Showing papers on "Insulin published in 1969"

Diabetogenic action of streptozotocin: relationship of dose to metabolic response.

Abstract: The relationship between the dose of intravenously administered streptozotocin (a N-nitroso derivative of glucosamine) and the diabetogenic response has been explored by use of the following indices of diabetogenic action: serum glucose, urine volume, and glycosuria, ketonuria, serum immunoreactive insulin (IRI), and pancreatic IRI content. Diabetogenic activity could be demonstrated between the doses of 25 and 100 mg/kg, all indices used showing some degree of correlation with the dose administered. Ketonuria was only seen with the largest dose, 100 mg/kg. The most striking and precise correlation was that between the dose and the pancreatic IRI content 24 hr after administration of the drug, and it is suggested that this represents a convenient test system either for both related and unrelated beta cytotoxic compounds or for screening for modifying agents or antidiabetic substances of a novel type. Ability to produce graded depletion of pancreatic IRI storage capacity led to an analysis of the relationship between pancreatic IRI content and deranged carbohydrate metabolism. Abnormal glucose tolerance and insulin response were seen when pancreatic IRI was depleted by about one-third, while fasting hyperglycemia and gross glycosuria occurred when the depletion had reached two-thirds and three-quarters, respectively. The mild yet persistent anomaly produced by the lowest effective streptozotocin dose, 25 mg/kg, exhibits characteristics resembling the state of chemical diabetes in humans and might thus warrant further study as a possible model. Finally, the loss of the diabetogenic action of streptozotocin by pretreatment with nicotinamide was confirmed and was shown to be a function of the relative doses of nicotinamide and streptozotocin and of the interval between injections.

Liver and kidney metabolism during prolonged starvation

Abstract: This study quantifies the concentrations of circulating insulin, growth hormone, glucose, free fatty acids, glycerol, beta-hydroxybutyrate, acetoacetate, and alpha amino nitrogen in 11 obese subjects during prolonged starvation. The sites and estimated rates of gluconeogenesis and ketogenesis after 5-6 wk of fasting were investigated in five of the subjects. Blood glucose and insulin concentrations fell acutely during the 1st 3 days of fasting, and alpha amino nitrogen after 17 days. The concentration of free fatty acids, beta-hydroxybutyrate, and acetoacetate did not reach a plateau until after 17 days. Estimated glucose production at 5-6 wk of starvation is reduced to approximately 86 g/24 hr. Of this amount the liver contributes about one-half and the kidney the remainder. Approximately all of the lactate, pyruvate, glycerol, and amino acid carbons which are removed by liver and kidney are converted into glucose, as evidenced by substrate balances across these organs.

Plasma amino acid levels and insulin secretion in obesity.

Abstract: Of 20 plasma amino acids measured, valine, leucine, isoleucine, tyrosine and phenylalanine were increased, and glycine decreased, in obese subjects compared with age- and sex-matched controls The concentration of each of the amino acids elevated in obesity correlated directly with serum insulin In addition, these were the amino acids most sensitive to the action of insulin in lowering plasma amino acid levels, as evidenced by a diminution in concentration after glucose infusion Despite a significantly greater increment in serum insulin in the obese group, the magnitude of the decline in amino acids after glucose administration was identical in the two groups Hyperaminoacidemia appears to be a manifestation of the insulin ineffectiveness characteristic of obesity Furthermore, hyperaminoacidemia may provide the feedback signal to the beta cell through which insulin resistance is accompanied by an appropriately augmented secretory rate of insulin

Increased feeding in response to decreased glucose utilization in the rat and monkey

Abstract: SMITH, GERARD P., AND ALAN N. EPSTEIN. Increased feeding in response to decreased glucose utili

Amino acid balance across tissues of the forearm in postabsorptive man. Effects of insulin at two dose levels

Abstract: Amino acid balance across skeletal muscle and across subcutaneous adipose tissue plus skin of the forearm has been quantified in postabsorptive man before and after insulin infusion into the brachial artery. Skeletal muscle released significant amounts of alpha amino nitrogen after an overnight fast. Most individual amino acids were released. Alanine output was by far the greatest. The pattern of release probably reflects both the composition of muscle protein undergoing degradation and de novo synthesis of alanine by transamination. A significant correlation was observed between the extent of release of each amino acid and its ambient arterial concentration. Elevation of forearm insulin in eight subjects from postabsorptive (12 μU/ml) to high physiologic levels (157 μU/ml) in addition to stimulating muscle glucose uptake blocked muscle alpha amino nitrogen release by 74%. Consistent declines in output were seen for leucine, isoleucine, tyrosine, phenylalanine, threonine, glycine, and α-aminobutyric acid. Alanine output was insignificantly affected. Doubling forearm insulin levels (from 10 to 20 μU/ml) in eight subjects increased muscle glucose uptake in three and blocked alpha amino nitrogen output in two although both effects were seen concurrently in only one subject. Changes in net amino acid balance after insulin could be accounted for by increased transport of amino acids into muscle cells or retardation of their exit. It is likely that ambient arterial amino acid concentrations are established and maintained primarily by the extent of muscle amino acid release. The individual amino acids whose outputs from forearm muscle decline after forearm insulinization correspond well with those whose levels fall systematically after systemic insulinization. This suggests that declines in amino acid levels after systemic insulinization are due to inhibition of muscle release. Doubling basal insulin approaches the threshold both for blockade of muscle amino acid output and stimulation of glucose uptake, effects which appear to occur independently.

Entero-insular axis.

Abstract: Evidence for an entero-insular axis is based upon studies showing that amino acids as well as glucose cause a greater and earlier release of islet cell hormones when administered via the gastrointestinal tract than occurs with comparable elevations in the plasma concentrations of the nutrients given intravenously. The ability of several gastrointestinal hormones to elicit immediate augmentation of insulin and glucagon secretion has been established. Gastrin, secretin, and pancreozymin in dogs all produce an immediate rise of insulin to a peak one minute after injection, but the response to gastrin is quantitatively trivial, while that to secretin is modest. However, pancreozymin elicits substantial release of both insulin and glucagon, and augments the insulinogenic and glucagonogenic effects of amino acids. The physiologic implications of such studies are considered.

Interaction of insulin with the cell membrane: the primary action of insulin

Abstract: Insulin can be covalently attached to a large polymers of Sepharose through the α-amino group of the N-terminal residue of the B chain, or through the e-amino group of its lysyl residue Such derivatives effectively increase the utilization of glucose, and suppress the hormone-stimulated lipolysis, of isolated fat cells The effects occur with concentrations of insulin-Sepharose that are nearly as low as those of native insulin, and the maximal responses are the same The results indicate that interaction of insulin with superficial membrane structures alone may suffice to initiate transport as well as other metabolic alterations

Insulin responses to glucose: evidence for a two pool system in man

Abstract: Four rapid glucose injections of 5 g each were administered to normal young adult subjects before, during, and after an infusion of glucose. After the first glucose pulse, insulin responses measured immunologically reached a peak between 3 and 5 min and rapidly returned to base line. A short glucose infusion of 300 mg/min decreased the rapid insulin response to a second glucose pulse (- 58%), but after a longer infusion (20 hr) the acute insulin response to a third pulse was restored to normal. Stopping the infusion was followed by return of glucose and insulin levels to prestudy base line within 1 hr, but a fourth glucose pulse was followed by a supernormal acute insulin response (+ 200%). Other observations during these studies showed that a short glucose infusion of either 100 mg/min or 300 mg/min produced a parallel rise in glucose and insulin, but continuation of the infusion for 20 hr was associated with a "paradoxical" fall in glucose and continued rise in insulin. These observations are considered incompatible with a simple linear model often used to describe the relation between plasma glucose and serum insulin. Instead, a two pool system-one for acute insulin release, and the other a time-dependent compartment for long term insulin responses-is suggested.

The Role of Cyclic AMP in the Control of Carbohydrate Metabolism

Abstract: Cyclic AMP plays an important role in the regulation of metabolism generally. Emphasis in the present review has been placed on carbohydrate metabolism, but lipid metabolism has also been discussed to some extent. The chief role of cyclic AMP in several tissues seems to be to facilitate or promote the mobilization of glucose and fatty acid reserves. In the liver, glucagon and the catecholamines cause an increase in the intracellular level of cyclic AMPby stimulating adenyl cyclase. This increase in the level of .cyclic AMP leads to a net increase in hepatic glucose production by at least three mechanisms: stimulation of phosphorylase activation, suppression of glycogen synthetase activity, and stimulation of gluconeogenesis. The catecholamines also stimulate adenyl cyclase in muscle and adipose tissue. Among the principal effects of cyclic AMP in these tissues are glycogenolysis in muscle and lipolysis in adipose tissue. Another role of cyclic AMP is to enhance or promote the release of insulin from pancreatic beta cells. Insulin then travels to the liver and adipose tissue to suppress the accumulation of cyclic AMP, and may also antagonize the action of cyclic AMP in muscle. Cyclic AMP is thus seen to mediate the actions of several catabolic hormones as well as promote the release of an anabolic hormone which acts in part by opposing cyclic AMP. Since cyclic AMP is involved in the release as well as several of the actions of insulin, the possible role of cyclic AMP in diabetes has been discussed. Human diabetes mellitus is recognized as the result of a basic genetic defect, the nature of which is undefined. One line of evidence implicates basement membrane thickening as an early event in the patho genesis of diabetes. Further study of the formation and breakdown of the basement membrane may therefore lead to a better understanding of the genetic defect. Whether or not cyclic AMP plays a regulatory role in basement membrane synthesis is presently unknown. Another defect recognizable in prediabetics is faulty insulin release in response to glucose infusion. This could be secondary to basement membrane thickening, but there is also evidence that the cyclic AMP mechanism may be defective. At another level, the role of cyclic AMP is more obvious: insulin deficiency leaves unopposed the actions of hormones which stimulate the production of cyclic AMP, thereby contributing to the glucose plethora and ketosis so often seen in the later stages of the disease.

Effects of secretin, pancreozymin, or gastrin on the response of the endocrine pancreas to administration of glucose or arginine in man

Abstract: Intravenous administration of porcine secretin or pancreozymin or synthetic human gastrin II resulted in raised increments in serum immunoreactive insulin during intravenous infusion of glucose in normal man. Enhancement of serum immunoreactive insulin by each hormone was associated with accelerated disposal of glucose. In response to prolonged intravenous infusion of arginine with pancreozymin there was a maintained rise in immunoreactive insulin and glucagon-like immunoreactivity in the blood. These effects of pancreozymin and arginine were not reproduced with secretin and arginine, and may have been due to the stimulation of glucagon secretion together with insulin by pancreozymin. Enteric infusion of hydrochloric acid, or stimulation of gastric acid secretion by betazole, presumed to cause release of endogenous secretin, led to enhancement of insulin secretion during intravenous infusion of glucose. Enteric infusion of arginine, presumed to cause release of endogenous pancreozymin, led to a rise in serum immunoreactive insulin not attributable to effects of circulating glucose and amino acids. It is concluded that secretin and pancreozymin released in response to physiological stimuli contribute to stimulation of the endocrine pancreas after ingestion of food.

Streptozotocin Diabetes in the Mouse and Guinea Pig

Abstract: A single injection of streptozotocin into mice produced an extensive necrosis of the beta cells resulting in permanent diabetes. The histological changes in the islets were similar to those described after the injection of alloxan. The regenerative capacity of beta cells which survived the cytotoxic injury was limited. Hypoglycemia induced by an injection of insulin or hyperglycemia induced by glucose injections sensitized the beta cells to streptozotocin. In contrast, injection of insulin antibody effectively protected the beta cells from the cytotoxic injury. Streptozotocin caused widespread necrosis of the beta cells of the guinea pig and the obese hyperglycemic mouse. Both these species had proven resistant to the diabetogenic effect of alloxan. Diabetic guinea pigs were observed for eight months, without reversion of the diabetic syndrome.

Some effects of anaesthesia and surgery on carbohydrate and fat metabolism

Abstract: SUMMARY The effects of emotional stress, nitrous oxide and halothane anaesthesia, a 1-minute period of hypoxia, and surgery, on the blood sugar, plasma free fatty acids (FFA) and insulin were investigated. The emotional stress of being brought to the operating theatre and the stress of surgery seem to be more important than anaesthesia in causing a rise in blood sugar and plasma FFA. There was a corresponding fall in levels of plasma insulin. The infusion of Phentolamine in two patients did not prevent the failure of insulin response to injected glucose during surgery. The clinical significance of this temporary state of glucose intolerance is discussed.

Circadian variations of blood sugar and plasma insulin levels in man.

Abstract: Blood sugar, plasma insulin, non-esterified fatty acids (NEFA), plasma cortisol, and urinary catecholamines were measured for 24 h in seven normal subjects receiving a standard diet. During the night, blood sugar and plasma insulin remained low, NEFA decreased progressively, and the excretion of catecholamines diminished. During the day, the insulin response appeared particularly important after the morning meal. This last observation was also made when normal subjects were given three identical meals at intervals of four and a half hours. Under these conditions, the postprandial elevations of blood sugar were not statistically different, but the plasma insulin rose significantly higher after the morning meal. These observations may be explained by the existence of a periodicity which would regulate the insulin secretion. It is also possible that the insulin liberated postprandially conserves a certain activity at the moment of the next meal, and still intervenes in the maintaining of blood sugar homeostasis. Later in the day, however, blood sugar homeostasis would necessitate a new synthesis of insulin, which would explain the delayed plasma insulin response to the evening meal.

Stimulation of insulin secretion by infusion of free fatty acids.

Abstract: The acute elevation of plasma free fatty acid (FFA) levels by direct infusion of sodium oleate into the plasma of conscious dogs was accompanied by the rapid onset of a 2- to 12-fold increase in plasma immunoreactive insulin, and, subsequently, a marked fall in plasma glucose, even in dogs receiving intravenous glucose throughout the infusion. The magnitude of both the insulin and glucose responses correlated with the mean FFA level during infusion. A large increase in plasma insulin and fall in glucose also occurred when glycerol was infused with oleate in order to simulate endogenous lipolysis more closely. Insulin levels in pancreaticoduodenal vein blood rose markedly during oleate infusion, while plasma ketone levels rose only slightly. In contrast to the effects of oleate infusion, elevation of plasma FFA to correspondingly high levels by triolein ingestion and intravenous heparin produced only small increases in plasma insulin, which did not correlate well with the FFA level reached, and small increases in plasma glucose. The results indicate that under certain conditions elevated FFA levels may be a potent stimulus of insulin secretion. This response is modified under other conditions such as during chylomicron removal under the influence of heparin. This effect may play a role in the regulation of lipolysis and ketone formation, but determination of the exact mechanism of FFA stimulation of the pancreas and its physiological significance will require further investigation.

Effects of ventricular pressure development and palmitate on glucose transport

Abstract: NEELY, J. R., R. H. BOWMAN, AND H. E. MORGAN. E$ects of ventricular~ressure development andpalmitate onglucose transport. Am.J. Physiol. 2 16(4) : 804-8 I 1. 1969.-The effect of ventricular pressure development and exogenous palmitate on glucose transport was studied in the isolated rat heart. when glucose was the only exogenous substrate provided, increased ventricular pressure development resulted in a threefold increase in the rate of glucose transport and net glycogenolysis. The presence of physiological concentrations of palmitate in the perfusate inhibited the accelerated rate of both glucose transport and glycogenolysis. The conclusion that glucose transport was the step in glucose utilization affected by ventricular pressure development and fatty acids was substantiated by the demonstration that palmitate inhibited the accelerated rate of 3Gmethylglucose transport associated with increased pressure development. Palmitate was also an effective inhibitor when transport was stimulated by insulin, but was ineffective when the process was accelerated by anoxia. Palmitate uptake was accelerated 5070y0 as ventricular pressure development was increased.

Role of free fatty acids in glucose homeostasis.

Abstract: There is considerable evidence that the rate of free fatty acid (FFA) oxidation plays a regulatory role in blood glucose homeostasis. Effects of FFA on glycolysis, gluconeogenesis, and blood glucose levels have been well documented in the rat. Attempts to assess their role in man have not yielded clearcut results; nevertheless, a role is suggested by the association of high plasma levels of FFA with glucose intolerance and insulin insensitivity in several endocrine and nutritional disorders. In addition, it has been shown that the hypoglycemia of individuals with Jamaican vomiting sickness is due to hypoglycin, an agent which inhibits FFA oxidation. Further studies are required to define more precisely the interrelationship between FFA and glucose metabolism in man. Pending such studies, theories which implicate excessive FFA metabolism in the pathogenesis of diabetes cannot be adequately evaluated.

Human Fetal Insulin Metabolism Early in Gestation: Response to Acute Elevation of the Fetal Glucose Concentration and Placental Transfer of Human Insulin-I-131

Abstract: Although insulin has been demonstrated in human fetal pancreas as early as thirteen weeks of gestation, the controls of insulin secretion in the human fetus and the magnitude of placental insulin transfer to the fetus are unknown. In pregnant women, scheduled for therapeutic abortions by abdominal hysterolomy at fifteen to twenty weeks of gestation, the fetal plasma insulin response to glucose infusion and insulin transfer across the placenta were studied as follows: (1) glucose was infused to eight fetuses in situ, and (2) insulin-I-131 was infused continuously for four to six hours to eight pregnant women via peripheral vein. Insulin was measured radioimmunologically and, following the infusion studies, was precipitated quantitatively by a double antibody method. During fasting, no difference was observed between fetal and maternal plasma glucose or in insulin levels. Although glucose administered to the fetus raised the fetal plasma glucose concentration without changing the maternal level, both fetal and maternal plasma insulin concentrations were unchanged at five and ten minutes. Human insulin-I-131 was not transferred across the placenta and no sequestration of insulin-I-131 occurred in the placenta. Early in human gestation the fetal pancreas appears to be the major source of fetal insulin, and the fetal insulin secretion rate may be relatively unresponsive to acute changes in blood glucose concentration. The placenta acts as a barrier to human insulin-I-131 but does not appear to sequester and catabolize insulin-I-131, as was previously demonstrated in human pregnancies at term.

Insulin biosynthesis in the rat: demonstration of two proinsulins

Abstract: Proinsulin, a single-chain precursor of insulin, has been detected in biosynthetic studies in vitro,1-4 and in crystalline preparations of insulin from several species.1, 5-7 It appears that proinsulin normally serves neither as a major storage nor secretory form of the hormone.8 Its primary functions seems to be to facilitate the efficient formation of the disulfide bonds of insulin.9 Although several species of fish have two insulins differing slightly in primary structure,10-12 the rat is the only mammal where this is known to be the case.13, 14 As the two rat insulins are nonallelic14 and presumably coded by two distinct genes, a separate proinsulin would be expected to precede each insulin. We have demonstrated the biosynthesis of both insulins15 and of a proinsulin corresponding to each in isolated islets of Langerhans, and have detected probable intermediates in the conversion of these proinsulins to insulin. Labeled peptide material corresponding to the free connecting segment of proinsulin (C-peptide) was detected in insulin-containing fractions isolated from incubated rat islets. It was noted that islets incubated in vitro secreted small amounts of newly synthesized proinsulin as well as the two insulins and essentially equivalent amounts of C-peptide. Increasing the glucose content of the medium selectively enhanced the incorporation of radioactivity into proinsulin and insulin and also seemed to increase the relative proportion of labeled proinsulin appearing in the medium.

Feeding and self-stimulation*

Abstract: Electrical stimulation of the lateral hypothalamus has effects that are strikingly similar to the effects of an appetizing morsel of food. Both elicit eating, and both are rewarding to a food-deprived animal. If the animal is overfed, both decrease in reward value and may cause aversion. The present paper reviews and previews work from our laboratory investigating the relationship between hypothalamic reward and feeding. Before beginning we shall briefly review some of the earlier studies that are particularly relevant. Stimulation of the lateral hypothalamus is extremely rewarding to the recipient animal (Olds, 1962). A rat will press a self-stimulation lever 3,000 times an hour for hours at a time. The same stimulus turned on continuously for a minute or two elicits voracious feeding (Margules & Olds, 1962; Hoebel & Teitelbaum, 1962; Wilkinson & Peele, 1962). FIGURE 1 illustrates that self-stimulation and feeding can be elicited interchangeably in the same experimental session (Hoebel, 1962). Such a close correspondence suggested that the reward of self-stimulation might be involved in the normal rewards of eating. It was also possible, however, that the effect was just a coincidence due to adjacent, but unrelated, neural systems. If feeding and self-stimulation are actually related, then experimental manipulations that affect feeding should also affect self-stimulation. Margules & Olds (1962) and Wilkinson & Peele (1962) reported that food deprivation augmented lateral hypothalamic self-stimulation. If, instead of being deprived, the animal was tube-fed, then self-stimulation decreased (Hoebel & Teitelbaum, 1962). Thus there was a direct interaction between feeding and hypothalamic self-stimulation. Satiety was coincident with decreased hypothalamic reward, When the satiety mechanism was experimentally damaged by ventromedial hypothalamic lesions which produced hyperphagia, self-stimulation increased to a rate as fast or faster than it was before tube-feeding. This result is depicted in the upper left-hand quadrant of FrcuRE 2 which summarizes our early findings. Stimulation of the same ventromedial region in the intact animal stopped both feeding and self-stimulation. This was consistent with the other results shown in FIGURE 2, but inconclusive in itself because medial stimulation causes aversion and might have distracted the animal. The crucial experiment was ventromedial hypothalamic depression. Ventromedial destruction by electrolysis, electrocauterization, or “reversible lesions” made by local application of procaine each augmented self-stimulation and feeding. These treatments sometimes irritate surrounding tissue (Reynolds, 1965), but their effect on behavior in our experiments was the result of ventromedial depression, not irritation to the neighboring lateral region. This conclusion follows from the observation that any of the three lesion techniques applied to the ventromedial hypothalamus increased behavior, whereas the same techniques applied to the lateral hypothalamus decreased the behavior (Epstein, 1960a; Hoebel, 1962 & 1965). Valenstein and colleagues

Sympathetic Regulation of Insulin Secretion: Its Relation to Diabetes Mellitus

Abstract: This review summarizes evidence showing inhibition of insulin release by epinephrine and norepinephrine. The receptor theory for catecholamine action is discussed and the inhibition shown to be mediated by α-adrenergic receptor stimulation; β-adrenergic receptors are also described which stimulate insulin release, indicating a unique dual receptor system in the pancreatic islet. The possible physiologic importance of these findings is suggested in a discussion of the carbohydrate intolerance found in patients with pheochromocytoma and during severe hypothermia in children. A possible relation of the inhibition of insulin release and the increased fatty acid mobilization caused by catecholamines to exacerbations of the diabetic syndrome is examined. It is postulated that the catecholamine release which is stimulated by volume depletion, infection, or stress may be an important "reversible" factor in some patients with diabetic ketoacidosis.

Immunoreactive insulin, glucose tolerance, and carbohydrate inducibility in types II, 3, IV, and V hyperlipoproteinemia.

Abstract: The elevation of plasma glycerides by a high carbohydrate diet (carbohydrate induction) has been systematically correlated with glucose tolerance, insulin output and ponderal index in normals and in patients with different types of hyperlipoproteinemia. Carbohydrate inducibility (ΔTG) was similar in normals and patients with Type II hyperlipoproteinemia. Delta TG was nearly always much greater than normal in Type III, and was quite heterogeneous in type IV. The scatter in ΔTG values in Type V patients was extremely great. The basal triglyceride and ΔTG were positively correlated only in Type IV. Abnormal glucose tolerance was present in approximately one third of Types II and III, one half of Type IV and 80 per cent of Type V patients. Hyperinsulinemia was present in most Type V patients, while a majority of Type II and III patients had relatively normal insulin levels. Approximately one third each of the Type IV patients had low, normal, and abnormally high insulin levels. Increasing insulin and insulinogenic indices were correlated with increased ATG in the normal, but not in any of the patient groups. In the specific groups of hyperglyceridemic patients in this study, plasma insulin levels did not appear to be a primary determinant of the degree of carbohydrate induction.

Immunoassayable insulin content of subcellular fractions of rat islets.

Abstract: Islets of Langerhans were isolated from rat islets by a modification of the collagenase digestion procedure. The islets were fractionated by centrifugation techniques and the presence of an enriched insulin secretion granule fraction was shown as well as the quantitative distribution of insulin in other fractions. The content of insulin relative to other proteins in individual fractions was estimated. Current literature on insulin content of islets and pancreas was discussed with respect to these results. (Endocrinology 85: 218, 1969)