bluuebunny/crossref_metadata_2025 huggingface dataset:
Studies of Insulin and Growth Hormone Secretion in a Subject with Hepatoma and Hypoglycemia
Authors: Colwell John A , Wilber John F
Published: December 2014

Studies of immunoreactive insulin (IRI) and human growth hormone (HGH) secretion were undertaken in a subject with chronic hypoglycemia associated with hepatoma. Fasting IRI concentrations were below 3 μU./ml. at glucose concentrations of 30 mg./100 ml. IRI secretion was not stimulated by acutely administered glucose, tolbutamide, glucagon or arginine. IRI concentrations rose after tolbutamide when plasma glucose was raised to 100 mg./100 ml. by sustained glucose infusion. Fasting ILA (muscle, adipose) levels were not elevated.

Fasting HGH concentrations were below 5 mμg./ml.; secretion was stimulated by arginine despite hypoglycemia. During glucose administration, HGH concentrations rose to 45 mμg./ml. as FFA levels fell from 2,250 to 233 μEq./L. Estimated total glucose utilization rate was high (7.5 mg./kg./hr. at a plasma glucose concentration of 100 mg./100 ml.).

Conclusions

(1) Glucose, or some metabolic product is required for human insulin secretion; (2) HGH secretion after arginine is not inhibited at low glucose concentrations; (3) FFA may exert an inhibitory role in HGH regulation; (4) Hypoglycemia in our subject with hepatoma was associated with increased glucose utilization, not with hyper-insulinism.
Effect of Resection of Adipose Tissue on the Diabetes and Hyperinsulinism of Benign Symmetric Lipomatosis
Authors: Colwell John A , Cruz Sidney R
Published: December 2014

Resection of 1,720 gm. of adipose tissue did not alter a chemical diabetic glucose tolerance and a late excessive plasma insulin rise in a patient with benign symmetric lipomatosis. This suggests that other factors than a feedback from adipose to the beta cell are responsible for the hyper-insulinemia of obesity.
Serum Insulin and Growth Hormone Values in Children during the Oral Glucose Tolerance Test
Authors: Cole Harold S , Epel Rosa
Published: December 2014

Three-hour oral glucose tolerance tests were performed on 125 nonobese children in three age groups: One-and-one-half to less than four years, four years to less than eight years and eight to twelve years of age. All children were in good health and had negative family histories for diabetes. Oral glucose was administered according to age and weight. Capillary blood was collected and analyzed for blood sugar and serum insulin and growth hormone.

All insulin and growth hormone analyses were performed on specimens from children whose blood sugar values during the oral glucose tolerance test conformed with previously established standards for normal controls.

No significant differences were found either for insulin or growth hormone at any of the testing periods between all age groups or between the sexes.

Insulin values reached their peak sixty minutes after ingestion of glucose and returned toward fasting levels at 180 min. The highest level of growth hormone was the fasting value. A decrease occurred after administration of oral glucose with a rising trend at the 180 min. testing period. Five control children who received a nonglucose-containing vehicle orally showed no statistically significant changes in growth hormone values due to the stress of multiple finger sticks.
Chemical Diabetes Mellitus in Childhood: Report of a Conference
Authors: Rosenbloom Arlan L , Drash Allan , Guthrie Richard
Published: December 2014

The recognition of chemical diabetes mellitus in children has led to questions of diagnostic criteria, methodology of testing, choice of populations to study and possible therapeutic approaches to the prevention of progression to overt (insulin-dependent) diabetes. Since the natural history of chemical diabetes in children includes spontaneous improvement as well as stability or progression of glucose intolerance, evaluation of the significance of abnormality and the effect of potential therapy is difficult. The oral glucose tolerance test (OGTT), despite problems in interpretation and methodology, remains the only generally accepted test for chemical diabetes in children. Criteria for interpretation of the OGTT in children used by pediatric investigators are similar to the Fajans and Conn standards for adults. Application of these criteria to certain high risk groups, including obese children, children with mild symptoms suggestive of hypoglycemia, and siblings of those with overt diabetes, has permitted the identification of 200 children with this stage of diabetes. Approximately 11 per cent have progressed to insulin dependency during one to seventeen years of observation. Data on treatment of these patients is limited to anecdotal reports or summaries of small groups of patients treated for variable periods with sulfonylurea drugs. It is not possible to recommend a therapeutic program for children with chemical diabetes, except in the case of the overweight child, where diet restriction may be as efficacious as in adults. Thus, testing of high risk persons and attempts at treatment should only be undertaken in an investigational setting.
Metabolic Clearance of Insulin in Man
Authors: Genuth Saul M
Published: December 2014

Metabolic clearance of insulin was measured, under circumstances of acutely and chronically altered endogenous plasma insulin, employing 1-131 bovine insulin (5 mc./mg., Abbott Laboratories) as tracer and the technic of constant infusion to equilibrium. Compared to normal subjects, clearance of radioiodinated insulin was unaffected by diabetes, was increased 25 per cent in obese subjects with hyperinsulinemia and did not change when their plasma insulin was reduced by seven days of fasting. Acute fourto fifteenfold elevation of endogenous insulin by glucose or tolbutamide injections to normal and obese subjects also failed to change clearance of radioiodinated insulin. These data support the assumption that alterations of plasma insulin in those circumstances largely reflect alterations in insulin secretion. However, in both normal and diabetic subjects, simultaneous clearances of unlabeled porcine insulin and radioiodinated insulin were also performed and disparate results obtained. Mean values were: unlabeled 861 ml./min. (Normals), 788 ml./min. (Diabetics) ; radioiodinated 227 ml./min. (Normals) ; 202 ml./min. (Diabetics). Ratio of unlabeled to radioiodinated clearance 3.8 (Normals), 4.1 (Diabetics). Because of this discrepancy, it is uncertain which clearance value affords the more accurate estimate of peripheral insulin delivery rate.
The Structure of Insulin
Authors: Hodgkin Dorothy Crowfoot
Published: December 2014

It is curious to read once again the text of the paper by Dr. Moses Barron1 which was first read by Fred Banting on October 30, 1920, and which stirred him so urgently to attempt the isolation of insulin. He stopped at the library casually on the way home from the medical school and looked at the first paper in Surgery, Gynecology and Obstetrics. Because he had to talk to students on the following day on the function of the pancreas and because its title was “The relation of the islets of Langerhans to Diabetes with special reference to cases of Pancreatic Lithiasis,” he took the journal home with him. The sentences he underlined were “Arnozan and Vaillard ligated the pancreatic ducts in rabbits and found that within twenty-four hours the ducts became dilated, the epithelial cells were desquamated and there were protoplasmic changes in the acinic cells … Ssobolew ligated the ducts in rabbits, cats and dogs. He found a gradual atrophy and sclerosis of the organ and relatively intact islets and no glycosuria.” At 9 p.m. Banting rang up Dr. Tew to say that he had an idea-that it might be possible to isolate the antidiabetic hormone from the islets by first allowing the acinar cells, containing digestive ferments, to atrophy. It was an idea so powerful that it changed his life and the lives of manv others.
Generalized Islet Hypertrophy and Beta-Cell Hyperplasia in a Case of Long-Term Juvenile Diabetes
Authors: Evans D J
Published: December 2014

A patient with juvenile diabetes died at the age of twenty-two of renal failure after fourteen years of known diabetes. The pancreas showed hypertrophied islets and hyperplasia of beta cells. Insulin dyshormonogenesis is suggested as a possible explanation for this unusual finding. The need for correlating histology with extraction procedures is pointed out.
The Effect of Insulin on Fat Cells: An Insulin Degrading System Extracted from Plasma Membranes of Insulin Responsive Cells
Authors: Crofford Oscar B , Rogers Nancy L , Russell Wilson G
Published: December 2014

The major effects of insulin on glucose, fatty acid and amino acid metabolism and on ion flux are initiated by the interaction of insulin with certain unidentified components of the cell membrane. These early events in the action of insulin were studied further with purified plasma membranes prepared from rat epididymal adipose cells.

The binding of 125I-labeled insulin to fat cell plasma membranes gives results quantitatively similar to those reported previously with unlabeled insulin. In addition, intact fat cells, plasma membranes from fat cells and a soluble extract from the plasma membranes contain a highly active insulin degrading system. Both the capacity of the plasma membranes to bind insulin and the insulin degrading activity of the membrane extract can be inhibited by the addition of unlabeled insulin to the incubation medium even though albumin is present in excess. The degraded products have not been fully identified but are soluble in 10 per cent trichloroacetic acid, nonreactive with anti-insulin guinea pig serum, nonadsorbable to a 125I adsorbing resin and, therefore, probably represent fragments of the insulin molecule. When isolated fat cells are treated with trypsin they become insulin unresponsive. Plasma membranes derived from such cells have a reduced capacity to bind insulin, and the insulin degrading system of the membranes or in the soluble extract from the membranes is inactive. This suggests that both the insulin receptor and the insulin degrading system are located on the external surface of the plasma membranes of the fat cells. It is postulated that an insulin degrading system of the plasma membrane may be one of the physiological mechanisms by which the response of fat cells to insulin is terminated.
Three-Dimensional Atomic Structure of Insulin and Its Relationship to Activity
Authors: Blundell T L , Cutfield J F , Cutfield S M , Dodson E J , Dodson G G , Hodgkin D C , Mercola D A
Published: December 2014

The three-dimensional structure of the insulin molecule has been determined by single crystal x-ray analysis. The two chains are compactly arranged with the A chain lying above a central helical region of the B chain. From each end of the helix the terminal residues extend as arms, and the A chain is enclosed between these. This limits the A chain to one surface of the molecule. Two surfaces, made up of B chain residues, are nonpolar and are buried by the aggregation of the molecule into a dimer and then into a hexamer. The insulin molecules of the 12,000 molecular weight dimer are related by an approximate twofold axis. Three such dimers can come together and in the presence of zinc ions form the stable 36,000 molecular weight hexamer. The three dimers have identical structures and are related by a threefold axis. The approximate twofold axis of the dimer is perpendicular to this. There is good evidence that insulin is stored in the granule as small crystals of this hexamer.

The A chain terminal residues A1 glycine, A5 glutamine, A19 tyrosine and A21 asparagine are on the surface of the molecule. They are invariant and not involved in the aggregation of the molecule. Their deletion affects both the structure and activity of insulin. Substitution at A1 glycine, especially of bulky groups, reduces activity substantially but seems to affect the molecular structure less. In proinsulin the connecting peptide appears to cover these residues. Therefore the surface A chain terminal residues apparently are important to the molecule's activity.
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.
Metabolic Clearance Rate of Growth Hormone in Juvenile Diabetes Mellitus
Authors: Lipman Richard L , Taylor Andrew L , Conly Patricia , Mintz Daniel H
Published: December 2014

The metabolic clearance rate (MCR) of radio-labeled growth hormone (GH) was measured in eleven recently diagnosed patients with juvenile-onset diabetes mellitus and in seven healthy nonhospitalized healthy children. The patients with diabetes mellitus demonstrated a significant reduction in MCR of GH as compared to the contrast group. Peripheral GH levels did not reach steady state conditions in the patients with diabetes, thus pituitary production rates of GH could not be evaluated in these patients. It is suggested that diabetes mellitus, even in its earliest clinically apparent stages is associated with a defect in the metabolic clearance of GH. Since the liver has been demonstrated to be the major organ responsible for GH clearance in man, it is evident that diabetes mellitus may be associated with a defect in the hepatic clearance mechanisms for growth hormone.
Failure of Sulfonylureas to Suppress Plasma Glucagon in Man
Authors: Pek Sumer , Fajans Stefan S , Floyd John C , Knopf Ralph F , Conn Jerome W
Published: December 2014

Others2 have reported that sulfonylureas suppress the release of glucagon and concluded that this is an important mechanism by which these compounds lower blood glucose. The studies reported here demonstrate the following: 1) oral administration of chlorpropamide for three days or rapid intravenous injection of tolbutamide did not induce a significant change in basal levels of immunoreactive glucagon (IRG) ; 2) intravenous infusion of tolbutamide in saline over thirty minutes did not evoke significant decreases in IRC; 3) tolbutamide added to solutions of arginine or of a mixture of ten amino acids (10-AA) failed to reduce the increases in IRG evoked by the infusion of these amino acid solutions in the absence of tolbutamide; and 4) tolbutamide injected rapidly at the midpoint of infusions of arginine or of 10-AA did not alter the steady rise in IRG induced by these amino acid solutions. In addition, tolbutamide failed to prevent hypoglycemia-induced increases in IRG. These results indicated that in man sulfonylureas do not suppress plasma levels of glucagon and that sulfonylurea-induced decreases in blood glucose are not mediated through suppression of glucagon release.
Decreased Sensitivity of the Pancreatic Beta Cells to Glucose in Prediabetic and Diabetic Subjects: A Glucose Dose-Response Study
Authors: Cerasi Eroi , Luft Rolf , Efendic Suad
Published: December 2014

The dose-response curve for glucose-induced insulin release obtained by infusing glucose at four to five different rates to normal subjects was sine-shaped, the insulin secretion starting at a blood glucose concentration of about 100 to 125 mg. per 100 ml. The steepest rise in plasma insulin occurred between blood glucose levels of 200 and 350 mg. per 100 ml. When blood sugar was increased further, the plasma insulin curve started to level off. There were no differences in the dose-response characteristics of the early and late insulin responses to glucose infusion. In prediabetic subjects variations in blood glucose concentration between the fasting level and about 300 mg. per 100 ml. were accompanied by only a minor insulin response. Further eleva-ation of blood glucose to 450 to 650 mg. per 100 ml. induced a normal initial insulin response in two out of the eight prediabetics, while the late response was normalized in almost all of them. Thus, the insulin-glucose dose-response curves in the prediabetics seemed to be similar to those of the normals but shifted toward higher blood glucose concentrations. In subjects with mild maturity-onset diabetes or glucose intolerance only, there seemed to exist a further shift to the right of the dose-response curves. These findings suggest that (1) the mechanisms governing the early and late insulin responses to glucose are of identical nature, and (2) the decreased insulin response to glucose in prediabetics and mild diabetics is a relative one, very high glucose concentrations being capable of eliciting normal responses. These findings are compatible with our hypothesis that the defective insulin release in prediabetes and diabetes is due to a decrease in the sensitivity of the glucose receptor of the pancreatic β cell which transmits the glucose signal for insulin release.
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.
Early Effects of Anti-Insulin Serum on Hepatic Metabolism of Plasma Free Fatty Acids in Dogs
Authors: Balasse Edmond O , Bier Dennis M , Havel Richard J
Published: December 2014

SUMMARY:Hepatic metabolism of free fatty acids was studied in six anesthetized fasted dogs before and for several hours after the abrupt induction of insulin deficiency. This was produced by injecting guinea pig anti-insulin serum in amounts capable of binding all circulating insulin for several hours. During each study, albumin-bound-I-C-14-palmitate and I-131-rose bengal were infused at a constant rate and serial sanv pies of arterial, portal and hepatic venous blood were obtained through appropriate intravascular catheters. Maximal changes were observed three to four hours after administration of anti-insulin serum. Mean arterial concentrations of glucose, free fatty acids, glycerol and triglyceride fatty acids of very low density lipoproteins increased twofold and that of ketone bodies, fourfold. Hepatic extraction ratio of free fatty acids was unchanged after anti-insulin serum so that the hepatic uptake of free fatty acids approximately doubled. During the control period, about 25 per cent of free fatty acids removed by the liver were converted to CO2, 11 per cent to triglyceride fatty acids of very low density lipoproteins and 25 per cent to ketones (assuming that ketones derived entirely from FFA). After anti-insulin serum, corresponding values were 14 per cent, 26 per cent and 51 per cent. The increased relative and absolute conversion of free fatty acids to ketones resembles that observed in chronically diabetic dogs withdrawn from insulin for forty-eight hours. However, the increased conversion of free fatty acids to triglyceride fatty acids of very low density lipoproteins observed in short-term deficiency of insulin contrasts with the greatly depressed conversion observed after two days of insulin lack.
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.
Pyridine Nucleotide Depletion in Pancreatic Islets Associated with Streptozotocin-induced Diabetes
Authors: Ho Chen-Kung , Hashim Sami A
Published: December 2014

An investigation of NAD-NADH concentrations in the pancreatic islets of rats following diabetogenic doses (65 mg./kg.) of streptozotocin (SZ), given singly or in combination with nicotinamide or nicotinic acid, is reported. After a given treatment of the animals, the pancreases were surgically removed. The concentrations of NAD and NADH were determined on islets isolated from freeze-dried sections of the pancreas. In the pancreatic islets of untreated control animals, the mean ± S.E. concentrations of NAD and NADU were 1,122 ± 5 7 and 129 ± 28 mμnmoles/gm. dry tissue, respectively. The NAD content of the islets decreased to 27 per cent of the control value one hour and to 12 per cent five hours after administration of SZ. NADH concentration five hours after SZ was significantly reduced from the control value. When nicotinamide was given thirty minutes before SZ, the depletion of NAD associated with SZ administration was prevented. When nicotinamide was given one hour after SZ, the depressed NAD concentration observed at this time was subsequently raised. In contrast, nicotinic acid given thirty minutes prior to SZ did not prevent depletion of NAD. The data suggest that streptozotocin-induced betacell deterioration may be etiologically related to depletion of cellular NAD.
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.
Elevation of Glycoprotein Fucose in Diabetes Mellitus
Authors: McMillan Donald E
Published: December 2014

The pattern of serum protein-bound carbohydrate elevation in diabetes mellitus has been investigated. Cation exchange chromatography on individual sera was followed by serial separation technics on diabetic and control serum pools. The protein-bound hexose elevation could be accounted for by elevated levels of several serum glycoproteins, especially haptoglobin, α1-acid glycoprotein, and α1-antitrypsin. In contrast, only a small portion of the fucose increase could be accounted for by the elevated glycoprotein levels. Fractionation of the serum proteins revealed the fucose increase to be produced by more than one glycoprotein. When ion exchange and gel filtration chromatography were combined to produce elution areas in which only one glycoprotein could be recognized immunologically, a pattern emerged. Three glycoproteins, whose major common source is the liver parenchymal cell, had increased fucose levels, while three immune globulins, not produced by this cell, had normal fucose levels. The demonstration of increased fucose content only in glycoproteins formed by liver cells suggests a metabolic basis for increased serum protein-bound fucose, and a mechanism relating increased hepatic gluconeogenesis and associated cytoplasmic oxidation-reduction changes to increased fucose synthesis is postulated.
In Vivo Effects of Insulin and Proinsulin on Diaphragm and Epididymal Fat Pads in Rats
Authors: Kitabchi Abbas E , Duckworth William C , Benson Bryant
Published: December 2014

By the use of the intraperitoneal injection method, the in vivo effect of various concentrations of insulin or pro-insulin alone and in combination has been studied on the conversion of glucose-U-C-14 into labeled lipid of epididymal fat pad and labeled glycogen of the diaphragm of rats. On a molar basis proinsulin is one eighth as effective as insulin in promoting glucose oxidation in both tissues. Proinsulin exerts no antagonistic or synergistic effect on insulin but exhibits an additive effect with submaximal concentrations of insulin.
Release and Production of Insulin by Isolated, Perifused Rat Pancreatic Islets: Control by Glucose
Authors: Hoshi Mitsuru , Shreeve Walton W
Published: December 2014

Rat pancreatic islets, isolated from the whole gland by digestion with collagenase, were incubated in a continuous flow system in which various concentrations of glucose were contained in the buffer solution. The pattern of release of immunoreactive insulin (IRI) consisted generally of successive main phases with multiple minor fluctuations within the broader cyclic release. Threshold and responsiveness of various phases of IRI release with different glucose concentrations and flow rates have been investigated.
Blood Cell and Plasma Amino Acid Levels Across Forearm Muscle During a Protein Meal
Authors: Aoki T T , Muller W A , Brennan M F , Cahill G F
Published: December 2014

To elucidate the role of blood cells in amino acid metabolism, substrate balance across the forearm was studied in a nitrogen-depleted subject fed 200 gm. of meat. After ingestion of the meal, there was the expected outpouring of amino acids from the splanchnic bed into the general circulation. Both cell and plasma levels of most amino acids in arterial blood increased rapidly. Whole blood arterio-deep venous amino acid differences frequently differed from that of plasma. In conclusion, it appears that both blood cells and plasma transport amino acids from the splanchnic bed to the periphery and that both participate actively in the deposition of amino acids in the forearm of the subject studied.
Insulin and Proinsulin Content of Pancreases from Diabetic and Nondiabetic Subjects
Authors: Rastogi G K , Sinha M K , Dash R J
Published: December 2014

The content of immunoreactive insulin (IRI) extractable with acid ethanol from the head, body and tail of the pancreas was. studied in thirty-two nondiabetics, eleven maturity-onset diabetics and four juvenile diabetics. In nondiabetics IRI content ranged from 0.1 to 4.8 U. per gram wet pancreas. The tail had the highest insulin content, but the body of the pancreas could be taken to represent the entire pancreas. The insulin content of pancreases from eleven maturity-onset diabetics ranged from 0.1 to 6.5 U. per gram wet pancreas. It showed a progressive decline with the duration of diabetes. The IRI content of pancreases from four juvenile diabetics was low. The proportion of proinsulinlike component, estimated by gel filtration in the pancreatic extracts, ranged from 0.2 to 5 per cent of the insulin peak and was not different in diabetics.
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.
Glucose, Insulin, and Free Fatty Acids in Uremia
Authors: Roth Donald A , Meade Robert C , Barboriak Joseph J
Published: December 2014

Glucose intolerance in uremia is well known. In response to the elevated blood glucose, serum insulin rises. We have again demonstrated this rise in serum insulin, especially after the first hour during glucose tolerance testing. Regardless of the mechanism or appropriateness of the insulin response, plasma FFA in uremic patients are markedly depressed when glucose is elevated or small amounts of insulin are infused. The low concentration of FFA accompanying glucose intolerance may be a significant abnormality in the metabolic economy of the uremic patient.
Light and Electron Microscopic Studies of Islet Amyloid in Diabetic Cats
Authors: Johnson Kenneth H , Stevens Jerry B
Published: December 2014

The light and electron microscopic characteristics of hyaline deposits present in the pancreatic islets of two aged diabetic cats are described. The hyaline deposits were consistent with amyloid when sections stained with periodic acid-Schiff (PAS), crystal violet, Puchtler's Congo red, and Masson's trichrome were examined by bright field illumination. Green birefringence with Congo red-stained sections and red birefringence with toluidine blue-stained sections were apparent with polarized illumination. In addition, fibrillar components typical of amyloid were ultrastructurally demonstrated in these deposits. Hypotheses regarding the cause of localized amyloidosis in pancreatic islets are considered. Future investigation of the pathogenesis of amyloid deposition in feline pancreatic islets is warranted to obtain a better understanding of the pathogenesis of maturity-onset diabetes in man and the cat.
Propranolol-induced Insulin Release in Isolated Rat Islets of Langerhans
Authors: Northrop Gretajo , Ryan Will G , Schwartz Theodore B
Published: December 2014

Immunoreactive insulin was measured in the medium following incubation of isolated rat islets of Langerhans in different concentrations of propranolol and propranolol plus glucose. Pretreatment with propranolol (20 μg./ml.) prevented glucose (3 mg./ml.)-mediated insulin release. Propranolol alone in concentrations up to 25 μg./ml. did not cause insulin release; however, at 50 μg./ml. this drug had strong beta-cytotrophic activity.
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 < 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.