bluuebunny/crossref_metadata_2025 huggingface dataset:
Topical Corticosteroid Response and Retinopathy in Juvenile-onset Diabetes Mellitus
Authors: Shin Dong H , Becker Bernard , Kolker Allan E
Published: September 2013

In a prospective study, 64 patients with insulin-dependent juvenile-onset diabetes mellitus were followed for eight to 12 years to determine if those with higher spontaneous intraocular pressures (IOPs) would be protected from the development of retinopathy. The patients were also classified initially as high (GG), intermediate (NG), or low (NN) responders on the basis of their IOP response to corticosteroid eyedrops. High responders were found to be considerably in excess (25 per cent) of the proportion found in the general population (6 per cent). Retinopathy developed significantly less often and was less severe in the high (GG) corticosteroid responders. Although the GG diabetics had significantly higher mean baseline IOPs than the less responsive NN and NG groups in each corticosteroid response category, the mean IOP of the group with retinopathy was not significantly different from that without retinopathy. This suggested that factors associated with the GG response other than increased IOP might be important in the relative resistance to diabetic retinopathy.
Nutrition and Somatomedin: III. Diabetic Control, Somatomedin, and Growth in Rats
Authors: Phillips Lawrence S , Orawski Arthur T
Published: September 2013

Observations of a growth hormone-resistant decrease in somatomedin activity associated with conditions of insulinopenia suggest that somatomedin and growth might be related to metabolic control in diabetes mellitus. We examined this relationship by comparing measures of insulin effect with serum somatomedin activity (porcine cartilage bioassay), cartilage growth activity (SO4 uptake in vitro), and change in body weight in streptozotocin-diabetic rats. A range of metabolic control was produced by administration of varied quantities of insulin over twoand four-day periods. Serum somatomedin activity was significantly correlated with serum glucose and Β-hydroxybutyrate (r = −0.69 and −0.76, respectively, p <0.001 for both) but not with free fatty acids. A level of serum glucose <240 mg./dl. or /3-hydroxybutyrate <1.3 mM at sacrifice was generally associated with serum somatomedin activity within the normal range. Urine glucose levels less than 0.1 gm./24 hr. were also associated with normal serum somatomedin activity. Insulin therapy sufficient to provide β-hydroxybutyrate less than 1.3 mM at sacrifice was associated with levels of serum somatomedin activity and cartilage growth activity comparable to those of normal animals and significantly greater than those of untreated diabetic animals. This level of insulin effect also permitted diabetic animals to gain weight at a rate comparable to that of normal animals.

These studies demonstrate a close relationship between insulin efficacy, serum somatomedin activity, cartilage growth activity, and weight gain and support the hypothesis that through somatomedin, insulin may contribute to growth.
Insulin, C-peptide, and Proinsulin in Nondiabetics and Insulin-treated Diabetics: Characterization of the Proinsulin in Insulin-treated Diabetics
Authors: Heding Lise G.
Published: September 2013

Immunoreactive insulin (IRI), C-peptide, and proinsulin were determined in 46 fasting nondiabetic persons. The means ± S.D. for IRI, C-peptide, and proinsulin (in pmol/ml.) in the 46 nondiabetics were 0.054 ± 0.027, 0.39 ± 0.12, and 0.014 ± 0.009, respectively. The molar ratio between C-peptide and IRI varied from 4.0 to 16.7, with a mean value of 7.9 ± 3.4. Proinsulin constituted 5–36 per cent of IRI, with a mean of 20 ± 10 per cent.

Sera from 24 diabetics aged 17–67 years treated with conventional crystalline insulin for durations of from one to 29 years (mean: 15 years), all of whom had circulating insulin antibodies, were extracted with acid ethanol. Total IRI varied from 2.0 to 22.6 pmol/ml. C-peptide was detectable in only three patients (0.05, 0.08, and 0.15 pmol/ml.). In contrast, human proinsulin was found in all patients and ranged from 0.09 to 9.4 pmol/ml., corresponding to 1 to 45 per cent of total IRI. Species-specific immunoassays for bovine and porcine proinsulin revealed the presence of bovine proinsulin in 23 of the patients (mean 0.36 ± 0.20 pmol/ml.) and porcine proinsulin in eight patients (mean 0.15 ± 0.13 pmol/ml.). Total proinsulin constituted 5 to 64 per cent, mean 22 per cent, of total IRI, while human proinsulin amounted to 1 to 45 per cent, mean 10 per cent, of IRI. Although no insulin secretion could be detected in 21 of the patients, as judged by the amount of C-peptide, the B-cell was still able to secrete proinsulin. Insulin antibodies bind a portion of the secreted proinsulin, thus prolonging its half-life and increasing its concentration in serum.
Clinical Evaluation of Metabolic Control in Diabetes
Authors: Molnar George D
Published: September 2013

This review examines the current status of the clinical evaluation of diabetic control. The assessment of the patient's symptoms and signs is important but requires laboratory confirmation. Major metabolic derangements usually occur before their clinical detection is feasible.

To be complete, the laboratory assessment of diabetic control should include the insulin concentration in blood or urine. At present insulin and other hormones assays have played mainly an investigative role.

Glucose measurements in blood and urine continue to be the standards for evaluation of diabetic control. Glucose tolerance tests or carefully timed preprandial and postprandial plasma glucose measurements on several successive days under consistent conditions of diet and exercise provide data for adequate evaluation of diabetic control. The addition of urinary glucose monitoring to the blood sampling makes the evaluation more complete. Glucose variability measurements in blood and/or urine provide useful data for characterizing patients, for comparing them with other diabetics, with nondiabetic normals, and with themselves from time to time.

Despite their limitations, urine glucose tests are valuable and worth evaluating so as to provide for each patient the most appropriate method of testing. Methods are described for screening patients for atypical blood-to-urine glucose relationships (“renal glucose threshold”) and for estimating such thresholds.

Among lipid metabolic indices of insulin deficiency the urinary ketone bodies are the most commonly measured in clinical medicine. Triglycerides and cholesterol elevations may in part reflect disturbed diabetic control and may warrant a trial of intensified antidiabetic therapy.

The protein metabolic changes of diabetes during hyperglycemia are measurable as decreased levels of plasma alanine and increased levels of branched-chain amino acids. By sensitive quantitative methods, albuminuria is also demonstrably increased during impaired diabetic control. Improved diabetic regulation restores these protein abnormalities toward normal. These newer refinements for evaluating diabetic control await clinical application.

Glycosylation of hemoglobin, identifiable by an increased proportion as hemoglobin A1c, is of special interest as a longer-term indicator of hyperglycemia.

As clinical interest in more complete normalization of diabetic metabolic changes is intensifying, a wider array of methods are becoming available for determining the degree to which metabolic control is normalized.
Islet Cell Survival Determined by Morphology An Immunocytochemical Study of the Islets of Langerhans in Juvenile Diabetes Mellitus
Authors: Gepts W , De Mey J
Published: September 2013

The cytologic composition of the pancreatic islets of 58 insulin-dependent diabetics with age of onset of the disease before the age of 40 and a duration of from a few days to 37 years was studied with the aid of Sternberger's immunocytochemical method. Four types of islet cells were stained with specific antisera: β cells (insulin), α cells (glucagon), D cells (somatostatin), and PP cells (pancreatic polypeptide).

β cells were found in 14 of 16 recent-onset cases, in seven of 14 patients having diabetes for less than 11 years, and in five of 28 patients in whom the disease had been present for a longer time. In all these cases, the number of β cells was well below normal. They showed cytologic features of functional hyperactivity.

The majority of the islets, even in recent-onset cases, were devoid of β cells and were composed of thin cords of islet cells. Immunocytochemical staining revealed that, contrary to the classic opinion, these cells are not inactive but are actively secreting glucagon or somatostatin. In many long-term juvenile diabetics, the glucagon-containing α cells appeared very numerous, but it remains to be ascertained whether this represents an apparant or a true hyperplasia.

Insulitis was found in 11 of the 16 recent-onset cases. In one case, the lymphocytic infiltration was found only in islets containing β cells but was strikingly absent in the islets composed of glucagon-, somatostatin-, and PP-cells.

Images of islet regeneration, with neoformation of β cells and other islet-cell types from centroacinar and ductular cells could still be detected focally in a few recent-onset cases. With a disease of longer duration, an atypical type of islet regeneration, originating in the epithelium of small- and medium-sized ducts, becomes more prevalent and produces islets solely composed of PP cells.
The Role of Calcium in Glucagon Release: Studies with Verapamil
Authors: Leclercq-Meyer V , Marchand J , Malaisse W J
Published: September 2013

The role of calcium transport into the pancreatic A2-cell in release of glucagon was studied in the perfused in vitro rat pancreas exposed to the organic calcium–antagonist verapamil (10 and 20 μM). As judged by the inhibitory effect of verapamil, a sufficient influx of calcium was required for glucagon release to be stimulated by either arginine (10 mM) or a lowering of the glucose concentration from 16.6 to 3.3 mM. However, such was not the case for glucose to inhibit the release of glucagon or when the A2-cell was established in a stimulated state during prolonged exposure to a low, 3.3 mM, glucose concentration. These findings suggest that the role of inwardly directed transport of calcium in the secretory process of the A2-cell is of a complex nature, being dependent on the type of stimulus employed (arginine or glucose) and, in the case of glucose, on the static or dynamic state of the cell. The intimate mechanisms by which calcium exerts such complex effects on the secretory process in the A2-cell remain to be elucidated.
Hypomagnesemia, a Risk Factor in Diabetic Retinopathy
Authors: McNair P , Christiansen C , Madsbad S , Lauritzen E , Faber O , Binder C , Transbøl I
Published: September 2013

The serum magnesium concentration was measured in 71 insulin-treated diabetic outpatients who had had the disease for 10 to 20 years. The patients were divided into two subgroups according to the severity of their retinopathy. As a whole the patients exhibited a definite hypomagnesemia (P < 0.001) that was most pronounced in the subgroup having the severest degree of retinopathy (P < 0.01). The subgroups were comparable regarding known risk factors implicated in diabetic retinopathy. Thus, hypomagnesemia appears to be an additional risk factor in the development and progress of this complication.
Glucose-induced Alterations of the Metabolism of an Isolated Capillary Preparation
Authors: Rasio Eugenio A , Morrison Anthony D
Published: September 2013

A preparation of blood capillaries was isolated from the rete mirabile of the eel swim bladder. The capillaries, incubated for two hours at 37° C. in Krebs-Ringer bicarbonate buffer with 5 mM glucose, contained 29.3 ± 4.6 nmoles of sorbitol per gram and released in the medium 725 ± 60 nmoles of fructose per gram. When glucose in the medium was raised from 5 to 30 mM, capillary sorbitol and medium fructose rose by approximately 100 per cent. There were no accompanying changes in capillary water content as determined by the ratio of wet weight to dry weight and by the difference between water-3H space and inulin-l4C space. Respiration of cap Diary tissue was lower at 30 mM glucose than at 5 mM glucose. The addition of 30 mM mannitol to a medium containing 30 mM glucose did not restore the oxygen uptake by capillary tissue to values obtained with a medium containing 5 mM glucose alone. It is concluded that the polyol pathway is operative in vertebrate blood capillaries. At high medium glucose concentration, the activity of the pathway is enhanced, respiration is depressed, and water content is unchanged.
Regional Pancreatic Concentration and In-vitro Secretion of Canine Pancreatic Polypeptide, Insulin, and Glucagon
Authors: Gingerich Ronald L , Lacy Paul E , Chance Ronald E , Johnson Melvin G
Published: September 2013

The regional concentrations and in-vitro secretions of canine pancreatic polypeptide (cPP), insulin, and glucagon were studied. CPP is found predominantly in the uncinate process of the dog pancreas, whereas insulin and, more markedly, glucagon predominate in the body and taO of the pancreas. In-vitro secretion studies of pancreatic pieces indicate that dibutyryl cyclic AMP (dcAMP) alone can stimulate cPP release whereas glucose and arginine alone have no effect. Arginine, but not glucose, potentiates this stknulant effect of dcAMP. These studies suggest that the cAMP generating system may play a role in regulation of cPP secretion.
Quantitative Determination of the Interaction Between Epinephrine and Various Insulin Releasers in Man
Authors: Efendić Suad , Luft Rolf , Cerasi Erol
Published: September 2013

Epinephrine significantly inhibited glucose-induced insulin release in man, the threshold dose being about 20 ng./kg. per minute. Maximal effect was attained with 60 ng./kg. per minute. In the presence of the threshold epinephrine dose, the dose-response curve for glucose-induced insulin release seemed to be displaced almost in parallel to the right of the control, suggesting competitive Inhibition. With the high epinephrine dose the inhibition of insulin release was of a noncompetitive nature.

Epinephrine did not significantly suppress insulin release induced by either arginine or tolbutamide as compared with the effect of these insulinagogues when given at normoglycemia. Only in the case of glucagon did the high epinephrine dose (90 ng./kg. per minute) markedly inhibit the insulinogenic effect of the hormone (p<0.001) even when the effect of glucagon at normoglycemia was used as control.

Since glucose exerted synergistk effects on insulin release in-duced by the other insulinagogues (arginine, glucagon, and tolbutamide), the insulinogenic effect of these insulinagogues In the presence of epinephrine was compared with their effect under hyperglycemie conditions similar to those obtained with epinephrine alone. It was found that epinephrine at a dose of 30 ng./kg. per minute totally inhibited the synergism between the hyperglycemie and the insulinagogues on insulin release. The greater the synergism—as with arginine and glucagon—the larger was the percentage inhibition by epinephrine. A threefold increase in the epinephrine dose further reduced the insulin response.

Our experiments suggest that epinephrine—in the doses used—inhibited the effect of glucose on insulin release. This effect occurred regardless of whether glucose was used as the sole stimulator of insulin release or was used in synergism with such insulinagogues as arginine, tolbutamide, or glucagon.
Effects of Ingestion of Triglyceride or Galactose on Secretion of Gastric Inhibitory Polypeptide and on Responses to Intravenous Glucose in Normal and Diabetic Subjects
Authors: Ross S A , Dupre J
Published: September 2013

Responses of plasma immunoreactive gastric inhibitory polypep-tide (IRGIP) to oral triglycéride or galactose were compared in normal and mildly diabetic (non-insulin-dependent) subjects. After triglyceride the responses of IRGIP were similar, but after galactose those of the diabetics were slightly exaggerated. Both stimuli evoked increments of plasma immunoreactive glucagon (IRG) in diabetics but not in normal subjects. Plasma immunoreactive insulin (IRI) did not change.

In normal subjects given oral triglyceride or galactose followed by intravenous (I.V.) glucose the early-phase response of plasma IRI was enhanced and glucose tolerance improved. In the diabet-ics, oral triglyceride did not affect insulin release or glucose tolerance after I. V. glucose; oral galactose elicited a slight increase of insulin release without improving glucose tolerance. In the diabetics the rise in plasma IRG after ingestion of triglyceride or galactose was maintained after I. V. glucose.

It is concluded that endogenous GIP is insulinotropic and that there is partial resistance to this action in diabetes. The results were compatible with feedback inhibition of GIP secretion by insulin and with the suggestion that the rise of plasma IRG associated with secretion of GIP in diabetics may be due to the glucagono-tropic action of this peptide.
Effect of Priming of Amino Acids on Insulin and Growth Hormone Response in the Premature Infant
Authors: Reitano G , Distefano G , Vigo R , Giunta L , Grasso S
Published: September 2013

Glucose, α-amino nitrogen, serum insulin, and HGH were studied in preterm infants during the first 24 hours of life.

Glucose infusion (1.25 gm.) resulted in a slight elevation of serum insulin. When this amount of glucose was infused during the last 30 minutes of a two-and-a-half-hour infusion of a mixture of essential amino acids, there was a rapid and striking increase in serum insulin. However, this increase was not associated with a faster glucose disposal rate. The administration of this mixture of amino acids doubled the basal level of α-amino nitrogen, and during the first two hours, before glucose infusion, it caused a significant rise of serum insulin and HGH. In both cases glucose caused an increase of HGH secretion that was not significantly different in the two groups of infants.
A Simplified Assay of Hemoglobin AIc in Diabetic Patients by Use of Isoelectric Focusing and Quantitative Microdensitometry
Authors: Spicer K M , Ållen R C , Buse M G
Published: September 2013

Isoelectric focusing (IEF) of human erythrocyte hemolysates on poly aery la mide slab gels over a pH gradient of 6 to 8 provides sufficient resolution of hemoglobin Ale (HbAIc) from other hemoglobin components (AIa, AIb, AII, S, and F) to allow quantification by high-resolution microdensitometry. Twice-chromatographed HbAIc alone and in admixtures with normal and diabetic hemolysates were employed to verify the identification and quantification of the Aie component. Relative concentration was determined as a per cent of the total hemoglobin absorption at 556 nm on acid-fixed, unstained gels. A total of 60 patient samples were examined by IEF, and, for 35 samples, both column chromatography and IEF determination were obtained, revealing excellent correlation between these two methods.
Effects of Glucose and Sorbitol on Proliferation of Cultured Human Skin Fibroblasts and Arterial Smooth-muscle Cells
Authors: Turner John L , Bierman Edwin L
Published: September 2013

To determine effects of metabolic abnormalities associated with diabetes mellitus on proliferation of diploid human cells, cultured human skin fibroblasts and arterial smooth-muscle cells were grown in media containing added glucose in the range often seen in diabetic subjects (10 to 30 mM, 180 to 550 mg./dl.). “High” glucose media enhanced proliferation of fibroblasts, with an “optimal” response at about 18 mM (325 mg./dl.). Equimolar sorbitol gave similar results, with the greatest increase in proliferation occurring at about the same concentration as for glucose (19 mM). Since neither equimolar mannitol nor sucrose produced such effects consistently, these results cannot be explained solely on the basis of hyperosmolarity. In contrast, arterial smooth-muscle cells failed to show a consistent growth response in the presence of either added glucose or sorbitol. These results suggest that studies with cultured human cells may be useful in assessment of responses to components of the disordered metabolic milieu of diabetes. Such studies of arterial smooth-muscle cells should also be useful for investigation of the mechanism of atherosclerosis in diabetes.
Aldosterone Responsiveness in Patients with Diabetes Mellitus
Authors: Christlieb A Richard , Kaldany Antoine , D'Elia John A , Williams Gordon H
Published: September 2013

Plasma aldosterone (PA) and plasma renin activity (PRA) were determined in 44 diabetics, of whom nine were normotensive but not nephropathic (group 1), 10 were hypertensive but not nephropathic (group 2), and 25 were hypertensive and nephropathic (group 3); they were kept in balance on a diet composed of 10 to 20 mEq. of sodium (Na) and 100 mEq. of potassium (K). Supine PA in group 1 was 38 ± 7 ng. per deciliter, whereas in normals it was 24 ± 2 ng. per deciliter (P < 0.05); beyond that, neither supine nor upright PA or PRA differed significantly from normal in groups 1 and 2. By contrast, in group 3, supine PA was 13 ± 1 ng. per deciliter and PRA 2.0 ± 0.2 ng./ml. and upright PA was 39 ± 7 ng. per deciliter and PRA 3.8 ± 0.5 ng./ml., all significantly lower than those in the other groups (P < 0.01). Nine patients, one in group 1 and eight in group 3, had low supine and upright PA and PRA; four had hyperkalemia. An additional nine patients in group 3 had low upright PA, with normal or low PRA; two had hyperkalemia. Of the 18 patients with low upright PA, K correlated with glucose (R = 0.46, P < 0.05). These results suggest (1) the renin-aldosterone system generally responds normally in diabetics without nephropathy but responds subnormally when nephropathy is present, (2) hyporeninemic hypoaldosteronism is frequent in diabetics with nephropathy but may occur in the absence of clinical nephropathy, and (3) hyperkalemia in some diabetic patients may be secondary to hypoaldosteronemia and hyperglycemia.
Bimodality of Fasting and Two-hour Glucose Tolerance Distributions in a Micronesian Population
Authors: Zimmet P
Published: September 2013

While frequency distributions of glucose concentrations in Caucasian populations are unimodal, bimodality has been described in the Pima Indians, a population with an extremely high prevalence of diabetes.

Venous plasma glucose concentrations at fasting and after a 75-gm. oral glucose load were determined in 596 Nauruans, a Micronesian population with a diabetes prevalence of the same order as the Pima Indians. In both sexes and in subjects 10 to 19 years, the frequency distributions of the logarithms of the fasting and two-hour glucose values were clearly unimodal. In most sex and age groups of 20 years and older, the frequency distributions of fasting and two-hour glucose values were bimodal and consistent with a model of two overlapping Gaussian distributions.

This population is characterized by marked obesity. However, there was no significant difference in the degree of obesity between subjects in the first and second curves of the bimodal distribution. This makes it unlikely that the bimodality is a consequence of the marked obesity seen in both the Pima and Nauru populations.

The data show that among Nauruans, as with the Pimas, the frequency distribution of glucose concentrations can be used to separate the population into normal and hyperglycemic groups.
Glycosylated Hemoglobin in Normal Subjects and Subjects with Maturity-onset Diabetes Evidence for a Saturable System in Man
Authors: Graf Ronald J , Halter Jeffrey B , Porte Daniel
Published: September 2013

Concentrations of glycosylated hemoglobin (GHb) are elevated in diabetes mellitus and are believed to reflect previous metabolic control. To better define possible determinants of GHb in man, we investigated the relationship between GHb and both fasting plasma glucose (FPG) and basal insulin (IRI) in 42 normal subjects and 29 patients with maturity-onset diabetes. Concentrations of GHb in diabetic subjects (12.7 ± 3.4, x ± S.D., per cent total hemoglobin) were significantly higher than in normal subjects (8.2 ± 1.2, p < 0.001). In normal subjects, FPG (r = 0.52) and GHb (r = 0.58) (both p < 0.001) correlated with age. GHb did not correlate with IRI in either group. However, GHb was closely associated with FPG in both normal (r = 0.60, p < 0.001) and diabetic (r = 0.85, p < 0.001) subjects. Linear regression analysis of the data for the two groups combined was highly significant (r = 0.91, p < 0.001). However, the slope of the regression line for GHb versus FPG seen in normal subjects was significantly steeper than that of diabetic patients (p < 0.005). A curve describing a nonenzymatic saturable model was also found to fit the data of the two groups combined (r = 0.85, p < 0.001), suggesting the possible existence of a saturable system for glycosylation in man.
The Effect of Endogenous Gastric Inhibitory Polypeptide on Glucose-induced Insulin Secretion in Mild Diabetes
Authors: May James M , Williams Robert H
Published: September 2013

Diabetic subjects have previously been found to have increased secretion of immunoreactive gastric inhibitory polypeptide (IR-GIP) in response to oral glucose or triglyceride compared with normal subjects. In the present study, a group of 19 diabetics was selected with milder glucose intolerance (fasting plasma glucose = 109 mg. per deciliter) than those reported previously. In these diabetics no enhancement of IRGIP responses was found to either 75 gm. oral glucose or 50 ml. oral corn oil when compared with 13 subjects with normal carbohydrate tolerance. Some of the subjects were obese and, when assessed independently from glucose tolerance, obesity was associated with higher integrated IRGIP responses to oral glucose but not to oral corn oil. The degree of obesity (92 to 154 per cent ideal body weight) did not correlate with fasting or stimulated IRGIP responses of the 32 subjects. One hour after ingestion of 50 ml. corn oil, when IRGIP concentrations were maximal but glucose and insulin remained unaffected, the diabetic subjects showed increased relative acute-phase insulin secretion to a 20 gm. pulse of intravenous glucose compared with that from a glucose pulse alone (p < 0.01). Subjects with normal carbohydrate tolerance had no increase in relative acute insulin response to glucose after triglyceride priming. The relative second-phase insulin response (10 to 30 min.) increased significantly with triglyceride priming in both diabetics (p < 0.01) and nondiabetics (p < 0.05). Although glucose disappearance rates (Kg) correlated with relative insulin responses, the increase in insulin secretion with triglyceride priming was not associated with an increase in Kg. Although obese subjects show increased stimulated GIP responses to oral glucose, patients with mild diabetes have normal GIP secretion to oral glucose and to triglyceride, but show a GIP-associated increase in both phases of glucose-induced insulin secretion.
Reduced Erythrocyte Deformability in Diabetes
Authors: McMillan Donald E , Utterback Nyle G , Puma John La
Published: September 2013

The flow properties of individual erythrocytes have been studied in glass micropipets 4 μ internal diameter. The pressure gradient required to establish a standard oscillatory movement over a 130-μ path in a three-second time period was measured in paired studies comparing diabetic and control erythrocytes suspended in Ringer solution. The pressure requirement was regularly elevated for the diabetic erythrocytes, averaging 50 per cent greater than the controls. Studies of erythrocytes comparing alloxan-diabetic rats with control rats demonstrated a similar elevation in required pressure. Red cells from subjects with hereditary spherocytosis offered less flow resistance than diabetic cells, and red cells from rheumatoid arthritics required no pressure increment. When erythrocytes are ejected from a 4-μ micropipet they return quickly to a discoid shape using stored elastic energy. Slow motion photography revealed that diabetic erythrocytes restore their shape less rapidly than nondiabetic erythrocytes, indicating that their reduced deformability is due to an elevation of either intraerythrocyte or membrane viscosity rather than to increased resistance to bending. Diabetes is regularly associated with an increased intracellular hemoglobin Alc; it is possible that hemoglobin Ale could raise intraerythrocyte viscosity. The observed disturbance in flow properties of individual erythrocytes is subtle. It would affect the flow of blood, particularly through active muscle, and modify the pressure exerted by individual erythrocytes on the muscle capillary wall.
Regional Distribution and Concentration of Pancreatic Polypeptide in the Human and Canine Pancreas
Authors: Gersell Deborah J , Gingerich Ronald L , Greider Marie H
Published: September 2013

The regional concentrations of pancreatic polypeptide (PP), insulin, and glucagon and the cellular distribution of PP were studied in 13 human and nine canine pancreases by radioimmunoassay, immunoperoxidase localization, and cell quantitation. PP concentration was highest in both the uncinate process and the head of the human pancreas and in the right lobe of the canine pancreas. In contrast, glucagon and insulin levels were higher in the body and tail of both the human and canine pancreases.

Human F-cells, which contain PP, were located primarily at the periphery of the islets, although a few F-cells were scattered throughout the ducts and acini. Canine F-cells were located in ducts, acini, and islets; the relative proportion of canine F-cells in the endocrine and exocrine tissues differed according to location.

Cellular quantitation of F-cells in both species correlated significantly with the tissue concentration of PP in all regions studied, validating the use of morphometric techniques to quantitate the regional distribution of PP.
Detection of Early Retinal Changes in Diabetes by Vitreous Fluorophotometry
Authors: Cunha-Vaz Jose G , Fonseca Jose R , Abreu Jose F , Ruas Manuel A
Published: September 2013

A series of 77 patients with overt diabetes and with apparently normal fundi on ophthalmoscopy and fluorescein angiography was examined by vitreous fluorophotometry. Breakdown of the blood-retinal barrier, which appears to be the earliest clinically detectable change in the retina in diabetes, was a constant finding. Quantitative measurement by vitreous fluorophotometry of the breakdown of the blood-retinal barrier could be correlated with degree of metabolic control and previous duration of diabetic disease. Significantly higher vitreous fluorophotometry values, indicating a more marked breakdown of the bloodretinal barrier, were recorded in patients under poor metabolic control than in patients whose diabetes was under relatively better control. Similarly, patients who had had diabetes for longer periods of time showed higher vitreous fluorophotometry values than those recorded in patients with diabetes of shorter duration.
Counterregulatory Hormonal Responses to Rapid Glucose Lowering in Diabetic Man
Authors: Lilavivathana Usah , Brodows Robert G , Woolf Paul D , Campbell Robert G
Published: September 2013

To define whether rapid rate of fall in blood glucose stimulates counterregulatory hormonal responses in diabetic man, blood glucose in eight hyperglycemic diabetic subjects was rapidly lowered by intravenous insulin administration. Despite precipitous declines in blood glucose, plasma epinephrine and growth hormone remained virtually unchanged. In contrast, norepinephrine and cortisol increased significantly (P < 0.025) in the face of hyperglycemia or euglycemia, while glucagon was suppressed (P < 0.025). A transient modest fall in mean arterial pressure and a rise in pulse rate were noted. No correlation was observed between glucose disappearance rate or decrement in glucose concentration and the hormonal responses. After sham insulin administration, no change was observed in plasma epinephrine, norepinephrine, and cortisol levels.

These findings suggest that rate of fall in blood glucose per se is not a primary signal for counterregulatory hormonal response. Cortisol but not growth hormone release during falling blood glucose in diabetic subjects can occur despite elevated blood glucose levels. The etiology of norepinephrine and cortisol change is unclear.
Is the Hypertriglyceridemia Associated with Insulin Deficiency Caused by Decreased Lipoprotein Lipase Activity?
Authors: Chen Yii-Der Ida , Risser Tranquilina R , Cully Michael , Reaven Gerald M
Published: September 2013

Questions have been raised as to whether reduced lipoprotein lipase (LPL) activity can account for the defect in plasma removal of very low density lipoprotein (VLDL) associated with insulin deficiency. In order to study this issue, streptozotocin-induced insulin deficiency was produced in 2-mo-old rats. Three groups of rats were studied: control, moderate diabetes (glucose > 200 < 350 mg/dl), and severe diabetes (glucose > 350 mg/dl). One week later food was withdrawn at 8 a.m., and the following measurements made at 2 p.m. (6 h after removal of food): (1) plasma glucose, insulin, and triglyceride (TG) levels; (2) VLDL-TG secretion rate; and (3) adipose tissue and skeletal muscle LPL activity. Rats with moderate diabetes had higher glucose and lower insulin levels than did control rats, and these differences were accentuated in rats with severe diabetes. Plasma TG levels were elevated (P < 0.001) in rats with moderate (↑99%) and severe diabetes (↑126%), and this was associated with a fall (P < 0.001) in VLDL-TG secretion. An increase in plasma TG levels, despite a decrease in VLDL-TG secretion, indicates the presence of a profound defect in VLDL-TG removal from plasma. However, muscle LPL of rats with severe diabetes and moderate diabetes was equal to that of control rats, and adipose tissue LPL was only moderately (P < 0.05) reduced (MD = ↓25%, SD = ↓32%). These results indicate that plasma TG levels rise in young, insulin-deficient rats as a result of a defect in removal of VLDL-TG from plasma. This removal defect is associated with normal muscle and only moderately reduced adipose tissue LPL activity, suggesting that the VLDL-TG removal defect associated with insulin deficiency may not be a simple function of a decrease in total (muscle + adipose tissue) LPL activity.
High Prevalence of Diabetes in Young Pima Indians: Evidence of Phenotypic Variation in a Genetically Isolated Population
Authors: Savage Peter J , Bennett Peter H , Gordon Senter R , Miller Max
Published: September 2013

Medical records of the Pima Indian population aged 0–24 yr were reviewed for a diagnosis of diabetes before initiation of glucose tolerance testing. None of 1556 subjects below age 15, but 6 of 657 aged 15–24, had a previous diagnosis. Of the six known diabetics, five had been treated with insulin and four had had ketoacidosis. Subsequently, plasma glucose levels were determined after a 75-g oral carbohydrate load in 1712 subjects aged 5–24 yr, which is about 78% of the eligible population. Previously diagnosed diabetes and asymptomatic hyperglycemia were more frequent in subjects 15–24 yr old than were reported in other populations. Glucose intolerance in young Pimas was associated with obesity. In Pima offspring, the presence of diabetes in both parents was related to glucose tolerance in those above but not below the age of 15 yr. Both asymptomatic hyperglycemia and insulin-requiring diabetes occurred frequently in young Pimas, suggesting that these syndromes represent the clinical spectrum of a single disease in the Pima Indian.
A Malignant Insulinoma Transformed into a Glucagonoma Syndrome
Authors: Ohneda Akira , Otsuki Masao , Fujiya Hiroshi , Yaginuma Nobuhisa , Kokubo Takeshi , Ohtani Haruo
Published: September 2013

A 55-yr-old man was admitted to the Hospital of Tohoku University in 1970, when physical examination and laboratory findings revealed malignant insulinoma with metastases to the liver. Streptozotocin treatment, totaling 79.5 g for 1 yr, improved his clinical symptoms. After discharge he was well until 1977, when he complained of palpitation and dyspnea, and he was hospitalized in September 1977 because of anorexia and a loss of body weight. Laboratory findings revealed anemia, with a decrease both in serum albumin and iron. His fasting blood glucose was 74 mg/dl and plasma insulin (IRI) 25 μU/ml. His plasma IRI increased slightly after the stimuli of glucose, arginine, and glucagon. In contrast, his plasma glucagon (IRG) increased at fasting (3372 pg/ml) and became markedly elevated after arginine or glucose was administered. After his final admission, diazoxide improved his symptoms temporarily; streptozotocin could not be administered because of dyspnea and palpitation. On 24 January 1978, he fell suddenly into a coma and 2 days later he died. An autopsy revealed a large pancreatic tumor and metastases to the liver. Measurement of hormones from the tissues revealed a smaller amount of IRI in the pancreatic tumor and liver metastases compared with that in the uninvolved pancreas. In contrast, IRG contents had increased in the pancreatic tumor and hepatic metastases. In addition to the insulin cells, numerous cells with glucagon and somatostatin were observed in morphologic examinations. This indicated a mixed endocrine pancreatic tumor exhibiting typical symptoms of insulinoma initially and a glucagonoma syndrome later.
A Simplified Method Using Somatostatin to Assess In Vivo Insulin Resistance over a Range of Obesity
Authors: Nagulesparan M , Savage Peter J , Unger Roger H , Bennett Peter H
Published: September 2013

Twenty-one nondiabetic subjects, their weights ranging from 56 to 165 kg, received an infusion of glucose (420 mg/min), insulin (0.77 mU/kg/min), and somatostatin (500 figlh) for 150 min. A steady state level of plasma insulin and glucose was attained after 90 min. Endogenous insulin secretion, determined by C-peptide measurement, and glucagon secretion remained suppressed throughout the period. With similar steady state levels of plasma insulin (SSPI) maintained in all subjects, the height of the steady state plasma glucose concentration (SSPG) was considered an index of total body sensitivity to insulin-mediated glucose uptake. A positive correlation between SSPG and the degree of obesity, as determined by the body mass index (BMI), was demonstrated (r = 0.70, P < 0.001). No correlation was found between SSPI and BMI. The fasting plasma insulin concentration correlated with BMI (r = 0.82, P < 0.0001) and SSPG (r = 0.80, P < 0.0001).

This method provides a simple safe measure of total body insulin resistance over a wide range of obesity and is independent of endogenous insulin secretion.
Bimodality of Glycosylated Hemoglobin Distribution in Pima Indians: Relationship to Fasting Hyperglycemia
Authors: Flock Eunice V , Bennett Peter H , Savage Peter J , Webner Caryll J , Howard Barbara V , Rushforth Norman B , Miller Max
Published: September 2013

Glycosylated hemoglobin (HbA1) concentrations were determined in 300 Pima Indians aged 15 yr and older. Frequency distributions of HbA, were unimodal in the 15-24-yr-old age group, but were bimodal in those aged 25 yr and over. The bimodality indicated that the subpopulation with diabetes could be identified by the presence of elevated HbA1 levels. This group was comprised primarily of subjects who also had fasting plasma glucose levels of < 140 mg/dl, but subjects with impaired glucose tolerance without fasting hyperglycemia had HbA1 levels that were not significantly higher than those with normal glucose tolerance. The prevalence of diabetic retinopathy was much higher in the subgroup with elevated HbA1 levels and increased with increasing HbA1 level. HbA1 levels and triglyceride concentrations showed only a modest association. HbA1 determinations provided no advantage over fasting or post challenge glucose levels in the diagnosis Of diabetes.
Immunoreactivity of Insulin Antibodies in Insulin-treated Diabetics: Significance of the Beta-chain Carboxyterminal Amino Acid (B-30) of Insulin
Authors: Kumar Dinesh
Published: September 2013

We investigated the immunoreactivity of the carboxyterminal amino acid residue of the beta-chain of insulin using sera from 22 insulin-resistant and 51 nonresistant diabetic patients. We used three insulins, human, porcine, and desalaninated porcine, which differ only at the B-30 amino acid residue. The binding of 125I-human and 125I-desalanine porcine insulins with antibodies was reduced compared with that of 125lporcine insulin. Two-thirds of the insulin-resistant sera differentiated porcine and desalanine porcine insulins and had lower avidities for the latter. Most of these sera had lower affinities for human insulin compared with other insulins. The antibodies that bind with 125I-desalanine porcine insulin showed equal avidities for the human and unmodified porcine insulins. Five insulin-resistant patients had been treated with the commercial desalanine (dalanated) porcine insulin. One had a prompt reduction in insulin requirements, and three others needed reduced maintenance dosages. Sera of these four cases, but not of the nonresponder, had lower avidities for desalanine porcine insulin compared with porcine insulin. These observations indicate that the amino acid alanine at the B-30 position in the insulin molecule can influence the immunoreactivity of insulin antibodies in human sera, and may be a potential immune determinant.
The Intravenous, Intraperitoneal, and Subcutaneous Routes of Insulin Delivery in Diabetic Man
Authors: Schade David S , Eaton R Philip , Friedman Neal , Spencer William
Published: September 2013

Successful implantation of an artificial pancreas requires the infusion of insulin into an appropriate anatomic site. Three sites being actively investigated include (1) intravenous (i.V.), (2) intraperitoneal (i.p.), and (3) subcutaneous (s.c). This study compared the rate, magnitude, and duration of insulin absorption from these three absorption sites as assessed by the appearance of “free” insulin into the plasma of 10 insulin-dependent diabetic subjects. The biologic effectiveness of insulin was assessed by the suppression of plasma glucose concentration following a 750-calorie meal.

Our results suggest that i.v. delivered insulin provides the most rapid increase in plasma free insulin concentration, followed by the i.p. and s.c. routes, respectively. In contrast, the elevation of plasma free insulin concentration was most prolonged with the s.c. route, followed by i.p. and i.v. routes, respectively. Compared with the i.v. and s.c. routes of insulin delivery, only 50% of the i.p. delivered insulin appeared in the plasma. The onset of the biologic activity of the insulin delivered by the three different routes during the 4½-h observation period was most rapid for the i.v. and least rapid for the s.c. route. These results suggest that all three routes may be appropriate sites for delivery of insulin from an artificial pancreas. However, because of the difference in absorption kinetics and the onset of biologic effectiveness of the delivered insulin, different quantities and timing of insulin delivery may be needed.
Effectiveness of Insulin Therapy on Altered Renal Calcium Transport in Diabetic Rats
Authors: Hoskins Beth , Feibelman Richard Y , Koury Albert M , Taylor Ralph
Published: September 2013

The uptake of 45Ca was measured in slices of kidney cortex from normal rats, streptozotocin-diabetic rats, and streptozotocin-diabetic rats treated early and late with insulin. Insulin therapy was performed such that blood glucose levels were controlled in half the treated diabetic animals but not in the others.

Considerably earlier than evidence of nephropathy (i.e., proteinuria and increased BUN levels) in streptozotocin-diabetic rats, there was a significant decrease in active uptake of calcium by the kidney. Insulin therapy, begun immediately upon diagnosis of diabetes, maintained normal calcium transport even when blood glucose levels were not controlled. On the other hand, insulin therapy, begun 1 mo after diabetes was confirmed but before evidence of nephropathy, did not restore calcium transport to normal whether or not blood glucose was controlled.

We conclude that this biochemical mechanism, which possibly may be implicated in the pathophysiology of diabetic nephropathy, is clearly influenced by duration of insulin deficiency and not by the degree in hyperglycemia.
Physiologic Responses of Juvenile-Onset Diabetic Boys to Muscular Work
Authors: Hagan R Donald , Marks James F , Warren Paul A
Published: September 2013

The cardiorespiratory and metabolic responses of juvenile-onset diabetic (Dia) and nondiabetic (Con) boys to light, moderate, and maximal treadmill work were investigated. No significant differences were observed between the Dia and Con subjects in cardiorespiratory responses to maximal and submaximal work. The mean values for the Dia boys during maximal treadmill work for ventilatory volume, oxygen uptake, heart rate, and lactic acid were 91.5 L/min, 54.9 ml/kg · min, 198 beats/min, and 7.0 m M/L, respectively. In the Dia boys, maximal-, light-, and moderate-intensity work produced significant plasma glucose decreases (P < 0.05) of 1.64, 3.23, and 7.2 mM/L, respectively. In the Con boys, the submaximal work bouts were performed without significant change in plasma glucose levels, but glucose levels after maximal work were elevated 1.58 mM/L. Light and moderate work in both groups produced no changes in plasma triglycerides, free fatty acids, or lactic acid. However, for the Dia boys, maximal work was associated with a significant increase of 0.36 mM/L in triglycerides.
Insulin Secretion and Cyclic Adenosine 3',5'-Monophosphate Levels in Pancreatic Islets of Fed and Fasted Rats: Time Course and Dose Kinetics During Glucose Stimulation
Authors: Bouman Paul R , Wolters Gerrit H J , Konijnendijk Willem
Published: September 2013

Incubation of pancreatic islets of fed rats at glucose 10 and 15 mM induced a rapid rise of the islet cyclic adenosine 3',5'-monophosphate (cAMP) content. Maximum levels were attained at 15 min and lasted until 30 min, after which cAMP declined again. Insulin secretion increased most rapidly from 15 min onward, i.e. after the rapid rise of cAMP. Islet cAMP at either 15 or 30 min showed its major concentration-dependent increase between glucose 7.5 and 10 mM. Glucose 15 mM did not further enhance the cAMP response, although this concentration increased insulin secretion more than two-fold over values observed at glucose 10 mM. Thus, the glucose dose-response relations for cAMP levels and insulin secretion appear to be different, indicating that factors other than cAMP alone determine the secretory response to glucose.

Fasting for 24 and 72 h progressively inhibited glucose-induced insulin secretion. At glucose 15 mM the secretory inhibition disappeared after 30–45 min, but at glucose 10 mM it persisted for at least 90 min. Increasing periods of fasting also progressively delayed and inhibited the cAMP response to glucose, most strongly at glucose 10 mM. Fasting for 24 h shifted the glucose dose-response curves for cAMP and insulin secretion to the right, but the maximum responses at glucose 37.5 mM were not significantly inhibited. The secretory inhibition appeared to be linearly related with the cAMP content in two different ways: (a) At fixed concentrations of glucose, the increasing inhibition of the cAMP response (at 15 min) as induced by 24 and 72 h of fasting correlated with the secretory inhibition over the initial 30 min. (b) At one fixed period of fasting (24 h), the variable percent inhibition of the cAMP response to graded concentrations of glucose (5–37.5 mM) correlated with the percent secretory inhibition at these concentrations.

These correlations were no longer apparent after 30 min of incubation. The results support the view that inhibition of the adenylate cyclase-cAMP system is a major determinant factor in fasting-induced impairment of insulin secretion during the initial 30 min of glucose Stimulation.