bluuebunny/crossref_metadata_2025 huggingface dataset:
Diminution of Bone Mass in Childhood Diabetes
Authors: Rosenbloom Arlan L , Lezotte Dennis C , Weber F Thomas , Gudat Jack , Heller Debbie R , Weber Mary Lou , Klein Sally , Kennedy Barbara B
Published: September 2013

Photon absorption measurements of forearm bone density in 196 insulin-dependent patients, age 6-26 years, were compared with findings in 124 controls. Expected density, gm. Ca/cm.2 bone width (M/W), was calculated from regressions of M/W on ulnar length for white and black male and female controls. There were no significant correlations between M/W differences from expected and serum Ca, Mg, P, or alkaline phosphatase levels, estimated physical activity level, insulin dosage, or the presence of joint contracture. White females averaged 8.2 per cent (±1 S.E.M.) loss of M/W, as against white male average loss of 4.7 per cent ± 1 and black female loss of 2 per cent ± 2 (p < 0.001); the black male population was too small for separate analysis. M/W loss > 10 per cent was seen in 29 per cent of white males, 19 per cent of blacks, and 48 per cent of white females (p < 0.02). When the groups were further divided into those with duration of diabetes ≤ five years and those with duration > five years, significant reduction in M/W average loss over time was seen with white females (10.6 per cent ± 1.2 to 3.7 per cent ± 1.5, p < 0.0001). Expression of this defect in bone mineralization is controlled by race and sex acting independently of each other.
Diabetes Mellitus in an Urbanized, Isolated Polynesian Population: The Funafuti Survey
Authors: Zimmet Paul , Seluka Alesana , Collins James , Currie Philip , Wicking Julie , DeBoer William
Published: September 2013

An epidemiologic study of diabetes in the urbanized Polynesian population of Funafuti has established a prevalence of 8 per cent in subjects aged 10 years and over. Of these, only 0.9 per cent were known diabetics, and the remainder were diagnosed on the basis of a plasma glucose level of at least 160 mg/lOO ml. two hours after a 75 gm. glucose load. A further 5.9 per cent had borderline diabetes as judged by a two-hour postload plasma glucose of 140-159 mg./ 100 ml. In those aged 20 years and over, the prevalence of diabetes was 10.1 per cent, similar to that reported in other accuHurated Polynesian groups.

The prevalence of both borderline diabetes and frank diabetes was twice as high in the females as in males. This difference appeared to be related to the greater degree of obesity in the females, but the prevalence was not related to parity. The increase in frequency of diabetes among these islanders coincides with a change of traditional island life style to that of urbanized Western populations. The results suggest that there may be 10 times the actual number of known diabetics in some Pacific populations.
Subcellular Localization of the Alterations in Phosphatidylinositol Metabolism Following Glucose-induced Insulin Release from Rat Pancreatic Islets
Authors: Clements Rex S , Rhoten William B , Starnes Willard R
Published: September 2013

The subcellular localization of the incorporation of 2-(3H)-myoinositol into Upids has been studied in isolated pancreatic islets of the rat. The recovery of lipid-bound myoinositol increased with time in the nuclear, mitochondriai, microsomal, and secretory granule fractions. The utilization of a nitration technique for the more complete separation of mitochondriai and secretory granule elements permitted us to show that the recovery of lipld-bound 2-(3H)-myoinositol increased most rapidly in the secretory granule fraction. A 30-minute exposure of prelabeled islets to a stimulatory concentration of D-glucose (3.0 mg./ml.) resulted in a statistically significant decrease in the amount of lipid-bound 2-(3H)-myoinositol that was recovered from the secretory granule fraction (p < 0.001). In contrast, exposure of islets to the elevated glucose concentration had no statistically significant effect on the recovery of Upid-bound radioactivity from other subcellular fractions. Since the majority of lipid-bound radioactivity associated with the secretory granule fraction could be recovered with the presumptive secretory granule membranes, these data suggest that the hydrolysis of phosphatidylinositol that accompanies glucose-induced insulin secretion from the rat pancreatic islet may be localized to the beta granule and, in particular, to it's limiting membrane.
Insulin and Brain Metabolism: Absence of Direct Action of Insulin on K+ and Na+ Transport in Normal Rabbit Brain
Authors: Thurston Jean Holowach , Hauhart Richard E , Dirgo John A , McDougal David B
Published: September 2013

In fed, unanesthetized rabbits, regular zinc insulin, 50 U./kg. intravenously, decreased plasma glucose levels 52 per cent, p = 0.002, 35 minutes after injection. In 15-hour-fasted, unanesthetized animals, the same dose of insulin decreased plasma glucose levels 68 per cent, p <0.001. Plasma K+ concentration was not affected by insulin injection in the fed animals; in fasted rabbits, plasma K+ levels fell 26 per cent, p = 0.006. Despite this unequivocal evidence of insulin action in both sets of animals, there was no change In the K+, Na+, or H2O content in the brains of the same animals 35 minutes after insulin injection.

These results, which give no evidence of a direct effect of insulin on electrolyte transport in brain, are in sharp contrast with those found in anesthetized rabbits, which suggested that insulin affects brain potassium and water content before any change in plasma glucose occurs.
Bone Mass and Bone Density in Maturity-type Diabetics Measured by the 125I Photon-absorption Technique
Authors: Leeuw I De , Abs R
Published: September 2013

Bone mineral content (BMC) and bone density (BMC/W) of the radius were measured in 138 maturity-type diabetics with the Norland-Cameron bone mineral analyzer and compared with the results of age- and sex-matched controls. In some age groups the mean cortical and trabecular bone mass and density seemed to be significantly higher among diabetic patients, especially in those treated with oral antidiabetic agents.

Individual analysis reveals the existence of two distinct diabetic populations—a small group with a tendency to bone loss and a large group with bone gain—when compared with nondiabetic subjects. The higher body weight in the second group can be the origin of this difference.

A survey of the already published papers on this subject shows that comparison of the results is impossible because of the heterogeneity in the methodology of material and methods used by the different authors.
Autonomic Neuropathy and Painless Myocardial Infarction in Diabetic Patients: Histologic Evidence of Their Relationship
Authors: Faerman Isaac , Faccio Enrique , Milei José , Nuñez Rodolfo , Jadzinsky Mauricio , Fox Dora , Rapaport Mauricio
Published: September 2013

Myocardial infarction is considered the prime cause of death among adult diabetic patients. In a great number of cases, during myocardial infarction the patients don't feel pain or it is atypical. Diagnosis can be neglected, and mortality increases.

In search of an explanation for the absence of pain in these patients, the authors studied the autonomie nerve fibers of the heart muscle with argentic and combined techniques, looking for lesions in the sympathetic or parasympathetic nerve fibers that conduct pain.

In the five cases of painless myocardial infarction studied, the nerve fibers showed typical lesions of diabetic neuropathy: beaded thickenings, spindle-shaped thickenings, fragmentation of fibers, and diminution of the number of fibers in the nerves.

The patients in the control group (five diabetics with painful infarction, five diabetics without infarction, five nondiabetics with painful infarction, and five nondiabetics without infarction) had no lesions.

These facts led us to assume that the absence of pain in diabetics with myocardial infarction could be due to a lesion of the afferent nerves that conduct pain.
Postprandial Plasma-glucose and -insulin Responses to Different Complex Carbohydrates
Authors: Crapo Phyllis A , Reaven Gerald , Olefsky Jerrold
Published: September 2013

We have studied the effects of dextrose, rice, potato, corn, and bread on postprandial plasma glucose and insulin responses in 16 subjects. All carbohydrate loads were calculated to contain 50 gm. of glucose. The data demonstrate (1) that dextrose and potato elicited similar plasma glucose responses whereas rice, corn, and bread elicited lower responses; (2) similarly, dextrose and potato elicited similar and greater plasma insulin responses than rice and corn, with the response to bread being intermediate; (3) when the study group was divided in half, on the basis of each subject's one-hour plasma glucose response to dextrose, the differences in the plasma glucose and insulin responses were greater in the subjects with the highest glucose response to dextrose than in the low responders. In conclusion, there is a range of plasma-glucose and insulin responses to different complex carbohydrates, with rice and corn producing the lowest response curves. Furthermore, these differences are accentuated in patients with reduced glucose tolerance.
An Islet Cell Carcinoma Containing Glucagon and Insulin: Chronic Glucagon Excess and Glucose Homeostasis
Authors: Boden Guenther , Owen Oliver E , Rezvani Iraj , Elfenbein Bruce I , Quickel Kenneth E
Published: September 2013

Described here is a patient who had an islet cell carcinoma containing both glucagon (glucagonoma) and insulin (insulinoma). Complete removal of the tumor was possible. Immunoreactive glucagon (IRG) could be extracted from all parts of the tumor (approximately 50 μg./gm.) and was shown to be fully bioactive. Immunoreactive insulin (IRI) could be extracted only from one section of the tumor (approximately 30 μg/gm.). The clinical and biochemical manifestations of the disease were dermatitis, diabetes, weight loss, anemia, hypoaminoacidemia, and hyperketonemia. The diabetes was characterized by low or normal fasting blood glucose concentrations and by unpaired glucose tolerance (Kg = 0.4). After complete removal of the tumor, the dermatitis cleared, the catabolic state changed into an anabolic state, blood amino acid concentrations increased, and blood ketone-body concentrations decreased. Fasting blood glucose concentrations, however, rose above 200 mg./dl., and glucose tolerance declined further (Kg = 0.15). Hourly blood sampling for 24 hours, intravenous and oral glucose tolerance tests, intravenous arginine and tolbutamide tolerance tests with serial determinations of IRG, IRI, and blood glucose were performed preoperatively and again two weeks and two months postoperatively. The results of these studies demonstrated marked abnormalities in the stimulation and suppression of glucagon and insulin release. In addition, they failed to demonstrate a glycemic effect on the chronically elevated glucagon concentrations in this patient, while identifying insulin as the dominant factor determining blood glucose homeostasis.
An Audio Urine-glucose Analyzer for Blind Diabetics
Authors: May Jonathan , Inman Stanford , Wilcox David E , Beckett Ronald S
Published: September 2013

At the instigation of one of the authors (J. M.)–a young man whose blindness is due to diabetic retinopathy–a urine-glucose analyzer was designed and constructed. Its purpose and function enable him to test his urine himself (free of dependence on others for this service) and, thereby, he can then determine and administer his doses of insulin. He and other young blind diabetics may value the degree of freedom from dependence on others tha the analyzer provides and feel it helps them to be able to work and care for themselves.

A description of the instrument, instructions for its use, and a summary of about 20 months' experience with it are submitted.
Use of Dexamethasone in Treatment of Insulin Lipoatrophy
Authors: Kumar Dinesh , Miller Leona V , Mehtalia Suresh D
Published: September 2013

To treat insulin lipoatrophy, small amounts of dexamethasone (4 micrograms/unit) were added to insulin injections in nine patients. Six cases showed significant improvement of dexamethasone-treated sites over that of control sites in six months. With the continued use of dexamethasone-containing insulin, they remained mostly free of atrophie areas during the follow-up period of over two years. Our experience suggests the usefulness of this therapy.
Influence of Streptozotocin Diabetes on Intestinal 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity in the Rat
Authors: Nakayama Hidetaka , Nakagawa Shoichi
Published: September 2013

Studies were undertaken to examine cholesterogenesis in the intestine of streptozotocin-diabetic rats by measuring incorporation of [214C] acetate into cholesterol and 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA reductase, EC 1.1.1.34) activity. In these diabetic rats, the intestinal mucosal weight and food consumption were markedly high. The incorporation of [214 C] acetate into cholesterol was significantly increased in all diabetic intestinal segments. However, the rates of production of fatty acids and carbon dioxide were not affected. Hepatic H MG-CoA reductase activities were markedly reduced during both the diurnal high and low periods in these diabetic rats, and there was no diurnal variation. In contrast, the specific activities of this enzyme in jejunal crypt cells during both the diurnal high and low periods were significantly higher in these diabetic rats without loss of diurnal variation. Total reductase activity per segment of intestine in jejunal and ileal mucosa (villi + crypt cells) was increased in these diabetic rats. Control rats had higher total and specific activity of ileal mucosal (villi + crypt cells) reductase than of jejunal mucosal reductase during the diurnal high period. The jejunal-ileal gradient in reductase activity and the incorporation of [214 C] acetate into cholesterol did not change significantly with streptozotocin-diabetic rats. The results indicate that in streptozotocin-diabetic rats, hepatic cholesterogenesis decreases but intestinal synthesis increases.
Monozygotic Triplets with Discordance for Diabetes Mellitus and Diabetic Microangiopathy
Authors: Ganda Om P , Soeldner J Stuart , Gleason Ray E , Smith Theresa M , Kilo Charles , Williamson Joseph R
Published: September 2013

A set of monozygotic triplets (PE. K., P. K., S. K.) has been studied. There is no diabetes in first-degree relatives. PE. K. developed insulin-requiring (60 U. NPH) diabetes at the age of 13 years. Over a period of 11 years since that time, numerous studies of insulin and growth-hormone secretion were performed on P. K. and S. K., including multiple oral glucose tolerance tests (OGTTs), cortisone-primed oral glucose tolerance tests (C-OGTTs), intravenous glucose tolerance tests (IVGTTs), and intravenous tolbutamide tests (IVTTs). The results of each test were compared with age- and sex-matched control subjects. P. K. developed insulin-requiring (56 U. NPH) diabetes after remaining discordant for eight years. Glucose, insulin, and growth-hormone responses during all tests were normal except during the IVGTT performed four months prior to the onset of diabetes. This last IVGTT revealed a glucose disappearance rate of 0.98 per cent per minute, and the slope of the regression line of serum-insulin response (IRI) on blood glucose (BG) was markedly decreased to 0.005 μU./ml. IRI/mg./dl. BG (controls, 0.340 ± 0.04; mean ± S. E. M.). The insulin responses in P.K. and S. K. were similar during all OGTTs, C-OGTTs, and IVTTs. S. K. has continued to maintain normal glucose tolerance and normal insulin and growth-hormone responses during all tests.

The histocompatibility antigen studies have revealed HLA-A2, AW24, BW15, and BW40 phenotype in these monozygotic triplets.

Muscle capillary basement membranes of the nondiabetic triplet were normal, whereas both diabetic triplets manifested evidence of capillary basement membrane thickening.

The clinical and biochemical profiles in these triplets and the capillary basement membrane data lend strong credence to the role of “nongenetic” determinants in the development of “genetic” diabetes as well as diabetic microangiopathy in juvenile-onset-type diabetes.
Peripheral and Autonomic Nerve Function in Newly Diagnosed Diabetes Mellitus
Authors: Fraser D M , Campbell I W , Ewing D J , Murray A , Neilson J M M , Clarke B F
Published: September 2013

Peripheral and autonomic nerve function was assessed in 10 newly diagnosed male diabetics (six insulin-treated and four sulfonylureatreated) with repeated observations over the subsequent six months. There was significant impairment of motor-conduction velocity in the common peroneal nerve at diagnosis in both treatment groups, with improvement following treatment in only the insulin-treated patients.

In contrast, although the blood glucose level fell in both groups, the mean level was significantly lower in the sulfonyhireatreated patients at two months and at each subsequent visit.

In the autonomic function tests significant abnormality was found in the electrocardiographic R-R-interval (beat-to-beat) variation in resting heart rate in two of the insulin-treated patients and all of the sulfonylurea-treated group, with improvement in only one of the latter. One patient in the sulfonylurea-treated group also showed an abnormal response to the Valsalva maneuver (expressed as the Valsalva ratio), and this remained abnormal throughout the period of study. All other patients had normal responses to the Valsalva maneuver and sustained handgrip test. None of the patients had postural hypotension. Abnormalities in autonomic nerve function in diabetics at diagnosis have not been previously reported.
Effect of Fasting and Streptozotocin in the Obese-hyperglycemic (ob/ob) Mouse: Apparent Lack of a Direct Relationship Between Insulin Binding and Insulin Effects
Authors: Marchand Yannick Le , Loten Ernest G , Assimacopoulos-Jeannet Françoise , Förgue Marie-Elisabeth , Freychet Pierre , Jeanrenaud Bernard
Published: September 2013

The decrease of insulin binding to plasma membranes of liver, adipose, and muscle tissues observed in obese-hyperglycemic (ob/ob) mice was reversed towards normal by prolonged fasting or streptozotocin treatment. The extent of mis reversal was related to that of the decrease in hyperinsulinemia of the obese mice. In contrast, binding of glucagon to liver plasma membranes was little influenced by fasting or streptozotocin treatment of obese animals. The relationship between insulin binding and metabolic effects of the hormone did not appear to be identical in all tissues. In muscle, insulin binding and insulin effect on glucose uptake and metabolism changed in parallel—i.e., when binding increased, tissue sensitivity to the hormone increased. In the liver, the increase in insulin binding that followed fasting or streptozotocin treatment was not accompanied by any detectable metabolic effect of insulin on hepatic metabolism. A similar situation appeared to prevail in adipose tissue. The varying relationships observed between the state of insulin binding to membranes and the target tissue responsiveness to the hormone probably reflect the multiplicity of the factors operative hi these processes and help us to understand why the over-all obese-hyperglycemic syndrome of ob/ob mice cannot be improved simply by decreasing endogenous hyperinsulinemia.
HLA Antigens in Japanese Patients with Diabetes Mellitus
Authors: Nakao Yoshinobu , Fukunishi Takanobu , Koide Misako , Akasawa Kazuyoshi , Ikeda Masaki , Yahata Mikio , Imura Hiroo
Published: September 2013

Lymphocytes of 84 Japanese patients with diabetes mellitus and 150 normal controls were tested for HLA antigens by the microcytotoxicity test. HLA-B12 was found in 37.5 per cent of 32 patients with juvenile-onset diabetes mellitus, 13.5 per cent of 52 patients with late-onset diabetes, and 9.3 per cent of 150 normal controls. In the insulin-dependent juvenile form, HLA-B12 was associated with the disease more frequently and at a significant level (p<0.0005). In Japanese patients with juvenile-onset insulin-dependent diabetes mellitus the association is with HLA-B12, not with HLA-B8 and BW15, as in Caucasian patients. There was no significant increase of HLA-B12 in patients with insulin-independent diabetes mellitus.
Effects of Experimental Diabetes and Genetic Obesity on Regional Blood Flow in the Rat
Authors: Lucas Paul D , Foy John M
Published: September 2013

Blood flow through various tissues of streptozotocin- and alloxan-diabetic and genetically obese rats was compared with that of controls by a radloisotopically labeled microsphere technique. Total cardiac output per unit body weight was unchanged in the diabetic groups but decreased in the obese animais. The proportion of cardiac output received by the kidney and organs of the gastrointestinal tract was increased in the diabetic animals. Tissue hyperplasia appeared to be largely responsible. Blood flow per unit weight was markedly increased in the fat tissue of diabetic rats but was reduced in that of the obese rats, indicating a positive relationship between fat mobilization and blood flow. Blood flow in the hindUmbs, tail, skin, and spleen were all reduced in at least one diabetic group. Most of the changes observed appeared to progress with the duration of diabetes. Possible hormonal and metabolic causes are discussed. Some of the experimental changes observed may form useful models for diabetic vasculopathy.
Alteration of Islet Cell Populations in Spontaneously Diabetic Mice
Authors: Baetens D , Stefan Y , Ravazzola M , Malaisse-Lagae F , Coleman D L , Orci L
Published: September 2013

Endocrine-cell populations in the islets of Langerhans of mutant mice with a severe hypoinsulinemic diabetes (obiob or dbldb on the C57BL/KsJ background) or with a mild hyperinsulinemic diabetes (ob/ob or db/db on the C57BL/6J background) were studied quantitatively by immunofluorescence and morphometry. In severely diabetic mice, islets presented a reduced proportion of insulin-containing cells buf increased glucagon-, somatostatin-, and pancreatic polypeptide (PP)-containing cells, as compared with islets of control (+/+) mice. An inverse change was observed in islets of mildly diabetic mice: islets were hypertrophie and composed mostly of insulin-containing cells, with decreased proportions of glucagon-, somatostatin-, and PP-containing cells.

In both types of diabetic syndromes, the changes in cell populations induced a qualitative alteration of cellular interrelationships in the affected islets.
Hyperchloremic Metabolic Acidosis in Diabetes Mellitus: A Case Report and Discussion of the Pathophysiologic Mechanisms
Authors: Hammeke M , Bear R , Lee R , Goldstein M , Halperin M
Published: September 2013

A 21-year old woman with poorly controlled diabetes mellitus was examined for persistent hyperchloremic metabolic acidosis. There was no evidence of ingestion of hydrochloric acid or its equivalent. Gastrointestinal loss of bicarbonate was absent. Proximal tubular bicarbonate reabsorption and distal nephron hydrogen-ion secretion were normal. Ammonia and net acid excretions were high, and thus there was no obvious cause for this acidosis.

Further study revealed a very large loss of β-hydroxy-butyrate in the urine that closely approximated net acid excretion. This loss of potential bicarbonate was the principal cause for the hyperchloremic metabolic acidosis. Phosphate, urate, and β-hydroxybutyrate fractional excretions were all abnormally high. Generalized aminoaciduria was also present, but the renal handling of glucose and bicarbonate was normal. With improved control of her diabetes, the generalized aminoaciduria disappeared, the urine β-hydroxybutyrate loss ceased, the fractional excretions of phosphate and urate approached normal, and the acidosis was rapidly corrected.
Comparison and Effects of Natural and Synthetic Glucose Tolerance Factor in Normal and Genetically Diabetic Mice
Authors: Tuman Robert W , Bilbo James T , Doisy Richard J
Published: September 2013

Glucose tolerance factor (GTF) is thought to be volatile in the dry state at certain temperatures. This property allowed us to measure the stable and the volatile chromium contents of three brewer's yeast GTF preparations and to investigate the possible relationship between the volatile chromium content and its biologic activity. Two forms of chromium were found in brewer's yeast extracts by flameless atomic absorption spectroscopy using two different methods of sample preparation. Three brewer's yeast GTF preparations were found to contain total Cr concentrations ranging from 0.40 to 0.81 μg. per milligram dry weight and volatile Cr concentrations ranging from 0.02 to 0.39 μg. per milligram dry weight. The biologic response obtained with each GTF preparation was linearly related to the concentration of volatile chromium present. These observations suggest that the volatile chromium fraction in brewer's yeast is biologically important, whereas the active component of these yeast preparations is probably a precursor of GTF.

The metabolic effects of synthetic chromium-nicotinic add-ammo acid complexes and a brewer's yeast GTF preparation were compared in normal and genetically diabetic mice. The synthetic preparations mimicked the effects of brewer's yeast GTF by lowering plasma glucose and triglyceride concentrations, although at different time courses. In addition, biologically active synthetic complexes have been synthesized and may contain no volatile chromium. Synthetic complexes of chromium-nicotinic acid-amino acids lowered blood glucose by only IS to 20 per cent in normal mice as against a 36 per cent reduction with brewer's yeast GTF. Further, a synthetic product produced a significant reduction in the elevated plasma concentrations of glucose and triglycerides in genetically diabetic mice (18 and 26 per cent, respectively). This is in contrast to the 29 per cent reduction in plasma glucose and a 56 per cent reduction in plasma triglycerides produced by GTF prepared from brewer's yeast. These findings suggest that the synthetic factors are similar to, but not identical with, the active GTF fraction extracted from brewer's yeast.
Heterogeneity of Circulating Human C-peptide
Authors: Kuzuya Hideshi , Blix Petra M , Horwitz David L , Rubenstein Arthur H , Steiner Donald F , Faber Ole K , Binder Christian
Published: September 2013

Values reported for serum C-peptide immunoreactivity in healthy individuals vary considerably. To assess factors that contribute to this finding, three human C-peptide assay systems were developed utilizing three distinct antisera that react differently with various C-peptide fragments.

Preparations of natural pancreatic and synthetic human C-peptide standards were compared immunologically in these systems. The curves of the natural C-peptide and the synthetic preparations were not identical. The relative immunoreactivity of each standard varied, depending on the particular antiserum used.

Serum C-peptide concentrations varied when measured in the different assay systems. Furthermore, the results of dilution and recovery tests and stability of the C-peptide during storage showed differences among the three assays. Gel filtration of serum indicated heterogeneity within the major C-peptide peak, and, in addition, a smaller peak of lower molecular weight material was present in some samples. Although degradation of serum C-peptide may occur during storage, fragments of C-peptide may also be secreted or arise during in-vivo metabolism.

Thus, the present studies indicate the need for careful standardization and checking of each particular assay system before its use in clinical studies.
The Handling of Insulin, Proinsulin, and C-peptide by the Isolated Rat Kidney
Authors: Rabkin Ralph , Ross Brian D , Mako Mary E , Rubenstein Arthur H
Published: September 2013

The renal handling of proinuslin, insulin, and C-peptide was studied in the isolated perfused rat kidney. At perfusate peptide concentrations below 12 ng./ml. (control value), the organ clearance of proinsulin (637 ± 74 μl. per minute) was significantly (P < 0.001) lower than that of insulin (1,276 ± 48 μl. per minute) and C-peptide (1,618 ± 218 μl. per minute). There was a significant (P < 0.001) inverse correlation between the organ clearance and the molecular size of the peptide (r = − 0.86). As the glomerular filtration rate was 53 per cent of the organ clearance of proinsulin, 16 per cent of the organ clearance of insulin, and 27 per cent of the organ clearance of C-peptide, it was evident that a mechanism for extracting these peptides from the peritubular circulation exists.

When kidneys were perfused with insulin in concentrations above 330 ng./ml., the organ clearance fell to approximately half the control value and its fractional urinary excretion increased several fold, indicating saturation of luminal absorption of filtered insulin. As the fall in organ clearance of insulin was larger than any decrease in the rate of insulin filtration that may have occurred, we conclude that at high insulin concentrations saturation of contraluminal uptake of insulin also occurs. Similarly, the organ clearance of C-peptide declined to 46 per cent of the control level at perfusate concentrations of 108 to 301 ng./ml. In contrast, despite perfusing kidneys with concentrations of proinsulin as high as 367 ng./ml., its organ clearance and fractional urinary excretion did not decline. There was no evidence of conversion of proinsulin to insulin or C-peptide.
A Model of Glucose-insulin Homeostasis in Man that Incorporates the Heterogeneous Fast Pool Theory of Pancreatic Insulin Release
Authors: Guyton John R , Foster Richard O , Soeldner J Stuart , Tan Meng H , Kahn Charles B , Koncz L , Gleason Ray E
Published: September 2013

Current physiologic knowledge about glucose-insulin homeostasis in liver, brain, pancreas, kidney, peripheral tissues, and central vascular organs has been synthesized to form a whole-system mathematical model of glucose metabolism in normal, ideal man. In addition to data of other workers, results from more than 100 intravenous glucose tolerance tests, including variable dosage, variable duration of infusion, and double pulse studies, were used to determine model structure and parameters. Model and clinical testing have focused particularly on the fast phase of insulin response to vascular glucose. The model incorporates blood circulation and equilibration of substances between vascular and interstitial spaces, and it assumes constant fractional clearance of insulin by liver and kidney. Studies using a double pulse of glucose suggest that the time derivative of glucose level is not the sole or predominant influence on fast phase insulin release, but that preinfusion glucose level and/or previous glucose exposure of the pancreas are also important. Variable dosage glucose studies suggest that the amount of insulin released during the fast phase rather than the insulin release rate is regulated by the glucose level. A two-pool, heterogeneous threshold mechanism for beta cell response to glucose is presented that is compatible with the clinical results.
Syngeneic Transplantation of Fetal Rat Pancreas: I. Effect of Insulin Treatment on the Reversal of Alloxan Diabetes
Authors: McEvoy Robert C , Schmitt Robert V , Hegre Orion D
Published: September 2013

Sixty-nine alloxan-diabetic male Fischer rats received syngeneic transplants of eight 18-days-postcoitum fetal pancreases at the renal subcapsular site. One half of the recipients were given 2 to 4 U. protamine-zinc insulin for seven days immediately after transplantation. This insulin-treatment regimen effectively normalized blood glucose rapidly. Forty-seven transplant recipients survived, and diabetes was reversed in all. Insulin treatment had no effect on recovery time or glucose tolerance. Those animals requiring longer periods to reach normoglycemia had impaired glucose tolerance. Some insulin-treated recipients returned to normoglycemia rapidly while others required an extended period. Those animals that showed rapid reversal exhibited elevated concentrations of plasma insulin both in the fasting state and during glucose tolerance tests. No pretransplant parameters could be identified as predictors of rapid reversal.
Immunopathology of Juvenile-onset Diabetes Mellitus: I. IgA Deficiency and Juvenile Diabetes
Authors: Smith William I , Rabin Bruce S , Huellmantel Alan , Thiel David H Van , Drash Allan
Published: September 2013

There is an increased prevalence (P < 0.001) of IgA deficiency in children with juvenile-onset insulin-dependent diabetes mellitus (9/366) but not in adults with insulin-dependent diabetes (0/421). The juvenile diabetics with IgA deficiency have other immune-associated diseases, such as thyroiditis and chronic active hepatitis, and have a history of infections. Four of the nine IgA-deficient diabetics we studied have autoantibodies to endocrine organs. Seven of eight have the HLA-B8, a proportion significantly (P < 0.05) greater than control populations. Based on the clinical findings of IgA deficiency and multiple autoantibodies in patients with ataxia-telangiectasia and chronic mucocutaneous candidiasis, diseases associated with thymus deficiency, we suspect that thymus deficiency and autoimmunity may play a role in the pathogenesis of some types of juvenile-onset diabetes mellitus. In addition, an excess morbidity of the IgA-deficient juvenile diabetic population may explain the lack of IgA deficiency in older insulin-dependent diabetic individuals.
Insulin Receptors on Monocytes from Patients with Ketosis-prone Diabetes Mellitus
Authors: Pedersen Oluf , Beck-Nielsen Henning , Heding Lise
Published: September 2013

I-125-Insulin binding to its receptor on monocytes was measured in 30 young, insulin-treated diabetic outpatients and in 13 newly diagnosed, ketotic diabetic patients before and after insulin treatment.

In insulin-treated diabetic outpatients, insulin binding was similar on average to that of 25 age-matched normal subjects. A slight but statistically significant negative relationship was found between the insulin concentration required to displace specific binding of I-125-insulin by 50 per cent and the plasma concentration of ketone bodies (R = −0.46, p < 0.02), indicating a positive correlation between apparent receptor affinity and the plasma concentration of ketone bodies. No correlation was found between insulin binding and total plasma insulin concentration.

Insulin binding to monocytes from newly diagnosed diabetic patients exhibited large variability. Based on the initial insulin binding values and the receptor response to insulin treatment, the patients could be divided into two groups. Group 1 comprised eight diabetic subjects who had had specific cell-binding fractions at an insulin tracer concentration above the median of normal subjects before therapy; after insulin treatment for 10 days, insulin binding was restored to normal. Group 2 consisted of five diabetic patients who had had specific cell-binding fractions at a tracer level below the median of normal subjects when admitted; insulin therapy caused no significant change in insulin binding. In both groups of newly diagnosed, diabetic patients, no correlation could be found between the cellular insulin binding and the plasma concentrations of insulin and ketone bodies.

We conclude that (1) insulin-treated diabetic outpatients have normal insulin binding to monocytes; (2) among newly diagnosed, ketotic diabetics with identical metabolic presentation, some may have a raised but reversible insulin binding initially, while others seem to have defective cellular insulin binding in addition to insulin deficiency; and (3) no consistent relationships exist between the plasma levels of insulin and ketone bodies and the insulin binding on monocytes from insulin-dependent diabetics.
Failure to Suppress Plasma Glucagon Concentrations by Orally Administered Glucose in Diabetic Patients After Treatment
Authors: Seino Yutaka , Ikeda Masaki , Kurahachi Hiroyuki , Taminato Tomohiko , Sakurai Hideo , Goto Yasuo , Inoue Yoshimichi , Kadowaki Seizo , Mori Kozaburo , Imura Hiroo
Published: September 2013

Plasma glucagon response to glucose in diabetic subjects was observed before and after treatment. In normal subjects, plasma glucagon concentrations decreased substantially after an oral glucose load. In all diabetic patients before treatment, plasma glucagon was not suppressed and rather tended to rise paradoxically despite pronounced hyperglycemia. In diabetics treated with sulfonylurea or insulin, basal plasma glucagon concentrations were significantly lower than those in patients who were not treated. However, plasma glucagon response to an oral glucose load was not normalized by successful treatment with sulfonylurea or insulin, in spite of improvement of glucose tolerance. These results suggest that the insensitivity of the A-cell to hyperglycemia exists after treatment, and this abnormal plasma glucagon response to glucose after treatment may be caused either by impaired response of endogenous insulin to glucose, which is sustained even after treatment, or by an intrinsic defect of the A-cell.
Functional Alteration of Islet Cells After Jejunal or Ileal Resection in Dogs
Authors: Tamura Katsuhiro , Kajiwara Tatehiro , Suzuki Takashi , Tobe Takayoshi
Published: September 2013

Functional alteration of the islet cells was investigated in dogs after the resection of different parts of the small intestine. Three weeks after jejunal or ileal resection, when the dogs might still have been in a catabolic state, insulin and pancreatic glucagon release in response to intravenously infused glucose and arginine was reduced. Three months after jejunal resection, both intravenous glucose tolerance and insulinogenic index in the intravenous glucose tolerance test were significantly below the preoperative values (P < 0.001, P < 0.05), while pancreatic glucagon release in response to arginine infusion showed almost normal levels in contrast to low response of insulin release. This functional alteration three months after jejunal resection was similar to that seen in diabetes meilitus. On the other hand, three months after ileal resection, insulin and pancreatic glucagon release was almost normal.

We conclude that the jejunum plays a more important role in the enteroinsular system than the ileum and that prolonged interruption of this enteroinsular axis can cause insular disorder and what could hypotheticaUy be called enterogenic chemical diabetes, in view of the altered glucose tolerance test and the alteration in insulin secretory response.
Comparison of the Early Time Courses of the Release of Insulin That Follow Injections of Tetragastrin, Tolbutamide, Xylitol, and Glucose into the Pancreatic Artery of Dogs
Authors: Kuzuya Takeshi , Kajinwna Hiroshi , Sando Hiroyuki , Hayashi Masaki , Ide Takehiko , Kosaka Kinori
Published: September 2013

The early time courses of insulin release were studied by injecting insulinotropic substances directly into a dog's pancreatic artery. Blood samples from the pancreatic vein were collected every five seconds continuously over 90 seconds and were assayed for their insulin concentrations. Injections were repeated two to five times, with intervals of 30 minutes. Insulin release was stimulated within one minute after injection of each of tetragastrin, tolbutamide, xylitol, and glucose, but the time courses of the release of insulin were different with different stimulants: Tetragastrin and tolbutamide increased insulin release faster than did glucose; xylitol produced a slower insulin release than did glucose. The slower insulin-releasing effects of glucose and xylitol than the other agents would be compatible with the theory that their metabolism is required to cause release of insulin, but it is also possible that the glucoreceptor mechanism may require a longer lag time than the other receptor mechanisms for the perception and transfer of the signal to release insulin.
Insular Amyloidosis and Diabetes Mellitus in Macaca Nigra
Authors: Howard Charles F
Published: September 2013

Amyloid in the islets of Langerhans increases with increasing severity of diabetes mellitus in Macaca nigra. The amount of insular amyloid was quantified, and diabetic monkeys averaged eight times more islet amyloid than did normal monkeys. The quantity of insular amyloid correlated significantly with glucose clearance in intravenous glucose tolerance tests and with serum glucose, triglycerides, immunoreactive insulin, and prebetalipoprotein measured after an overnight fast. As with human beings, insular amyloid appeared to be more prevalent in aging monkeys. The results support the hypothesis that the interrelated islet pathologic and metabolic events, which result in the appearance of insular amyloid concomitant with islet cell necrosis, may contribute more to maturity-onset diabetes in aging individuals than has been heretofore realized.
Disposition of 131I Proinsulin in the Rat Comparisons with 131I Insulin
Authors: Izzo Joseph L , Roncone Angela M , Helton Deirdre L , Izzo Mary Jane
Published: September 2013

The patterns of disposition of intravenously injected doses of 131I proinsulin and 131I insulin were compared in the rat with respect to plasma clearance, uptake, and degradation in selected organs and tissues, and rates of accumulation of degraded products in plasma and urine. Small doses of 131I insulin (4 mμg.per 100 gm. rat body weight) were cleared from plasma approximately twice as rapidly as large doses (4 μg. per 100 gm. rat body weight) and three times as rapidly as equi molar small doses (6 mμg. per 100 gm. rat body weight) or large doses (6μg.per 100 gm. rat body weight) of 131I proinsulin. Conversely, the relative rate of accumulation of 13lI-labeled degradation products in plasma after injection of low doses of 13lI insulin was about twice as rapid as the rate of accumulation after large doses and about three times as rapid as the rate of accumulation after either small or large doses of 13lI proinsulin. Peak uptake and degradation in the liver at one minute was greatest after injection of low doses of 13lI insulin (28.8 ± 2.5 per cent of injected radioactivity), less after injection of large doses (15.1 ±1.5 per cent), and least after injection of low doses (5.5 ± 0.9 per cent) or high doses (4.6 ±0.6 per cent) of 131I proinsulin. In contrast, peak uptake and degradation in the kidneys at seven to eleven minutes was greatest after injection of low doses (24.7 ± 2.7 per cent) or high doses (27.5 ± 1.2 per cent of 13lI proinsulin), least after injection of low doses (9.6 ±0.6 per cent) of 13lI insulin, and intermediate after injection of high doses (17.5 ±2.6 per cent). No large differences were noted in patterns of uptake of radioactivity in muscle, fat, or skin compartments. Excretion of degraded products in urine was more delayed after 13lI proinsulin injections. An inverse relationship was noted between initial concentration of hormone in plasma and uptake by the liver. Compared to 131I insulin, the hypoglycemie effect of 13lI proinsulin was weaker (58 per cent) and more delayed in onset. No evidence of conversion of l3lI proinsulin to 131I insulin was noted.

The studies indicate that the differences in dose dependency in plasma clearance and degradation of 131I insulin and 131I proinsulin can be attributed to differences in relative uptakes and degradation by the liver and kidneys. The liver appeared to be the major organ involved in the removal and degradation of insulin, whereas the kidney appeared to be the major organ involved in the case of proinsulin. The hepatic process was rapid but relatively saturable, whereas the kidney process was slower but relatively unsaturable. The inverse relationship between initial concentration of hormone in plasma and uptake by liver suggests that the ratio may provide a sensitive index of the role of the liver in plasma hormone clearance.
Age-related Glucose Intolerance in Hyperthyroid Patients
Authors: Ikejiri Kenji , Yamada Takashi , Ogura Hajime
Published: September 2013

In an attempt to study age-related metabolic abnormalities, glucose intolerance and serum insulin were examined in normal subjects and hyperthyroid patients. For comparison, serum concentrations of thyroxine (T4), triiodothyronine (T3), and total cholesterol were also measured in normal subjects and hyperthyroid patients.

Although serum T4 concentration remained unchanged, serum T2 concentration decreased significantly in an elderly group of normal subjects. Similarly, serum T4 did not change with age and serum T2 decreased slightly but progressively with age in hyperthyroid patients. In addition, serum total cholesterol concentration increased progressively with age in normal subjects.

Oral glucose tolerance decreased with age in normal subjects despite the same timing, peak level attained, and total magnitude of insulin response for old and young subjects. Although the severity of hyperthyroidism decreases with age, age-related glucose intolerance was much more apparent in hyperthyroid patients because of the age-related decrease of basal concentration, the peak level attained, and the total magnitude of insulin response. It is suggested that age-related glucose intolerance is magnified by the hyperthyroid state.
Induction of Defective Insulin Secretion and Impaired Glucose Tolerance by Clonidine Selective Stimulation of Metabolic Alpha-adrenergic Pathways
Authors: Metz Stewart A , Halter Jeffrey B , Paul Robertson R
Published: September 2013

Clonidine is an antihypertensive drug that markedly suppresses plasma catecholamine levels. In an attempt to investigate the effects of suppression of endogenous catecholamine secretion on glucose homeostasis and glucoregulatory hormones, we administered oral clonidine to 20 normal male subjects, two patients with transsections of the cervical spinal cord, and one patient with an insulinoma. Unexpectedly, after a single dose of 0.5 ing. given to normal subjects, insulin concentrations fell and plasma glucose rose 12 ± 1 mg./dl. (p < 0.001; n = 6) without an increase in glucagon. After four days of clonidine treatment, plasma glucose again was elevated (Δ = +11 ± 3 mg./dl.; p < 0.01), while basal plasma insulin and glucagon levels remained unchanged. The acute insulin response to an intravenous glucose injection of 5 gm. decreased from 33 ± 7 to 11 ± 2 μU./ml. (n = 8; p < 0.01), and KG declined from 0.80 ± 0.13 to 0.53 ± 0.06 per cent per minute (p < 0.01). Similar responses were seen in the paraplegic patients. In contrast, expected responses to clonidine were not observed in the insulinoma patient preoperatively; these normal responses were restored after resection of the tumor. All metabolic alterations induced by clonidine were reversed by infusion of phentolamine, an alpha-adrenergic blocking agent.

We conclude that clonidine causes hyperglycemia and inhibits insulin secretion through an alpha-adrenergic mechanism. Since plasma catecholamine concentrations and vascular tone were markedly reduced by clonidine, this drug appears to selectively stimulate metabolic adrenergic pathways different from those operative in vasomotor regulation.