bluuebunny/crossref_metadata_2025 huggingface dataset:
Reversal of Abnormalities in Ocular Fluorophotometry in Insulin-dependent Diabetes After Five to Nine Months of Improved Metabolic Control
Authors: White Neil H , Waltman Stephen R , Krupin Theodore , Santiago Julio V
Published: September 2013

Abnormalities in ocular fluorophotometry occur in human and experimental diabetes mellitus. To determine the reversibility of these abnormalities, we studied prospectively 11 intensively treated and 25 conventionally treated insulin-dependent diabetics (IDD) preselected because of abnormal vitreous fluorophotometry. Among the 25 IDD treated conventionally with one or two insulin injections daily, hemoglobin A1C concentrations remained elevated and fluorescein concentration, 1 h after the intravenous injection of fluorescein (7 mg/kg), did not change significantly in either the anterior chamber or the posterior vitreous.

Among 11 IDD treated intensively with home blood glucose monitoring and pumped subcutaneous insulin or three or more injections daily, hemoglobin A1C fell dramatically (10.4 ± 0.7% to 7.5 ± 0.2%) and anterior chamber fluorescein concentration decreased (73.9 ± 7.7 to 49.5 ± 5.3 ng/ml). Two patients with proliferative retinopathy showed no improvement in their massive vitreous fluorescein accumulation and subsequently required photocoagulation. In the nine subjects without proliferative retinopathy, vitreous fluorescein accumulation decreased in eight (10.6 ± 0.7 to 6.5 ± 0.5 ng/ml) and was normal in six after 1 yr. The only subject with increasing vitreous fluorescein accumulation also had concurrent worsening of background retinopathy.

These studies support the hypothesis that moderate abnormalities in ocular fluorophotometry are due to reversible changes in ocular tissues, such as retinal pigment epithelium. Fluorescein leakage emanating from the advanced vascular or retinal abnormalities of proliferative retinopathy were not reversed with the degree and duration of metabolic control achieved in the present study. The long-term significance of the reversal of moderate abnormalities in fluorophotometry is not clear at the present time.
Diabetes-Obesity Syndromes in Mice
Authors: Coleman Douglas L
Published: September 2013

Several different rodent models are available for metabolic studies on the development of diabetes. Although the abnormalities associated with each diabetes type have many features in common, the documentation of several different genes being involved makes it unlikely that the various syndromes will be reduced to a single disturbance in one metabolic pathway. The severity of the diabetes produced depends on the interaction of the individual mutation with genetic factors in the inbred background of the host. Establishing the nature of these gene-host interactions in rodents should aid us in understanding similar interactions that occur in human diabetes. The development of the syndrome in most models is similar and includes hyperinsulinemia, hyperphagia, and'attempts at increasing insulin supply by β-cell hyperpiasia and hypertrophy in the early stages. Hyperglycemia, obesity, and severe diabetes are secondary features that result from a combination of insulin resistance and a failure to sustain the secretion of the large amounts of insulin. Most models utilize ingested food and stored food reserves more efficiently. This increased metabolic efficiency extends to heterozygotes that are normal in all respects having only one dose of the deleterious gene. Establishing this increased metabolic efficiency in heterozygotes lends credence to the thrifty gene hypothesis of diabetes and suggests a mechanism whereby some deleterious diabetes genes may be favored in the human population. The best studied mouse models, and those for which the most complete information is available, are those caused by single genes, e.g., yellow, obese, diabetes, tubby, and fat. In the other models, the mode of inheritance is either polygenic or otherwise unclear, features which interfere with the interpretation of the data. This report briefly summarizes the developing syndrome in each model, points out any differences, and suggests the most appropriate areas where future research should be most productive in the light of contemporary studies.
Kidney Complications
Authors: Brown David M , Andres Giuseppe A , Hostetter Thomas H , Mauer S Michael , Price Robert , Venkatachalam M A
Published: September 2013

Diabetic glomeruiosclerosis in man and in all spontaneousonset and chemically induced diabetes in experimental models is characterised by diffuse increase in mesangial matrix and glomerular basement membrane thickening. The most prominent features of the biochemical changes in the glomerular basement membrane are increase in the collagen-like components, decreased sialic acid, and increased giucosylation. However, the heterogeneity of the various glycoprotein components of the glomerular basement membrane and related components of the mesangium make comparative biochemistry difficult, increased glomerular blood flow with no apparent alterations in the glomerular filtration coefficient in diabetes may be attributed to altered vascular control mechanisms which may include both hormonal mediation as well as changes in end-organ responsiveness. Although proteinuria is a common manifestation of diabetic involvement of the glomerulus, there is little biochemical or physiologic evidence as to the specific causes of increased glomerular filtration apparatus permeability. Further information as to the pathogenesis of diabetic vascular disease of the kidney and the ability to reverse pathologic changes by correction of the metabolic milieu will require analysis of carefully selected animal models. Particular care in experimental design must include the ability to integrate pathology, physiology, and biochemistry in each model in order to relate the information to human renal diabetic complications.
Complications of Pregnancy and Fetal Development
Authors: Farrell Philip M , Engle Michael J , Frantz Ivan D , Goldman Allen S , Kalkhoff Ronald , Kemnitz Joseph W , Perelman Robert , Stern Judy S , Susa John B
Published: September 2013

Although the outcome of pregnancy for women with diabetes meilitus has improved in recent years, the infant of the diabetic mother has an increased risk of major clinical problems, particularly in the early neonatal period. These include birth injury due to macrosomia, neonatal hypoglycemia, respiratory distress syndrome, and serious congenital anomalies. Because of the great difficulties encountered during attempts to investigate these problems in clinical research protocols, there is a continuing need to establish appropriate animal models of the diabetic pregnancy. Studies carried out over the past decade, primarily with chemically-induced diabetes have suggested techniques which might be useful. In general, the choice of the animal to be studied will depend on the hypotheses being addressed. For instance, small animals such as rabbits and rats made diabetic with streptozotocin have been successfully used for investigation of fetal lung development. Furthermore, the rat model has been helpful for evaluation of fetal anomalies associated with maldevelopment of the spine and central nervous system. Larger animals, such as the nonhuman primate, are more appropriate for studying placental function and amniotic fluid composition in diabetic pregnancies. The task group on pregnancy and fetal development recommends that animal models of diabetes meilitus be used for a more extensive hormonal and metabolic characterization of diabetic mothers during pregnancy, for investigation of placental physiology with respect to the transfer of substrates from mother to fetus, for systematic and comprehensive study of mechanisms controlling fetal lung development, and for delineation of the pathophysiology of neonatal hypoglycemia. it is further recommended that animal models of spontaneous diabetes such as the BB/W rat be used in future studies dealing with pregnancy and fetal development. Because females with spontaneous diabetes show reduced conception rates, there is a pressing need to enhance the fertility of these animals in order to intensify studies on fetal development.
Insulin Resistance in Diabetic Ketoacidosis
Authors: Barrett Eugene J , DeFronzo Ralph A , Bevilacqua Stefano , Ferrannini Eleuterio
Published: September 2013

The effect of “low-dose” (6–10 U/h) insulin treatment on the rate of decline of plasma glucose concentration was determined in 15 diabetic subjects admitted in ketoacidosis (plasma glucose = 948 ± 79 mg/dl) and in six normal volunteers rendered hyperglycemic by a combined infusion of somatostatin and glucose (plasma glucose = 653 ± 28 mg/dl). The fractional glucose turnover and the half-time of the fall in plasma glucose during insulin treatment were both 10-fold reduced (P < 0.001) in the diabetics as compared with the controls. In the ketoacidotic subjects, the mean glucose clearance during insulin treatment was only 8% of that in the controls (P < 0.001). In the normal subjects, tissue glucose clearance during insulin treatment of the hyperglycemia (5.8 ± 0.7 ml/min · kg) was similar to that measured in the same subjects using a standard technique to quantitate insulin sensitivity (euglycemic insulin clamp).

In the ketoacidotic patients, a history of prior insulin therapy, but not the degree of hyperglycemia at the time of admission, was associated with a more rapid rate of decline of plasma glucose in response to insulin treatment. We conclude that marked insulin resistance is present in virtually all diabetics in ketoacidosis.
In Vivo Deactivation of Peripheral, Hepatic, and Pancreatic Insulin Action in Man
Authors: Gray R S , Scarlett J A , Griffin J , Olefsky J M , Kolterman O G
Published: September 2013

The in vivo deactivation of insulin action has been studied in 10 lean, nondiabetic subjects using a modification of the euglycemic glucose clamp technique. Following cessation of 40- and 120-mU/m2/min insulin infusions, the serum insulin levels fell to one-half their initial values (mean ± SE) of 126 ± 7 and 350 ± 14 μU/ml in 7 ± 1 and 8 ± 1 min, respectively. The mean incremental glucose disposal rates (IGDR) fell more slowly following discontinuation of the 40- and 120-mU/m2/min insulin infusions, so that the time required for the IGDRs to fall to one-half their initial values (D50 IGDR) were were 42 ± 5 and 78 ± 5 min, respectively. Mean hepatic glucose output was totally suppressed during the 40- and 120-mU/m2/min insulin infusions, remained completely suppressed following cessation of the infusions for 50 and 80 min, and subsequently returned to basal levels. The times required for the HGOs to return to one-half their basal levels (R50 HGO) were 59 ± 8 and 119 ± 6 min, respectively. The times required for insulin action to decrease to one-half the initial values in the periphery (D50 IGDR) and in the liver (R50 HGO) were correlated with the preceding steady-state glucose disposal rates in individual subjects (r = 0.75, P < 0.001 and r = 0.58, P < 0.05, respectively). The suppression of endogenous insulin secretion by exogenous insulin infusions was also studied in 4 subjects during a total of 5 euglycemic glucose clamps; the mean basal serum C-peptide level was 0.67 ± 0.24 pmol/ml before administration of the exogenous insulin, fell to 0.34 ± 0.17 pmol/ml during the steady-state phase of the study, and remained suppressed throughout the duration of the deactivation phase of the glucose clamp. Residual pancreatic insulin secretory capacity was demonstrated by a rise in the serum C-peptide level to 1.77 ± 0.50 pmol/ml at 120 min following a standardized meal given at the conclusion of the deactivation phase of the glucose clamp.

These results demonstrate that the deactivation of insulin action in the periphery, liver, and pancreas lags behind the disappearance of insulin from the plasma. The mechanisms responsible for this lag in in vivo deactivation are not known for certain, but may include slower clearance of insulin form tissue compartments than form the plasma, the necessity for the target tissues to generate specific deactivation signals, or a slow rate of decay of saturable steps in the cellular activation process.
Beta-Cell Dysfunction in Nondiabetic HLA Identical Siblings of Insulin-Dependent Diabetics
Authors: Hollander Priscilla H , Asplin Christopher M , Kniaz Daniel , Hansen John A , Palmer Jerry P
Published: September 2013

B-cell function was tested in siblings of insulin-dependent diabetics (IDD). From previous studies, it is now recognized that the risk of developing IDD is highest in those sharing both haplotypes (S2H) and lowest in those sharing neither haplotype (SOH) with the diabetic. Insulin secretion in response to intravenous arginine and glucose was evaluated in S2H, SOH, and matched controls. Intravenous arginine and glucose elicited an exaggerated acute phase of insulin secretion in S2H compared with controls when analyzed as incremental insulin area 0–10′, peak level attained, and mean insulin levels postinjection. Insulin responses to arginine and glucose in SOH and matched controls were identical. We hypothesize that the increased beta-cell activity found in S2H predisposes their beta-cells to damage by environmental factors and may be part of the mechanism conferring the increased risk of IDD in S2H.
Contractile and Electrical Characteristics of Extensor Muscle from Alloxan-Diabetic Rats: An In Vitro Study
Authors: Grossie J
Published: September 2013

Diabetes mellitus was produced by withholding insulin from female rats previously treated with alloxan. In vitro studies of contractile and electrical properties of the extensor digitorum longus muscle were analyzed at various periods following cessation of insulin treatment. In severely diabetic ketoacidotic rat muscles it was observed that both direct and indirectly induced twitch and tetanic tensions were significantly reduced to the same degree. Resting membrane potentials were significantly reduced but repolarized when external chloride was removed. Indirectly induced action potential amplitude and rate of depolarization were significantly depressed and there was a significant increase in action potential duration. Specific membrane in action potential duration. Specific membrane resistance decreased significantly but transiently due largely to an increase in chloride conductance and specific capacitance increased significantly. After extended periods of milder diabetes, specific tetanic tension decreased slightly while specific twitch tension was unchanged in both direct and indirectly induced contractions. Resting potentials were only slightly reduced. Indirectly elicited action potential amplitude and rate of depolarization were slightly reduced. Specific membrane resistance was significantly increased largely due to decreases in chloride conductance. Specific capacitance was unchanged.
Decreased Insulin Binding, Glucose Transport, and Glucose Metabolism in Soleus Muscle of Rats Fed a High Fat Diet
Authors: Grundleger Melvin L , Thenen Shirley W
Published: September 2013

The relationship between diet and insulin sensitivity was examined in isolated soleus muscle from 10-wk-old lean Zucker rats. Rats were fed either a high fat or high carbohydrate diet that had 67% of calories as fat or carbohydrate, respectively, for 10 days. Plasma insulin but not plasma glucose concentrations were significantly elevated in high-fat-fed rats, indicating that a state of insulin resistance existed. The mechanisms responsible for the insulin resistance were studied by measuring insulin binding, 2-deoxyglucose uptake, and glucose metabolism in soleus muscle. The soleus muscle from the high-fat-fed rats bound significantly less insulin than high carbohydrate control rats under equilibrium binding conditions. The 35% decrease in insulin binding at maximal insulin concentrations resulted from a decrease in insulin receptor number but no change in receptor affinity. Maximal insulin-stimulated 2-deoxyglucose uptake was reduced in soleus muscle from high-fat-fed rats when compared with high carbohydrate controls.

A decrease in postmembrane basal and insulin-stimulated glucose utilization was produced by high rat feeding and varied depending upon the pathway involved. An estimate of glycolysis (3H2O) formation from [5-3H]glucose) and glucose oxidation (14CO2 production from 14C-glucose) demonstrated a greater decrease in basal and insulin-stimulated utilization than in [5-3H]glucose conversion to [3H]glycogen. These results suggest that multiple sites are responsible for the observed insulin resistance in soleus muscle after high fat feeding.
Nonenzymatic Browning via the Maillard Reaction in Foods
Authors: Saltmarch Miriam , Labuza Theodore P
Published: September 2013

Nonenzymatic glycosylation of human hemoglobin has recently received increased attention because of its relevance to diabetes mellitus. The reaction of carbohydrates and protein, often called the Maillard reaction, is well known in the food industry. The Maillard reaction is actually a complex scheme of many reactions and is the primary type of nonenzymatic browning that can occur in dehydrated or semimoist foods during storage. This reaction results from reducing compounds, primarily sugars, reacting with proteins, peptides, amino acids, or free amine groups and results in changes in the aesthetic, functional, and nutritional properties of the food in which the reaction occurs.

In the present review, no attempt is made to cover all the literature. Rather, attention is given to the various chemical and physical factors that can affect the Maillard reaction in foods. Chemical factors include the type and amount of initial reactant species, pH, water content or water activity, and the presence of substances such as liquid humectants and bisulfite. In addition physical factors such as processing and storage temperature, atmospheric oxygen, and packaging during storage can affect the Maillard reaction in foods.
Clinical Application of Glycosylated Hemoglobin Measurements
Authors: Goldstein David E , Parker K Michael , England Jack D , England Jack E , Wiedmeyer Hsiao-Mei , Rawlings Sharon S , Hess Randall , Little Randie R , Simonds John F , Breyfogle Russell P
Published: September 2013

Glycosylated hemoglobin measurement has been shown to be a potentially useful tool for both a variety of research applications and for the management of patients with diabetes mellitus. None of the methods available to quantitate glycosylated hemoglobins is ideal. We have reviewed a number of critical methodologie considerations for Chromatographie procedures including the effects of sample storage under various conditions, and the importance of removing labile components prior to analyses. We have developed a method for the colorimetrie determination of glycosylated hemoglobins that is more rapid than methods reported previously, that correlates well with results using high-performance liquid chromatogra-phy, and that can he standardized between laboratories. We have reviewed our experience using glycosylated hemoglobin in a large population of diabetic youths. We have presented a method for developing realistic goals for glucose control using glycosylated hemoglobin and for using glycosylated hemoglobin as a patient education and care reinforcement tool.
Quantitative Evaluation of Cardiac Parasympathetic Activity in Normal and Diabetic Man
Authors: Pfeifer Michael A , Cook Daniel , Brodsky Joel , Tice David , Reenan A , Swedine Sally , Halter Jeffrey B , Porte Daniel
Published: September 2013

Heart rate and RR variation (the standard deviation of the mean RR interval for a 5-min period) were evaluated as measurements of cardiac parasympathetic nervous system activity in fasting supine diabetic (N = 22) and comparable age normal (N = 22) subjects. The rate of breathing did not effect heart rate, but was inversely related to the RR variation (r = 0.89, P < 0.01). Heart rate was increased (P < 0.0001) and RR variation decreased (P < 0.05) during β-adrenergic stimulation with isoproterenol and during parasympathetic blockade with atropine (both P < 0.0001). Hence, the cardiac effects of β-adrenergic stimulation may mimic the effects of diminished parasympathetic function. To evaluate parasympathetic control of RR variation, independently of possible effects of increased sympathetic activities, studies were performed during β-adrenergic blockade with propranolol. RR variation during propranolol was less both in 14 diabetic subjects without clinical symptoms of autonomic neuropathy (P < 0.005) and in 8 diabetics with clinical symptoms of autonomic neuropathy (P < 0.001) when compared with 22 age-comparable normal subjects. The measurement of RR variation was very reproducible with a day-to-day coefficient of variation of 9.7 ± 2.8﹪ (x̄ ± SEM) in diabetic subjects with stable hyperglycemia. It is concluded that supine RR variation during a deep respiratory rate and during β-adrenergic blockade is a sensitive, quantitative, and reproducible method to evaluate parasympathetic nervous activity in normal and diabetic subjects. Furthermore, cardiac parasympathetic activity may be diminished in diabetic subjects before clinical symptoms of autonomic neuropathy are evident.
Transplantation of Islets and Bone Marrow Cells to Animals with Immune Insulitis
Authors: Naji Ali , Bellgrau Donald , Anderson Arthur , Silvers Willys K , Barker Clyde F
Published: September 2013

The results of islet transplantation in an animal model of spontaneous immune insulitis were studied to see whether this disease process might damage transplanted tissue. Since the insulitis occurs only in “BB” rats (which are not genetically uniform) syngeneic grafts could not be used, therefore allograft rejection was avoided by rendering “BB” rats tolerant of WF transplantation antigens by inoculating them neonatally with WF bone marrow cells. Despite the resultant tolerant state, which permitted successful engraftment of WF skin and islets transplanted to artificially diabetic “BB” rats, tolerant “BB” rats with spontaneous diabetes accepted transplanted WF islets only briefly before they were destroyed by immune insulitis.

“BB” rats were found to have abnormalities in immune response (delayed skin graft rejection and decreased alloreactivity in mixed lymphocyte response). However, the immune response was more normal in “BB” rats that were treated neonatally with WF bone marrow. Moreover, “BB” rats inoculated with WF bone marrow neonatally were found less likely to become diabetic than untreated “BB” controls. It is suggested that the chimeric state (persistence of WF bone marrow cells) may be responsible for the improved immune response and perhaps for the decreased susceptibility to diabetes.
Comparison of Insulin Secretion and In Vivo Insulin Action in Nonobese and Moderately Obese Individuals with Non-insulin-dependent Diabetes Mellitus
Authors: Reaven Gerald M , Doberne Leonard , Greenfield Michael S
Published: September 2013

Insulin secretion and in vivo insulin action were quantified in nonobese and moderately obese patients (approximately 30% overweight) with non-insulin-dependent diabetes mellitus (NIDDM), matched for severity of diabetes. Insulin secretion was assessed by determining plasma insulin responses to a test meal given at noon, and in vivo insulin action by the insulin clamp technique. No significant differences were noted between the two groups for either variable. Thus, it cannot be assumed that the cause of hyperglycemia in patients with NIDDM differs between nonobese and moderately obese subjects.
Ten-Year Prognosis of Impaired Glucose Tolerance in Siblings of Patients with Insulin-dependent Diabetes
Authors: Rosenbloom Arlan L , Hunt Sarah S , Rosenbloom Edith K , Maclaren Noel K
Published: September 2013

We traced 105 of 140 siblings of children with insulin-dependent diabetes (IDD) who had had oral glucose tolerance tests (OGTT) 10–12 yr earlier. Siblings with abnormal tests by screening criteria (8.3 mmol/L at 1 h, 7.2 at 2 h, N = 44) included all 6 who subsequently developed IDD after 3 mo to 7 yr (5.7% of entire group, 13.6% of abnormal screenees). The National Diabetes Data Group criterion for children (7.8 mmol/L at 2 h) identified 19 siblings, including 5 of the 6 who later developed IDD (26% of abnormals). Subsequent full 4-h OGTT, including analysis of insulin responses, did not improve predictability for subsequent IDD. Thus, siblings of IDD were identified at high risk (14–26%) or at low risk (0–1%) for subsequent IDD by a simple 2-h OGTT. The prolonged latency in the development of IDD indicates that, among siblings of IDD, this disorder may be already chronic for years by the time of clinical onset.
Calcium Intake Regulates 1,25-Dihydroxy-Vitamin D Formation in the Diabetic Rat
Authors: Wilson H D , Horst R L , Schedl H P
Published: September 2013

Duodenal calcium absorption and serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations are decreased and body growth is arrested in the streptozotocin-diabetic rat taking commercial chow with high (1.2–2%) calcium content. Treatment with insulin restores 1,25-(OH)2D3, calcium absorption, and body growth to normal. We hypothesized that the depressed 1,25-(OH)2D3 in diabetics is due in part to the minimal requirement for vitamin-D-mediated intestinal calcium transport under conditions of arrested growth and high calcium intake. We tested this hypothesis by comparing the response of serum 1,25-(OH)2D3 concentration to low (0.02%) and normal (0.5%) calcium diets in control and streptozotocin-diabetic rats. To evaluate response to short-term insulin treatment, serum 1,25-(OH)2D3 was measured after 12 or 36 h of treatment. Serum 1,25-(OH)2D3 concentrations in the 0.5% calcium diet groups were 175, 25, and 120 pg/ml for control, diabetic, and insulin-treated 36-h groups, respectively. Low calcium diets increased concentration to 625, 100, and 370 pg/ml for controls, diabetics, and insulin-treated 36-h groups, respectively. In conclusion, the diabetic retains the ability to respond to calcium deficiency, even in the insulin-deficient state. Low calcium intake, in addition to enhancing 1,25-(OH)2D3 formation in diabetics, also modulates the response to insulin treatment. These studies demonstrate that the regulatory factor(s) suppressing serum, 1,25-(OH)2D3 in diabetes is not simply insulin deficiency per se. Implications of these findings for diabetes are discussed.
Beneficial Effects of Physical Training in Rats with a Mild Streptozotocin-induced Diabetes Mellitus
Authors: Tancrède Gilles , Rousseau-Migneron Suzanne , Nadeau André
Published: September 2013

The present studies have been designed to evaluate the effects of physical training in rats with a diminished insulin reserve. Mild diabetes mellitus was induced in rats with 45 mg/kg streptozotocin. Physical training was done on a treadmill, with a progressive program, twice daily, 5 days per week, for 10 wk in control and diabetic rats. At the end of the training program, a significant diminution in body weight gain and in epididymal fat pad weight was observed in both trained groups, as compared with sedentary controls. Sixty-four hours after the last exercise, control (N = 16), control-trained (N = 14), diabetic (N = 17), and diabetic-trained (N = 15) rats were submitted to an intravenous glucose tolerance test (0.5 g/kg). Arterial blood samples were collected at −15, 0, 2, 4, 6, 10, 15, 30, 45, and 60 min during the test in unanesthetized and precannulated rats for plasma glucose and insulin determinations. In normal rats, physical training induced a sharp decrease in the basal insulin levels (36 ± vs. 101 ± 6 μ/ml; P < 0.001) without any significant changes in glucose levels (122 ± 4 vs. 129 ± 2 mg/dl; P < 0.05). After the glucose loading there was no significant change in the glucose tolerance curve, although the insulin values remained lower throughout the test in the trained group. In the diabetic rats, the elevated basal glucose levels were significantly diminished in the trained group as compared with the untrained diabetic group (177 ± 22 vs. 306 ± 37 mg/dl; P < 0.001), although the basal insulin values were similar in both groups (51 ± 7 vs. 54 ± 9 μ/ml; P > 0.05). The improvement in the glucose tolerance of the diabetic-trained rats was further confirmed by the glucose disappearance rate constant that was significantly increased (3.6 0.4 vs. 2.0 ± 0.3; P < 0.01), although not fully restored to normal (6.3 ± 0.2; P < 0.001). These data clearly show that in rats with a diminished insulin reserve, a 10-wk running program greatly improved the glucose homeostasis. Measurements of circulating insulin suggest that, although an effect on insulin secretion cannot be totally excluded, the beneficial effect of physical training on diabetes mellitus is probably best explained by an increase in insulin sensitivity.
Kinetics of Somatostatin Receptor Migration in Isolated Pancreatic Islets
Authors: Draznin Boris , Leitner J Wayne , Sussman Karl E
Published: September 2013

Eighty-seven percent of the total cellular pool of somatostatin (SRIF) receptors in pancreatic islets are located intracellularly. Upon glucose stimulation (300 mg/dl) of insulin release, 8–15% of intracellular SRIF receptors are translocated to the plasma membrane. Affinity of SRIF receptors does not change during their migration and the total cellular pool of receptors remains constant. With prolonged glucose stimulation, surface membrane somatostatin receptor concentration reaches a maximum level at 60 min.
Prolonged Hypoglycemic Effect in Diabetic Dogs Due to Subcutaneous Administration of Insulin in Liposomes
Authors: Stevenson Ralph W , Patel Harish M , Parsons John A , Ryman Brenda E
Published: September 2013

The biologic action of insulin entrapped in liposomes (phospholipid vesicles) has been investigated following subcutaneous injection to dogs made diabetic with a combination of alloxan and streptozotocin. The fate of the liposomally entrapped material was determined by injecting rats subcutaneously with either 125l-insulin or the labeled polysaccharide 14C-inulin, incorporated in liposomes labeled with 3H-cholesterol.

Injection of liposome insulin (0.75 U/kg) to five diabetic dogs resulted in a mean (± SEM) blood glucose fall from 16.4 ± 0.8 to 2.9 ± 0.4 mmol/L. The glucose level had still not returned to baseline after 24 h and, correspondingly, immunoreactive insulin (IRI) could still be detected in frozen and thawed plasma 24 h after injection. In contrast, the hypoglycemic effect of the same dose of free insulin with or without empty liposomes virtually ended within 8 h and IRI levels returned to baseline by 3 h after injection.

In experiments on rats with liposomally entrapped 125l-insulin or 14C-inulin the proportion of the injected dose of tracer recoverable by excision of the injection site remained constant after about 1 h and 70% of the dose was still fixed in subcutaneous tissue for at least 5 h thereafter. When the plasma collected 3 h after subcutaneous injection of labeled liposomes containing 125I-insulin was passed through a column of Sepharose 6B, 50–75% of the 125I-activity was found in the fractions associated with intact liposomes. One possibility for the persistence of the hypoglycemic effect and of measurable IRI following injection of liposome insulin could be the presence of intact liposomes in the circulation for many hours after absorption had ceased.
Inhibition of Glucagon Secretion by Exogenous Glucagon in the Isolated, Perfused Dog Pancreas
Authors: Kawai K , Unger R H
Published: September 2013

To determine if glucagon can inhibit its own secretion, exogenous glucagon was perfused in the isolated canine pancreas at concentrations ranging from 90 to 1050 pg/ml during either stimulation or suppression of endogenous glucagon secretion. When endogenous glucagon secretion was completely suppressed by the addition of 200 mg/dl of glucose to the perfusate, the concentration of glucagon in the venous effluent ranged from 80.8 to 89.9% of the level perfused; these deficits of 10–20% were attributed to uptake and/or degradation of exogenous glucagon by the pancreas. By contrast, when endogenous glucagon secretion was stimulated by perfusing with 10 mM arginine or by glucopenia of 25 mg/dl, there was a significant increase in the glucagon deficit (the efflux glucagon level during glucagon perfusion minus the sum of the pre-perfusion efflux level of endogenous glucagon and the concentration of glucagon perfused); only 60–76% of the expected glucagon concentration was present in the venous efflux. This increase in deficit is assumed to reflect suppression of endogenous glucagon. The glucagon deficit rose progressively with the perfused concentration of glucagon until the deficit reached the approximate level of endogenous glucagon, at which no further increase occurred, suggesting that suppression at that point was complete. To determine if the glucagon-suppressing action of glucagon was mediated by an increase in glucagonstimulated insulin or somatostatin secretion, these hormones were measured in the various experiments. Insulin and somatostatin increased significantly when glucagon was perfused with the glucose arginine-containing solution but did not rise significantly when the glucopenic buffer was used, although suppression of endogenous glucagon was similar in each instance. It is concluded that glucagon suppresses glucagon secretion. Evidence that insulin and/or somatostatin mediate this action could not be obtained.
Evidence for Genetic Admixture as a Determinant in the Occurrence of Insulin-dependent Diabetes Mellitus in U.S. Blacks
Authors: Reitnauer Pamela J , Go Rodney C P , Acton Ronald T , Murphy Catherine C , Budowle Bruce , Barger Bruce O , Roseman Jeffrey M
Published: September 2013

In recent years, it has been proposed that genetic admixture may have played a role in the increased frequency of insulin-dependent diabetes mellitus (IDDM) in young U.S. blacks relative to African blacks. In support of this proposal, the similar associations of specific markers of the major histocompatibility complex (MHC) with IDDM in U.S. blacks with respect to U.S. whites have been cited. To determine whether racjal admixture was a factor in the increased prevalence, we did three analyses of admixture. In the first we used nine genetic markers (ABO, Rh, Fy, Hp, Gc, PI, OR, Tfr, and Gm) and determined that there was significantly greater than zero genetic contribution from whites in our sample of U.S. black IDDM patients (9.6 ± 2.3%, P < 0.01) when a sample of U.S. blacks without IDDM was used as one “parental” population. In the next two analyses, we estimated the amounts of genetic contribution from whites in the U.S. blacks with and without IDDM using reported gene frequencies for West African blacks for four genetic markers (ABO, Rh, Fy, and Hp). The estimate of admixture (21.4 ± 2.8%) for the black IDDM sample was greater than that for the U.S. black controls (17.9 ± 2.3%), although the difference was not significant. Our estimate of genetic contribution from whites, 21.4% for black IDDM patients, supports the assumptions of 20% admixture which MacDonald and Rotter and Hodge used to test their respective models for the inheritance of IDDM. These results support the hypothesis that admixture with the white population is, in part, responsible for the increase in prevalence of IDDM seen in U.S. blacks.
Comparison of Peripheral and Portal Venous Insulin Administration on Postprandial Metabolic Responses in Alloxan-Diabetic Dogs: Effects of Identical Preprogrammed Complex Insulin Infusion Waveforms
Authors: Fischer U , Rizza R A , Hall L D , Westland R E , Haymond M W , Clemens A H , Gerich J E , Service F J
Published: September 2013

The optimal route for insulin administration by insulin infusion devices has not been established. To assess the differences between the peripheral venous and portal venous routes of insulin administration on postprandial metabolic responses, six alloxan-diabetic dogs were studied on four occasions. On the first, the insulin infusion rates given by the Biostator for disposal of a mixed meal were recorded electronically. On two subsequent occasions, these insulin infusion profiles were administered by a peripheral vein. On an additional occasion, the identical insulin infusion profile was given via the portal vein. No differences were observed in basal or peak plasma glucose, insulin, glucagon, branched chain amino acids, and lactate concentrations between portal and peripheral venous insulin administration. Furthermore, no differences in isotopically ([2-3H]glucose) determined rates of systemic glucose appearance and disappearance were observed between the two routes. Although preprandial plasma alanine concentrations were greater when insulin was infused via the portal vein, the postprandial increments did not differ from those observed during infusion of insulin by a peripheral vein. These studies suggest that under the current experimental conditions, there appears to be no difference in the disposition of a mixed meal, measured as net whole body glucose appearance and disappearance rates, when insulin is administered in an open-loop fashion via either a peripheral or the portal vein.
Insulin Regulation of Sugar Transport in Isolated Pancreatic Acini from Diabetic Mice
Authors: Williams John A , Bailey Anne C , Preissler Margaret , Goldfine Ira D
Published: September 2013

Insulin-stimulated sugar transport was studied in isolated pancreatic acini prepared from streptozotocintreated mice. In this tissue, insulin increased the uptake of two nonmetabolized D-glucose analogues, [3H] 2-deoxy-D-glucose (2DG), and [3H]3-O-methyl-D-glucose (30MG), but had no effect on the uptake of [3H] L-glucose. A significant effect of insulin on 2DG uptake was seen at 100 pM, whereas a maximal effect required a concentration of 100 nM. The action of insulin on 2DG uptake was time-dependent; 90 min was required for a maximal hormonal effect. This increase in 2DG uptake was due to a greater than twofold increase in the maximal rate of uptake (Vmax); no significant effects were seen on Km.

The mode of insulin action on sugar transport was investigated further. In pancreatic acinar cells, insulin did not alter either membrane potential or 45Ca2+ efflux, two proposed mechanisms for regulation of sugar transport in other tissues. The action of insulin was not due to either contamination with cholecystokinin (CCK) or an action via the CCK receptor. CCK is known to stimulate sugar transport in isolated pancreatic acini via the elevation of intracellular Ca2+. The effect of insulin on 2DG uptake, however, was additive to that of CCK; conversely, dibutyryl cyclic GMP, a known competitive antagonist of CCK, had no effect on insulin stimulation of 2DG uptake, insulin increased 2DG uptake in the presence of 10 μM puromycin, a concentration sufficient to inhibit greater than 90% of protein synthesis. Dihydrocytochalasin B, a compound known to alter acinar cell motility by disrupting microfilaments, progressively blocked insulin stimulation of 2DG uptake over a drug concentrationrange of 1–15 μg/ml These data suggest, therefore,that the time-dependent increase of sugar transport by insulin is unrelated to electrical potential, 45Ca2+ efflux, and new protein synthesis, but may result from a microfilament-related translocation of glucose carrier sites to the plasma membrane.
Effect of Diabetes on the Glycosaminoglycan Component of the Human Glomerular Basement Membrane
Authors: Parthasarathy Narayanan , Spiro Robert G
Published: September 2013

The glycosaminoglycan (heparan sulfate) component of glomerular basement membranes from human kidneys of diabetic and nondiabetic subjects has been quantitated after isolation from protease digests of the membranes on OEAE-cellulose microcolumns. A significant decrease (P < 0.005) in the glycosaminoglycan content of diabetic membranes was observed. Heparan sulfate was identified as the predominant glycosaminoglycan in both diabetic and control subjects and the extent of its sulfation appeared to be similar. The reduced level of glycosaminoglycan in the diabetic glomerular basement membrane was accompanied by a significant elevation of hexoses, which are primarily associated with the collagen component, suggesting that a redistribution of basement membrane macromolecules occurs in the diabetic state. Since heparan sulfate has been implicated as a major component of the glomerular anionic filtration barrier, its decreased content in diabetic basement membranes may contribute to the proteinuria observed in this disease.
The Role of Glucose in the In Vitro Regulation of Cell Cycle Kinetics and Proliferation of Fetal Pancreatic B-Cells
Authors: Swenne Ingemar
Published: September 2013

To study the cell cycle and regulation by glucose of Bcell proliferation, B-cell-rich pancreatic islets of rat fetuses (22 days gestational age) were maintained in tissue culture at various glucose concentrations. The proliferating islet cells were synchronized with hydroxyurea and their rate of progress through the cell cycle studied by pulse labeling with 3H-thymidine and after exposure to colchicine.

The time for a full cell cycle was estimated to 14.9 h and could be subdivided into a G1 phase of a duration of 2.5 h, an S phase of 6.4 h, a G2 phase of 5.5 h, and an M phase of 0.5 h. Although glucose significantly stimulated B-cell proliferation, the progression of cells through the cell cycle was similar at different glucose concentrations. The experiments furthermore suggested that only a limited pool of islet cells was able to proliferate. Glucose seemed to stimulate B-cell proliferation by increasing the number of cells entering the cell cycle.

From the cell cycle data it was possible to calculate the rate of formation of new B-cells, which ranged from 4.2%/24 h in 2.7 mM glucose to 10.4%/24 h in 16.7 mM. When the accumulation of mitotic figures during colchicine treatment was used as an alternative method for estimation of newly formed B-cells the cell birth rates were found to be 3.1 and 6.0%/24 h at 2.7 and 16.7 mM glucose, respectively.

The notion that only a small fraction of B-cells takes part in proliferation would explain the limited regenerative capacity of this cell type. It remains to be established whether such a limitation is of significance in the development of maturity-onset diabetes.
Diazoxide and D600 Inhibition of Insulin Release: Distinct Mechanisms Explain the Specificity for Different Stimuli
Authors: Henquin J C , Charles S , Nenquin M , Mathot F , Tamagawa T
Published: September 2013

The mechanisms by which diazoxide and D600 affect insulin release have been compared in experiments using isolated rat islets. Diazoxide (20–400 (JLM) and D600 (1–50 μM) produced a dose-dependent inhibition of glucose-stimulated release. Diazoxide also inhibited the insulinotropic effect of leucine and related substances (ketoisocaproate and BCH), but not that of potassium or of arginine and other cationic amino acids. Diazoxide suppressed glucose and leucine stimulation of Ca uptake in islet cells, but had no effect on the stimulation by potassium and arginine. By contrast, D600 suppressed the effect of all these agents on both Ca uptake and insulin release. Theophylline partially antagonized the inhibitory effect of D600 on release, in the presence of diazoxide, theophylline was much less effective, except when combined with cationic amino acids. Diazoxide inhibition of glucose-induced release was prevented by phentolamine, but hot by dihydroergotamine and yohimbine, two other blpckers of a-adrenergic receptors. Epinephrine abolished the insulinotropic effect of arginine alone or with theophylline. Diazoxide increased 86Rb+ efflux from islet cells, whereas D600 and epinephrine decreased it. The acceleration of efflux by diazoxide was inhibited by D600 and phentolamine, but not by epinephrine or dihydroergotamine. It thus appears that the effects of diazoxide on B-cells are not due to activation of α-adrenergic receptors. The results suggest that, in contrast to the direct blockade of Ca channels by D600, the blockade of these channels by diazoxide is secondary to the hyperpolarization of the B-cell membrane. Since the latter results from an increase in K permeability, the inhibitory effects of diazoxide are restricted to stimulators that depolarize the B-cell membrane by decreasing its K permeability (glucose, leucine, and related substances) and do not affect the stimulation by K and cationic amino acids, which depolarize by other mechanisms.
Interaction of Glucose and Epinephrine in the Regulation of Insulin Secretion
Authors: Beard James C , Weinberg Clarice , Pfeifer Michael A , Best James D , Halter Jeffrey B , Porte Daniel
Published: September 2013

To determine whether the elevated plasma glucose levels produced by epinephrine (EPI) in vivo offset important islet effects of EPI in man, the acute insulin responses (AIR: IRI Δ 2–5 min) to 5 g i.v. arginine were measured at varying EPI and glucose levels. After infusion of EPI at 80 ng/kg/min for 45 min, achieving venous plasma EPI levels of 1140 ± 121 pg/ml, the AIR was indistinguishable from that seen in 10 untreated subjects (EPI versus untreated: 59 ± 11 versus 41 ± 5 μU/ml, ± SEM, P = NS), but plasma glucose had risen to 165 ± 8 mg/dl. When this glucose rise was matched in each subject by a glucose clamp infusion (GLU) with no EPI infusion, AIR increased to 467 ± 82% of that during EPI (N = 8, P < 0.001). With glucose subsequently clamped at a higher level, 256 ± 5 mg/dl, the AIR to arginine during GLU alone was 220 ± 17% of that during EPI + GLU (N = 7, P < 0.001). A qualitatively similar inhibitory effect on AIR to arginine was also observed using a lower dose of EPI (15 ng/kg/min, giving a venous plasma EPI level of 192 ± 19 pg/ml). To quantitate the opposing effects of plasma glucose and EPI on the AIR to arginine, a multiple linear regression analysis using glucose and EPI levels was performed. This analysis showed that AIR is positively correlated with plasma glucose (P < 0.001), negatively correlated with log [EPI] (P < 0.001), and negatively correlated with their product, glucose × log [EPI] (P < 0.01). The changes in glucose and EPI explained 90% of the variation in AIR observed within each subject (R2 = 0.896). These studies demonstrate that EPI inhibits AIR to arginine over a wide range of glucose levels, but that the B-cell-stimulating effect of hyperglycemia can obscure this inhibition. The data suggest that the development of hyperglycemia during stress states may compensate for the inhibitory effect of EPI on B-cell function, thereby maintaining normal basal and stimulated insulin levels.