGE2 also interfered with the response of the plasma glucose level to insulin.
Conclusions: (1) DMPGE2 is a potent antilipolytic agent in vivo, as well as in vitro. This efficacy contrasts with the absence of an antilipolytic effect of PGE2 in vivo, although both substances suppress lipolysis in vitro. This discrepancy may be explained by the fact that DMPGE2, unlike PGE2, is not rapidly metabolized in the pulmonary circulation. (2) DMPGE2 has an effect on ketogenesis, in addition to its antilipolytic effect, in animals with DKA but not in normal animals. This may be enhancement of hepatic ketogenesis, interference with the peripheral disposal Of ketones, or both.
Decreased Sympathetic Vasomotor Tone in Diabetic Orthostatic Hypotension
Authors: Hilsted Jannik 
Published: September 2013

In normals, subcutaneous blood flow in the ankle region, measured by means of the 133Xe washout technique, decreases about 45% when the position of the ankle is changed from cardiac level to 50 cm below the heart. A sympathetic vascular axon reflex is responsible for this flow reduction.
A normal response [mean blood-flow reduction, 49% (range, 40 to 64%)] was found in seven diabetics without neuropathy. In nine diabetics with autonomic neuropathy (beat-to-beat variation in heart rate ≤ 15 min−1 during hyperventilation), the reduction in blood flow on lowering of the ankle was also normal. A significant deterioration of the response was found in six diabetics with autonomic neuropathy, including orthostatic hypotension, in whom blood flow increased 23% (range, −35 to +77%). Autoregulation of blood flow, i.e., constancy of blood flow in the ankle region on lowering and elevating of the ankle 20 cm below and above cardiac level was intact in the patients with orthostatic hypotension, indicating a normal vascular smooth muscle function.
In conclusion, in diabetic patients with orthostatic hypotension, the subcutaneous axon reflex is absent. This may be one of several factors responsible for their orthostatic hypotension.
Glomerular Basement Membrane Metabolism in the Diabetic Rat: In Vivo Studies
Authors: Brownlee Michael , Spiro Robert G 
Published: September 2013

The effect of diabetes on the metabolism of the renal glomerular basement membrane has been studied in the rat with the aid of injected tracer doses of tritiated proline. At various times after administration of the labeled amino acid, the specific radioactivities of the proline and hydroxyproline of the basement membranes from alloxan diabetic rats were determined and compared with those of age-matched normal rats. In both normal and diabetic animals the incorporation of radioactivity into the basement membrane was slow and, after a maximum was reached, an extended period of almost constant specific activity of proline and hydroxyproline was observed. The diabetic basement membrane, however, differed from the normal by attaining specific activities of the amino acids which were about twice as high as normal (P &lt; 0.001 at 42 h after injection of radioisotope). Although the proline concentration of serum and renal cortical fluid was the same in normal and diabetic rats, there were substantial differences in the specific activity of this precursor amino acid in these pools that had to be taken into account to compare the two types of animals.
The results of the present study are consistent with an accelerated rate of glomerular basement membrane polypeptide synthesis and proline hydroxylation in diabetes.
Characteristics of the Dopaminergic and Noradrenergic Systems of the Pancreatic Islets
Authors: Zern Ruthann T , Foster Lea B , Blalock Judith A , Feldman Jerome M 
Published: September 2013

The catecholamines norepinephrine (NE) and dopamine (DA), known inhibitors of insulin secretion, have been identified in the pancreatic islets only semiquantitatively by their histochemical fluorescence spectrum. Using collagenase digestion of golden hamster pancreas, we isolated islets and quantitated the NE and DA content with sensitive and specific radioenzymatic assays. We compared the NE and DA concentrations in islets with the median eminence and cerebral cortex of the golden hamster, tissues known to contain catecholamines. Under basal conditions, NE is in higher concentration than DA in all three tissues and is highest in the islets in a much greater concentration than is found in the median eminence. DA is present in measurable quantities in all three tissues and, in the islets, its concentration is comparable with that in the median eminence.
Treatment of the hamster with a precursor of the two catecholamines, L-dopa, produced a significant accumulation of DA in the islets and median eminence over the basal values. This L-dopa-induced increase in DA was heightened in the islets and reached significantly higher than control levels in the cortex by a pretreatment of the hamster with tranylcypromine (tran), a monomine oxidase inhibitor. Pretreatment with tran alone, however, produced no change in DA over control values.
The NE content of pancreatic islets was not altered by administration of L-dopa, tran, or L-dopa plus tran. The NE content of the median eminence was increased by the administration of tran. L-dopa plus tran did not result in an additional increase in the NE content of the median eminence. The administration of tran plus L-dopa (but not the administration of either agent alone) increased the NE content of the cortex over control levels. The present study suggests that inhibition of insulin secretionafter L-dopa administration is due to an increased concentration of DA rather than NE in the pancreatic islets.
Plasma Vasopressin in Uncontrolled Diabetes Mellitus
Authors: Zerbe Robert L , Vinicor Frank , Robertson Gary L 
Published: September 2013

Concentrations of the antidiuretic hormone, arginine vasopressin, were measured in 28 patients with severe hyperglycemia to determine if abnormalities in hormonal regulation of water excretion could contribute to the extreme dehydration of uncontrolled diabetes mellitus. Vasopressin levels were markedly elevated in both nonketotic and ketotic patients, indicating that vasopressin deficiency plays no role in the polyuria that accompanies hyperglycemia. Instead, the observed increases in vasopressin represent an ineffective effort to conserve water in the face of an overwhelming solute diuresis caused by the glucosuria.
The reasons for such marked elevations in plasma vasopressin in these diabetic patients are multifactorial. Both groups of diabetic patients had evidence of hypovolemia, which was sufficient in magnitude to stimulate vasopressin release. Furthermore, nausea provided an independent stimulus to vasopressin secretion in many patients. Osmotic stimulation might have resulted from the large fraction of unidentified plasma solutes, but this factor alone was not sufficient to explain the markedly increased concentrations of vasopressin. Whether such elevations in vasopressin could have metabolic and/or hemodynamic effects in uncontrolled diabetes remains to be established.
Effect of Leucine on the Pyridine Nucleotide Contents of Islets and on the Insulin Released—Interactions In Vitro with Methylene Blue, Thiol Oxidants, and p-Chloromercuribenzoate
Authors: Ammon Hermann P T , Hoppe Erika , Akhtar Muhammad S , Niklas Herbert 
Published: September 2013

In the presence of glucose (2 mg/ml), leucine (10 mM) noticeably increased islets' NADPH contents as well as the NADPH:NADP ratio; the changes occurred as soon as 1 min after its addition. NADH concentrations were also increased by leucine. The NADPH:NADP ratio as well as insulin release stimulated by glucose plus leucine were markedly decreased by methylene blue. The thiol oxidants diamide and tert-butyl hydroperoxide also inhibited insulin secretion in response to glucose plus leucine. Employing the perfused pancreas technique, the insulin-releasing action of p-chloromercuribenzoate was further enhanced by leucine. The combined effects were inhibited by tert-butyl hydroperoxide, however.
Our data suggest that the insulin-releasing action of leucine depends on the islets' NADPH and reduced glutathione (GSH); in addition, leucine may contribute to insulin secretion by increasing the islet NADPH:NADP ratio and the NADH:NAD ratio. From the data, we assume that the observed increase of NADPH may lead via GSH to an increase in the number of such thiol groups in the β-cell membrane, which are believed to be related to stimulation of insulin release and, thus, to increase the sensitivity of the β-cell to stimulation by glucose and/or leucine.
Somatostatin Release from Isolated Perfused Rat Pancreas: Possible Role of Endogenous Somatostatin on Insulin Release
Authors: Kadowaki Seizo , Taminato Tomohiko , Chiba Tsutomu , Mori Kozaburo , Abe Hiromi , Goto Yasuo , Seino Yutaka , Matsukura Shigeru , Nozawa Masumi , Fujita Takuo 
Published: September 2013

In order to elucidate the role of endogenous somatostatin in the control of insulin and glucagon secretion, glucagon- or insulin-induced somatostatin release from the isolated perfused rat pancreas was studied.
Immunoreactive somatostatin was persistently released for 60 min in response to perfusion by 5.5 mM glucose at concentrations ranging between 10 and 15 pg/ml. The addition of glucagon (10−8, 10−7, and 10−6 M) caused a dose-related increase of somatostatin release. In contrast, insulin release, especially its first phase, was suppressed when concentrations of glucagon were increased. The addition of insulin (10−7 M and 10−6 M) had no significant effect on somatostatin and glucagon release.
These results raise the possibility that endogenous somatostatin and glucagon together regulate insulin secretion, suggesting a close interrelationship between insulin, glucagon, and somatostatin secretion within the iSlet.
Hepatic Glucose-6-Phosphatase Activities and Correlated Ultrastructural Alterations in Hepatocytes of Diabetic Rats
Authors: Garfield Sanford A , Cardell Robert R 
Published: September 2013

Cell fractionation, enzyme analysis, and electron microscopy were used to study the effects of streptozotocin-induced diabetes and insulin replacement on liver structure and function. In liver homogenates from diabetic rats, glucose-6-phosphatase (G-6-Pase) activity was stimulated about 21/2-fold over that found in normal animals. Analyses of isolated rough and smooth microsomes from diabetic rats for G-6-Pase activity showed a fourfold increase in the smooth microsomes and a small increase in enzyme activity in rough microsomes when compared with these fractions from control animals. Associated with the increased enzyme activity was a reduction in liver glycogen. Insulin treatment of the diabetic rats caused a fall in homogenate G-6-Pase levels to approximately normal values and stimulated the accumulation of hepatic glycogen. Administration of insulin to these animals also caused a decrease in G-6-Pase activity, which was most pronounced in the smooth microsomes.
Studies with the electron microscope revealed ultrastructural alterations in livers of the diabetic rats, which were most striking in the periportal region of the lobule. Periportal hepatocytes from diabetic rats displayed dispersed particles of glycogen separated by cytoplasm rich in SER rather than dense masses of glycogen with little SER, as is characteristic of these cells in normal animals. Centrilobular cells from the diabetic animals displayed some disorganization of the RER and a dispersed pattern of glycogen with abundant SER, similar to the pattern found in these cells from normal animals. After insulin treatment the periportal cells appeared normal morphologically, whereas the centrilobular hepatocytes displayed regions of both dense masses and dispersed glycogen. In the glycogen masses, little SER was found; however, in the areas of dispersed glycogen particles, an abundance of this organelle was evident.
We conclude from these studies that diabetes causes an increase in amount of hepatic smooth endoplasmic reticulum (SER), especially within periportal hepatocytes. The results of cell fractionation indicate that membranes of the smooth endoplasmic reticulum are enriched in G-6-Pase. We interpret these results to indicate that diabetes causes hepatocytes to form additional smooth endoplasmic reticulum with specialized membranes, at least with respect to G-6-Pase. It is suggested that this cellular specialization is a response of the hepatocyte to the diabetic state, namely, a demand for increased hepatic glucose production and release into the blood stream, thus contributing to the hyperglycemia characteristic of this disease. Insulin administration to the diabetic animals reverses the above alterations.
Effects of Orotate Administration on the Normal Rat Kidney: Similarity to Changes Observed in Diabetes Mellitus
Authors: Dumler Francis , Cortes Pedro , Levin Nathan W , Spargo Benjamin H , Rubenstein Arthur H , Verghese Chacko P 
Published: September 2013

Glomerular filtration rate, tubular reabsorptive capacity, and renal size are increased early in the course of human insulin-dependent diabetes mellitus. In short-term experimental diabetes in rats, renal weight, total protein, and RNA content are greater than in control rats. These changes are associated with a 12% increase in the cortical uridine 5-triphosphate (UTP)/DNA ratio. We measured the UTP content in the renal cortex of long-term diabetic rats and studied the effects of long-term orotate feeding (0.5%) as a means of UTP pool expansion.
Rats with streptozotocin-induced diabetes for six months had a 42% increase in serum creatinine concentration and an 18% increase in width of the glomerular basement membrane (GBM). Renal cortex UTP/DNA/kg was 54% higher than in control rats. Long-term orotate feeding of diabetic rats produced further deterioration of function and increase in basement membrane width. All diabetic animals developed cataracts bilaterally.
Chronic orotate feeding in nondiabetic animals produced thickening of the GBM when compared with age-matched controls (2330 ± 24 vs. 2056 ± 16 Å; P &lt; 0.01) that were morphologically undistinguishable from diabetic GBM. UTP/DNA/kg body weight were no different from control values. Chronic orotate feeding for 15 mo was associated with a higher renal cortex glycogen content and an increase in creatinine clearance. No animal in this group had cataracts.
Orotate feeding did not change plasma concentrations of glucose or insulin and was associated with increased glucagon concentrations in both diabetic and nondiabetic rats. We postulate that the renal changes induced by orotate, which resemble those of diabetes, are mediated through alterations in pyrimidine metabolism.
Hemoglobin AIC as an Index of Long-term Blood Glucose Regulation in Diabetic Pregnancy
Authors: Kjærgaard Jens-Jørgen , Ditzel Jørn 
Published: September 2013

To evaluate hemoglobin AIc (Hb AIc) as an indicator of prolonged glucose control in pregnant diabetics, four groups of subjects were studied—16 pregnant diabetic, 13 pregnant nondiabetic, 12 nonpregnant diabetic, and 18 healthy control subjects.
Hb AIc was significantly lower in the pregnant diabetic than in the nonpregnant diabetic subjects, 7.8% ± 1.6 vs. 9.9% ±1.9 (mean ± SD). No difference was present in the nondiabetic groups (4.0% ± 0.7 vs. 4.3% ± 0.8, respectively). Hb AIc correlated significantly with the average glucose concentrations of the preceding 60 days in both diabetic groups, suggesting that the lower concentration of Hb AIc in pregnant as compared with nonpregnant diabetic patients was because of better control of blood glucose. This was also borne out by the average of fasting glucose levels being 6.1 ±1.7 mmol/L in the pregnant diabetic and 10.7 ± 2.2 mmol/L in the nonpregnant diabetic subjects
The Effect of Pronounced Hypoglycemia on Monoamine Metabolism in Rat Brain
Authors: Agardh Carl-David , Carlsson Arvid , Lindqvist Margit , Siesjö Bo K 
Published: September 2013

The cerebral metabolism of catechol and indole amines was studied in paralyzed and lightly anesthetized (70% N2O) rats in which severe hypoglycemia was induced by insulin. When blood glucose concentrations fell towards 1 μmol·g−1 and the electrocorticogram (EEG) showed high-amplitude slow waves with interspersed polysplkes, the tissue contents of dopamine (DA), norepinephrine (NE), and 5-hydroxytryptamine (5-HT) were reduced. The rate of hydroxylation of tyrosine, measured as accumulation of dihydroxyphenylalanine (dopa) following inhibition of aromatic L-amino acid decarboxylase with NSD 1015, rose in cortex and striatum, while tryptophan hydroxylation increased moderately in cortical tissue.
Aggravation of the hypoglycemia with cessation of spontaneous EEG activity was accompanied by progressive reduction in tissue contents of DA, NE, and 5-HT and by accumulation of 5-hydroxyindole acetic acid (5-HIAA). In this period, tyrosine hydroxylation rate was reduced in limbic areas and in striatum, but not in the cortex, while tryptophan hydroxylation was reduced in limbic areas only.
When recovery was induced for 45 min by i.v. glucose following 30 min recording of isoelectric EEG, there was extensive recovery of tissue concentrations of DA and 5-HT but incomplete recovery of NE concentrations. Tyrosine hydroxylation rate was increased in all areas, but tryptophan hydroxylation either remained at control levels (striatum and cortex) or fell (limbic area).
It is concluded that severe hypoglycemia leads to a gross derangement of brain monoamine metabolism, which seems to include an increase in NE turnover during both the precomatose phase and the recovery phase.
Ten-year Follow-up of Subjects with Impaired Glucose Tolerance: Prevention of Diabetes by Tolbutamide and Diet Regulation
Authors: Sartor Gunnar , Scherstén Bengt , Carlström Sven , Melander Arne , Nordén Åke , Persson Gunnar 
Published: September 2013

In a diabetes detection survey carried out between 1962 and 1965, 2477 (1.1%) of 228,883 subjects had Clinistix-positive glucosuria after a carbohydrate-rich luncheon meal. Of these 2477, 578 displayed impaired tolerance to oral glucose without having manifest diabetes. From this group, 267 men were divided into five groups and subjected to the following treatments and controls: (a) diet regulation and 0.5 g tolbutamide t.i.d. (N = 49), annual oral glucose tolerance test (OGTT); (b) diet regulation and one placebo tablet t.i.d. (N = 48), annual OGTT; (c) diet regulation only (N = 50), annual OGTT; (d) no treatment (N = 61), annual OGTT; and (e) no treatment, OGTT at follow-up (N = 59 at follow-up). In addition, a control group was included comprised of men with normal OGTT (N = 52). At follow-up, 29% of those without diet regulation and medication (group e; N = 59) had developed diabetes. Of those on diet regulation, but without active medication (group b plus group c, N = 98), 13% had diabetes. No individual maintaining tolbutamide and diet regulation (N = 23) had progressed to diabetes. In this group, 80% of those later examined (N = 11) had serum tolbutamide concentrations in the therapeutic range. No individual with initially normal OGTT developed diabetes or impaired OGTT.
The findings suggest that normal oral glucose tolerance signifies little risk of progress to impaired glucose tolerance and manifest diabetes, whereas impaired glucose tolerance is associated with a high risk of progression to diabetes. In addition, it seems possible that treatment with diet regulation, in combination with tolbutamide, may prevent or postpone progression from impaired glucose tolerance to manifest diabetes.