bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucoreceptor Mechanisms in Islets of Langerhans
Authors: Matschinsky F M , Landgraf R , Ellerman J , Kotler-Brajtburg J 
Published: December 2014

A widely accepted concept has been that metabolites of glucose or factors associated with glucose metabolism, rather than glucose itself, trigger insulin release from the β cells. If this concept is correct, levels of metabolites or cofactors or of both should change within seconds of the glucose pulse. To examine the hypothesis, glucose, glucose-6-P, 6-P-gluconate, fructose-l,6-P2 plus triose-P, 3-P-glycerates plus P-enolpyruvate, ATP, ADP and P-creatine were measured in slices of individual rat islets after intravenous infusion of glucose in vivo or perfusion of the isolated pancreas with glucose in vitro. Tissue samples were obtained by quickfreezing methods as early as fifteen seconds and as late as sixty minutes following the glucose load. Insulin levels in serum and perfusate were measured concomitantly.
Insulin levels in peripheral blood rose within one minute of injection of glucose in vivo. Penetration of glucose, although very rapid, was carrier-mediated. Most of the metabolites and cofactors measured were unchanged during the first five minutes of glucose infusion. After one hour of hyperglycemia there was a marked rise in all metabolites and cofactors except ATP.
In the perfused pancreas, insulin secretion increased within 0.5 minute of the glucose stimulus and the typical biphasic response was observed. The glucose content of islets increased threefold within 0.25 minute and sixfold within 0.5 minute. The levels of all other metabolites measured were virtually unchanged during the early phase of the endocrine response, in spite of the eightfold increment in the glucose of the medium and the almost tenfold rise of insulin release.
The constancy of the islet's metabolite pattern when the islets were exposed to high glucose—particularly during the early transition phase—is remarkable, since glycolytic flux was supposedly increased severalfold.
The fact that the metabolite profile of the islets is so precisely maintained within a narrow range makes it unlikely that any of the metabolites measured might serve as triggers for insulin release. It is more likely that the glucose molecule itself exerts its releasing action by stimulating glucoreceptors located on the cell membrane.
A Threshold Distribution Hypothesis for Packet Storage of Insulin: II. Effect of Calcium
Authors: Grodsky Gerold M , Francisco San 
Published: December 2014

Phases of insulin release were studied in the perfused pancreas with glucose or calcium used as stimulators. Stimulation patterns included constant prolonged single steps, restimulations and staircase stimulations. Except at low concentrations, glucose elicited early spikes of insulin and the slowly rising second phase. In single-step experiments, total insulin in the spikes increased with higher glucose concentration. However, time patterns were the same; ratios of initial secretion rate to total insulin secreted were constant. Total insulin in the spikes was a skewed sigmoidal function of glucose concentration; mathematical differentiation of this function approximated a bell-shaped distribution curve. Staircase experiments showed that insulin released as a spike at each step did not correlate with the increment of glucose but rather with the available insulin for a given glucose concentration, minus that released in previous steps.
A two-compartmental model for insulin storage has been expanded by the hypothesis that labile insulin exists as a bell-shaped distribution of packets that rapidly release insulin when their sensitivity or threshold to glucose has been reached.
Glucose was maintained at permissive concentrations and calcium was perfused as continuous single steps with restimulation and as staircases. Results were qualitatively like those with glucose. Spike responses, in terms of time, were similar to each other; total insulin released as spikes depended on that insulin releasable by an absolute calcium concentration minus that released in any previous step. It was concluded that glucose and calcium act together or sequentially on the insulin packets whose threshold to stimulator varies according to a bell-shaped distribution density.
6-Aminonicotinamide (6-AN) as a Diabetogenic Agent: In Vitro and in Vivo Studies in the Rat
Authors: Ammon H P T , Steinke Jurgen 
Published: December 2014

The effect of 6-aminonicotinamide (6-AN), an antimetabolite mainly of NADP synthesis, on insulin release, was studied. Adults rats were pretreated with 6-AN (35 mg./kg.); six hours later, the in vitro insulin response of isolated islets to glucose was significantly reduced from 561 ± 41 to 175 ± 22μU. of immunoreactive ingiilin (IRI) per five islets per ninety minutes incubation time. On the other hand, in vitro addition of NADP or NADPH (1 or 10 mM) to islets from pretreated rats, restored insulin release. In control islets, addition of NADP or NADPH showed little effect. It is unlikely that 6-AN affected insulin synthesis in vivo, as extractable insulin content of islets did not change (1.5 ± 0.1 vs. 1.4 ± 0.1 mU. IRI per single islet). In vivo studies with 6-AN pretreated rats showed marked hyperglycemia (344 ± 25 vs. 139 ± 11 mg./100 ml.) after a six-hour fast and still significant hyperglycemia following a twenty-four-hour fast (282 ± 33 vs. 94 ± 6). When challenged by intraperitoneal glucose, insulin failed to rise significantly in the 6-AN treated animals.
It is thus possible to produce a new variant of experimental diabetes by interfering with NADPH metabolism within the beta cell. Our data suggest that glucose is involved in insulin release as a generator of NADPH via the pentose-phosphate shunt.
Neutral Regular Insulin
Authors: Jackson Richard L , Storvick Waldemar O , Hollinden C Stephen , Stroeh Lowell E , Stilz John G 
Published: December 2014

Significant process improvements developed in recent years have resulted in the production of a better quality of insulin suitable for formulation as soluble insulin at a neutral pH. The neutral regular insulin (NRI) selected for study and clinical trial was an unbuffered preparation obtained by simple neutralization of an acid regular insulin solution (ARI) to pH 7.4. Buffering appeared unnecessary and either phenol or methylparaben may be used as a preservative. Beef and pork insulins were readily soluble at neutral pH which suggested that purity is the prerequisite for solubility.
NRI was compared with commercial ARI prepared from the same zinc-insulin crystals. NRI was shown to be more stable when stored at room temperature or above. Degradation reactions in NRI were similar to those in ARI but occurred at a slower rate. Mixtures of NRI or ARI with prolonged acting insulins showed comparable biological activity even though ARI affects the pH of the mixture.
The results of this investigation have shown NRI to possess sufficient advantage over ARI to warrant consideration as a pharmaceutical form of soluble regular insulin and as a replacement for the conventional acidic form.
Effect of Weight Reduction on in Vitro Adipose Tissue Lipolysis and Cellularity in Obese Adolescents and Adults
Authors: Knittle J L , Ginsberg-Fellner F 
Published: December 2014

Adipose tissue cellularity, in vitro glycerol release, and in vivo glucose metabolism were examined in ten markedly obese subjects, ages thirteen to fifty-four, before and after weight reduction.
Prior to reduction adipose cells were larger and exhibited higher rates of lipolysis than smaller postreduction cells. Incubations containing epinephrine, epinephrine plus insulin and insulin alone also revealed significant decreases in absolute rates of glycerol release in the postreduction state. However, when the data were expressed as per cent change, in vitro hormonal activity did not appear to be influenced by changes in cell size. Weight reduction was also accompanied by improvement in oral glucose tolerance tests, lower fasting levels of plasma free fatty acids and decreased values of circulating immunoreactive insulin, fasting and following oral glucose. Studies of adipose cell number revealed that obese adolescents display hypercellularity comparable to that observed in obese adults. As in the adult, weight loss resulted in improved glucose tolerance and a decrease in adipose cell size without a significant change in total adipose cell number.
Thus decreased rates of lipolysis of smaller adipocytes were associated with the improved lipid and glucose metabolism found in obese subjects after weight reduction.
Stability of Insulin Preparations
Authors: Pingel M , Vølund Aa 
Published: December 2014

The stability of seven types of pharmaceutical insulin preparations was determined by a bioassay (mouse convulsion method) and a radioimiminoassay after storage for different periods at 4° C., 15° C., 25° C., 37° C., or 45° C. in the dark. The seven insulin preparations were: Ordinary Insulin, Protamine Zinc Insulin (PZI), the Lente insulins (Ultralente, Semilente and Lente), Rapitard and Aetrapid.
Full biological potency was registered in all the insulin preparations under study after five years of storage at 4° C. The biological potency (P(t,T)) as function of time (t) and absolute temperature (T) can be expressed by the formula: Using the values observed, the constants P0 (initial potency), α, and β were calculated for each type of insulin preparation. According to the formulas the loss in biological potency for all the insulin preparations will be less than 10 per cent after storage for sixty-nine years at 5° C., ten years at 15° C., twenty months at 25° C., three months at 35° C. or ten days at 45° C. The activation energy (Ea), the half-life (t0.5) and the temperature coefficient (Q10) were calculated for each of the seven insulin preparations using α and β. The rate of disappearance of biological insulin activity was found to increase four- to fifteenfold with a temperature increase- of 10° C.
The decline in inmiunological activity was less than that in biological activity, especially in cases where the loss in biological potency was substantial. It is concluded that the immunoassay is no reliable substitute for the bioassay of unknown insulin preparations.
Structure/Function and Structure/Immunoreactivity Relationships of the Glucagon Molecule and Related Synthetic Peptides
Authors: Assan Roger , Slusher Norman 
Published: December 2014

Various synthetic glucagon-related peptides have been studied with respect to the biological activity in man, and to the immunoreactivity toward two different glucagon antisera.
From the biological study and comparison with the results previously obtained, it appears that the lipolytic potency can be dissociated from other biological activities: The structure responsible for lipolysis is contained inside the [19-22] amino-acid sequence while the structure necessary for glycogenolytic and insulinogenic actions is located inside the [24-29] amino-acid sequence.
The radioimmunological studies show the presence of two anti genie sites inside the glucagon molecule: One (N-terminal + central portion) is also present in some catabolic fragments of glucagon circulating in blood and must also be present in the entero glucagon (GLI) molecule. This site appears to be the one most often bound by glucagon antisera.
Hypoglycemic Action of Fenfluramine in Diabetes Mellitus
Authors: Turtle J R , Burgess J A 
Published: December 2014

Fenfluramine has been demonstrated to have a biphasic effect on glucose removal by skeletal muscle during forearm perfusion. A prompt early increase in glucose removal by skeletal muscle, lasting 90 to 120 minutes, disappeared with the release of free fatty acids. The metabolic effect of fenfluramine on glucose removal occurred without increase in lactate release, suggesting complete oxidation of glucose by skeletal muscle.
The effect of fenfluramine on blood glucose was assessed in maturity onset and insulin-requiring diabetics. The drug was most suitable as a hypoglycemic agent when administered immediately before a meal in order that the maximum hypoglycemic action occurred during the period of post-absorption hyperglycemia. When administered before a meal fenfluramine consistently lowered blood glucose levels in maturity onset diabetes mellitus for at least two hours. A similar but less marked action was seen in insulin-requiring diabetics. Blood glucose levels were lowered by fenfluramine in diabetics who were maintained on diet alone or diet plus tolbutamide without the risk of lactic acidosis and without any direct effect on insulin secretion.
Dietary Diabetes: The Influence of a Low Carbohydrate Diet on Forearm Metabolism in Man
Authors: Jackson R A , Advani Usha , Perry Gillian , Rogers J , Peters N , Day Sally , Pilkington T R E 
Published: December 2014

Forearm glucose uptake and lactate balance across the forearm were determined in normal subjects during 100-gm. oral glucose tolerance tests (GTT) before and after a lowcarbohydrate diet; in addition, β-hydroxybutyrate and acetoacetateresponses were measured following carbohydrate restriction. After a low-carbohydrate diet, glucose tolerance was significantly impaired (dietary diabetes) and the rise in seruminsulin levels was frequently, but not invariably, delayed. Forearm glucose utilization, however, was not significantly decreased at any phase of the GTT or during the GTT as a whole.
With a normal diet, lactate levels rose immediately after glucose loading, reaching peak concentrations at sixty minutes and falling progressively thereafter; this rise was associated with lactate utilization by the forearm and the subsequent fall in plasma concentrations with lactate release. In contrast, following carbohydrate restriction lactate concentrations were initially reduced by glucose administration, this reduction taking place despite continuing lactate release from the forearm. These results suggest that after glucose loading the shape of the lactate response curve is not determined primarily by changes in peripheral lactate balance.
Marked elevation in basal FFA, β-hydroxybutyrate, and acetoacetate levels accompanied carbohydrate restriction. FFA and β-hydroxybutyrate concentrations were immediately decreased and acetoacetate levels initially increased by glucose loading, the latter declining only during the second hour of the GTT; throughout the test, acetoacetate was taken up by the forearm while β-hydroxybutyrate was released. Basal FFA and β-hydroxybutyrate concentrations were not correlated with the degree of glucose intolerance induced in the volunteers.
The results show that the impairment of glucose tolerance following carbohydrate restriction is not the result of decreased peripheral glucose utilization. It is suggested that the major cause of dietary diabetes is a delay in the hepatic uptake of the glucose load and that this is primarily the. result of low hepatic glucokinase activity rather than delayed insulin secretion.
A Critique of Methods in Reported Studies of Long-term Vascular Complications in Patients with Diabetes Mellitus
Authors: Kaplan Moreson H , Feinstein Alvan R 
Published: December 2014

From 149 papers that referred to the development of vascular complications in patients with diabetes mellitus, we selected thirty-three that could be used for analysis of methodology. Eight of these reports contained inception cohorts in which a valid statistical risk could be calculated from the target events (cited in the numerators) and the initial states (cited in the denominators). Twenty-five reports contained longitudinal prevalence groups that were suitable only for appraisal of the target events cited in the numerators.
The denominator populations in the cohort studies were usually reported without reproducible specifications of the proportionate sources of the cohort, the criteria for diagnosing diabetes mellitus, and the criteria for excluding patients from the investigation. Although most of the starting patients were “recovered” in reports of final results, the denominators of different results were often unstable, reflecting an absence of suitable initial data.
The initial state of the cohorts was usually reported for age and sex, less commonly for metabolic features of the diabetes, and rarely for comorbid diseases that were unrelated to diabetes. The initial-state retinopathy, nephropathy, hypertension, peripheral vascular and cardiac ailments that were “related” to diabetes were reported infrequently. When reported, these conditions were not always specified with reproducible diagnostic criteria or cited quantitatively for prevalence in the cohort.
The incidence of subsequent vascular complications was usually reported without satisfactory distinctions between the occurrence of a new complication and a change in the state of a previous one. The complications were generally cited with “objective” data that did not indicate the concomitant symptomatic and other functional effects. Few of the cohort investigators took appropriate advantage of the opportunity to correlate subsequent complications with different “risk factors” of the initial state. In longitudinal prevalence studies, the complications were correlated mainly with duration and regulation of the diabetes, but seldom with the initial distinctions of the patients.
Since these problems arise from defects in selecting, specifying, and analyzing the original and subsequent clinical condition of the treated patients, and since the randomized assignment of treatment does not deal with these problems, a predominantly statistical approach to therapeutic trials cannot be expected to resolve the existing scientific controversies about treatment.
Studies on the Human Glomerular Basement Membrane: Composition, Nature of the Carbohydrate Units and Chemical Changes in Diabetes Mellitus
Authors: Beisswenger Paul J , Spiro Robert G 
Published: December 2014

The basement membrane has been isolated in purified form from pooled normal human glomeruli and shown by detailed analyses to be composed of glycoprotein material. The peptide portion was characterized by the presence of large amounts of glycine, as well as by the occurrence of a substantial number of hydroxyproline, hydroxylysine, and cystine residues. Approximately 7 per cent of the weight of the membrane was found to be made up of sugar residues.
The membrane was extensively solubilized by digestion with bacterial collagenase, and a study of glycopeptides obtained after additional Pronase treatment indicated the occurrence of glucosylgalactose disaccharide units linked to hydroxylysine as well as heteropolysaccharides consisting of N-acetylneuraminic acid, fucose, galactose, mannose and hexosamines similar to those previously found in the bovine glomerular basement membrane.
Chemical analyses of glomeruli obtained from diabetic and nondiabetic kidneys indicated that the former contained more basement membrane-like material. Furthermore basement membranes isolated from the diabetic glomeruli had a composition different from those obtained from control subjects. The diabetic membranes were found to have a significant increase (P &lt; 0.01) in their hydroxylysine content and in the number of glucosylgalactose disaccharides linked to this amino acid. The increase in hydroxylysine was accompanied by a decrease in the lysine level so that the sum of these amino acids remained unchanged from the normal. Changes of lesser significance were observed in hydroxyproline, glycine, valine and tyrosine with the former two amino acids showing an increase and the latter two a decrease from the nondiabetic level. No change was found in the number of the heteropolysaccharide units.
These results suggest an overproduction in the diabetic state of those subunits of the basement membrane that are rich in hydroxylysmejand its glycosidically linked disaccharide unit. Such alterations in the subunit composition may lead to an abnormal packing of the peptide chains and thereby form the basis for the detective filtration function observed in diabetes.
Carbohydrate and Lipid Metabolism in Relation to Body Composition in Myotonic Dystrophy
Authors: Björntorp Per , Schröder Gustav , Orndahl Gustaf 
Published: December 2014

Body composition and carbohydrate and lipid metabolism were examined in seventeen patients with myotonic dystrophy (MD). Body cell mass and body fat were determined with isotope dilution methods. Adipose tissue fat cell weight was measured and total fat cell number of the body could be estimated. Fasting concentrations of blood glucose, plasma triglyceride, cholesterol, and insulin as well as of glucose and insulin after ingestion of 100 gm. of glucose were also determined.
In comparison with pertinent controls, MD patients showed no difference in body weight, although body composition was markedly altered with decreased body cell mass and increased body fat mass. Patients without physical impairment showed no derangements, of metabolism. However, disabled MD patients with pronounced decrease of body cell mass had decreased glucose tolerance and increased levels of fasting plasma insulin and lipids. It was concluded that deranged lipid or carbohydrate metabolism is not a primary characteristic of MD but a phenomenon secondary to muscular impairment and atrophy. Intact muscle function is probably important in regulation of lipid and carbohydrate metabolism.
Electron Microscopic Quantification of Diabetic Microangiopathy
Authors: Siperstein Marvin D , Raskin Philip , Burns Henry , Ann Johnson Alice , Sill Mary Jo 
Published: December 2014

1. Several methods of quantifying muscle capillary basement membrane width have been evaluated with the aim of determining whether variations in technic may influence the sensitivity of detecting significant capillary basement membrane thickening in diabetic subjects.
2. The results demonstrate that fixation of tissue in osmic acid followed by determination of mean basement membrane thickness reveals significant basement membrane thickening in over 90 per cent of diabetic subjects.
3. The error in estimation of mean basement membrane width due to oblique sectioning of diabetic capillaries is shown to be small, i.e. approximately 10 per cent. By contrast, measuring only the minimum basement membrane thickness of a capillary may underestimate diabetic basement membrane hypertrophy by from 20 to 40 per cent.
4. As compared to osmic acid fixation, glutaraldehyde leads to a very significant increase in the basement membrane width affecting normal capillaries relatively more than diabetic capillaries.
5. As a result, either fixation in glutaraldehyde or measurement of minimum basement membrane thickness may lead to a marked decrease in the sensitivity of the quantitative basement membrane technic. A procedure that employs both glutaraldehyde fixation and measurement of only minimum basement membrane width would appear to detect microangiopathy in only 45 per cent of diabetic subjects.