bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated Pancreatic Glucagon in Obesity
Authors: Starke A A R , Erhardt G , Berger M , Zimmermann H
Published: September 2013

Because of conflicting reports on plasma levels of total immunoreactive glucagon (IRG) in obesity, we investigated, by gel filtration, the individual IRG fractions in grossly obese patients (N = 16; BMI 40 ± 2) as compared with normal weight subjects (N = 18). Mean total IRG was 142 ± 12 pg/ml in normal subjects and 190 ± 15 pg/ml (P < 0.02) in obese subjects. IRG3500 was 16 ± 2 pg/ml in normal subjects and 34 ± 5 pg/ml (P < 0.005) in the obese subjects. Obese patients with normal glucose tolerance demonstrated 30 ± 5 pg/ml IRG3500 (N = 11; P < 0.01) as compared with those who were obese with impaired glucose tolerance (42 ± 12 pg/ml, N = 5; P < 0.0025), although the total IRG of the latter group (173 ± 31 pg/ml) was not different from that of normal subjects. IRG9000 was of comparable magnitude in the entire groups of obese and normal subjects. A wide variability of big plasma glucagon levels was found in all three groups, mean levels not being significantly different. These data suggest that plasma IRG3500 levels are elevated in grossly obese patients, particularly in those patients with impaired glucose tolerance, a finding that may be masked by mere measurements of total plasma IRG.
Effects of Physical Training and Diet Therapy on Carbohydrate Metabolism in Patients with Glucose Intolerance and Non-insulin-dependent Diabetes Mellitus
Authors: Bogardus Clifton , Ravussin Eric , Robbins David C , Wolfe Robert R , Horton Edward S , Sims Ethan A H
Published: September 2013

The effects of 12 wk of physical training in addition to hypocaloric diet (DPT group, N = 10) on body composition, carbohydrate (CHO) tolerance, and insulin secretion and action were compared with the effects of diet therapy alone (D group, N = 8) in CHO-intolerant and non-insulin-dependent diabetic subjects.

Fat mass, fat-free mass (FFM), mean fasting plasma glucose, serum C-peptide, and insulin concentrations decreased similarly in both groups. The mean plasma glucose response to a mixed meal decreased approximately 20% in both treatment groups, and, after i.v. glucose, decreased 12% in the D group (P < 0.05), but did not change in the DPT group (NS between groups). The acute serum insulin response (0–6 min) after IG increased significantly in the DPT group only (NS between groups).

The mean basal endogenous glucose production (BEGP) decreased 17% (P < 0.025) in the DPT group and by 31% (P < 0.01) in the D group (NS between groups). Hepatic sensitivity to insulin, estimated by BEGP suppression during the euglycemic clamp, increased significantly by 25% in both groups. Total glucose disposal during the euglycemic clamp increased from 3.51 ± 0.04 milligrams of glucose per kilogram of fat-free mass per minute (mg/kg-FFM/min) to 4.45 ± 0.54 mg/kg-FFM/min (P < 0.05) in the DPT group, but no change occurred in the D group (NS between groups). Separation of total glucose disposal rates into CHO oxidative and nonoxidative rates using indirect calorimetry during the euglycemic clamp showed that the mean CHO oxidation rate increased in the D group (P < 0.05), but not in the DPT group (NS between groups). There was, however, a significant difference in the mean CHO nonoxidative rate between the two groups (P < 0.05), increasing in the DPT group but decreasing in the D group.

In both groups, the improvements in fasting plasma glucose and meal tolerance appeared to be attributable mostly to decreased BEGP, with increased hepatic sensitivity to insulin. However, glucose disposal was accomplished by different mechanisms in the two groups.
The Insulin Sensitivity Index: Correlation in Dogs Between Values Determined from the Intravenous Glucose Tolerance Test and the Euglycemic Glucose Clamp
Authors: Finegood Diane T , Pacini Giovanni , Bergman Richard N
Published: September 2013

We previously proposed the insulin sensitivity index, S1as an absolute measure of whole body tissue sensitivity to insulin. S1 is defined, in the physiologic range of insulin action, as the effect of insulin to augment glucose's ability to reduce its own plasma level. This parameter can be determined from the frequently sampled intravenous glucose tolerance test (IVGTT) by using a digital computer to find the coefficients of a minimal mathematical model of glucose kinetics. In the present study we compared, in normal dogs, S, determined from the IVGTT to an analogous parameter “S1(clamp)” calculated from the euglycemic glucose clamp (EGC). Fifteen pairs of experiments (1 IVGTT and 1 EGC) were performed on 12 animals. IVGTTs: After glucose injection (0.3 g/kg), frequent blood samples were taken over the subsequent 3 h. KG ranged from 1.7 to 4.7 %/min, and integrated insulin from 0.4 to 5.9 (μU/ml) min for 0–60 min. S1 varied over a ninefold range from 1.0 to 9.1 × 10−4 (min−1)/μU/ml), with a mean of 4.3 ± 0.7 × 10−4. Fractional glucose disappearance rate independent of insulin (p1) was 4.3 ± 0.5 %/min. EGCs: Low-rate insulin infusion (8 mU/min from 1 to 150 min) elevated plasma insulin (INS) from 15 ± 4 to 43 ± 10 μU/ml. Glucose was infused (GINF) at 119 ± 20 mg/min to maintain euglycemia. Moderate insulin infusion (40 mU/min: 151–300 min) further elevated plasma insulin (to 176 ± 37 μU/ml) and the requisite glucose infusion (to 372 ± 36 mg/min). S1(clamp) was calculated in steady state as the increase in glucose infusion per increment in insulin above basal, normalized to the basal glucose and body weight [GINF/(Gb × BW × δINS)]. S1(clamp) ranged from 3.1 to 40.5 × 10−4 (dl/kg/min)/μU/ml). The values of S1 and S1(clamp) were highly correlated (r = 0.82, P < 0.005).

These studies suggest that the insulin sensitivity index, S1determined from the IVGTT is a useful measure of insulin sensitivity, which is capable of differentiating sensitivities among a normal population.
The Influence of Genetic Background on the Susceptibility of Inbred Mice to Streptozotocin-induced Diabetes
Authors: Wolf Joyce , Lilly Frank , Shin Seung-Il
Published: September 2013

Multiple low-dose injections of streptozotocin (STZ) induce a delayed but progressively increasing state of hyperglycemia in mice. Different inbred strains of mice show different susceptibility to this treatment. We examined whether genetic factors associated with the H-2 complex influence the susceptibility or resistance, using a selected group of 12 inbred and 5 congenie resistant strains of mice. We found that different congenie strains differed significantly in their susceptibility to STZ-induced diabetes, suggesting that H-2-asso-ciated genes do influence the susceptibility. However, at least some inbred strains sharing the same H-2 haplotype also differed in their susceptibility, indicating that genes outside the H-2 complex may also affect the susceptibility. Therefore, there appear to be at least two genes, one within and one or more outside the H-2 complex, that determine the susceptibility to multiple low doses of STZ.
Serum Somatomedin-C Concentrations in a Rabbit Model of Diabetic Pregnancy
Authors: D'ercole A Joseph , Bose Carl L , Underwood Louis E , Lawson Edward E
Published: September 2013

We have developed and validated a method for measuring immunoreactive somatomedin-C (Sm-C) in serum of rabbits, and have shown that during midgestation (11–26 days; gestation = 31 days) serum Sm-C concentrations are higher in normal pregnant animals than in pregnant diabetic animals. Sm-C concentrations in the serum of 28-day gestation fetuses of diabetic rabbits (3.14 ± 0.25 U/ml) were significantly higher than in the fetuses of nondiabetic rabbits (2.31 ± 0.23 U/ml; P < 0.05). Fetuses from litters of the most severely hyperglycemie diabetic mothers (glucose > 250 mg/dl) had higher serum Sm-C (3.66 ± 0.41 U/ml) than those of mothers who were mildly hyperglycemie (2.71 ± 0.2 U/ml). Although these differences were not statistically significant, fetuses from the former litters accounted in great part for the difference between the fetuses of diabetic and normal pregnancy. The diabetes-related increment in Sm-C does not appear to be due to insulin, since fetal insulin concentrations were not different between the normal and diabetic litters (normal, 50.0 ± 3.6 μU/ml versus diabetic, 49.6 ± 7.6 μU/ml). Despite their elevation in serum Sm-C, fetuses from litters of diabetic rabbits were growth retarded in weight (26.8 ± 6.9 g and 33.8 ± 6.9 g, diabetic versus normal pregnancy; P < 0.05) and in length (7.9 ± 0.7 cm and 8.6 ± 0.7 cm, diabetic versus normal pregnancy; P < 0.025). We speculate that these discrepancies between growth and Sm-C might be secondary to the toxic effects of glucose on embryonic growth and that later in gestation, the excessive energy provided to the fetus might stimulate Sm-C synthesis.
Behavioral Manipulation of the Diabetic Phenotype in ob/ob Mice
Authors: Surwit Richard S , Feinglos Mark N , Livingston Elizabeth G , Kuhn Cynthia M , McCubbin James A
Published: September 2013

The genetically obese mouse (C57BL/6J ob/ob) is a commonly used model of non-insulin-dependent diabetes mellitus. However, our studies demonstrate that, while the animal is significantly hyperinsulinemic, it in fact does not show consistent hyperglycemia in the resting state. During stress, both obese animals and their lean littermates become hyperglycemie, but the magnitude of the hyperglycemia is exaggerated in the obese mice. Obese animals also show an exaggerated plasma glucose increase in response to epinephrine injection. This increase in plasma glucose is accompanied by a decrease in plasma insulin in response to both stress and epinephrine. Our findings suggest that environmental stimuli influence the expression of diabetes in the C57BL/6J obese mouse and therefore must be considered in studies of this animal model of diabetes.
A Comparison of the Relative Effects of Obesity and Non-insulin-dependent Diabetes Mellitus on In Vivo Insulin-stimulated Glucose Utilization
Authors: Hollenbeck C B , Chen Y -D I , Reaven G M
Published: September 2013

Insulin clamp studies were carried out in 50 individuals, 25 with normal glucose tolerance and 25 with non-insulin-dependent diabetes mellitus (NIDDM). Both diagnostic groups were further subdivided on the basis of body mass index (BMI) into an obese (BMI > 28 kg/ m2) or nonobese group (BMI < 28 kg/m2). The obese and nonobese subjects in each diagnostic category had similar plasma glucose levels in response to an oral glucose challenge. In addition, insulin-stimulated glucose utilization, as assessed by determination of glucose metabolic clearance rate (MCR), was not different as a function of obesity. Glucose MCR (mean ± SEM) in obese subjects (mean BMI = 32.1) with normal glucose tolerance was 162 ml/min/m2, as compared with a value of 205 ml/min/m2 in nonobese individuals (mean BMI = 23.8). This difference was not statistically significant. Similarly, glucose MCR in obese patients (mean BMI = 34.7) with NIDDM was 55 ml/min/m2, as compared with a value Of 80 ml/min/ m2 in nonobese subjects (mean BMI = 24.9) with NIDDM. However, as can be seen from the above data, glucose MCR in patients with NIDDM, either nonobese or obese, was markedly reduced (P < 0.001) when compared with that of normal subjects. These data emphasize the profound effect of NIDDM on reducing in vivo insulin action, and point out that the impact of obesity on insulin resistance is minor in comparison.
Insulin Therapy in Obese, Non-insulin-dependent Diabetes Induces Improvements in Insulin Action and Secretion that Are Maintained for Two Weeks After Insulin Withdrawal
Authors: Andrews W John , Vasquez Barbara , Nagulesparan Murugasu , Klimes Iwar , Foley James , Unger Roger , Reaven Gerald M
Published: September 2013

The effects of rigorous insulin treatment on insulin action (insulin clamp) and secretion (plasma insulin response to glucose) were studied in 13 obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Improvements were documented in fasting (P < 0.0001) and postprandial (P < 0.0001) plasma glucose concentrations, insulin secretion after oral glucose (P < 0.001), and insulin action (P < 0.005) after 30 days of therapy. Mean integrated plasma insulin response to glucose increased 2.5-fold after insulin therapy, but this improvement varied considerably from patient to patient. Insulin action also increased with insulin treatment and the resulting values were no longer significantly different from a weight- and age-matched group of subjects with normal glucose tolerance. However, there was considerable patient-to-patient variation in the degree to which insulin action was enhanced. The insulin-induced improvements in glucose tolerance persisted for at least 2 wk after insulin withdrawal, and were associated with continued increased insulin secretion and insulin action. In conclusion, control of hyperglycemie for 1 mo led to improvements in both insulin secretion and action in a series of obese patients with NIDDM that persisted for at least 2 wk after cessation of therapy.
Insulin-stimulated Glucose Disposal Increases with Time in Patients with Non-insulin-dependent Diabetes Mellitus
Authors: Liu G , Chen Y-D I , Hollenbeck C B , Lardinois C K , Reaven G M
Published: September 2013

The relative effects of time versus ambient glucose concentration on insulin-stimulated glucose uptake was estimated by performing 5-h insulin clamp studies in patients with NIDDM. Each experimental subject was studied three times, at steady-state plasma insulin levels ∼2000 μU/ml, but at different steady-state, plasma glucose concentrations (studies A, B, and C). Study A consisted of a 5-h clamp, with plasma glucose level maintained at the basal level of fasting hyperglycemia; study B differed in that the basal level of fasting hyperglycemia was reduced during the first hour to ∼80 mg/dl, and maintained there for the next 4 h; and study B was carried out by clamping the patient at the basal glucose level for 2 h, lowering the glucose concentration to approximately 80 mg/dl during the third hour, and then clamping at this level for the last 2 h. The glucose metabolic clearance rate (MCR) was calculated from 60 to 120 min and from 240 to 300 min during each study, and the results indicated that values for glucose MCR were time dependent, being significantly greater (20–60%) in the fifth than in the second hour in two (studies A and B) of the three studies. In contrast, glucose MCR was independent of plasma glucose concentration, and relatively constant in each subject, as long as it was measured during the same time period. The time-dependent increase in glucose MCR was associated with an approximate 30% increase in steady-state plasma insulin concentrations when comparing the second and fifth hours. These data emphasize the time-dependent increase in insulin-stimulated glucose disposal that occurs in insulin clamp studies, and point out the potential difficulties in interpretation that can evolve from sequential estimates of insulin-stimulated glucose disposal. In addition, they provide additional evidence that measurement of glucose MCR can be used to compare insulin stimulated glucose disposal in patients with NIDDM under the conditions used in these studies.
Chronic Hyperinsulinemia in the Fetal Rhesus Monkey: Effects of Physiologic Hyperinsulinemia on Fetal Growth and Composition
Authors: Susa John B , Neave Charles , Sehgal Prabhat , Singer Don B , Zeller W Patrick , Schwartz Robert
Published: September 2013

One of the hallmarks of the hyperglycemic-hyperinsulinemic infant of the diabetic mother (IDM) is macrosomia and selective organomegaly. Primary hyperinsulinemia, with insulin levels similar to those observed in human IDMs at delivery, was produced in the fetal rhesus monkey during the last third of gestation. The effects of this physiologically relevant hyperinsulinemia, in the absence of hyperglycemia, on fetal growth were studied. Fetal macrosomia, with a 23% increase in total body weight, was observed in physiologically hyperinsulinemic fetuses. A similar 27% increase in weight was produced by fetal insulin levels that were 10 times higher. A logarithmic correlation was observed between fetal birth weight ratio and fetal plasma insulin concentration. In contrast to this increase in weight, skeletal growth, as measured by crown-heel length and head circumference, was not affected by hyperinsulinemia. Only cardiomegaly was found in the low-dose hyperinsulinemic fetuses, whereas cardiomegaly, hepatomegaly, and splenomegaly were produced by hyperinsulinemia in which insulin levels were in the highest range. Compositional analysis of heart and skeletal muscle indicated no differences in the protein, RNA and DNA concentration, or in the protein-to-DNA ratio in hyperinsulinemic fetuses. We interpret these data as indicating that fetal insulin plays the predominant role in controlling the normal, as well as the augmented, fetal weight characteristic of the human infant of the diabetic mother.
Immunologic Studies on the Induction of Diabetes in Experimental Animals: Cellular Basis for the Induction of Diabetes by Streptozotocin
Authors: Kim Young Tai , Steinberg Carl
Published: September 2013

Repeated low doses of streptozotocin (STZ, 40 mg/kg body wt) gradually induce hyperglycemia in mice after a latent period of 5–7 days. The ability of STZ to induce hyperglycemia varies in different mouse strains. Repeated low doses of STZ fail to induce diabetes in T-cell-deficient mice, suggesting a crucial role of T-cells in the induction of diabetes by this procedure. Transfer of spleen cells from mice rendered diabetic by repeated low doses of STZ failed to induce hyperglycemia in the recipients. However, pretreating the recipients with a single low dose Of STZ permitted efficient transfer of the diabetic state, suggesting that the immunologie reaction resulting in diabetes was actually specific for an STZ-modified beta cell.
Stimulation of Retinal Capillary Pericyte Protein and Collagen Synthesis in Culture by High-Glucose Concentration
Authors: Li Weiye , Shen Shuyu , Khatami Mahin , Rockey John H
Published: September 2013

The influence of glucose concentration on cell multiplication and protein synthesis was studied in synchronized, long-term cultures of bovine retinal microvessel pericytes. The cell multiplication rate and the mitotic rate were reduced in media containing 20 mM glucose to 57% and 54%, respectively, of that obtained in media containing 5 mM glucose. Elevated glucose, however, did not change the DNA content of individual cells.

Protein and collagen synthesis were measured by the incorporation of radioactive proline and lysine, or the posttranslational production of hydroxyproline and hydroxylysine, respectively. High glucose stimulated protein and collagen synthesis per cell 2.2 ± 0.10 (SD) and 2.1 ± 0.06 times, respectively. Aspirin (0.5 mM), an inhibitor of nonenzymatic glycosylation, did not alter the effect of elevated glucose concentration on protein and collagen synthesis.
Mechanism of Improvement in Glucose Metabolism After Chronic Glyburide Therapy
Authors: Simonson Donald C , Ferrannini Eleuterio , Bevilacqua Stefano , Smith Douglas , Barrett Eugene , Carlson Rodney , DeFronzo Ralph A
Published: September 2013

The effect of glyburide on glucose metabolism was examined in 10 non-insulin-dependent diabetic subjects (NIDDM) and 7 young, control subjects. After 3 mo of glyburide treatment in NIDDM, fasting plasma glucose declined from 198 to 141 mg/dl (P < 0.01) without change in fasting insulin levels. Basal hepatic glucose production (HGP) was slightly elevated in NIDDM versus controls (2.35 versus 2.18 mg/kg · min, P = NS) and was positively correlated with the fasting glucose concentration (r = 0.93, P < 0.001). With chronic glyburide therapy, HGP declined to 1.72 mg/kg · min (P < 0.01 versus preglyburide) and remained highly correlated with the fasting glucose concentration (r = 0.85, P < 0.005). Basal glucose clearance in NIDDM was reduced by 48% compared with age-matched controls (1.22 versus 2.32 ml/kg · min, P < 0.001) and was unchanged after 3 mo of glyburide. Thus, the most important factor responsible for the decline in fasting plasma glucose concentration was an inhibition of hepatic glucose output. The decrease in basal hepatic glucose production and fasting plasma glucose concentration occurred without any change in fasting plasma insulin or C-peptide concentration.

Insulin-mediated glucose metabolism (insulin clamp technique) was reduced by 55% in NIDDM (2.91 versus 6.39 mg/kg · min, P < 0.001). After glyburide, insulin-mediated glucose metabolism increased by 26% to 3.67 mg/kg · min (P < 0.01). This increase in tissue sensitivity to insulin was unassociated with any change in insulin binding to monocytes. Beta cell secretion of insulin (hyperglycemie clamp technique) was markedly impaired in NIDDM (mean plasma insulin response: 24 versus 54 μU/ml, P < 0.001). After glyburide, the plasma insulin response increased to 36 μU/ ml (P < 0.01). These results indicate that improved glucose tolerance in NIDDM after glyburide results from both enhanced tissue sensitivity to insulin and increased insulin secretion.

Glyburide administration to young, healthy, control subjects also increased insulin-mediated glucose metabolism (from 6.45 to 7.61 mg/kg · min, P < 0.05) without any change in insulin binding to monocytes. Insulin secretion, however, was unaltered. Thus, the primary mechanism responsible for the improvement in glucose metabolism in young controls was enhanced tissue sensitivity tO insulin.
Influence of Physical Training on Formation of Muscle Capillaries in Type I Diabetes
Authors: Wallberg-Henriksson Harriet , Gunnarsson Rolf , Henriksson Jan , Östman Jan , Wahren John
Published: September 2013

The effects of physical training on skeletal muscle morphology and enzyme activities were compared in 10 male, type I diabetic subjects and 10 healthy, male, control subjects. The training program consisted of running for 45 min, three times per week for 8 wk. Muscle biopsies were obtained before and after the training period from the lateral portion of the gastrocnemius muscle. Pretraining maximal oxygen uptake was similar in the two groups (diabetic subjects 42 ± 1 versus control subjects 43 ± 2 ml × kg−1 × min−1), and the training resulted in an identical increase (+ 13%, P < 0.01). Muscle capillarization (number of capillaries per muscle fiber) increased on the average in the control group (+ 14 ± 4%, P < 0.01), but was unchanged in the diabetic group (0 ± 4%). Capillary density, expressed as number of capillaries per unit muscle cross sectional area, also increased on the average in controls (8 ± 4%, P < 0.05) but failed to do so in the diabetic patients (–8 ± 6%, NS). The activities of the mitochondrial enzymes citrate synthase (+ 26–27%, P < 0.01–0.05) and succinate dehydrogenase (+ 24–25%, P < 0.05) increased significantly and similarly in the two groups, whereas training did not result in significant changes in the activities of the glycolytic enzymes 6-phosphofructokinase and glyceraldehyde-phosphate dehydrogenase. Glycemie control in the diabetic group did not improve with the training, as evaluated from hemoglobin A1 and home-monitored blood glucose.

The findings suggest that, compared with controls, the ability to form new skeletal muscle capillaries in response to physical training may be deficient in patients with type I diabetes mellitus of long standing, while the increase in mitochondrial enzyme activities is normal. A deficient formation of new capillaries may be an expression of the microangiopathy of this disorder.
Renal Subcapsular Islet Cell Transplantation
Authors: Toledo-Pereyra Luis H , Bandlien Karl O , Gordon Debra A , MacKenzie Gerald H , Reyman Theodore A
Published: September 2013

Islet cell transplantation has been associated with ultimate graft rejection. This preliminary study investigates the use of the renal subcapsular region as a site for placement of canine islet cell allografts. A new noncollagenase mechanical technique was used for preparation of the allografts. Animals in group I (N = 6) died of hyperglycemie in 4.0 ± 1.89 days (X ± SD) after pancreatectomy without subsequent islet cell transplant. Normoglycemia and excellent survival (>60 days) was obtained in pancreatectomized animals in group II (N = 6) and in group III (N = 6), who received an islet cell allograft to the renal subcapsular site. Group II recipients were given no immuno-suppression, and animals in group III received minimal immunosuppression with azathioprine. Dependence on the islet cell allograft for maintenance of normoglycemia was confirmed in the majority of the recipients by nephrectomy, to remove the graft, with resulting hyperglycemia and death. One normoglycemic animal in group II died on day 6 from peritonitis. One recipient in group II was normoglycemic at >1 mo after removal of the first graft by nephrectomy, followed by retransplantation of islet cells from a third-party donor. Two other recipients are being studied on a long-term basis, and have been normoglycemic for >6 mo and >4 mo after transplantation. These studies encourage further investigation in this area for application of islet cell transplantation in man, and elucidation of the possible mechanisms for prolongation of islet cell allograft survival at the renal subcapsular site.
Reversal of Diabetic Cataract by Sorbinil, an Aldose Reductase Inhibitor
Authors: Beyer-Mears A , Cruz E
Published: September 2013

Aldose reductase is implicated in the pathogenesis of diabetic cataracts; therefore, inhibition of this enzyme subsequent to cataractogenesis may represent a therapeutic approach for restoration of lens physiology. In the present study, the effect of aldose reductase inhibition subsequent to stage I cataract formation was investigated in the streptozocin-induced diabetic rat. Our results indicated that the aldose reductase inhibitor sorbinil, a spirohydantoin, arrested further progression and promoted a reparative process despite continuation of hyperglycemia and elevated lens glucose. Quantitative analysis of scanning electron micrographs indicated that the afflicted lens regions were contained and their cellular components stabilized with regard to fiber hydration and interdigitation. The reparative process included: normalization of lens sorbitol, gradual recovery of existing fiber contour and interdigitation, production of new fibers, and partial restoration of lens myo-inositol content.
Biosynthesis of Glucagon (IRG3500) in Canine Gastric Mucosa
Authors: Hatton T W , Yip C C , Vranic M
Published: September 2013

The canine gastric mucosa has previously been shown to contain considerable amounts of a polypeptide with the immunologic and physicochemical characteristics and biologic activity of glucagon (IRG3500). Using mucosal pieces that remained viable for at least 8 h, we have demonstrated that IRG3500 is synthesized in this extrapancreatic tissue. Gel filtration and electrophoresis of extracts of mucosal pieces incubated with 3Htryptophan, 3H-leucine, or 35S-methionine revealed small amounts of labeled, newly synthesized gastric IRG3500. No labeling of gastric IRG3500 was observed when the mucosa was incubated with 3H-proline, an amino acid not found in glucagon, in the presence of cycloheximide, or in isolated rat hepatocytes. Small amounts of newly synthesized IRG3500 were specifically immunoprecipitated by C-terminally directed glucagon antiserum gamma globulins. The rate of gastric IRG3500 biosynthesis in vitro was apparently unchanged in mucosal pieces from pancreatectomized dogs and unaffected by increased glucose or glucose lack during incubations. Thus we have provided evidence that a hormone of the endocrine pancreas can be synthesized in extrapancreatic tissues.
Altered Bile Acid Metabolism in Nonobese, Spontaneously Diabetic (NOD) Mice
Authors: Uchida Kiyohisa , Makino Susumu , Akiyoshi Takashi
Published: September 2013

Cholesterol and bile acid metabolism was examined in nonobese, spontaneously diabetic (NOD) female mice before and after the development of diabetes. After the development of glucosuria, the plasma and liver cholesterol levels, gallbladder bile weight after 5-h fasting, biliary cholesterol, phospholipid and bile acid concentrations, the lithogenic index, the pool size of bile acids, and fecal sterol excretion markedly increased, but fecal bile acid excretion and fractional turnover rates for the cholic acid and chenodeoxycholic acid groups decreased. The distribution percentage of bile acids in the small intestine did not change, but it increased in the gallbladder and decreased in the large intestine. One striking finding was a change in the bile acid composition: increases were recorded in cholic and deoxycholic acids while decreases occurred in bile acids derived from chenodeoxycholic acid, such as β-muricholic and ursodeoxycholic acids in the bile and α-muricholic, β-muricholic, ω-muricholic, and hyodeoxychollc acids in the feces. Therefore, the cholic acid group/chenodeoxycholic acid group (CA/CDCA) ratio increased in the bile, feces, and small and large intestines after the development of diabetes. These changes were very similar to those observed in alloxan-treated mice, suggesting that the changes found in NOD mice are caused by insulin deficiency.
Regulatory Role of Fructose-2,6-Bisphosphate in Pancreatic Islet Glucose Metabolism Remains Unsettled
Authors: Burch Pamela Trueheart , Berner Donna K , Najafi Habiba , Meglasson Martin D , Matschinsky Franz M
Published: September 2013

Fructose-2,6-P2 was measured in perifused, isolated rat pancreatic islets. Fructose-2,6-P2 was present in pancreatic islets at low levels approximately equal to fructose-2,6-P2 content of liver from fasted rats. In islets perifused with glucose at physiologic concentrations, fructose-2,6-P2 was increased from 0.8 μM in the presence of 5.5 mM glucose to 1.0 μM at 10 mM glucose and 1.3 μM at 16.7 mM glucose, but did not increase further at higher glucose concentration. Therefore, only modest increases in the phosphofructokinase-1 activator, fructose-2,6-P2, occur at glucose concentrations stimulating insulin secretion.
Time Dependence of Insulin Action in Muscle and Adipose Tissue in the Rat In Vivo: An Increasing Response in Adipose Tissue with Time
Authors: James D E , Burleigh K M , Kraegen E W
Published: September 2013

The relative time dependency of enhancement of glucose metabolism by insulin in individual tissues has not been examined previously in vivo. Using the glucose clamp technique in the rat combined with radiolabeled 2-deoxyglucose (3H or 14C-2DG) administration, we have estimated a glucose metabolic index (Rg') in major insulin-sensitive tissues at two different times (between 40–55 min and 80–95 min) after onset of hyperinsulinemia (insulin levels of approximately 130 mU/L). At the completion of the clamp (125 min), eight different skeletal muscles and three different adipose tissue beds were rapidly removed for estimation of Rg', based on the accumulation of intracellular tracer 2DG-6-phosphate (2DGP). Insulin-stimulated Rg' was 60–70% higher at 80–95 min than at 40–55 min after elevation of insulin levels in all three adipose tissue beds (P < 0.01). In contrast, insulin-stimulated whole body glucose utilization and Rg' in all skeletal muscles were not significantly different at these two times. The constancy of insulin action in skeletal muscles during the 2-h euglycemic clamp, as determined in these studies, does not support the concept that the glucose clamp represents an integral of many rapidly changing individual tissue responses. In conclusion, while the amount of insulin-stimulated glucose uptake in adipose tissue is low compared with muscle, the fraction increases with duration of insulin elevation. This effect may have significant implications in hyperinsulinemic States.
Prevention of Defective Axonal Transport in Streptozocin-diabetic Rats by Treatment with “Statil” (ICI 128436), an Aldose Reductase Inhibitor
Authors: Tomlinson David R , Townsend Julie , Fretten Pamela
Published: September 2013

This investigation examined the effect of treatment of streptozocin-diabetic rats with the aldose reductase inhibitor “Statil” (25 mg/kg/day p.o.) on axonal transport in cholinergic neurons of the sciatic and vagal nerves and on nerve polyol and sugar levels. Three weeks of experimental diabetes caused deficits in the accumulation of choline acetyltransferase activity proximal to 24-h constrictions in the left sciatic and vagus nerves. These deficits did not develop in age-matched, similarly diabetic rats that were treated with the aldose reductase inhibitor. The inhibitor prevented completely the build-up of sorbitol and markedly reduced the build-up of fructose in the sciatic nerves of the treated diabetic rats. The inhibitor also prevented the depletion of myo-inositol that was seen in the untreated diabetic animals. It is suggested that these findings indicate a possible approach to the elucidation of the pathogenesis of cardiac vagal dysfunction in diabetes mellitus.
Effects of Prior High-Intensity Exercise on Glucose Metabolism in Normal and Insulin-resistant Men
Authors: Devlin J T , Horton E S
Published: September 2013

The effects of prior high-intensity cycle exercise (85% VO2 max) to muscular exhaustion on basal and insulinstimulated glucose metabolism were studied in obese, insulin-resistant, and normal subjects. Six obese (30.4% fat) and six lean (14.5% fat) adult males underwent two separate, two-level hyperinsulinemic-euglycemic clamp studies (100-min infusions at 40 and 400 mU/m2/min), with and without exercise 12 h earlier. Carbohydrate oxidation was estimated by indirect calorimetry using a ventilated hood system, and endogenous glucose production by D-(3-3H)-glucose infusion. Glycogen content and glycogen synthase activity (GS %l) were measured in vastus lateralis muscle biopsies before and at the end of each insulin clamp procedure.

After exercise, the obese and lean subjects had comparably low muscle glycogen concentrations (0.10 versus 0.08 mg/g protein, respectively), and equal activation of muscle GS activity (54.4 versus 45.3 GS %l, respectively). In the obese subjects, insulin-stimulated glucose disposal was increased significantly, but not totally corrected to normal. In both groups there was a comparable increase in nonoxidative glucose disposal (NOGD), whereas glucose oxidation was decreased and lipid oxidation was increased. Thus, the major effect of prior exercise was to increase insulin-stimulated glucose disposal in the obese subjects and to alter the pathways of glucose metabolism to favor NOGD and decrease glucose oxidation.

No correlation was found between the exercise-induced increase in GS %l and NOGD, except in the normal subjects during maximal insulin stimulation. Thus, glycogen synthase activity does not appear to be ratelimiting fpr NOGD at physiologic insulin concentrations. Our findings suggest that a single bout of glycogendepleting exercise can increase glucose disposal for at least 12–14 h in obese subjects with insulin resistance.
Effects of Gestational Hyperglycemia on Glucose Metabolism and Its Hormonal Control in the Fasted, Newborn Rat During the Early Postnatal Period
Authors: Nurjhan N , Ktorza A , Ferre P , Girard J R , Picon L
Published: September 2013

To evaluate the effects of gestational hyperglycemia on glucose metabolism and its regulation in the fasted rat during the early postnatal period, unrestrained rats were continuously infused with glucose during the last week of pregnancy. Control rats were infused with distilled water. Newborns were studied during the first six postnatal hours.

At birth, newborns from glucose-infused rats, compared with controls, showed higher plasma glucose levels, increased plasma insulin, and lower plasma glucagon and catecholamine concentrations.

Between birth and 2 h postpartum, newborn rats from both groups exhibited a marked hypoglycemia, which was, however, more severe in newborns from glucose-infused rats (15 mg/dl) than in controls (26 mg/dl). During the first four postnatal hours, plasma insulin concentration remained higher, while plasma glucagon and catecholamine concentrations remained lower in newborns from hyperglycemic rats. At 6 h, the glycemia reached normal values and the concentrations of the different hormones were similar in controls and newborns from glucose-infused mothers.

Concurrently, in the newborns from glucose-infused rats, hepatic glucose production was altered, as they were unable to mobilize liver glycogen stores during the six postnatal hours. Despite slightly delayed phosphoenolpyruvate carboxykinase induction, the rate of gluconeogenesis from 10 mmol/L lactate estimated on isolated hepatocytes was higher in newborns from hyperglycemic mothers than in controls.

These results show that gestational hyperglycemia compromises the metabolic and hormonal adaptation of the newborn rat to early extrauterine life; the striking feature of these neonates is the absence of mobilization of liver glycogen stores, which can probably be explained by fetal and neonatal hyperinsulinism associated with the defect of counterregulatory hormones.
Importance of Glucose Per Se to Intravenous Glucose Tolerance: Comparison of the Minimal-Model Prediction with Direct Measurements
Authors: Ader Marilyn , Pacini Giovanni , Yang Yeon J , Bergman Richard N
Published: September 2013

Glucose disappearance after an oral or intravenous challenge is a function of the effects of both endogenously secreted insulin and of glucose itself. We previously introduced the term “glucose effectiveness,” or SG, defined as the ability of glucose per se to enhance its own disappearance independent of an increment in plasma insulin. The present investigation, performed in conscious dogs, was undertaken to quantify this glucose effect by minimal-model-based analysis of insulin and glucose dynamics after a frequently sampled intravenous glucose tolerance test (FSIGT). The values from the standard FSIGT were then compared with direct measurementsobtained from experiments in which the dynamic insulin response to glucose was suppressed with somatostatin (SRIF). In addition, we examined SG values from the modified FSIGT protocol, which involves both glucose and tolbutamide injections. Protocol I (N = 9): FSIGTs were performed and the glucose and insulin data were analyzed by computer. KG was 2.65 ± 0.28 min−1, S1 was 4.09 ± 0.34 × 10−4 min−1/(μU/ml), and SG was 0.033 ± 0.004 min−1. Protocol II (N = 6): FSIGTs were performed on animals in which SRIF was infused (0.8 μg/min−1kg) to obliterate the dynamic insulin response to glucose injection. Before the FSIGT, insulin and glucagon were infused intraportally to reattain basal glycemia. Without dynamic insulin, KG was reduced to 0.96 ± 0.18 min−1 (P < 0.0001). However, SG, estimated from the exponential rate of fall of plasma glucose in the absence of dynamic insulin, was similar to the standard FSIGTs: 0.025 ± 0.004 (P > 0.25). Protocol III (N = 6): modified FSIGTs wereperformed using glucose and tolbutamide injections for a better estimate of model parameters. Model parameters S1 and SG, and the KGwere not different from standard FSIGTs (P > 0.3). In fact, the value of SG (0.028 ± 0.003 min−1) was nearly identical to the direct measure from protocol II. Therefore, the effect of glucose per se on glucose decline, estimated by modeling the standard and modified FSIGTs, was confirmed by a direct measurement with the endogenous insulin response suppressed with SRIF. Also, the time course of the insulin effect to enhance net glucose disappearance from plasma [leff(t)] was calculated from the data of protocol II, and was the same as the time coursepredicted by the model. These studies demonstrate the ability of the computer modeling approach to separate insulin-dependent and glucose-dependent glucose disappearance, and represent a direct confirmation of the minimal model. More important, they confirm that glucose per se, independent of the dynamic insulin response, is a very significant factor in the determination of glucose tolerance.
Diabetes Induced by Streptozocin Results in a Decrease in Immunoreactive Beta-Endorphin Levels in the Pituitary and Hypothalamus of Female Rats
Authors: Forman L J , Marquis D E , Stevens R , Adler R , Vasilenko P
Published: September 2013

Immunoreactive beta-endorphin (IR-BE) was measured by radioimmunoassay in the anterior pituitary (AP), neurointermediate lobe of the pituitary (NIL), and hypothalamus of female rats4 wk after being made diabetic by a single injection of streptozocin (STZ). STZ-induced diabetes resulted in a significant reduction in the content and concentration of IR-BE in the AP and the content of IR-BE in the hypothalamus. Total hypothalamic protein was also significantly diminished. IR-BE levels in the NIL were unchanged. Column chromatography indicated that the reduction in IR-BE in the AP of the diabetic female rats represented a decrease in peptides that co-eluted withbeta-endorphin and beta-lipotropin. In the hypothalamus, the reduction in IR-BE was represented solely by a decrease in a peptide co-eluting with beta-endorphin. Beta-lipotropin was not detectable in the hypothalami of control or diabetic female rats. These results suggest that, in the rat,diabetes may produce alterations in the mechanism(s) that regulate endogenous opiate levels in the pituitary and hypothalamus.
The Influence of T-Lymphocyte Precursor Cells and Thymus Grafts on the Cellular Immunodeficiencies of the BB Rat
Authors: Francfort John W , Naji Ali , Silvers Willys K , Barker Clyde F
Published: September 2013

To determine whether abnormal T-lymphocyte precursor cells or an abnormal thymus is responsible for the immunologic deficiencies of spontaneously diabetic BB rats, thymus grafts or T-cell-depleted bone marrow cells were exchanged between diabetes-prone and nondiabetes-prone animals. Analysis of peripheral lymphocyte populations from these recipients with monoclonal antibodies, a fluorescence activated cell sorter, and mixed lymphocyte culture tests indicate that an abnormal thymus is not responsible for the immunodeficiency of BB rats, but that the defect resideswithin the lymphocyte precursor pool.
Gastric Acid and Pancreatic Polypeptide Responses to Sham Feeding Are Impaired in Diabetic Subjects with Autonomic Neuropathy
Authors: Buysschaert Martin , Donckier Julian , Dive Alain , Ketelslegers Jean-Marie , Lambert André E
Published: September 2013

To assess the relationship between cardiac and extracardiac dysfunction in diabetic autonomic neuropathy, the gastric acid output and the pancreatic polypeptide (hPP) secretion in response to sham feeding were evaluated in diabetic patients with (group 1) and without (group 2) cardiac autonomic neuropathy (CAN), and in normal subjects (group 3). All patients assigned to the group with CAN exhibited an impaired beat-to-beat heart rate variation during deep breathing. The basal gastric acid output was comparable in the three groups (1.3 ± 0.5, 2.8 ± 1.5, and 3.9 ± 1.5 mmol/h, respectively). In contrast, the gastric acid output stimulated by sham feeding was significantly lower in patients with CAN (5.3 ±1.3 mmol/h) thanin diabetic subjects without CAN (14.0 ± 3.5 mmol/h; P < 0.01) and in controls (10.9 ± 3.1; P < 0.05). The maximal gastric acid secretion capacity, determined after pentagastrin injection, was similar in all patients. Mean basal hPP concentrations were comparable in the three groups (185 ± 53 pg/ml, 131 ± 29 pg/ml, and 116 ± 19 pg/ml). In the controls and diabetic subjects without CAN, a significant mean 60% increase of the hPP levels above basal values was observed during sham feeding. In contrast, no significant hPP response occurred in the group with CAN. These data suggest that diabetic CAN is associated with dysfunctions of the vagal pathways controlling the gastric acid output and the hPP secretion. Moreover, the results demonstrate a strong association between cardiac autonomic neuropathy and gastric vagal neuropathy (P < 0.001).
Retrograde Axonal Transport of 125I-Nerve Growth Factor in Rat Heal Mesenteric Nerves: Effect of Streptozocin Diabetes
Authors: Schmidt Robert E , Plurad Santiago B , Saffitz Jeffrey E , Grabau Gary G , Yip Henry K
Published: September 2013

The retrograde axonal transport of intravenously (i.v.) administered 125I-nerve growth factor (125I-NGF) was examined in mesenteric nerves innervating the small bowel of rats with streptozocin (STZ) diabetes using methods described in detail in the companion article. The accumulation of 125I-NGF distal to a ligature on the ileal mesenteric nerves of diabetic animals was 30–40% less than in control animals. The inhibition of accumulation of 125I-NGF in diabetic animals was greater at a ligature tied 2 h after i.v. administration than at a ligature tied after 14 h, which suggests that the diabetic animals may have a lag in initiation of NGF transport in the terminal axon or retardation of transport at some site along the axon. The 125I-NGF transport defect was observed as early as 3 days after the induction of diabetes, a time before the development of structural axonal lesions, and did not worsen at later times when dystrophic axonopathy is present. Both the ileal mesenteric nerves, which eventually develop dystrophic axonopathy in experimental diabetes, and the jejunal mesenteric nerves, which never develop comparable structural alterations, showed similar 125I-NGF transport deficits, suggesting that the existence of the transport abnormality does not predict the eventual development of dystrophic axonal lesions. Autoradiographic localization of 125I-NGF in the ileal mesenteric nerves of animals that had been diabetic for 11–13 mo demonstrated decreased amounts of 125I-NGF in transit in unligated paravascular nerve fascicles. There was, however, no evidence for focal retardation of transported 125I-NGF at the sites of dystrophic axonal lesions.
HLA Heterogeneity of Insulin-dependent Diabetes Mellitus at Diagnosis: The Pittsburgh IDDM Study
Authors: Eberhardt Mark S , Wagener Diane K , Orchard Trevor J , LaPorte Ronald E , Cavender Druie E , Rabin Bruce S , Atchison R Wayne , Kuller Lewis H , Drash Allan L , Becker Dorothy J
Published: September 2013

Although some previous studies have suggested that insulin-dependent diabetes mellitus (IDDM) is a heterogeneous condition with variant forms being associated with HLA-DR types, the evidence, thus far, is conflicting. To address this issue, we have examined the presenting characteristics of a consecutive admission series of 200 newly diagnosed cases of IDDM from the Children's Hospital of Pittsburgh. Because HLA-DR frequencies vary by race, data are presented only for the 172 white cases with complete HLA-DR typing. HLADR3 was found more frequently among male cases and DR4 among female cases (P < 0.005). Generally, patients with DR4 presented with a severer clinical picture, being more likely to have impaired consciousness and significant dehydration. In addition, patients with DR4 were more likely to be acidotic, ketotic, and to more frequently report a recent viral infection. This latter finding was supported by a greater frequency of antibodies to Coxsackie-B viruses in the DR4 cases at presentation. These results therefore suggest that there is considerable heterogeneity in IDDM, at least in presenting characteristics, according to HLA-DR type.