bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Obesity, Hyperinsulinemia, and Glucose Intolerance on Insulin Action in Adipose Tissue of Sixty-Year-Old Men
Authors: Bolinder Jan , Lithell Hans , Skarfors Einar , Arner Peter 
Published: September 2013

The relative effects of obesity alone, and in combination with fasting hyperinsulinemia and glucose intolerance, on the peripheral action of insulin in adipose tissue were investigated in twenty-four 60-yr-old men, who had been followed for 10 yr. They were divided into four groups of six subjects each on the basis of the following criteria: (1) normal body weight, normal fasting insulin level, and normal glucose tolerance; (2) moderate obesity, normal fasting insulin level, and normal glucose tolerance; (3) moderate obesity, fasting hyperinsulinemia, and normal glucose tolerance; and (4) moderate obesity, fasting hyperinsulinemia, and newly developed, moderate, untreated fasting hyperglycemia and/or glucose intolerance (i.e., mild type II diabetes mellitus). Specific adipocyte insulin binding and the effects of the hormone on adipose tissue lipolysis and glucose oxidation were determined. Insulin receptor binding per cell and per cell surface area were similar in all four groups. Regarding antilipolysis, the insulin sensitivity was the same in all groups and the maximum effect was significantly increased in the three obese groups, as compared with the normal-weight control group. In groups 1–3, insulin stimulated adipose tissue glucose oxidation in a dose-dependent way, and the sensitivity and responsiveness to insulin were comparable. In contrast, in the obese glucose-intolerant subjects (4) there was no significant effect of insulin on glucose oxidation when the hormone was added in increasing concentrations of ≤35 nmol/L. The basal glucose oxidation was similar in all four study groups. The in vivo insulin tolerance was gradually reduced in groups 2–4, as compared with the normalweight control group.
It is concluded that, in 60-yr-old men, obesity per se,or in combination with fasting hyperinsulinemia, does not inhibit insulin action on glucose metabolism in adipose tissue, although the in vivo insulin action is reduced. Only when obesity is accompanied by glucose intolerance does insulin reduce the glucose utilization of adipose tissue. In this situation the resistance to insulin is solely due to postreceptor defects of insulin action. The antilipolytic effect of insulin is enhanced in obese 60-yr-old men, whether or not the overweightness is accompanied by hyperinsulinemia and/or glucose intolerance.
In Vivo Deactivation of Proinsulin Action on Glucose Disposal and Hepatic Glucose Production in Normal Man
Authors: Glauber H S , Revers R R , Henry R , Schmeiser L , Wallace P , Kolterman O G , Cohen R M , Rubenstein A H , Galloway J A , Frank B H , Olefsky J M 
Published: September 2013

We have studied the deactivation of the in vivo actions of insulin and biosynthetic human proinsulin (recombinant DNA) to stimulate the glucose disposal rate (GDR) and to inhibit hepatic glucose output (HGO) in man. Twelve healthy, lean, young subjects were studied using a modification of the euglycemic glucose clamp technique. Subjects received 4-h infusions on separate occasions of insulin (15 mU/m2/min equivalent to 0.54 μg/m2/min) or proinsulin (2.75 μg/m2/min), achieving steady-state serum levels of 32 ± 3 μU/ml (equivalent to 0.23 ± 0.02 pmol/ml) and 3.7 ± 0.2 pmol/ml, respectively. Suppression of HGO was similar (83–84%) with proinsulin and insulin, but stimulation of GDR above basal was greater with insulin (3.41 ± 0.43 versus 1.98 ± 0.28 mg/kg/min, P &lt; 0.001).
Following cessation of the hormone infusions, serum proinsulin concentration fell in a biphasic fashion with half-times of 25 and 146 min for the two phases. Serum half-disappearance time for insulin was 5 min. Deactivation of the hormone's effects to stimulate GDR was 50% complete by 35 min after insulin and 71 min after proinsulin. In contrast, 50% of the recovery times for the effect on suppression of HGO were 55 min after insulin and 188 min after proinsulin. Serum glucagon levels did not differ significantly after the insulin and proinsulin infusions.
In summary: (1) Deactivation of proinsulin and insulin's effects to suppress HGO proceeds more slowly than deactivation of their effects to stimulate GDR; and (2) There is a markedly prolonged and disproportionately delayed deactivation of proinsulin's effects on suppression of HGO. This later finding may prove of therapeutic value in the treatment of diabetes mellitus.
The Prevalence of Islet Cell Antibodies in Japanese Insulin-dependent and Non-insulin-dependent Diabetic Patients Studied by Indirect Immunofluorescence and by a New Method
Authors: Kobayashi Tetsuro , Sugimoto Tadao , Itoh Tokuji , Kosaka Kinori , Tanaka Toshiaki , Suwa Seizo , Sato Kaoru , Tsuji Kimiyoshi 
Published: September 2013

Islet cell antibodies (ICA) were measured in Japanese patients with insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) by a standard, indirect immunofluorescence method (IF method) and by a newly established, threelayer immunofluorescence method applying a biotin-avidin system (BAS method). In addition, the relationship between ICA and HLA was studied in IDDM patients.
ICA titers detected by the BAS method correlated well with those determined by the standard IF method (rs = 0.987, P &lt; 0.01). The BAS method had about an eightfold higher sensitivity for ICA than the IF method.
The overall prevalence of ICA detected by the BAS method (ICA-BAS) versus that by the IF method (ICAIF) was 41% (82/198) versus 28% (56/198) in IDDM patients and 3% (19/593) versus 2% (14/593) in patients with NIDDM. In IDDM patients, ICA-BAS was all positive &lt;1 mo after the onset of diabetes, while the prevalence of ICA-IF was 83% (20/24) during the same period. The prevalence of ICA-IF decreased rapidly with the duration of disease, reaching a value of 6% (3/55) in the patients with a disease duration of 10 yr or more. The incidence of ICA-BAS also decreased with the duration of disease, although to a lesser degree than ICA-IF. No association was found between HLA types and persistence of ICA-BAS or -IF.
These results suggest that pancreatic autoimmune processes occur in almost all Japanese IDDM patients. Although IDDM is less common in Japan than among Caucasians, the prevalence of ICA seems to be the same. The higher sensitivity of the BAS method may be of significant diagnostic value, especially in patients with a long duration of disease.
Renin Secretion by the Spontaneously Diabetic Rat
Authors: Cohen Andrew J , McCarthy Donna M , Rossetti Ronald R 
Published: September 2013

Renal function studies and measurements of in vivo plasma renin activity (PRA), kidney renin content, and renin secretion by isolated, perfused kidneys were performed in spontaneously diabetic and nondiabetic Bio Breeding/Worcester (BB/W) rats. Diabetic animals evidenced hyperglycemia, glycosuria, and plasma volume expansion. After dietary sodium deprivation, plasma volume fell to levels equivalent to those of sodium-deprived, nondiabetic rats.
Dietary sodium deprivation evoked a larger proportional increase in PRA among diabetic than nondiabetic animals, although PRA before sodium restriction was equivalent in the two groups.
Basal renin release (RR) was higher from isolated, perfused kidneys from diabetic rats than from nondiabetic kidneys. Diabetic kidneys, moreover, displayed increased kidney renin content (KRC). By contrast, while isoproterenol (10−5 M) stimulated a nearly fivefold increment in RR from nondiabetic, perfused kidneys, a negligible effect was observed in diabetic kidneys. The dose-response curve of renin secretion (as a proportion of total renal content) in response to isoproterenol was shifted downward. Hence, while KRC and spontaneous RR by isolated, perfused kidneys were increased, the increment in PRA with salt depletion and the renin-secretory response to isoproterenol in vitro were impaired. We propose that specific defects in renin secretion, in particular, the response to betaadrenergic stimulation, may be operative in diabetes.
Persistence of Polymicrobial Abscesses in the Poorly Controlled Diabetic Host
Authors: Bessman Alice N , Sapico Francisco L , Tabatabai Meher , Montgomerie John Z 
Published: September 2013

Polymicrobial infections are frequently found in soft tissue infections of the lower extremities in diabetic patients. The relative susceptibility to and persistence of soft tissue polymicrobial infections of diabetic and nondiabetic mice using bacteria commonly found in clinical foot infections were studied. Subcutaneous abscesses were induced in three groups of diabetic and nondiabetic mice using: (1) E. coli and enterococcus, (2) enterococcus and Bacteroides fragilis (B. fragilis), and (3) E. coli and B. fragilis. Abscesses were removed at 1 and 2 wk for total colony counts. At 1 wk, there was a significantly greater bacterial growth in the abscesses of the diabetic mice compared with the nondiabetic mice only in the group injected with enterococcus and B. fragilis. There were significantly higher colony counts in the diabetic compared with the nondiabetic mice in all three groups at 2 wk after injection of the bacteria. Two weeks after injection of inocula containing B. fragilis, both in combination with E. coli or enterococcus, all nondiabetic mice had eradicated B. fragilis from the abscesses, but significant numbers of B. fragilis persisted in the abscesses of the diabetic mice. In the diabetic mice, the presence of enterococci was more synergistic for growth of B. fragilis than was the presence of E. coli.
These studies demonstrate that the bacteria of polymicrobial soft tissue infections persist for a longer period of time in the diabetic compared with the nondiabetic host. In addition, B. fragilis has increased pathogenicity in the diabetic compared with the nondiabetic host, particularly in the presence of enterococci.
Binding and Internalization of Insulin and Insulin-Like Growth Factors by Isolated Brain Microvessels
Authors: Frank H J L , Pardridge W M , Morris W L , Rosenfeld R G , Choi T B 
Published: September 2013

Isolated brain capillaries were used as a model system to test for binding and internalization of insulin and insulin-like growth factors (IGF) I and II. At 37°C, the maximum specific binding of the 125I-labeled peptides was 48.0 ± 0.8%/mg capillary protein for IGF I, 40.6 ± 1.4% for IGF II, and 15.1 ± 0.6% for insulin. The concentration of unlabeled peptide needed to cause a 50% decrease in the maximum binding (ID50)was 22 ng/ml (2.9 nM), 25 ng/ml (3.3 nM), and 7 ng/ml (1.2 nM) for IGF I, IGF II, andinsulin, respectively. Unlabeled insulin competed poorly for the IGF I receptor, requiring 5000 ng/ml (667 nM) to cause a 50% reduction in binding, and did not compete at all for the IGF II receptor at concentrations up to 105 ng/ml (17.8 μM).
The IGF I receptor was further characterized by reduced polyacrylamide gel electrophoresis ofthe disuccinimidyl suberate cross-linked 125I-labeled IGF I receptor. The gel showed a distinct band at 133,000 M1 that was abolished by 0.6 μg/ml (80 nM) unlabeled IGF I but not by 10.0 ng/ml (1780 nM) unlabeled insulin.
Peptide internalization was monitored by the acidwash technique. Only 22% of the bound IGF I was internalized, but 50% of the insulin and 43% of the IGF II were acid resistant. Capillaries prelabeled with internalized 125I-insulin could then export radioactivity into fresh, insulin-free media in a time- and temperature-dependent manner. However, high-performance liquid chromatography (HPLC) and trichloroacetic acid (TCA) analysis of the released material showedthat it consisted mostly of degraded peptide.
These studies show that brain capillaries have separate receptors for insulin, IGF I, and IGFII. The endocytosis of these peptides is in the order of insulin &gt; IGF II &gt;IGF I, the same order as their distribution in cerebrospinal fluid (CSF) and brain, based on published data. Although the HPLC data do not support the general conclusion that the blood-brain barrier functions as a selective peptide-hormone transporter, this may be the result of cellular damage because the capillaries are ATP depleted.
Vitamin D Metabolites and Their Binding Protein in Adult Diabetic Patients
Authors: Nyomba B L , Bouillon R , Bidingija M , Kandjingu K. , Moor P De 
Published: September 2013

Vitamin D metabolites and vitamin D—binding protein were measured in the serum of nonketotic Bantu and Caucasian insulin-requiring diabetic subjects from Zaire and Belgium, respectively. In Caucasian diabetics, whether untreated (N = 18) or insulin treated (N = 26), no abnormalities were found. The Bantu diabetics (N = 20) were more insulin-deficient and had a poorer glucose control than the Caucasians. They presented, compared with Bantu controls, a significant decrease in the serum concentrations of 25-hydroxy-vitamin D3 (26 ± 10 vs. 35 ± 14 μg/L, P &lt; .01), 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] (38 ± 15 vs. 58 ± 17 ng/L, P &lt; .001), and vitamin D-binding protein (303 ± 55 vs. 356 ± 41 mg/L, P &lt; .001). The decreased concentrations of vitamin D metabolites in the adult Bantu diabetic patients may be partly explained by a concomitant decrease in the concentration of vitamin D-binding protein, possibly due to insulin deficiency. The ratio between the molar concentrations of 1,25-(OH)2D3 and vitamin D-binding protein, used as an index of the free hormonal level, was also decreased, in association with a decreased serum calcium level.
In conclusion, no abnormalities in vitamin D metabolism were found in Caucasian insulin-dependent diabetics, whereas low serum 1,25(OH)2D3 concentrations and hypocalcemie were found in poorly controlled Bantu diabetic subjects.
Initial Phase II Clinical Studies on Midaglizole (DG-5128): A New Hypoglycemic Agent
Authors: Kawazu S , Suzuki M , Negishi K , Ishii J , Sando H , Katagiri H , Kanazawa Y , Yamanouchi S , Akanuma Y , Kajinuma H , Suzuki K , Watanabe K , Itoh T , Kobayashi T , Kosaka K 
Published: September 2013

Midaglizole (DG-5128), 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenylethyl]pyridine dihydrochloride sesquihydrate, is a new type of oral antidiabetic agent that has an α2-adrenoceptor-antagonizing effect. As previously reported, midaglizole reduces plasma glucose, mainly by stimulation of insulin secretion, and inhibits epinephrine-induced platelet aggregation in normal human subjects.
In this study, the clinical safety and efficacy of shortterm administration of midaglizole were evaluated in 47 patients with non-insulin-dependent diabetes mellitus (NIDDM). After an observation period on diet or sulfonylurea treatment (1 patient was on insulin), patients received 150–250 mg 3 times a day of midaglizole for 2–4 wk, (some patients continued treatment for &gt;4 wk).
In 20 of the patients first treated with diet and then switched to midaglizole treatment, fasting plasma glucose (FPG) decreased significantly from 187 ± 10 mg/ dl (mean ± SE) to 147 ± 13 mg/dl (P &lt; .05) and 120 ± 6 mg/dl (P &lt; .01) 2 and 4 wk, respectively, after administration of midaglizole. Glycosylated hemoglobin (HbA1 also decreased from 12.0 ± 0.7 to 11.3 ± 1.1 and 10.7 ± 0.6% after 2 and 4 wk, respectively. In 23 of the patients whose treatment was changed from sulfonylureas to midaglizole, FPG, and HbA1 levels were maintained at the same values obtained before administration of midaglizole. In patients treated with midaglizole for &gt;12 wk, FPG and HbA1 were kept at the lowered levels.
Moreover, midaglizole treatment showed a clear inhibitory effect on postprandial hyperglycemia and onFPG, reflecting the general improvement in the daily plasma glucose curve with significantly reduced fluctuation. In the oral glucose tolerance test, midaglizole significantly improved glucose tolerance, potentiated insulin secretion, and tended to depress glucagon secretion.
No abnormal findings attributable to midaglizole were noted in clinical and laboratory examinations, except for diarrhea and soft stools in 4 cases (8.5%) out of 47. No hypoglycemic symptoms were observed in this trial.
Thus, midaglizole is clinically effective for NIDDM because it improves the daily plasma gluocse curve, with decreased fasting and postprandial hyperglycemia, in addition to amelioration of oral glucose tolerance accompanied by accelerated insulin secretion.
Hyperinsulinemia Does Not Compensate for Peripheral Insulin Resistance in Obesity
Authors: Prager Rudolf , Wallace Penny , Olefsky Jerrold M 
Published: September 2013

Based on previous steady-state measures of the biologic activity of insulin, it was thought that postprandial hyperinsulinemia in obesity compensated for insulin resistance. However, we recently demonstrated kinetic defects in insulin action in insulin-resistant nondiabetic obese subjects: activation of insulin-stimulated glucose disposal was slower and deactivation was faster in obese than in normal subjects. In view of these kinetic defects in peripheral insulin action and of the fact that insulin is normally secreted in a phasic manner after meals, we postulated that the hyperinsulinemia of obesity does not compensate for insulin resistance and that the abnormal kinetics of insulin action in obesity are functionally important. To test this hypothesis, oral glucose tolerance tests (OGTTs) were performed in five control (mean age, 33 ± 2 yr) and five obese (mean age, 41 ± 5 yr) subjects. All controls had normal glucose tolerance; two obese subjects had normal and three had impaired glucose tolerance. After the results of the OGTTs were available, euglycemic clamp studies were performed in which insulin was infused in a phasic stepped fashion to mimic the rise and fall of mean peripheral insulin levels during the OGTTs. Each subject was clamped at both the “normal” and “obese” OGTT insulin profiles.
During the OGTT, glucose and insulin levels were significantly elevated in the obese subjects compared with controls. Insulin-stimulated glucose disposal rates and total incremental glucose disposal (IGD) over 4 h were markedly reduced in obese compared with control subjects at the lower (normal) insulin-infusion profile (3 ± 1 vs. 41 ± 5 g, P &lt; .001) and at the higher (obese) insulin-infusion profile (15 ± 4 vs. 72 ± 6 g, P &lt; .001). Furthermore, during the normal insulin profile in controls compared with the obese insulin profile in obese subjects, IGD was still significantly reduced in the obese subjects (41 ± 5 vs. 15 ± 4 g, P &lt; .001). At the lower as well as the higher insulin infusion, suppression of hepatic glucose output was not significantly different between obese and control subjects, as assessd by analysis of variance.
In conclusion, our data demonstrate three important points. 1) Kinetic defects in the onset and decay of peripheral insulin action are functionally important in obesity when insulin is infused to match the physiological rise and fall of OGTT insulin levels. 2) Postprandial hyperinsulinemia in obesity only partially compensates for the peripheral insulin resistance. 3) The relative postprandial hyperglycemia in obesity may promote glucose disposal via the mass action of glucose and may be an important compensatory factor serving to normalize peripheral glucose disposal in insulin-resistant obese subjects.
Persistent Impairment of Insulin Secretory Response to Glucose in Adult Rats After Limited Period of Protein-Calorie Malnutrition Early in Life
Authors: Swenne Ingemar , Crace Caroline J , Milner R David G 
Published: September 2013

The effect of a limited period of protein-calorie malnutrition in young rats on glucose tolerance, insulin secretory response to glucose, and tissue composition in the adult was studied. Three-week-old rats were weaned onto semisynthetic diets containing either 5% protein (low protein; LP) or 15% protein (control; C) and maintained for 3 wk on their respective diets. At 6 wk of age all rats were returned to a commercial rat chow diet (18% protein). Glucose tolerance, insulin secretory response to glucose, and the protein/DNA ratio in liver, skeletal muscle, heart, kidney, small intestine, and lung were investigated at 3, 6, and 12 wk of age. Rats receiving LP diet failed to gain weight, but growth resumed immediately when they were transferred to commercial rat chow. They did not, however, catch up with C rats. Glucose tolerance and insulin secretory response to glucose remained similar between 3 and 12 wk in C rats. In 6-wk-old LP rats, glucose tolerance was impaired, and the insulin secretory response to glucose was absent. At 12 wk of age the glucose tolerance of the LP rats had normalized, but the insulin secretory response was still blunted. In 6-wk-old LP rats there was an inhibition of the age-dependent increase in cell size, shown by lowered protein/DNA ratios in all tissues studied. This decrease in cell size persisted at 12 wk in liver, skeletal muscle, heart, and lung.
We conclude that protein-calorie malnutrition early in life persistently impairs the insulin secretion. The persistently lowered protein/DNA ratios in many tissues may be related to this lowered capacity for insulin secretion. The individual could have an impaired ability to respond to diabetogenic and nutritional challenges, and it is thus possible that the early malnutrition may predispose for diabetes.
Somatomedin-C in Human Fetal Pancreas: Cellular Localization and Release During Organ Culture
Authors: Hill David J , Frazer Astrid , Swenne Ingemar , Wirdnam Paul K , Milner R David G 
Published: September 2013

The presence of somatomedin-C/insulin-like growth factor I (SM-C/IGF-I) was investigated in human fetal pancreatic glands obtained after prostaglandin-induced abortion at 14-17 wk of gestation. Pancreatic explants were cultured in medium containing 11.1 or 22.2 mM glucose and 20% fetal calf serum for 8-10 days. During this period they were exposed, on two separate occasions, to serum-free culture medium for 24 h. SM-C/ IGF-I and insulin were measured radioimmunologically in the serum-free media and in acid-ethanol-extracted homogenates of the cultured explants. SM-C/IGF-I was measurable in the conditioned media only after extraction by reverse-phase chromatography to remove somatomedin- binding proteins. On gel filtration at neutral pH of extracted medium samples, the immunoreactive SM-C/IGF-I was recovered in the region of the homogenous peptide with an apparent molecular weight of 7000-8000. Explants cultured in 22.2 mM glucose contained more SM-C/IGF-I and had a tendency to release more of the peptide into the culture medium than explants cultured in 11.1 mM. There was no difference in insulin content or release between the two groups. By immunocytochemistry, SM-C/IGF-I was localized to the β-cells of the endocrine pancreas in both freshly fixed tissue and cultured explants.
We conclude that the human fetal pancreas contains SM-C/IGF-I and secretes the peptide during tissue culture. The presence of SM-C/IGF-I in the islets of Langerhans may contribute to the growth and development of the insulin-producing β-cell.