bluuebunny/crossref_metadata_2025 huggingface dataset:
6-Phosphogluconate/Glucose-6-Phosphate Ratio in Rat Pancreatic Islets During Inhibition of Insulin Release by Exogenous Insulin
Authors: Akhtar Muhammad S , Verspohl Eugen , Hegner Dietmar , Ammon Hermann P T
Published: September 2013

Inhibition of glucose-stimulated insulin release by exogenous insulin has been demonstrated in pancreatic islets to be associated with a decrease of the NADPH/NADP ratio and the pentosephosphate cycle activity.

Batches of five islets were incubated for 15 and 90 minutes in 1 ml. of KRB buffer with 2 per cent albumin containing 3mg/.ml. glucose and 0, 200, 400, or 800 μU./ml. of rat insulin, and the glucose-6-phosphate (G6P) and 6-phosphogluconate (6PG) contents were determined by enzymatic cycling.

In response to a rise in the concentration of insulin, the 6PG/G6P ratio decreased. A close relationship was observed between this decrease of 6PG/G6P ratio and the net insulin release, the absolute rate of glucose oxidation via the pentose phosphate cycle, and the NADPH/NADP ratios measured under similar conditions. The results suggest that exogenous insulin, directly or indirectly, regulates the pentose cycle activity in the pancreatic islets at the G6P dehydrogenase step.
Uniphasic Insulin-secretory Response in the Pancreatic Vein of Dogs After an Enteric Glucose Load
Authors: Chacra Antonio R , Fujita Yoshikuni , Herron Arthur L , Seltzer Holbrooke S
Published: September 2013

The insulin secretory response to an enteric glucose load was measured in 11 dogs after intrajejunal instillation of a 25 per cent glucose solution (1.75 gm./kg.) in five minutes. Insulin outflow rate was measured every minute for 10 minutes, then at increasing intervals through 60 minutes. Starting at two minutes after onset of glucose loading, mean arterial plasma glucose rose steadily throughout the hour. This was paralleled by a similarly progressive rise in mean pancreatic venous plasma insulin output starting at seven minutes and peaking at 50 minutes, despite partial masking by a simultaneous fall in pancreatic venous plasma flow rate after the fourth minute. The data indicate that the normal insulin response to an enterically administered glucose stimulus is a smoothly rising uniphasic one, in contrast to the typical biphasic insulin response to a “square-wave” intravenous glucose stimulus.
The Immediate Insulin-secretory Response of the Rat Pancreas to Glucose Compared with Tolbutamide and Other Secretagogues
Authors: Lenzen Sigurd
Published: September 2013

Insulin secretagogues induced characteristic secretory responses of the pancreas. While tolbutamide provoked an immediate insulin secretory response of the perfused rat pancreas, after a short delay insulin secretion appeared in response to glyceraldehyde, glucose, and mannose after different characteristic latent periods. Glucose and tolbutamide competed for insulin from the same rapidly available hormone pool during the immediate insulin-secretory response of the perfused pancreas. The mechanism of their secretory action differed.

There was a latent period between arrival of glucose at the pancreatic β-cells and the insulin-secretory response when the perfu-sate was switched from a medium without glucose to a medium with 16.7 mM glucose. However, when the preperfusion medium contained a substimulatory glucose concentration, this latent period was diminished or nearly abolished. The increment in glucose concentration necessary for insulin release was reduced con-comitantly. The ability of glucose to sensitize pancreatic β-cells was concentration-dependent and time-dependent. Only mannose was able to substitute for glucose in its capacity to virtually abolish the latent period. Glyceraldehyde, dihydroxyacetone, and leucine only reduced the latent period. L-glucose, 3-O-methylglucose, fructose, and pyruvate were ineffective. Tolbutamide desensitized the β-cell to glucose stimulation and prolonged the latent period.

It is proposed that both glucose and tolbutamide initiate insulin secretion by interaction with a common receptor site. They differ, however, in that glucose but not tolbutamide sensitizes pancreatic β-cells. Tolbutamide cannot fully replace glucose.
The Size of the Loading Dose as an Important Determinant of the Results of the Oral Glucose Tolerance Test: A Study in Subjects with Slightly Impaired Glucose Tolerance
Authors: de Nobel E , Van 't Laar A
Published: September 2013

In the oral glucose tolerance test (OGTT), divergent doses of glucose remain in use by virtue of the prevailing conviction that the size of the loading dose hardly affects the outcome of the test. We compared the results of OGTTs with 100-gm. and 50-gm. loads in 85 patients, who were selected for slightly impaired glucose tolerance (plasma glucose at 120 minutes after 100 gm. of glucose was between 130 and 200 mg./dl.) The mean between-load difference in this group appeared to be nearly three times as great (54 mg./dl. at 120 minutes) as reported in the literature for normal subjects. The small impact of the dose in normal subjects could be confirmed in a group of 22 controls. As subjects with normal and with slightly impaired glucose tolerance react divergently to a change in the glucose dose, tests with different loads are not comparable and select different populations. The results can therefore also not be converted to one another by conversion formulas. The finding might be explained by the delay of the additional rise of the plasma insulin in patients after the higher load.
Prevalence of Diabetes Mellitus in School-age Children in Minnesota
Authors: Kyllo Carole J , Nuttall Frank Q
Published: September 2013

The prevalence of diabetes in Minnesota school-age children was found to be one per 529 students (1.89 per 1,000), 95 per cent of whom were receiving insulin. Data were obtained by a mail survey of the public schools in the state. Enrollment in public schools represents 90 per cent of the student population in Minnesota, and data were received from 96 per cent of the public schools. This return rate by schools accounts for 95 per cent of the total student enrollment. Diabetes increased linearly with age, representing a yearly prevalence increase of 0.16 cases per 1,000 students.
On the Role of the Proinsulin C-peptide
Authors: Steiner Donald F
Published: September 2013

Intracellular cleavage of protein and polypeptide precursors is now recognized as a widely occurring biosynthetk: mechanism. As this field has developed, proinsulin and its cleavage patterns and secretory products have served as useful models for investigations of other systems. A particularly relevant aspect of the proprotein concept is the simple mechanism it provides for the coordinate synthesis and discharge of related peptides from endocrine or other secretory cells. This report reviews briefly the role of the proinsulin C-peptide, first in terms of its special biosynthetk: functions, which are unique to the assembly of the two-chain insulin structure, and then with regard to its more general implications for other biosynthetk and secretory systems.
Syntheses of C-peptides and Human Proinsulin
Authors: Yanaihara Noboru , Yanaihara Chizuko , Sakagami Masanori , Sakura Naoki , Hashimoto Tadashi , Nishida Toshinobu
Published: September 2013

Syntheses of human, dog, rat, and duck C-peptides and their analogues and preliminary results on the total synthesis of human proinsulin are described.

In the syntheses of the C-peptides, chain elongation was performed exclusively by the azide-fragment condensation method in solution. The synthetic human, dog, rat, and duck C-peptides and their analogues were proved to be homogeneous by several analytic means. With these synthetic peptides, radioimmunoassay systems for dog, rat, and duck C-peptides were developed.

For the total synthesis of human proinsulin, 10 protected peptide hydrazides were prepared, and the linearly protected hexaoctacontapeptide having the proposed sequence of human proinsulin was constructed by the azide-fragment condensation method in solution starting from the C-terminal undecapeptide (HP 75–86). After deblocking of the α-amino protection, the partially protected hexaoctacontapeptide was treated with sodium in liquid ammonia. The ensuing sulfhydryl form was converted to the S-sutfonate form, which was reduced and then air-oxidized. The oxidized material was purified by gel filtration on Sephadex G-50 (fine) followed by ion-exchange chromatography on DEAE-cellulose. The crossreactivity in the insulin radioimmunoassay of the ensuing product was 62.5 per cent of porcine proinsulin on a weight basis at B/B0 = 60 per cent.

Acid hydrolysis and amino acid analysis of this product gave the theoretically expected ratios. In addition, this peptide, as well as the S-sutfonate form of the hexaoctacontapeptide, showed displacement curves superimposable on that of synthetic human C-peptide on an equimolar basis in the human C-peptide radioimmunoassay (antiserum 527). These results confirm the synthesis of human proinsulin.
C-peptide Immunoreactivity (CPR) in Urine
Authors: Kuzuya Takeshi , Matsuda Ayako , Sakamoto Yoshikazu , Tanabshi Shinobu , Kajinuma Hiroshi
Published: September 2013

Human urinary C-peptide immunoreactivity (CPR) was measured by a double-antibody radioimmunoassay using synthetic human C-peptide. Urine CPR was stable as long as one year, if stored frozen. Urine CPR was eluted by gel filtration as a single peak in the region that corresponded to 125I-labeled C-peptide. Even in a patient with insulin antibody whose serum contained a CPR fraction with higher molecular weight, urine CPR was eluted in its expected region.

Normal subjects excreted 81 ± 36 μg. CPR per day. Urine CPR excretion was very low in juvenile-onset diabetics, variable in adult-onset diabetics and liver disease patients, and increased in patients on corticosteroid treatment. Diurnal changes and a 50-gm. glucose tolerance test revealed that urine CPR excretion rate increased in parallel with plasma CPR levels. The responses of diabetic patients were smaller and more sluggish. Urine CPR excretion tended to be decreased in patients with renal diseases and extremely low in those on regular hemodialysis. CPR was positively correlated with serum creatinine. Urine CPR was not increased in patients with marked β2-microglobulin excretion.

Highly significant correlations were observed between 24-hour urine CPR values and fasting plasma CPR or summed CPR after glucose load. Thus, urine CPR seems to provide a good means to assess B-cell function, and it is particularly suitable to monitor B-cell function continuously or when multiple blood samplings are not practical. Continuous measurement of daily urine CPR in diabetic patients on glibenclamide treatment revealed that improvement of blood sugar control could occur without preceding increases in total daily B-cell secretion.
HLA, Islet Cell Antibodies, and Types of Diabetes Mellitus
Authors: Nerup J , Platz P , Ryder L P , Thomsen M , Svejgaard A
Published: September 2013

Insulin-dependent diabetes mellitus, in contrast to non-insulindependent diabetes mellitus, is associated with HLA factors B8, BW15, and B18.

Recent studies have shown the association to be even stronger with HLA, DW3, and DW4 and have produced evidence for the existence of two “diabetogenic” genes predisposing to insulindependent diabetes in different ways. Evidence to suggest the existence of a gene—associated with DW2—that protects against the disease is accumulating.

Islet cell antibodies are a feature of insulin-dependent diabetes mellitus and can be seen, in most cases, at the time of diagnosis.
Islet Function in Diabetics with Persistent Islet Cell Antibodies
Authors: Theophanides C G , Pyke D A , Watkins P J
Published: September 2013

Seventeen (14 per cent) of 121 long-term insulin-treated diabetics were found to be positive for islet cell antibodies. Their duration of diabetes ranged between five and 45 years. Thirteen of these 17 patients were tested for the persistence of islet cell function by measurement of C-peptide. There was no detectable C-peptide in 12 patients, confirming that islet function had ceased. The significance of the persistence of islet cell antibodies in diabetes is unknown
C-Peptide in Conditions Other Than Diabetes Mellitus
Authors: Horwitz David L , Rubenstein Arthur H , Mako Mary E , Cruz Angelita , Blix Petra M
Published: September 2013

Measurement of serum and urinary C-peptide has been shown to be of value in several conditions other than diabetes mellitus. It is particularly useful because it can distinguish endogenous beta cell secretion from exogenously administered insulin and because circulating insulin-binding antibodies do not interfere with its measurement. Because the liver removes little, if any, C-peptide, peripheral blood values may more accurately reflect beta cell secretion than do peripheral insulin levels.

Clinically, serum C-peptide has been most useful in diagnosing hypoglycemic disorders. Diagnosis of insulinomas is facilitated in both diabetic and nondiabetk patients, and surreptitious insulin injection is readily detected. In studies of insulin regulation, circulating C-peptide has been used to demonstrate suppression of endogenous insulin secretion by exogenous insulin. Peripheral insulin and C-peptide levels have been compared in studies of the role of the liver in states of altered insulin homeostasis. Because of its higher urinary clearance, determination of urinary C-peptide is preferable to urinary insulin measurement in situations where frequent blood sampling is impossible or difficult to accomplish.
Immunoreactive Glucagon Responses to Oral Glucose, Insulin Infusion and Deprivation, and Somatostatin in Pancreatectomized Man
Authors: Werner Phillip L , Palmer Jerry P
Published: September 2013

In a group of pancreatectomized subjects, immunoreactive glucagon (IRG) concentrations were normal after an overnight fast, increased after oral glucose, were not suppressed by somatostatin (SRIF) or insulin, and in two of four subjects they rose with an arginine infusion. Even though the SRIF infusion failed to lower IRG, there was a fall in plasma glucose concentration in both subjects. In two subjects, endogenous hyperglycemia occurred during insulin withdrawal without a rise in IRG, and, in one subject, mild diabetic ketoacidosis developed with only a minimal rise in IRG.

These results support the presence of an extrapancreatic source of IRG in man. Secretion from these extrapancreatic alpha cells appears to be regulated differently than secretion from pancreatic alpha cells.
Alloxan Stimulation and Inhibition of Insulin Release from Isolated Rat Islets of Langerhans
Authors: Weaver Daniel C , McDaniel Michael L , Naber Stephen P , Barry C David , Lacy Paul E
Published: September 2013

The rate of alloxan-induced insulin release was measured from rat islets maintained in a simple perifusion system. Insulin release during the five-minute exposure to alloxan reached its maximum rate after two to three minutes of the exposure and then rapidly declined. This insulin release was dependent upon extracellular calcium and was associated with an increased 45Ca uptake by isolated islets. Once exposed to alloxan, however, the islets did not release insulin when stimulated again with D-glucose or alloxan. These effects of alloxan on insulin release (stimulation and subsequent inhibition) and the increased 45Ca uptake were prevented by the presence of 3-0-methyl-D-glucose during the alloxan exposure. These findings indicate a close correlation between alloxan-induced insulin release and the subsequent inhibition of further insulin release.

D-glucose, when present during the entire five-minute exposure to alloxan, protected competitively against alloxan inhibition of insulin release. In addition, D-glucose, when present immediately after brief (one to three minutes) alloxan exposures, reversed some of the subsequent inhibition of insulin release. These findings suggest that alloxan and D-glucose were competing for a common site on the β-cell. The possibility of this site being a receptor responsible for the initiation of insulin release is discussed.
In-vitro and In-vivo Responsiveness of Muscle and Adipose Tissue to Insulin in Rats Rendered Obese by a High-fat Diet
Authors: Susini C , Lavau M
Published: September 2013

The influence of insulin on [6-14C] glucose metabolism was assessed in vitro and in vivo in epididymal adipose tissue and diaphragm of rats fed either a low-fat (9 per cent fat cal.) or a high-fat diet (72 per cent fat cal.) In vitro, diaphragm of fat-fed rats showed a lower glucose uptake than that of rats fed the low-fat diet, but had identical glycogen labeling and lactic acid production and a strongly reduced 14CO2 production. Responsiveness of these pathways to insulin was unaltered by the fat content of the diet. The adipose tissue of fat-fed rats versus that of rats fed the low-fat diet showed: a higher lactic acid production and more efficient glycerogenesis and glycogenesis, all of these pathways being responsive to insulin; a lower glucose uptake and a strongly depressed fatty acid labeling, these two pathways being unresponsive to insulin. In-vivo labeling of glycogen in diaphragm in both basal and insulin-stimulated conditions was identical in the two groups of rats. In adipose tissue the amount of 14C sequestered in the ghyceride-glycerol moiety was the same in the two groups in basal and insulin-stimulated conditions, whereas the labeling of the fatty acid moiety and its increment with insulin were reduced by more than 99 per cent by the high-fat diet.

These results show that alterations in fat content of the diet lead to differences in response to insulin that are pathway- and organ-specific.
Noninvasive Estimation of Myocardial Performance in Patients with Diabetes: Effect of Alcohol Administration
Authors: Rubier Shirley , Sajadi M Reza M , Araoye Matthew A , Holford Fred D
Published: September 2013

Systolic time intervals (STIs) were determined in 19 diabetic patients under age 50 (mean age 35.2 years) and 24 normal control subjects (mean age 30.6 years). Preëjection period (PEP), left ventricular ejection time (LVET), and PEP-LVET ratio were obtained by the conventional manner. Preëjection period index (PEPI) and left ventricular ejection time index (LVETI) were derived by Weissler's formula.14 The isovolumic relaxation time (IVRT) was measured: (1) from the aortic component of the second heart sound of the phonocardiogram to the rapid opening anterior motion of the anterior leaflet of the mitral valve on echocardiogram (A2D1), (2) and to the “0” point of the apexcardiogram (A2O). PEP, LEVT, PEPI, LVETI, and PEP/LVET ratio were statistically similar in diabetics and controls. However, the A2D1 was longer in diabetics (71.2 ± 3.4 msec.) than in control subjects (59.5 ±3.1 msec.) (p < 0.02). Effects of oral ethanol (0.7 gm./kg.) administered over 20 minutes to 12 diabetics (group 1) and seven control subjects (group 2) were studied before and at 15, 30, 60, and 90 minutes after ingestion.

No change in STIs occurred in group 2 (controls) but the heart rate, PEPI, and PEP/LVET ratio rose in group 1 (diabetics). There were significant differences in PEPI and PEP/LVET ratio between groups 1 and 2, 30 and 60 minutes after alcohol. IVRT remained unchanged. Maximum blood alcohol levels for both groups were comparable at 60 minutes, (67.8 ± 5.2 mg./100 ml. in group 1 and 66.7 ± 7.5 mg./100 ml. in group 2). Glucose levels, although higher in group 1, remained stable throughout for both groups. Lactate levels, after alcohol ingestion, were comparable in both groups. Although the only evidence of myocardial dysfunction noted in diabetic patients in the resting state was the increase in IVRT, their response to alcohol revealed further changes in cardiac function not seen with such low doses of ethanol in normal individuals.
Loss of Insulin Response to Ingested Amino Acids After Jejunoileal Bypass Surgery for Morbid Obesity
Authors: Moxley Richard T , Lockwood Dean H , Amatruda John M , Tobin Jordan D , Pozefsky Thomas
Published: September 2013

Amino acid tolerance tests were performed before and after jejunoileal bypass surgery for morbid obesity to determine whether an enteric factor(s) originating in the bypassed jejunum and/or ileum potentiates the insulin response to oral nitrogen loading.

Preoperati vely a 30-gm. mixture of amino acids given orally evoked a larger peak insulin response than an intravenous load yielding comparable plasma amino acid elevations (82 ± 17 μU./ml. versus 38 ± 8 μU./rnl., p < 0.05). Four months after operation, basal insulin concentrations were 46 per cent (p < 0.001) of preoperative values. After surgery the response to intravenous amino acids was preserved when expressed as percentage increase above basal. In contrast, the peak increment and the percentage increase in insulin secretion after 30-gm. oral amino acid loading was significantly blunted (p < 0.005). A smaller amino acid load (16.5 gm.) was given preoperatively to duplicate the plasma amino acid elevations seen postoperatively with the 30-gm. mixture given by mouth. The insulin response postoperatively was still significantly lower (167 ± 33 per cent versus 98 ± 16 per cent, p < 0.05). After various explanations for the diminished postoperative insulin release following oral amino acid ingestion are considered, the results are best explained by the loss of an enteric insulinotrophic factor(s) normally released by the bypassed portions of jejunum or ileum in response to ingested protein.
Physical Characteristics of Insulin Receptors on Renal Cell Membranes
Authors: Blanchard Richard F , Davis Paul J , Bias Susan D
Published: September 2013

Certain physical characteristics of the insulin-kidney-membrane interaction in dog renal cortex have been defined. Two classes of binding sites were identified: the high-affinity-low-capacity site had a Ka of 1.3 × 109 M1 and a capacity of 43 fmols per milligram membrane protein. The lower-affinity site Ka was 3.7×107 M-1. Saturabili t y of receptor sites could not be demonstrated at any insulin concentration. At 21° C, binding of insulin was maximal after 60 minutes of incubation, with a t1/2of <1.0 minute. Specific binding of 125I-insulin was proportional to protein concentration when the fraction of insulin bound was not excessive. Proinsulin and desoctapeptide insulin displaced labeled insulin in proportion to their known biologic activities (insulin>proinsulin>desoctapep-tide insulin). Arginine vasopressin and glucagon did not compete with native (labeled) insulin for binding sites. The kinetic properties of the kidney insulin-receptor sites are similar to those previously reported for liver and fat cell receptors.

A comparison of specific binding of 125I-insulin to kidney and liver membranes in the presence of various cation concentrations showed no enhancement of binding in either tissue by NaCl as high as 2 M and KC1 up to 50 mM. In contrast, 25 mM CaCl2 caused an increase in specific binding from 3.8 to 7.7 fmols 125I-insulin per milligram protein in kidney and from 1.0 to 2.1 fmols per milligram protein in liver. MgCl2 (10 mM) increased binding of insulin from 3.5 to 7.3 fmols per milligram in kidney and from 1.0 to 2.1 fmols per milligram in liver. EDTA (2mM) had no intrinsic effect on binding but reversed (by 50 per cent) the Ca2+ -mediated enhancement of binding. Divalent cations appeared to influence both high and low affinity sites.

125I-insulin degradation occurred as a function of total insulin concentration in the kidney membrane system and reduced the amount of “bindable” free hormone. The process was not saturable below 10-6 M insulin. Degradation effects influenced calculated equilibrium constants to a minimal degree.
Immunologic Insulin Resistance
Authors: Davidson John K , DeBra Donald W
Published: September 2013

The efficacy of sulfated beef insulin for plasma glucose control in 35 patients with immunologie insulin resistance was studied. Patients were on a mean dose of 550 U./day (range 200–2,000) of U-500 regular beef insulin. Mean maximum 125I-insulin-binding capacity was 191 mU./ml. serum (range 13–1,080). Mean in vivo half-life (T½) of 125I-regular beef insulin was 614 minutes (range 114–1,300), as against a mean T½ of 13.9 minutes (range 11.8–16.5) in normal controls.

Treatment was successful in 34 patients and unsuccessful in one with lipoatrophic diabetes. The mean initial dose of sulfated insulin was 89 U./day (range 15–400) and at three months was 66 U./day (range 20–400). Twenty-eight patients who responded and survived have been on sulfated insulin for a mean of 39 months (range 2–66) and are on a mean dose of 25 U./day (range 0–100). The mean maximum binding capacity fell to 9 mU./ml. (range 0–34) during therapy (p<0.01). Mean 125I-insulin T½ fell from 614 to 249 minutes after sulfated insulin therapy (p<0.001). A comparative study of 15 patients on consecutive days showed a 35sulfated insulin T½ of 60 minutes (range 15–94) and a mean 125I-regular insulin T½ of 246 minutes (range 62–560, p<0.001).

These results indicate that sulfated insulin is less antigenic than regular beef insulin and combines less avidly with human antibodies to regular beef insulin. The response to sulfated insulin therapy was significantly better than the response reported by other investigators to pork insulin or to steroid therapy in similar patients.
Monoamine Oxidase, Catechol-O-methyltransferase, and Norepinephrine Levels in Mice with the Hereditary Obese-hyperglycemic Syndrome
Authors: Feldman Jerome M , Henderson Joan H
Published: September 2013

There is some evidence that there are abnormalities in catecholamine metabolism in patients with obesity and diabetes mellitus. In this study we determined the tissue levels of catecholamine-metabolizing enzymes (monoamine oxidase [MAO] and catechol-O-methyltransferase [COMT]) and norepinephrine (NE) in mice with the hereditary obese-hyperglycemic syndrome (ob/ob mice). The ob/ob mice have greater MAO activity in their kidneys (+ 43 per cent), testes (+ 51 per cent), and white adipose tissue (+ 87 per cent) than their normal-weight Httermates. There is no difference in MAO activity of pancreas, liver, brain, brown fat, heart, and islets of Langerhans in ob/ob and normal mice. The ob/ob mice have less COMT activity in their liver (−39 per cent) than normal mice. There is no difference in COMT activity in the kidney, testis, pancreas, and brain between ob/ob and normal mice. The Michaelis constant of kidney MAO for the tryptamine substrate is similar in normal and obese mice, suggesting that the increased MAO activity is due to a greater amount of tissue MAO rather than an altered affinity of MAO for the tryptamine substrate.

The ob/ob mice have a persistent elevation in MAO activity despite eugiycemia (older mice) and a reduction in weight (caloric restriction), suggesting that the elevated MAO activity in ob/ob mice is a primary rather than a secondary disturbance. The total NE content of kidney, white fat, and brown fat is similar in ob/ob and normal mice. The islet NE content is less than 3 pg. per islet in ob/ob and normal mice.
Circulating Alanine Disposal in Diabetes Mellitus
Authors: Chochinov R H , Bowen H F , Moorhouse J A
Published: September 2013

Alanine was selected for study as a representative circulating glucose precursor in relation to the question of the source of the excess circulating glucose in diabetes mellitus. U-l4C alanine and U-14C glucose infusions were given to healthy subjects and to subjects with untreated mild maturity, severe maturity, and juvenile diabetes. Comparative studies after a 24-hour fast were made in healthy and in mildly diabetic subjects. The alanine production rate was unaltered by fasting or diabetes. The glucose production rate was unaltered by fasting but increased in diabetes in relation to the severity of the disease. The fractions of alanine-to-glucose and of glucose-from-alanine were increased by fasting. The effect of diabetes was different. The fraction of alanine-to-glucose was much less in mild maturity diabetes than in health, and it was increased only in juvenile diabetes. In all the diabetic groups the glucose-from-alanine fraction was much less than in health. In every group the change in the alanine oxidation rate was reciprocal to that in the alanine-derived glucogenesis rate. The results are consistent with the possibility that the principal source of the excess circulating glucose in diabetes is glycogen.
The Characterization of Somatostatin-like Immunoreactivity in Human Serum
Authors: Kronheim S , Berelowitz M , Pimstone B L
Published: September 2013

We describe the characterization of somatostatin-like immunoreactivity (SRIF-LI) found by radioimmunoassay (RIA) to be present in normal human serum. Degradation by serum of 125ITyr1 SRIF in the assay, as assessed by chromatoelectrophoresis and immunoprecipitation, was overcome by using EDTA in the assay buffer and Trasylol in the blood samples. Serum samples thus Obtained from 48 normal subjects revealed a bimodal distribution of SRIF-LI; 92 per cent (group 1) had a mean level of 0.274 ±0.009 ng. per milliliter. What was measured in these sera showed identity to synthetic SRIF on serial dilutions, Sephadex G-2S chromatography, and thin-layer chromatography, and it was shown to be immunbreactive by an antibody-Sepharose affinity system. Higher levels (1.0 ± 0.041 ng. per milliliter) were found in 8 per cent of the sera; 50 per cent of this material behaved identically as serum SRIF-LI from group 1. The remainder proved to be heterogeneous, consisting of two peaks of large molecular weight, both of which shared immunologic identity with synthetic SRIF as shown by binding to the antibody-Sepharose affinity system. Their further nature is unknown.
Nonuniform Distribution and Grouping of Insulin Receptors on the Surface of Human Placental Syncytial Trophoblast
Authors: Michael Nelson D , Smith Robert M , Jarett Leonard
Published: September 2013

These studies were designed to investigate the cytologic localization and topographic distribution of insulin receptors in human placental villi. Biochemical studies showed placental villi to specifically bind l25I-insulin. Radioautographic studies showed the specific binding to be localized to the surface of the syncytial trophoblast. Topographic distribution of insulin binding was determined with ferritin-insulin. Initial studies using ferritin-insulin containing some oligomers of ferritin revealed the insulin receptors to be specifically associated with the glycocalyx region of the surface membranes of microvilli. No insulin receptors were detectable in association with the intermicrovillous plasma membrane even though its glycocalyx is in direct continuity with the glycocalyx of microvilli. Monomeric ferritin-insulin showed the same nonuniform distribution of the insulin receptor, which suggests that there is not complete freedom of lateral mobility of the insulin receptors in the surface membrane of this tissue. The insulin receptors were found to occur as singletons or in groups of two or more. Incubations with monomeric ferritin-insulin at 4δ or with tissue prefixed with formaldehyde showed that the groups of insulin receptors were naturally occurring, i.e., they are present prior to and independent of insulin binding and thus not secondary to ligand-induced aggregation. The physiologic meaning of the nonuniform distribution and the groups of insulin receptors is unclear at present.
Epinephrine Enhancement of Potassium-stimulated Immunoreactive Insulin Secretion Role of Beta-adrenergic Receptors
Authors: Hiatt Nathan , Davidson Mayer B , Chapman Lloyd W , Sheinkopf Jack A
Published: September 2013

Although epinephrine stimulates insulin release by activation of beta-adrenergic receptors, its dominant effect (mediated by stimulation of alpha-adrenergic receptors) is an inhibition of insulin secretion that is powerful enough to suppress the secretory activity of insulin's most potent stimulants. The insulin-secretory response to potassium chloride (KC1) infusion, however, is not suppressed; in fact, in ureter-ligated dogs simultaneously infused with 360 μg. epinephrine per hour and 2 mEq. KC1 per kilogram per hour, insulin release is actually increased about threefold (over controls). Propranolol blockade of beta-adrenergic receptors essentially abolishes the insulin response to KCI infusion, with and without epinephrine. It is unlikely that KCI, like epinephrine, provokes insulin release by direct stimulation of the beta-adrenergic receptors of the beta cells of the pancreatic islets. However, potassium in some way enhances the beta adrenergic (secretory) activity of epinephrine and blunts its usually dominant alpha-adrenergic (inhibitory) effect.
The Site of Insulin Resistance in Acute Uremia
Authors: Mondon Carl E , Dolkas Constantine B , Reaven Gerald M
Published: September 2013

In order to define the mechanism of glucose intolerance in acutely uremic rats, various studies were carried out 24 hours after bilateral nephrectomy. Glucose removal following intravenous glucose was significantly (p < 0.001) decreased in uremic rats compared with sham-operated rats (k = 2.1 ± 0.03 per cent vs. 5.1 ±0.2 per cent). This deterioration in glucose tolerance was associated with higher insulin levels in uremic rats from one to 40 minutes after glucose administration, suggesting that insulin resistance accounted for the decrease in glucose removal by uremic rats. To identify the site of the insulin resistance, we compared the ability of insulin to enhance net glucose uptake by isolated perfused liver and muscle (hindlimb) preparations obtained from uremic and shamoperated rats. Insulin suppressed glucose outflow from perfused livers of uremic rats at least as well as it did from livers of shamoperated rats, and suppression occurred at both maximal (> 600 μU./ml.) and threshold (75 μU./ml.) perfusate insulin levels. In contrast, there was a significant decrease in the ability of insulin (mean perfusate level = 225 μU./ml.) to enhance glucose uptake of perfused hindlimbs of uremic as compared with sham-operated rats. These results suggest that the insulin resistance of acute uremia may be due primarily to decreased insulin-mediated uptake of glucose by skeletal muscle without any decrease in sensitivity of the liver to insulin.
Multiple Daily Insulin Injections in the Treatment of Diabetic Retinopathy: The Job Study Revisited
Authors: Ashikaga T , Borodic G , Sims E A H
Published: September 2013

Data based on the prospective study of Job et al.1 are reanalyzed while initial number of microaneurysms and duration of patient follow-up are controlled. The reported statistical difference in the rate of microaneurysm increase between the single-and the multiple-daily-injection groups may be due to a difference in a subgroup who had a larger number of microaneurysms initially and who were studied for a shorter period of time. No uniform difference was observed in the results of their treatment between the groups given a single injection and those given multiple injections. While this does not invalidate the conclusions of the study, it does point out the need for greater control in conducting future studies.
Pancreatic Islet Isotransplantation: Effects of Age and Organ Culture of Donor Islets on Reversal of Diabetes in Rats
Authors: Selawry Helena , Harrison Joy , Patipa Michael , Mintz Daniel H
Published: September 2013

Pancreatic islets were isolated by identical collagenase digestion from two groups of Wistar-Lewis rats, of both sexes, according to body weight: I, or young and <200 gm., and II, or old and >400 gm. These islets were transplanted into 27 male rats that had streptozotocin-induced hyperglycemia and a fasting plasma glucose of 350 to 400 mg./dl. Thirteen of the rats received islets from group I (1,000 islets per rat injected into the portal vein), nine of which responded promptly with a drop in plasma glucose to less than ISO mg./dl. that was sustained for the remaining 12 months of the study. Fourteen were recipients of old-group islets, and none had a lowering of plasma glucose. Ultrastructural and functional analyses of freshly isolated islets of young and old donors revealed them to be identical. Histology of livers of recipients six weeks after transplantation showed numerous well-granulated islets in responded but no islet tissue in nonresponders. An investigation of membrane characteristics of islets of young and old donors, with concanavalin A (Con A) binding used as a probe, showed that freshly isolated islets of both young and old donors were unable to bind Con A. However, islets of young donors could bind Con A after storage in tissue culture medium 199 for one hour, whereas islets of old donors required at least four hours of maintenance before the capacity to bind Con A could be demonstrated. Ability of islets of young and old donors to bind Con A appeared to correlate with the capacity of the islets to survive and to induce normoglycemia after intraportai injection into isogeneic recipients.
C-Peptide Secretion During the Remission Phase of Juvenile Diabetes
Authors: Heinze E , Beischer W , Keller L , Winkler G , Teller W M , Pfeiffer E F
Published: September 2013

C-peptide secretion was studied in eight juvenile diabetics during the remission phase of the disease. The release of C-peptide was measured after a (1) normal intravenous glucose tolerance test, (2) a double glucose tolerance test, (3) an arginine infusion, and (4) after an intravenous glucose tolerance test followed by an arginine infusion. Under all conditions the intravenous glucose load had only a minimal effect on the secretion of C-peptide, while arginine alone or after the intravenous glucose tolerance test stimulated the release of the peptide in all patients. Pretreatment with glucose did not augment the effect of arginine on C-peptide release.

The results indicate that during the remission phase of juvenileonset diabetes the endocrine pancreas does not recognize glucose as an appropriate signal for C-peptide release and cannot transform the amplifying effect of glucose into a higher hormonal secretion rate.
The Effects of Goldblatt Hypertension on Development of the Glomerular Lesions of Diabetes Mellitus in the Rat
Authors: Mauer S Michael , Steffes Michael W , Azar Silvia , Sandberg Susan Kupcho , Brown David M
Published: September 2013

Rats with classic Goldblatt (two-kidney) hypertension had diabetes induced by streptozotocin. After four months of diabetes, glomeruli of the unclipped kidney of hypertensive diabetic rats had markedly increased diabetic changes, including mesangial matrix thickening and mesangial immunoglobulin (IgG and IgM) and complement (C3) localization, when compared with glomeruli of the contralateral-clipped kidneys. Further, glomeruli of the unclipped kidneys of hypertensive diabetic animals had more mesangial thickening and IgG and IgM staining than glomeruli of normotensive diabetic rats. Although glomeruli of clipped kidneys in hypertensive diabetic rats had less mesangial thickening than glomeruli of normotensive diabetic rats, this did not reach statistical significance. However, these glomeruli did have significantly less IgG, IgM, and C3 staining compared with glomeruli of normotensive diabetic animals. Mesangial thickness in glomeruli of clipped and unclipped nondiabetic hypertensive rats did not differ from that in normal animals. However, there was less mesangial IgG staining in clipped than in unclipped kidneys of nondiabetic hypertensive rats or in kidneys of normal animals. We have interpreted these results to imply that alterations in nephron hemodynamics combine with the diabetic state to influence the rate of development of diabetic glomerulopathy in rats.
Restoration of the Acute Insulin Response by Sodium Salicylate: A Glucose Dose-related Phenomenon
Authors: Chen Mei , Robertson R Paul
Published: September 2013

Adult-onset diabetics have markedly diminished or absent acute insulin responses to glucose that can be partially restored by sodium salicylate infusion. To determine whether this restoration of the acute insulin response is glucose dose dependent and whether complete restoration can be achieved, adult-onset diabetics with a mean fasting plasma glucose value of 216 ± 20 mg. per deciliter (x ± S.E.) were stimulated with various doses of intravenous glucose. Restoration occurred in a glucose dose-dependent manner. Complete restoration could not be achieved with the maximal tolerable glucose dose (80 gm.). Second phase insulin secretion also improved in a glucose dose-dependent manner. These findings are compatible with the hypothesis that defective insulin secretion in adult-onset, hyperglycemic diabetics is not due to absolute deficiency of insulin but may be a result of defective recognition of glucose signals by pancreatic B-cells—a defect that can be partially reversed by sodium salicylate.
Secretory Capability of Islets Transplanted Intraportally in the Diabetic Rat
Authors: Pipeleers D G , Pipeleers-Marichal M A , Karl I E , Kipnis D M
Published: September 2013

Long-term islet-transplanted rats were examined for their ability to secrete insulin and glucagon and maintain normal glucose homeostasis under various experimental conditions. Normal glucose tolerance and insulin secretion were noted in nonstressed transplanted animals after oral glucose loading, whereas the intravenous administration of glucose resulted in a prompt but reduced insulin release associated with a slower return to basal glucose concentrations. Both the insulin and glucagon responses of nonstressed transplanted rats to arginine were comparable to those seen in normal animals. In transplant rats, stress severely impaired glucose homeostasis, as indicated by a marked rise in plasma glucose and a significant decrease in plasma insulin under basal conditions. These abnormalities were prevented by either alpha-adrenergic blockade or adrenalectomy. Stress also severely impaired both oral and intravenous glucose tolerance tests in transplant animals and markedly inhibited insulin secretory responses to tolbutamide and theophylline. Control and transplant rats exhibited comparable plasma epinephrine and norepinephrine values under basal conditions and in response to stress. The stress-induced impairment in glucose homeostasis of transplant rats was attributed to an increased sensitivity of the transplanted A- and B-cells to catecholamines secondary to their denervated state. Transplanted islet cells exhibited appropriate adaptive responses to chronic modulating factors such as a 48-hour fast and the administration of cortisol. However, cortisol-treated rats were unable to sustain a sufficient secretion of insulin to maintain normal carbohydrate tolerance, and consequently there was a reappearance of the diabetic state.
Further Characterization of the Impaired Bactericidal Function of Granulocytes in Patients with Poorly Controlled Diabetes
Authors: Nolan Charles M , Beaty Harry N , Bagdade John D
Published: September 2013

Granulocytes of patients with diabetes mellitus have an impaired capability to engulf bacteria, but it is not clear whether subsequent intracellular killing, which has separate energy sources, is also defective.

We separately assayed engulfment and intracellular killing of Staphylococcus aureus 502a by granulocytes of 17 diabetic patients with fasting hyperglycemia to better characterize the phagocytic defect. Diabetic granulocytes engulfed a smaller proportion than controls of a 106 inoculum of bacteria after 20 minutes of incubation in vitro (56.8 ± 9.4 per cent versus 72.4 ± 3.6 per cent, mean ± S.E. of 10 patients and paired controls, p < 0.05), but after 60 minutes of incubation this defect had disappeared. Intracellular killing of staphylococci by granulocytes from seven diabetics (68.6 ± 8.9 per cent of a 106 inoculum) was less (p < 0.01) than that of paired controls (80.3 ± 4.5 per cent) after two hours of incubation. Seven patients were retested during a period of improved diabetes' control; intracellular killing of staphylococci by granulocytes of six of the seven increased considerably and either exceeded the paired control value or approached it to within 75 per cent.

These data suggest that a primary defect exists in intracellular killing of staphylococci by granulocytes from poorly controlled diabetics in addition to that previously shown in engulfment. This bactericidal activity becomes more efficient when the diabetes is brought under better control.
Intestinal Very Low Density Lipoprotein Secretion in Insulin-deficient Rats
Authors: Risser Tranquilina R , Reaven Gerald M , Reaven Eve P
Published: September 2013

The intestine's contribution to endogenous, triglyceride (TG)-rich lipoprotein production was compared in control and diabetic rats. Male rats were given either streptozotocin (45 mg. per kilogram) or saline. After one week, hyperglycemic animals were divided into a moderately diabetic group (glucose < 300 mg. per deciliter) and a severely diabetic group (glucose > 300 mg. per deciliter). In some animals, mesenteric lymph duct fistulas were prepared, and rats were restrained and given saline intraduodenally. After an overnight fast, lymph was collected in three two-hour periods for quantification of intestinal TG production. Other animals subjected to sham, lymph duct surgery and overnight restraint were injected with Triton WR 1339, and the ensuing increment in plasma TG concentration was used to quantify total body TG secretion. Results in control rats subjected to surgery and restraint showed the mean (± S.E.) intestinal TG secretion rate to be 3.2 ± 0.2 mg. per hour; this value represented 11 per cent of total body TG secretion. Under identical conditions, intestinal TG secretion increased (p < 0.01) by 70 per cent in moderately diabetic rats; this value represented 24 per cent of total TG secretion. In contrast, intestinal TG secretion in severely diabetic rats represented only 11 per cent of the total TG secretion: this value reflected a significant (p < 0.01) reduction in both intestinal and total body TG secretion. Electron microscopy indicated that the lymph lipoprotein particles in all animals studied were of very low density (VLDL) size. Thus, although the intestine contributes a relatively small amount of VLDL-TG to the plasma pool in control and severely diabetic rats, it appears to be a significant source of very low density lipoprotein–triglyceride (VLDL-TG) in animals with moderate insulin deficiency.
Impairment of Glucose-induced Insulin Secretion and Glucose Tolerance During Colchicine Treatment
Authors: Shah Jayendra H , Wongsurawat Nirandon
Published: September 2013

The effect of acute and chronic colchicine treatment on glucose induced immunoreactive insulin secretion and glucose tolerance was examined in fasting, unanesthetized, and unrestrained rats with indwelling jugular vein and aortic catheters. In the first study, intravenous glucose tolerance tests were performed by rapidly administering a glucose pulse (150 mg. intravenously) one hour after acute treatment with colchicine (0.5 mg. per kilogram of body weight, intravenously) or vehicle (control). Acute colchicine treatment caused significant suppression of glucose-induced insulin secretion and also markedly impaired glucose disappearance rates. In the second study, chronic colchicine treatment (in the lower dose of 0.2 mg. per kilogram of body weight, intraperitoneally, daily for 10 days) caused significant suppression of biphasic insulin secretion in response to a primed-constant glucose infusion (150 mg. of glucose pulse followed by 6 mg. per minute constant glucose infusion for 60 minutes) as compared with control rats (vehicle injection, intraperitoneally, daily for 10 days). Due to this marked decrease in biphasic insulin secretion, serum glucose concentrations were significantly higher between 10 and 45 minutes in the colchicine-treated rats than in the control rats.

Therefore, acute and chronic colchicine treatment causes marked inhibition of glucose-induced insulin secretion and impairment of glucose tolerance in the intact rat. These observations suggest there is a need to evaluate carbohydrate metabolism in patients receiving colchicine treatment.