bluuebunny/crossref_metadata_2025 huggingface dataset:
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.
Exercise-induced Fall of Blood Glucose in Insulin-treated Diabetics Unrelated to Alteration of Insulin Mobilization
Authors: Kemmer F W , Berchtold P , Berger M , Starke A , Cüppers H J , Gries F A , Zimmermann H
Published: September 2013

To investigate whether leg exercise accelerates the absorption of exogenous insulin from Its subcutaneous depot in insulin-treated diabetics, and whether the glycemie response to exercise in these patients is related to alterations in the insulin absorption process, we studied nine insulin-dependent diabetics and four normal subjects during rest and exercise. The diabetics received the regular dose of intermediate-acting insulin, reduced by 20 U, and their morning breakfast. One hour after the meal, 20 U regular insulin (Actrapid, labeled with 125I or unlabeled) was injected into the arm or the leg. Exercise (90 ± 10 W) was initiated 35 min later for three consecutive 10-min periods. In controls, no insulin was injected. Plasma glucagon and C-peptide levels were not changed during exercise, but blood ketone bodies and lactate levels increased significantly. Whether the insulin was injected into the moving or resting limb, external counting over the injection site demonstrated no exercise-induced alteration of the disappearance of 125I-radiation during the exercise period, but revealed a small postexercise enhancement of 125I disappearance only after leg injection. Determination of plasma insulin levels in four diabetics with newly insulin-treated diabetes revealed that circulating insulin had increased by 70% 30 min after the subcutaneous administration of regular insulin and had then plateaued for 45 min. Leg exercise had no additional effect on plasma insulin levels during the physical activity. In normals, exercise lowered circulating plasma insulin to a level approximately one-fifth that in diabetics. Regardless of the insulin injection site, there was an identical glycemie response to exercise, i.e., a pronounced fall of glycemia by 15% immediately and by 50% 30 min after the onset of exercise. In normals glucose homeostasis was not disturbed by exercise. This study demonstrates that moderate leg exercise does not necessarily accelerate the absorption of exogenous insulin; however, it can induce an acute and profound fall in glycemia, which presumably is due to the presence of a fixed hyperinsulinemic state in these patients rather than an alteration of the mobilization of insulin from its subcutaneous depot. Although this study investigated only a specific situation, the results indicate the possibility that exercise-induced hypoglycemia in insulin-treated diabetics is not necessarily prevented by changing the insulin injection site to nonmoving parts Of the body.
Autoantibodies to Islet Cells in Diabetes Mellitus
Authors: Kaldany Antoine
Published: September 2013

Numerous reports have confirmed the presence of islet cell antibodies in diabetic patients. These are found mostly in newly diagnosed insulin-dependent diabetic patients and in patients who have autoimmune polyendocrine disorders. Antibodies to beta cells, somatostatin, and glucagon-producing cells have been described as well. All these antibodies give strictly intracytoplasmic staining. It is therefore difficult to understand their role in the pathogenesis of pancreatic damage, the presence of another antibody is thus postulated.
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 < 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.
Glucose-Insulin Response to Oral Glucose in a Healthy Obese Population
Authors: Young Robert L , Fuchs Robert J , Woltjen Myron J , Cooperman Michael T
Published: September 2013

The characteristics of the glucose and insulin responses during the glucose tolerance test (GTT) in obese people as a group have not been established. We analyzed glucose and insulin levels during GTT in 160 healthy obese patients who averaged 42% over ideal body weight. Statistical upper limit of normal for 2-h glucose was 260 mg/dl in women and 206 mg/dl in men. Although there was a significant correlation between insulin and glucose levels in both sexes and between insulin and degree of obesity in women, r values were relatively low (r < 0.4 for all). High insulin levels and delayed peak insulin were present in the majority of patients with normal GTT and absent in many of the most obese patients. Results indicate that upper limits of normal glucose for GTT in the obese are much higher than currently accepted criteria.
Treatment of Streptozotocin-Diabetic Dogs With a Long-Acting Somatostatin Analog
Authors: Lien E L , Greenwood J , Sarantakis D
Published: September 2013

A long-acting somatostatin analog, Wy-41,747, improved glucose homeostasis in steptozotocin-diabetic dogs. In insulin-withdrawn, fasted dogs, a single 100 μg/kg s.c. injection of Wy-41,747 significantly suppressed plasma glucagon levels for 2 h (a nadir of 53 ± 8% of basal being reached at 1 h) and plasma glucose for 3 h (77 ± 5% of basal); even more potent suppression of glucagon and glucose levels was observed during experiments with 500 μ/kg of Wy-41,747. During meal studies, the combined administration of Wy-41,747 (100 μ/kg) and insulin resulted in lower postprandial glucagon and glucose levels than did the administration of insulin alone. When the somatostatin analog was given alone to fed animals, a rise in glucose occurred 4-5 h after the meal, suggesting the possibility of delayed absorption under these conditions. Improved glucose tolerance profiles followed oral administration of glucose or 14C-3-O-methyl glucose; a normal or near-normal time course of absorption was observed with diminished peak plasma glucose or 14C levels. No major malabsorption of carbohydrate occurred in the 14C-3-O-methyl glucose study, since only low levels of 14C were found in the feces of peptide-treated dogs. No undesirable gastrointestinal effects were noted during these studies. In conclusion, administration of a singlesubcutaneous dose of the long-acting somatostatin analog Wy-41,747 to streptozotocin-diabetic dogs lowered fasting plasma glucose levels and augmented insulin action in lowering postprandial glucose levels.
Effects of Dietary Fiber on Glucose Tolerance of Normal Men
Authors: Munoz Juan M , Sandstead Harold H , Jacob Robert A , Johnson Luann , Mako Mary E
Published: September 2013

26 g of dietary fiber sources—hard red spring wheat bran (HRS), soft white wheat (SWW), corn bran (CB), soy hulls (SH), freeze-dried apple powder (AP), and freeze-dried carrot powder (CP)—was fed to 15 men as part of a mixed diet. Oral glucose tolerance and one hour postprandial serum glucose were measured after one month of each fiber source and were compared with findings measured after one month of the diet without added fiber. The subjects' energy intakes and expenditures were nearly constant throughout the study. The fiber sources contained 50.8% (HRS), 44.1% (SWW), 92.1% (CB), 86.7% (SH), 25.6% (AP), and 31.0% (CP) fiber. Oral glucose tolerance improved significantly when subjects ate CB, SH, AP, and CP. Corrected insulin response at the glucose peak (CIRp) and peripheral insulin sensitivity (GTp) improved when subjects were fed CB, SH, AP, and CP. Fasting plasma glucagon and plasma glucagon responses to oral glucose were significantly lower after feeding AP or CP. Hard spring wheat bran was associated with higher fasting plasma glucagon and a similar plasma glucagon response to oral glucose compared with those of controls. Postprandial serum glucose concentrations were significantly lower when subjects were fed fiber-supplemented (CB and SH) diets than when they were fed the same diet without fiber. Effects of the dietary fiber sources on carbohydrate metabolism seemed dependent on the composition of the source. Improved oral glucose tolerance was associated with improved insulin release and peripheral insulin sensitivity and decreased plasma glucagon concentrations.
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.
Ultracytochemical Calcium Distribution in B Cells in Relation to Biphasic Glucose-stimulated Insulin Release by the Perfused Rat Pancreas
Authors: Klöppel Günter , Bommer Gerhard
Published: September 2013

Calcium distribution in B cells of the isolated perfused rat pancreas was examined by the pyroantimonate precipitation technique in relation to the insulin secretory pattern of the perfused pancreas in response to 3 mM or 20 mM D-glucose or 20 mM D-glucose in calcium-depleted ethylene glycol tetra-acetic acid (EGTA) medium. Perfusion fixation after various time intervals from 3 to 30 min allowed appropriate relation to. secretory phases. Qualitative and quantitative evaluation of the precipitation patterns revealed a significant increase in cell membrane associated precipitates after 3–5 min of perfusion with 20 mM glucose compared with the results after perfusion with 3 mM glucose. After 10–30 min of perfusion with 20 mM glucose there was an additional significant increase in precipitates located in the cytoplasm and the halos of the secretory granules. Perfusion with 20 mM glucose in calcium-deprived EGTA medium strongly reduced the number of precipitates within the B cells. The resujts suggest that cell membrane associated calcium may be involved in exocytosis, and by its sudden increase may trigger the first phase of insulin secretion. The calcium stores in the cytoplasm and the granules may be of importance for long-term regulation of insulin release.
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 < 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.
Epidemiologic Survey of Juvenile-Onset Diabetes in Montreal
Authors: West R , Belmonte M M , Colle E , Crepeau M P , Wilkins J , Poirier R
Published: September 2013

Active search of hospital records was used to survey insulin-dependent juvenile-onset diabetics younger than 17 years resident in General Montreal at the time of onset of symptoms during a seven-year period (1971–1977). A mean annual incidence of 8.8/100,000 was found with variation from year to year (5.8 to 10.3). Eighty percent were five years of age or more at time of diagnosis, and the increase with advancing age was similar to that seen in other studies including the somewhat earlier increase in incidence among females. Seasonal peaks were noted in some but not all years and were more marked in years of high incidence and among males. More cases occurred in areas of high socioeconomic level as measured by average family income. The estimated incidence among siblings of diabetics is 15 times the incidence in the general population. Ten percent of diabetics have a first degree relative who is insulin dependent.
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
Venezuelan Encephalitis Virus–induced Alterations in Carbohydrate Metabolism in Genetically Diabetic Mice
Authors: Rayfield Elliot J , Seto Yoshiko , Goldberg Steven L , Schulman Robert H , Walker George F
Published: September 2013

We previously reported in this journal that the TC-83-vaccine strain of Venezuelan encephalitis (VE) virus results in a sustained diminution of glucose-stimulated insulin release in golden Syrian hamsters, persisting as long as 90 days after viral infection. This study was designed to examine the metabolic and pathologic consequences of TC-83 VE virus infection in C57 BL/Ks mice (+/+) and in genetic variants of this strain homozygous (db/db) and heterozygous (db/+) for the diabetic gene, db. Five-week-old mice of each genetic variant were inoculated subcutaneously, in groups of 18, with 100,000 plaque-forming units (PFU) of TC-83 that had not been passaged in chick embryo cells or with diluent (control mice). The clinical course in all three groups of mice following VE inoculation was mild, with a 5 to 10% mortality. By light microscopy, control +/+, TC-83 VE-infected +/+, control db/+, and TC-83 VE-infected db/+ pancreases manifested no appreciable difference in morphology. Uninfected db/db mice showed typical changes, including a definite decrease in the number of aldehyde fuchsin-staining granules in beta cells. TC-83 VE-infected db/db mice exhibited a profound decrease in pancreatic beta cell granulation on aldehyde fuchsin staining. After TC-83 VE inoculation, the most striking alterations in carbohydrate metabolism occurred in db/db mice, which showed further worsening of glucose tolerance 120 min after intraperitoneal glucose as well as significantly decreased basal and glucose-stimulated immunoreactive insulin (IRI) levels. After TC-83 VE infection, pancreatic IRI content was not decreased in +/+ or db/+ mice but was virtually absent in db/db mice. The data support the ability of TC-83 VE to inhibit glucose-stimulated IRI release in three genetic variants of C57 BL/Ks mice. In addition, this model demonstrates the heightened susceptibility of the remaining diabetic beta cells in the db/db mice to subsequent infection with a pancreatropic virus.
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.
Effects of Sodium DL-Lactate on Insulin Secretion in Anesthetized Dogs
Authors: Federspil G , Zaccaria M , Pedrazzoli S , Zago E , DePalo C , Scandellari C
Published: September 2013

The effect of sodium DL-lactate administration on insulin release in anesthetized dogs has been studied. Eleven mongrel dogs were infused with sodium DL-lactate for 20 min at the rate of 20 mg/kg · min. Lactate infusion produced simultaneous increases in blood glucose and plasma insulin levels in the pancreatico-duodenal vein. To determine whether lactate stimulated insulin secretion directly, sodium DL-lactate was rapidly injected into the pancreatic artery of six dogs; this pulse induced a significant increase in insulin release from pancreatic B-cells, even in the absence of a measurable change in blood glucose. Diazoxide, when infused in six dogs, blocked lactate-induced insulin secretion. These findings indicate that lactate, as do other circulating energy fuels, may play a role in the physiologic control of insulin secretion.
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.
Diabetic Neuropathy in the Mutant Mouse [C57BL/ks(db/db)]: A Morphometric Study
Authors: Robertson David M , Sima Anders A F
Published: September 2013

Detailed studies of peripheral nerves were undertaken in the mutant diabetic mouse of the [C57BL/ks(db/db)] strain using electrophysiologic and morphometric techniques.

Electrophysiologic studies showed severely impaired motor nerve conduction velocity (MNCV), which developed promptly during the early phase of the diabetic syndrome. Morphometric changes occurred first after 20 wk of diabetes in both myelinated and unmyelinated fibers. There were both loss and shrinkage of myelinated fibers, most pronounced in the sural nerve and the ventral root. Changes appeared late in the dorsal root and in the peroneal and vagus nerves. Unmyelinated fibers showed both shrinkage and loss of axons, presumably involving sympathetic and afferent somatic fibers.

Teased fiber studies and calculations of axon-myelin ratios confirmed our earlier suggestion18 that the neuropathy is primarily axonal in nature.

The temporal discrepancy between functional and structural impairments in the present model strongly suggests a metabolic cause of the early neuropathy. This was further supported by the positive effect of insulin treatment on MNCV during the early phase of diabetes, whereas, during the late phase, treatment failed to show any effect.
Overnight Basal Insulin Requirements in Fasting Insulin-dependent Diabetics
Authors: Clarke William L , Haymond Morey W , Santiago Julio V
Published: September 2013

Overnight basal insulin requirements to maintain eugycemia were determined in six insulin-requiring diabetic subjects using a feedback-controlled (closed loop) insulin infusion system. Mean hourly insulin infusion rates, required to maintain plasma glucose concentrations at approximately 100 mg/dl, were remarkably stable from 2400 h to 0600 h; however, a twofold to threefold increase in insulin requirements was observed in each subject between 0600 h and 0900 h. This increase in amount of basal insulin required was not associated with increases in plasma glucagon or growth hormone concentrations, but occurred simultaneously with normal diurnal increases in plasma cortisol. These findings suggest that normal diurnal increases in plasma cortisol, independent of the content of the morning meal, contribute to the increased amount of morning insulin required in diabetic subjects. Programs designed for optimal open loop insulin delivery may benefit from modifications designed to coincide with this increase in amount of basal insulin required in the early morning.
The Effect of Aprotinin on the Absorption of Subcutaneously Injected Regular Insulin in Normal Subjects
Authors: Berger Michael , Cüppers Hans J , Halban Philippe A , Offord Robin E
Published: September 2013

The effect of aprotinin on the absorption of regular insulin was assessed in normal man. Ten units of Actrapid insulin were subcutaneously injected together with 1.4 mg aprotinin (i.e., 0.5 ml of Trasylol) or an equivalent volume of physiologic saline (controls) into the thighs of overnight-fasted normal subjects. Aprotinin caused an increase in the rate of insulin entry into the circulation; the absolute amount of insulin that was detected in the circulation during the course of the experiment was also higher. In addition, the onset of the hypoglycemic action of exogenous insulin was significantly accelerated when insulin was administered together with aprotinin. These data suggest that aprotinin increases the absorption rate of subcutaneously injected insulin from its depot into the circulation, possibly by an inhibition of the local degradation of exogenous insulin at the injection site.
Effects of Oxygen, Temperature, and Time of Culture on the Survival of Mouse Thyroid and Pancreas Allografts
Authors: Talmage David W
Published: September 2013

Organ culture of mouse thyroid for 3 wk resulted in survival of allografts. The time in culture has been reduced to 4 days by increasing the oxygen pressure to 1300 mm and to 1 day by culture at 1700 mm and pretreatment of the donor with hydrocortisone. Of 25 BALB/c thyroid grafts cultured for 24 h at 1700 mm O2 and 37°C, 24 maintained function for 3 wk in C57B1/6 mouse recipients. Culture at room temperature (22–26°C) for 1 day was less effective in preventing rejection, and increasing the oxygen tension was not effective. These culture conditions have been applied to mouse pancreas, and survival of the organ was judged by morphologic and histochemical analysis. Lowering the temperature to 22°C resulted in survival for twice as long as at 37°C. This was true for partial O2 pressure of 600 mm in which beta cell granulation persisted for 4 days at 22° and only two days at 37°C. At a higher O2 pressure (1300 mm), beta granulation persisted for 2 days at 22°C and only 1 day at 37°C. Macrophages cultured in 600 mm O2 survived more than 4 days at 37°C and 30°C, but less than 2 days at 26°C. Since macrophages may play a role in rejection of allografts, culture at 22°C and alteration of O2 tension may select the desired cell types and enhance allograft survival.
Suppression of Rejection of Allogeneic Islet Tissue in the Rat
Authors: Morris P J , Finch D R , Garvey J F , Poole M D , Millard P R
Published: September 2013

A variety of immunosuppressive agents was used to prevent rejection of allografts of isolated rat islets of Langerhans injected into the portal vein or spleen, of fetal pancreases placed beneath the kidney capsule, or of vascularized hemipancreases. The agents included antilymphocytic serum (ALS), cyclophosphamide, Cyclosporin A, azathioprine, prednisolone, and donor-specific antiserum. Prolonged tissue culture of fetal pancreas and implantation of xenogeneic neonatal rabbit pancreases in Nucleopore bags were also carried out with the aim of suppressing rejection. In the face of a strong histocompatibility barrier, (DA x Lewis) F1 to Lewis, neither azathioprine nor prednisolone prolonged islet survival, whereas cyclo-phosphamide and Cyclosporin A prolonged survival by several days. ALS was an effective agent, prolonging islet survival by 26–50 days. Passive enhancement with donor-specific antiserum was modestly effective in DA to Lewis, but much more effective in the heterozygous [(DA x Lewis) F1 to Lewis or DA] combination. Survival of fetal pancreas was most prolonged by ALS, especially (DA x Lewis) F1 to Lewis, with a median survival time of 45 days. In contrast, Cyclosporin A, passive enhancement, and culture for 21 days were ineffective. Cyclosporin A was significantly effective only in prolonging function of the vascularized pancreas for up to 28 days.
Specific Immunosuppression for Fetal Pancreas Allografts in Rats
Authors: Mullen Yoko
Published: September 2013

This paper is a review of our current work, evaluating the effectiveness of specific immunosuppressive treatment for prolongation of rat fetal pancreas allo-graft survival. Passively given antidonor antibodies that markedly prolong kidney and heart allograft survival had little effect on allogeneic whole fetal pancreases grafted onto the subcapsular space of the kidney. In contrast, the combination of pretreatment with donor antigen followed by procarbazine hydrochloride (PCH) and antilymphocyte serum (ALS) had a marked effect on fetal pancreas survival. The efficacy of the treatment increased when allograft incompatibility was smaller. Thus, a single injection of both PCH and ALS induced lifelong unresponsiveness to Lewis (LEW) fetal pancreases in 80% of Fischer (F344) recipients across this weak, non-H-1 incompatibility. These allografts were fully functional and completely reversed the host diabetes. Specificity of unresponsiveness was confirmed by prolonged survival of donor-type skin but acute rejection of third-party skin allografts on these recipients. Fetal pancreases surviving more than 300 days in an allogeneic recipient were fully capable of eliciting a rejection reaction in a secondary recipient. When the immunogenetic barrier was greater, stronger immunosuppressive treatment was necessary. In intermediate incompatibility, F344 to LEW, and strong H-1 incompatibility, (LEW x BUF) F1 to LEW, a total of 8–10 injections of PCH and ALS given on alternate days was needed to extend pancreas survivals from 14 days, characteristic of the controls, to 50–70 days with substantial improvement of the host diabetes. Additional approaches for increasing the efficacy of immunosuppressive treatment are discussed.
Immunosuppression and Organ Transplantation Tolerance Using Total Lymphoid Irradiation
Authors: Slavin Shimon , Strober Samuel , Fuks Zvi , Kaplan Henry S
Published: September 2013

Total lymphoid irradiation (TLI) is a method which delivers irradiation daily in fractionated doses (200 rads) to lymphoid organs while shielding bones, lungs, and the majority of the gastrointestinal tract. TLI is lym-phocytopenic in mice, rats, dogs, and humans, and both T cells and B cells are eliminated from the circulation. During the recovery phase in mice, B cells appear before Thy 1.2-bearing T cells, and TL-positive T cells are abundant in the spleen and lymph nodes. These T cells exhibit nonspecific suppressive activity on antibody production and cell-mediated immune responses. TLI permits establishment of specific and long-lasting tolerance to alloantigens. Permanent acceptance of allogeneic bone marrow cells without graft-versus-host disease was achieved in rats and dogs across major histocompatibility barriers. Recipients were tolerant to allografts of skin, hearts, and kidney from animals syngeneic to marrow donors or to organs from the marrow donor. This approach may be suitable for pancreas transplantation in diabetes.
Segmental Pancreatic Transplantation with Duct Ligation or Drainage to a Jejunal Roux-en-Y Loop in Nonuremic Diabetic Patients
Authors: Groth C G , Lundgren G , Gunnarsson R , Arner P , Berg B , Östman J
Published: September 2013

The results of seven segmental pancreas transplantations in diabetic patients, using a jejunal Roux-en-Y loop for drainage of digestive enzymes, are presented. An initial case with pancreatic duct ligation is also included. The patients ranged in age from 30 to 45 yr, with duration of diabetes from 8 to 24 yr, and were incapacitated but not uremic. Immunosuppression was attempted with azathioprine, prednisone, and antilymphocyte globulin, and, in one patient, thoracic duct drainage was added. The pancreas tolerated at least 16 min of warm ischemia and at least 4 h of cold storage; flushing with a balanced electrolyte solution was optimal. Six of the grafts provided control of blood glucose for 7–51 days, and, in one patient, an intravenous glucose tolerance test was normal at 7 and 21 days. Five of the grafts failed due to rejection 7–51 days after transplantation, and one was removed at 14 days, while still functioning, due to bleeding. In one case, early detection of rejection by a rise in postprandial blood glucose was treated and reversed by corticosteroid administration. Two failed in the immediate postoperative period from vascular thrombosis. Drainage of pancreatic secretions from a fistula was a Common problem.
Evaluating the Benefits of Human Islet Transplantation
Authors: Goetz Frederick C
Published: September 2013

For important ethical and practical reasons, present human trials of islet transplantation in diabetes are restricted to subjects already committed to immunosup-pression by the need for kidney transplantation. Following the morphology of the transplanted kidney for possible reversal of diabetes-related changes may be the most valuable technique for demonstrating benefit from the restoration of islet function. Amelioration of diabetic vascular disease is the compelling reason for efforts to achieve effective islet transplantation.
Immunologic Problems in Islet Transplantation
Authors: Barker Clyde F , Naji Ali , Silvers Willys K
Published: September 2013

Rapid rejection of islet allografts is due to both cellular and antibody mechanisms. Isolated islets transplanted intraportally across a major histocompatibility complex (MHC) barrier in rats are rejected in 3–5 days. However, with MHC identity, the median survival time can be as long as 30.5 days. In mice, isolated islets transplanted between H-2-compatible strains survive no more than 1 wk, only a few days more than with an H-2-incompatible cross. In addition, in certain strains of rats and mice, islet isografts from male donors are rejected by female recipients. Fetal pancreases transplanted beneath the kidney capsule (Lewis to Fisher) are rapidly rejected by 4 days, although long-established grafts of fetal pancreas are not vulnerable to rejection in contrast to adult islets. Minimizing histoincompatibility has been unsuccessful in overcoming rejection because of the universal vulnerability of transplanted islets, and attempts to minimize immunogenicity by use of fetal tissue have not prevented rejection; however, culture of donor tissue may prove helpful in reducing immunogenicity. Transplantation of islet tissue into immunologically privileged sites has not resulted in reliable reversal of diabetes. immunosuppression by pharmacologie agents such as cyclophosphamide, azathioprine, and corticosteroids was of minor effectiveness, but antilymphocytic serum was quite effective in rodents, even on xeno-grafts when the injections were continued. Immunologic tolerance produced at birth by donor lymphopoietic cells permits later engraftment of isolated donor islets or whole pancreas. However, enhancement by anti-donor antibody has not been greatly effective in protecting islets against rejection. The possibility that autoimmunity to islet tissue might interfere with the function of transplanted islets was tested in three types of possible autoimmunity: (1) repeated small doses of streptozotocin, (2) encephalomyocarditis virus, and (3) “BB” rats. In all three cases, transplanted islets were effective in reversing experimental diabetes.
Resistance to Insulin but Not to Glucagon in Lean Human Hypertriglyceridemics
Authors: Steiner George , Morita Soichiro , Vranic Mladen
Published: September 2013

Glucose kinetics were studied in a group of nonobese humans with endogenous hypertriglyceridemia before, during, and after an infusion of graded increments of glucagon. The tracer methods employed permitted glucose turnover to be quantitated under non-steady state conditions. The rates of glucose production, disappearance, and fractional disappearance were related to the range of glucagon and insulin levels in each individual. The findings in hypertriglyceridemics were compared with those in lean normals of the same relative body weight and the same extracellular fluid volume per kg, as reflected by their apparent glucose space. Glucose production and serum insulin were each positively correlated to plasma glucagon concentrations in both hypertriglyceridemics and normals. Thus, with respect to these parameters, the hypertriglyceridemics were not resistant to glucagon. During the glucagon infusion, the glucose concentration rose more in the hypertriglyceridemics than in the normals because of a reduced total rate of glucose disappearance in the hypertriglyceridemics. In the normals the fractional disappearance rate of glucose was positively related to serum levels of insulin, whereas in the hypertriglyceridemics it was lower than normal and did not change in relation to insulin concentration. This demonstrated that, at least with respect to glucose utilization, lean hypertriglyceridemics can be resistant to insulin even in the absence of obesity.