bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucose Intolerance and Aging: Evidence for Tissue Insensitivity to Insulin
Authors: DeFronzo Ralph A 
Published: September 2013

The relative contributions of impaired insulin secretion and of impaired tissue sensitivity to insulin to the glucose intolerance of aging were examined in 84 healthy volunteers, ranging in age from 21 to 84 yr, employing the hyperglycemie and euglycemic insulin clamp techniques, respectively.
HYPERGLYCEMIC CLAMP. The blood glucose concentration was acutely raised and was maintained at 125 mg/dl above basal levels for 2 h. Since the glucose concentration was held constant, the glucose infusion rate was an index of glucose metabolism (M). In young subjects, M averaged 9.48 ± 0.40 mg/kg · min compared with 6.48 ± 0.28 in old subjects (P &lt; 0.001). When all subjects were considered together, a progressive age-related decline in M was observed (r = –0.665, P &lt; 0.001). The plasma insulin response (I) was biphasic, with an early burst within the first 6 min, followed by a phase of gradually increasing insulin concentration. No difference in either the early or late phases of insulin secretion was observed between young and old subjects. Consequently, the M/l (×100) ratio, an index of tissue sensitivity to endogenous insulin, decreased from 14.90 ± 1.01 to 10.98 ± 0.81 mg/kg min per μU/ml (P &lt; 0.005).
EUGLYCEMIC INSULIN CLAMP. The plasma insulin concentration was acutely raised and was maintained at about 100 μU/ml above basal levels by a primed continuous infusion of insulin. The blood glucose concentration was held constant at the basal level by a variable glucose infusion. M/I (×100), again, was a measure of tissue sensitivity to insulin (exogenous) and was decreased in old (4.95 ± 0.31 mg/kg · min per μU/ml) versus young (6.95 ± 0.45) subjects (P &lt; 0.001). Hepatic glucose production was measured with tritiated glucose during the euglycemic clamp study; it declined similarly in young (to 0.13 ± 0.05 mg/kg · min) and old (to 0.09 ± 0.03 mg · min) subjects.
In conclusion, under the present experimental conditions, employing intravenous glucose and/or insulin, impaired tissue sensitivity to insulin is the primary factor responsible for the decrease in glucose tolerance observed with advancing age. Since hepatic glucose production is normally suppressed by insulin in old subjects, the site of insulin resistance must reside in peripheral tissues. Beta cell response to glucose, as determined by the hyperglycemie clamp technique, cannot account for the age-related decline in M.
The Insulin Receptor and Insulin of the Atlantic Hagfish: Extraordinary Conservation of Binding Specificity and Negative Cooperativity in the Most Primitive Vertebrate
Authors: Muggeo M , Van Obberghen E , Kahn C R , Roth J , Ginsberg B H , De Meyts P , Emdin S O , Falkmer S 
Published: September 2013

The North Atlantic hagfish, a cyclostome that is representative of the most primitive vertebrates still alive, diverged from the other vertebrates about 500 million years ago. Hagfish insulin, which differs from porcine insulin in 18 (38%) of its amino acids, had a potency of 5-10% that of porcine insulin in stimulating glucose oxidation and deoxyglucose transport in rat adipocytes and was 5-10% as potent as porcine insulin in binding to insulin receptors on rat adipocytes and human (IM-9) lymphocytes. Like all other naturally occurring insulins, hagfish insulin accelerated the dissociation of 125I-porcine insulin from insulin receptors and the degree of the acceleration was related to its occupancy of the receptor. The insulin receptor of the hagfish erythrocyte showed the time, temperature, and pH dependence of binding and the negative cooperativity that are characteristic of all other insulin receptors. That the negative cooperativity is fully conserved in such an ancient insulin and receptor suggests that it is an important functional feature of this hormone-receptor system.
The hagfish receptor showed the same absolute affinity and rank order of preference for insulins and insulin analogues (chicken &gt; pork &gt; proinsulin &gt; guinea pig &gt; desoctapeptide) found with other receptors of less primitive vertebrates, which supports the conclusion that the receptor for insulin is functionally better conserved evolutionary than the hormone. However, uniquely, hagfish insulin was more potent in binding to hagfish receptors than to mammalianreceptors; with all other species of insulins studied, the affinity of the hormone for homologous receptor was the same as for receptors of heterologous species.
Lipoproteins in the Plasma and Hepatic Perfusates of the Zucker Fatty Rat
Authors: Witztum Joseph L , Schonfeld Gustav 
Published: September 2013

The Zucker fatty rat develops marked hyperlipidemia characterized by elevations in all lipoproteins. The compositions of these lipoproteins are altered. The purpose of our study was to determine the hepatic contribution to the alterations seen in plasma.
Zucker fatty rats and lean controls were fed ad libitum. Fatties gained more weight than leans. Levels of lipids were determined chemically, and apoproteins A(ApoA)-I and B(ApoB) by radioimmunoassay (RIA). Very low density lipoproteins (VLDL) (d &lt; 1.006) and VLDL density subfractions were isolated by ultracentrifugation. VLDL size and density distributions were assessed by column chromatography and ultracentrifugation, respectively. Compositions were studied by isoelectric focusing (IEF) and polyacrylamide gel electrophoresis. Livers from fatty and lean controls were perfused in vitro and whole perfusates and perfusate VLDL were studied as for plasma.
Triglyceride (TG) increased ∼10-fold in fatty plasma, cholesterol (Choi) twofold, and ApoA-I fourfold, but ApoB was ∼40% lower. The VLDL of fatties were larger, TG-enriched, and less dense. Although total VLDL-protein was elevated, the proportion of the VLDL-protein that was ApoB and ARP was low. Therefore, VLDL-protein was enriched with ApoC. ApoB and ApoE contents of VLDL subclasses varied directly with particle density, while ApoC varied inversely. Changes in ApoC subspecies were also noted. For any given VLDL subfraction, fatty VLDL had less ApoB and ApoE and more ApoC than the corresponding VLDL subfraction in the lean controls.
Compared with livers of lean, the livers of fatty rats secreted VLDL that were larger, TG-enriched, and less dense. Here, too, VLDL-protein was higher because of relative increases in non-ApoB proteins. ApoB and ApoE content varied directly with particle density in VLDL subfraction of the perfusates, while ApoC varied inversely; for any given VLDL subfraction, fatty VLDL had less ApoE and more ApoC than analogous fractions in lean controls, though levels of ApoB were similar. As in plasma, the distribution of the ApoC subspecies differed in the perfusate VLDL of fatty and lean animals. Thus, the hepatic secretion of altered VLDL could explain many of the changes seen in the VLDL of plasma. However, differences remained between perfusate and plasma VLDL, which may be due to alterations introduced by intravascular catabolism and/or by lipoproteins secreted from the gut.
Although plasma ApoA-I levels were fourfold higher in fatty, the hepatic secretion of ApoA-I was similar in the fatty and lean rats. The contribution of the liver to plasma pools of A-I was calculated as 34.8% in lean and 10.7% in fatty. These data are consistent with the concept that the gut, not the liver, is the major contributor to plasma ApoA-I.
The Effect of Age on Glucose Tolerance: Studies in a Micronesian Population with a High Prevalence of Diabetes
Authors: Zimmet P , Whitehouse S 
Published: September 2013

Venous plasma glucose concentrations before and two hours after a 75 g carbohydrate load were determined on 597 Nauruans, a Micronesian population with one of the highest diabetes prevalence rates yet recorded in the literature.
A marked increase in both the mean fasting and postload plasma glucose concentrations with age for both sexes was noted for the total population.
In this population the frequency distributions of fasting and two-hour plasma glucose show bimodality, separating the population into normal and hyperglycemic subpopulations. Analysis of mean fasting and two-hour glucose concentrations of subjects in the normal and hyperglycemic components shows that the increase in mean glucose with age in the Nauruan population is mainly the result of an increasing proportion of subjects falling into the hyperglycemic (diabetic) component with increasing age. Only small changes in mean glucose concentrations with age were noted in subjects in the normal component.
Percentile distributions of both fasting and postload glucose concentrations indicate that there is a dramatic age-related increase in glucose concentrations in the higher percentiles (70th and 90th) in both males and females. This finding is consistent with the hypothesis of two subpopulations in which the glucose concentrations increase significantly with age in one (higher percentiles) and remain relatively constant in the other (lower percentiles).
The data indicate that, while there is a rise in glucose concentrations with increasing age, it does not necessarily represent diabetes. The major contribution to this age-related rise is due to the increasing number of diabetics with age, and the diabetics can be separated from the rest of the population on the basis of percentile analysis and bimodality of glucose distributions.
Hepatic Effects of Chlorpropamide: Inhibition of Glucagon-stimulated Gluconeogenesis in Perfused Livers of Fasted Rats
Authors: Blumenthal Stanley A , Whitmer Kyra Riegle 
Published: September 2013

In perfused livers of rats fasted for 24 h, glucagon (5 × 10−10 M) significantly elevated tissue and perfusate levels of cyclic AMP and caused a twofold increase in glucose formation from lactate. Chlorpropamide (0.8 × 10−3 M) consistently blocked these effects. Measurements of metabolic intermediates suggest that chlorpropamide may inhibit gluconeogenesis by antagonizing the action of glucagon on the phosphoenolpyruvate cycle.
In the experiments described, chlorpropamide did not lower hepatic ATP concentration or energy charge, and exerted its effects at perfusate concentrations comparable to serum concentrations reported in patients on maintenance doses of the drug.
Cultured Hepatoma Cells as a Model System for Studying Insulin Processing and Biologic Responsiveness
Authors: Hofmann Cecilia , Marsh Jon W , Miller Bonnie , Steiner Donald F 
Published: September 2013

SUMMARY
Monolayer cultures of minimal deviation hepatoma cells (H4-II-E-C3′) bound and degraded insulin specifically, the apparent Ki value for insulin inhibition of both processes being 1 × 10−8 M, indicating that cellbound 125l-insulin is the substrate for subsequent hormone degradation in these cells as in isolated hepatocytes.1 The time course of insulin binding to its receptor depended on hormone concentration and temperature. Degradation of insulin also depended highly on temperature, with little or no degradation occurring at less than 20°C, a temperature below which a membrane–lipid phase transition may block hormone translocation or uptake. The effects of various agents on the binding and degradation of 125l-insulin also were tested. Agents believed to inhibit intralysosomal degradation of various proteins also inhibited the degradation of 125l-insulin by H4 cells (chloroquine, ammonium chloride, procaine, and lidocaine); inhibitors of energy production (dinitrophenol, sodium cyanide) inhibited degradation; an agent which inhibits microtubule function (vinblastine) blocked insulin degradation; and methylamine, reported to prevent receptor aggregation,2 also interfered with insulin processing. These findings are consistent with a model for cellular insulin processing, comprising receptor binding, clustering of receptors, endocytotic uptake, intralysosomal degradation, and extracellular release of some degradation products. H4 cells were highly sensitive to insulin. The KE for a half-maximal response of hormone-stimulated incorporation of 14Cglucose into glycogen was 10−11 M insulin, corresponding to less than 1% receptor occupancy. This response was also mimicked by concanavalin A at a concentration of 10 μug/ml. Vinblastine and chloroquine both significantly inhibited insulin-stimulated glucose incorporation into glycogen without affecting basal levels. However, since these inhibitory effects were not relieved by addition of excess insulin, it seemsunlikely that their action on glycogen synthesis was exerted only at the level of the generation of an active intermediate or degradation product from hormone-receptor complexes. The hormone-sensitive H4 cells thus provide a useful system for further studies examining the role of insulin-receptor uptake in hormone action, receptor regulation, and signal termination.
The Effect of Improved Diabetic Control on Plasma Lipid and Lipoprotein Levels: A Comparison of Conventional Therapy and Continuous Subcutaneous Insulin Infusion
Authors: Pietri Angel , Dunn Fredrick L , Raskin Philip 
Published: September 2013

We studied short-term changes in plasma lipid levels in type I diabetics treated with either a conventional insulin regimen or continuous subcutaneous insulin infusion. Mean plasma glucose dropped from 260 ± 18 to 134 ± 8 mg/dl when conventional treatment was used and from 194 ± 18 to 108 ± 8 mg/dl with CSII. Both forms of therapy were associated with a significant fall in plasma triglyceride levels. However, only CSII treatment produced significant changes in total plasma cholesterol and LDL cholesterol levels. Total cholesterol fell from 195 ± 17 mg/dl to 161 ± 11 mg/dl and LDL cholesterol fell from 129 ± 13 mg/dl to 102 ± 9 mg/dl.
We conclude that improved diabetic control by any method is effective in lowering plasma triglyceride levels, but it requires almost perfect metabolic control to affect plasma cholesterol and LDL cholesterol levels. The changes in plasma lipid and lipoprotein achieved with CSII may favorably alter the prediction for the development of premature atherosclerosis in our patients.
Reduced Perikaryal Volume of Lower Motor and Primary Sensory Neurons in Early Experimental Diabetes
Authors: Sidenius P , Jakobsen J 
Published: September 2013

The volume of nerve cell bodies of the anterior horn of the fifth lumbar segment and of the fifth lumbar dorsal root ganglion were measured by stereological methods in rats with 4-wk duration of streptozotocin diabetes and in age-matched controls. The perikaryal volume of motor and sensory neurons was reduced by 18% in diabetic rats and a shift between the number of A- and B-cells was observed in the dorsal root ganglion.
The findings are in accordance with our earlier observation of reduced axonal size of myelinated fibers in the common peroneal nerve. Furthermore, the data lead us to suppose that the nervous system abnormalities in early diabetes are not exclusively restricted to the peripheral nerves.
Abnormal Sciatic Nerve Myo-inositol Metabolism in the Streptozotocin-diabetic Rat: Effect of Insulin Treatment
Authors: Clements Rex S , Stockard Cecil R 
Published: September 2013

The metabolism of myo-inositol and its hospholipids has been studied in the sciatic nerves of control, two weeks' streptozotocin-diabetic, and insulin-treated diabetic rats. The concentrations of glucose, fructose, and sorbitol were increased and the concentration of myo-inositol was decreased in the sciatic nerves of the diabetic animals; these abnormalities were only partially corrected by insulin therapy that was adequate to obviate hyperglycemia. Whereas the space of distribution of 2-3H-myo-inositol was found to exceed the total water space of the nerves of control animals, the 2-3H-myo-inositol space approximated the water space in the nerves of diabetic animals and was only slightly increased after insulin therapy. During the first 2 h after the intraperitoneal injection of 2-3H-myo-inositol, the recovery of radioactivity in nerve lipids was decreased by 69% in the untreated diabetics and by 77% in the insulin-treated diabetics. Analysis of the individual phosphoinositides revealed a proportional increase in the radioactivity recovered with phosphatidylinositol and a decrease in the recovery with triphosphatidylinositol in the diabetic nerves.
CDP-diglyceride:inositol transferase activity was decreased by 44% in homogenates of sciatic nerves from untreated diabetic rats, but it was normal in nerve homogenates from insulin-treated diabetics. The pattern of incorporation of radioactivity into phospholipids after 1 h of incubation of nerve homogenates with 2-3H-myo-inositol was similar to that observed in vivo. The fractional recovery of radioactivity with phosphatidylinositol was increased, whereas the recovery of label as triphosphatidylinositol was decreased by 11% in the presence of homogenates of sciatic nerves from diabetic rats.
These observations indicate that 2 wk of acute streptozotocin diabetes results in a decrease in the sciatic nerve content and space of distribution of myo-inositol and suggests that nerve myo-inositol transport may be defective in the diabetic animal. The observed abnormalities in the amount and pattern of incorporation of 2-3H-myo-inositol into diabetic nerve phospholipids could be explained, in part, by decreased activities of CDP-diglyceride:inositol transferase and phosphatidylinositol 4-phosphate kinase activities in the diabetic nerves. However, the fact that the incorporation of 2-3H-myo-inositol into phospholipids was decreased in the nerves of insulin-treated—diabetic animals despite a normal CDP-diglyceride:inositol transferase activity suggests that defective myo-inositol transport may also contribute to the abnormal neural phosphoinositide metabolism in this model. The possibility that these abnormalities are related to the development of the structural and functional changes associated with diabetic neuropathy requires further investigation.
A Detailed Study of Risk Factors for Retinopathy and Nephropathy in Diabetes
Authors: West Kelly M , Erdreich Linda J , Stober Judy A 
Published: September 2013

Indexes of retinopathy and nephropathy were studied in a large population of diabetics using standardized methods. In each of 973 subjects, more than 100 other variables were also measured: this made It possible to take into account many confounding factors when we examined the relationships of these variables to microangiopathy.
The most powerful risk factor for microangiopathy was duration of diabetes, but frequency of both retinopathy and nephropathy was impressively related to the level of plasma glucose at the time of examination. This latter relationship was independent of the effects of other variables. Risk of retinopathy was also related to factors that were probably associated with higher previous plasma glucose levels—need for insulin therapy, history of ketonuria, present level of plasma triglyceride, leanness, and younger age of onset of diabetes. In subjects with a systolic blood pressure of less than 170 mm Hg and who did not have proteinuria, no significant relationship was found between blood pressure and frequency of retinopathy, but, when the systolic pressure was greater than 169 mm Hg, rates of retinopathy were excessive, even In those subjects without proteinuria. Several other factors had no significant relationship to retinopathy or nephropathy: these included age, level of education, smoking, and plasma cholesterol. Rates of severe nephropathy were somewhat greater In men than in women, but this difference was not statistically significant. Rates of retinopathy and of mild proteinuria were similar in men and women. After adjustment for duration of diabetes, the risk of retinopathy was no higher in the 102 subjects with two diabetic parents than in the 254 who had no family history of diabetes.
Development of Insulin Release by Fetal Rat Pancreas In Vitro: Effects of Glucose, Amino Acids, and Theophylline
Authors: Kervran Alain , Randon Jacques 
Published: September 2013

The dynamics of insulin release by pieces of fetal rat pancreas from 17.5 to 21.5 days of gestation was measured in an in vitro perifusion system. Interactions between glucose, theophylline, and a mixture of 12 amino acids at physiologic concentration (mix. A.A.) were studied.
On day 17.5, 13.9 m M glucose induced only a small (10 min) early phase of insulin release. The late phase of insulin secretion appeared on day 18.5 and gradually increased as the gestation proceeded. The mix. A.A. (9 mM) or theophylline (5 mM) potentiated the two phases of insulin release induced by 13.9 mM glucose from days 18.5 to 21.5 of gestation. On day 21.5, the combination of theophylline and mix. A.A. at 2.2 mM glucose stimulated insulin release by fetal pancreas.
The dose-dependent curves of the early phase of insulin release, due to glucose or glucose and mix. A.A. (9 mM), showed half maximal responses in the term fetal pancreas at glucose concentrations of 7.2 and 4 mM, respectively. The values were 7.9 and 5.9 mM for the late phase.
The results indicate that the mechanisms controlling biphasic insulin release develop during the late fetal life in the rat. Transition from the fetal to adult type of insulin secretion more likely parallels quantitative, rather than qualitative, changes within the B cells.
Androgen Sensitization of Streptozotocin-induced Diabetes in Mice
Authors: Maclaren Noel K , Neufeld Michel , McLaughlin Judith V , Taylor Glen 
Published: September 2013

Male mice are more sensitive to the diabetogenic effect of streptozotocin (SZ) than female mice. These studies were designed to determine whether sex hormones could be responsible.
A single intraperitoneal (i.p.) dose of 80 mg SZ/kg regularly induced acute severe diabetes in 45 day old male CD-1 mice beginning after 1 day, whereas females of the same age and strain remained euglyce-mic for 75 days after the same SZ dose. With 120 mg SZ/kg, similar female mice developed a mild, delayed hyperglycemia 41 days after injection. Inbred strains (DB A/2 J) demonstrated a similar sex relationship.
In 45 day old male CD-1 mice, pretreatments with antiandrogen (SCH.13521) reduced the hyperglycemie effect of SZ when compared with control male mice given the same SZ dose (P &lt; 0.001). Castration of male CD-1 mice before SZ also caused a milder hyperglycemia than in sham-operated control mice (P &lt; 0.001). Pretreatment with estrogens before SZ in male CD-1 mice had little effect.
Female CD-1 mice, given 10 mg testosterone twice before the 120 mg SZ/kg injection, showed an increased sensitivity to SZ-induced diabetes when compared with female control mice or with female mice pretreated with only 1 mg testosterone (P &lt; 0.001). Examination of the pancreases of these animals showed that the testosterone effect was accompanied by enhanced β cell destruction and increased and more centrally placed α cells within islets.
Phenobarbital when given daily for 7 days before the SZ injection potentiated the diabetogenic effect of SZ in male CD-1 mice and in female mice.
These studies are consistent with an important action of testosterone in potentiating the pancreatic /3 cell toxicity of SZ. The similar synergistic effect of phénobarbital may help to clarify the biochemical mechanism of SZ-induced pancreatic β cell destruction.