Showing papers on "Insulin published in 1973"

The sorbitol pathway and the complications of diabetes.

Abstract: SINCE the introduction of insulin therapy 50 years ago, ketoacidosis and infections are no longer the main problems in the care of diabetic patients. Today, the diabetic patient faces the developme...

The glucose-alanine cycle.

Abstract: Alanine is quantitatively the primary amino acid released by muscle and extracted by the splanchnic bed in postabsorptive as well as prolonged fasted man. The hepatic capacity for conversion of alanine to glucose exceeds that of all other amino acids. Insulin inhibits gluconeogenesis by reducing hepatic alanine uptake. In contrast, in diabetes, an increase in hepatic alanine extraction is observed in the face of diminished circulating substrate. In prolonged fasting, diminished alanine release is the mechanism whereby gluconeogenesis is reduced. In circumstances in which alanine is deficient, such as pregnancy and ketotic hypoglycemia of infancy, fasting hypoglycemia is accentuated. Augmented glucose utilization in exercise and hyperpyruvicemia consequent to inborn enzymatic defects are accompanied by increased circulating levels of alanine. These data thus suggest the existence of a glucose-alanine cycle in which alanine is formed peripherally by transamination of glucose-derived pyruvate and transported to the liver where its carbon skeleton is reconverted to glucose. The rate of recycling of glucose carbon skeletons in this pathway appears to occur at approximately 50% of that observed for the Cori (lactate) cycle.

Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect.

Abstract: Despite excessive glucagon responses to infusion of arginine, plasma glucagon did not rise in six juvenile-type diabetics during severe insulin-induced hypoglycemia, whereas glucagon in the controls rose significantly. Thus in diabetics pancreatic alpha cells are insensitive to glucose even in the presence of large amounts of circulating insulin. An intrinsic defect common to both alpha and beta pancreatic cells-failure to recognize (or respond to) plasma glucose fluctuations-may be operative in juvenile diabetes.

A simple method for the determination of serum free insulin levels in insulin-treated patients.

Abstract: A method for the determination of free, active insulin in the sera of insulin-treated diabetics is described. This involved radioimmunoassay after extraction of free insulin with polyethylene glycol. Recovery tests with cold insulin showed 73 per cent recovery of free insulin and no recovery of bound insulin. The fasting free insulin levels were slightly lower in the patients than in normal persons; exceptions were some patients with complications expected to cause insulin resistance at the peripheral tissue level. Free insulin levels did not correlate with total insulin levels, antibody titers, insulin requirements or conditions of insulin treatment. A very slight increase of insulin was observed after glucose loading in insulin-treated patients, but a marked increase of the free insulin level followed by an exaggerated increase in the total insulin level was observed in a patient with the insulin autoimmune syndrome. The diurnal changes of the free insulin suggested the dynamic states of this fraction and its usefulness for determining control of diabetes with insulin.

The influence of genetic background on the expression of the obese (ob) gene in the mouse

Abstract: A new congenic strain of obese mice, C57BK/KsJ-ob, has been developed for comparison with the C57BL/6J-ob congenic strain While obese mice of both strains are characterized by obesity, hyperphagia, and hyperglycemia, the C57BL/Ks obese mice have severe diabetes, marked hyperglycemia, temporarily elevated plasma insulin concentrations, and typical degenerative changes in the islets of Langerhans In contrast, the C57BL/6J obese mice have mild hyperglycemia and marked hyperinsulinemia coupled with hypertrophy and hyperplasia of the islets of Langerhans The severe diabetic condition produced by obese (ob) on the C57BL/KsJ background is similar, if not identical, to that produced by the diabetes (db) gene on the same background The metabolic disorder produced by these mutations is associated with the capacity of the islets to respond to an increased demand for insulin The islet response, whether atrophy or hypertrophy, appears to be due to the interaction of the obese and diabetes genes with modifiers in the genetic background rather than the specific consequences of the particular gene The markedly different diabetic syndromes that result when the obese mutation is on different genetic backgrounds emphasize the importance of strict genetic control in studies with obese-hyperglycemic mutants

The origin, hormonal nature, and action of hepatotrophic substances in portal venous blood

Abstract: SUMMARY The origin of hepatotrophic factors in splanchnic venous blood was investigated by modifyingthe portal venous inflow to different parts of the canine liver while leaving the arterial bloodsupply and biliary drainage intactIn one variety of experiment, termed partial transposition, the liver portion perfused with thetotal splanchnic venous blood underwent weight gain and hepatocyte hypertrophy, hyperplasia,and glycogenation compared with the portion perfused with venous blood from thehindquarters, kidneys, and adrenal glands, but the combined weight of the total liver remainedconstant in spite of the rapidly evolving regional disproportions The lobar changes were welldeveloped within one to two months At this time, the hepatic lobes supplied with splanchnicvenous blood had higher concentrations of glucokinase and lower concentrations of cyclic 3 ′,5′-adenosine monophosphate and active phosphorylase than the lobes receiving hindlimb andadrenorenal venous blood, indicating that the biochemical environment of the different liverregions was drastically different by virtue of being under specific hormonal controlThe dissociation was even more dramatically illustrated by dynamic studies in which thedestruction of cyclic 3 ′, 5′-adenosine monophosphate by phosphodiesterase was blocked withaminophylline thereby permitting estimation of the rate of formation of cyclic 3 ′, 5′-adenosinemonophosphate In addition, the modifying effect of tolbutamide-induced endogenous insulinupon exogenously administered glucagon was evaluated by serial determinations of cyclic 3 ′,5′-adenosine monophosphate These investigations with the aminophylline and tolbutamide-glucagon tests demonstrated the anabolic role of insulin and the opposing roles of bothglucagon and epinephrine in contributing to liver homeostasis Epinephrine and glucagoncaused striking increases in cyclic 3′, 5′-adenosine monophosphate, and insulin had theconverse effectAnother type of preparation involving partition of the splanchnic venous blood between theliver portions was termed splanchnic flow division The substances responsible for the hepatichypertrophy, hyperplasia, glycogenation, and weight gain were shown to emanate mainly, ifnot virtually exclusively, from the pancreatic-gastroduodenal-splenic venous drainage Incontrast, intestinal nutritional substrate and hormones from the intestine or adrenal gland werenot profoundly influential in either promoting or preventing the morphologic or glycogenconcentration changes The concentrations of cyclic 3′, 5′-adenosine monophosphate,phosphorylase, and glucokinase in the two sides of the liver did not follow as distinctive apattern as in the partial transposition experiments However, the aminophylline andtolbutamide-glucagon tests revealed the same type of major dissociation of cyclic 3′, 5′-adenosine monophosphate as with the partial transpositions Particularly impressive was theway in which trace doses of tolbutamide-induced endogenous insulin on the side nourished bypancreatic venous blood restrained the cyclic 3′, 5′-adenosine monophosphate response toexogenous glucagon, whereas the other liver fragment which was not so covered by insulinhad completely uninhibited rises in cyclic 3′, 5′-adenosine monophosphateThe conclusion from these experiments is that the hepatotrophic factors previously reportedfrom our laboratories and by other investigators to be in splanchnic venous blood are pancreatichormones and specifically insulin and glucagon Of these, insulin is anabolic and glucagon ismainly catabolic but not exclusively so, since glucagon also has the anabolic effect ofstimulating gluconeogenesis The insulin-glucagon relationship and the interrelationship ofthese hormones to others, such as epinephrine, in the moment to moment regulation of nutrient

Fuels, Hormones, and Liver Metabolism at Term and during the Early Postnatal Period in the Rat

Abstract: The metabolic response to the first fast experienced by all mammals has been studied in the newborn rat. Levels of fuels and hormones have been compared in the fetal and maternal circulations at term. Then, after cesarean section just before the normal time of birth, sequential changes in the same parameters were quantified during the first 16 h of the neonatal period. No caloric intake was permitted, and the newborns were maintained at 37°C. Activities of three key hepatic enzymes involved in glucose production were estimated. Marked differences in maternal and fetal hormones and fuels were observed. Lower levels of glucose, free fatty acids, and glycerol but higher levels of lactate, α-amino nitrogen, alanine, and glutamine were present in the fetus. Pyruvate, glutamate, and ketone bodies were not significantly different. The combination of a strikingly higher fetal immunoreactive insulin and a slightly lower immunoreactive glucagon (pancreatic) resulted in a profound elevation in the insulin-to-glucagon ratio, a finding consistent with an organism in an anabolic state. The rat at birth presents a body composition with respect to fuels available for mobilization and conversion which is dominated by carbohydrate and protein, since little fat is present. However, at birth a transient period of hypoglycemia occurred, associated with a rapid fall in insulin and rise in glucagon, causing reversal of the insulin-to-glucagon relationship toward ratios such as were observed in the mother. After a lag period, hepatic activities of phosphorylase, glucose-6-phosphatase, and phosphoenolpyruvate carboxykinase increased. Concurrent with these enzyme changes, the blood glucose returned to levels at or above those of the fetus. Interestingly, the fall observed in levels of the gluconeogenic precursors, lactate and amino acids, preceded the rise in enzyme activities and restoration of blood glucose. After 4 h, however, hypoglycemia recurred, during a period of decreasing hepatic glycogen content and blood lactate, pyruvate, and glycerol levels but of stable or increasing amino acid concentrations. Hepatic gluconeogenesis in this phase of depleted glycogen stores was insufficient to maintain euglycemia. Substrates derived from fat showed early changes of smaller magnitude. The rise in free fatty acids which occurred was less than twofold the value at birth, though this rise persisted up to 6 h. Whereas glycerol rose transiently, acetoacetate did not change and β-hydroxybutyrate concentration fell. Both ketone bodies showed a marked rise at 16 h. at a time of diminished free fatty acid levels. Plasma growth hormone, though higher in the fetal than the maternal circulation, showed no consistent change during the period of observation. The changes in levels of the endocrine pancreatic hormones at birth were appropriate in time, magnitude, and direction to be implicated as prime regulators of the metabolic response during the neonatal period in the rat.

Comparison of the effects of anoxia and whole heart ischemia on carbohydrate utilization in isolated working rat hearts.

Abstract: The rates of utilization of glycogen and exogenous glucose by hearts perfused at low coronary flows and high perfusate oxygen tension (ischemia) and by hearts perfused at high coronary flows and low perfusate oxygen tension (anoxia) were studied in the isolated, working rat heart. Ischemic tissue had a glycolytic rate that was 25% of the anoxic rate and 50% of the control rate. Inhibition of carbohydrate utilization during ischemia was due to a lower flux through the glycolytic pathway and not to a lower rate of glucose transport or substrate availability. Insulin and elevated perfusate glucose increased glucose transport and caused accumulation of free intracellular glucose, but ischemia still inhibited glucose utilization. Insulin failed to maintain tissue levels of high-energy phosphates or to prevent mechanical failure in ischemic hearts. In the absence of insulin, tissue lactate increased tenfold during 20 minutes of ischemia, although it increased only threefold in anoxic tissue. The increased tissue lactate in ischemic hearts corresponded to the inhibition of glycolysis and to the failure of mechanical performance. Insulin caused a further increase in tissue lactate during ischemia. These findings illustrate several important differences between anoxia and ischemia and suggest that insulin may be more harmful than it is beneficial in severely ischemic tissue.

Interrelationship of islet metabolism, adenosine triphosphate content and insulin release

Abstract: The oxidation of some exogenous substrates and their effects on ATP content and insulin release in mouse pancreatic islets were measured. The ATP concentration of islets incubated without exogenous substrate shows a gradual decrease, which can be prevented by glucose or mannose (20mm) or leucine (2.5mm); d-glyceraldehyde (5mm) is as effective as glucose (5mm); fructose or N-acetylglucosamine (20mm), pyruvate (10mm) and dl-3-hydroxybutyrate (2mm) are less effective; galactose (20mm), acetate (10mm), octanoate (2mm) and succinate (10mm) have no ATP-maintaining ability. Islets oxidize glucose, mannose, glyceraldehyde, leucine and, less readily, N-acetylglucosamine and glucosamine; galactose, however, is poorly metabolized. Mannoheptulose inhibits the oxidation of glucose but not of glyceraldehyde. Insulin release, measured over a 2h incubation, is stimulated by glucose, mannose, leucine, glyceraldehyde or glucosamine but not by fructose or N-acetylglucosamine. The latter, however, potentiates the effects of glucose or glyceraldehyde (5mm) or leucine (2.5mm) on release; the potentiating effects are inhibited by mannoheptulose, which also blocks glucose-, but not glyceraldehyde- or leucine-stimulated release. In the presence of glucose (20mm), metabolic inhibitors depress insulin release and islet ATP content in parallel. However, rates of insulin release and ATP content measured after incubation with various combinations of exogenous substrates do not appear to be correlated. Sulphonylureas stimulate insulin release but decrease islet ATP concentrations. These results provide further evidence of a close association between the metabolic activity of exogenous substrates and their ability to initiate insulin release. Glucoreceptor models are formulated in the light of these observations and discussed.

Insulin-like activity of concanavalin A and wheat germ agglutinin--direct interactions with insulin receptors.

Abstract: Concanavalin A and wheat germ agglutinin are as effective as insulin in enhancing the rate of glucose transport and in inhibiting epinephrine-stimulated lipolysis in isolated adipocytes. These lectins, also like insulin, inhibit basal as well as epinephrine-stimulated adenylate cyclase activity of membranes obtained from homogenates of fat cells. Low concentrations of wheat germ agglutinin enhance the specific binding of insulin to receptors of fat cells and liver membranes. Higher concentrations of this plant lectin, as well as of concanavalin A, competitively displace the binding of insulin to receptors in these tissues. These effects are equally apparent in insulin-binding proteins solubilized from membranes, indicating that the plant lectins interact directly with insulin receptors. All of the effects observed with the plant lectins are reversed by simple sugars that bind specifically to these plant proteins. Agarose derivatives of the plant lectins effectively adsorb solubilized insulin-binding proteins, and these can be eluted with buffers containing specific simple sugars. The possible implications of these findings to certain biological properties (mitogenicity) of these lectins and to the mechanism of action of other growth-promoting substances are considered.

Metabolism of Proinsulin, Insulin, and C-Peptide in the Rat

Abstract: The renal extraction and excretion of bovine proinsulin, insulin, and C-peptide and the contribution of the kidney to their total metabolic clearance rate (MCR) were studied in the rat. Metabolic clearance rates were measured by the constant infusion technique and plasma and urine concentrations of each polypeptide were determined by radioimmunoassay. The MCR of insulin (16.4+/-0.4 ml/min) was significantly greater than that of either proinsulin (6.7+/-0.3 ml/min) or C-peptide (4.6+/-0.2 ml/min). Metabolic clearance rates were independent of plasma levels over a range of steady-state plasma concentrations varying from 1 to 15 ng/ml.In contrast to the differences in their metabolic clearance rates, the renal disposition of the three polypeptides was similar, being characterized by high extraction and very low urinary clearance. The renal arteriovenous difference of proinsulin, insulin, and C-peptide averaged 36, 40, and 44%, respectively, and was linearly related to their arterial concentration between 2 and 25 ng/ml. When glomerular filtration was markedly reduced or stopped by ureteral obstruction, the renal extraction of proinsulin, insulin, and C-peptide was invariably greater than the simultaneously measured extraction of inulin, indicating that these polypeptides are removed from the renal circulation by both glomerular filtration and direct uptake from peritubular capillary blood. The fractional urinary clearance of each polypeptide never exceeded 0.6%, indicating that more than 99% of the amount filtered was sequestered in the kidney. The renal removal of proinsulin and C-peptide from the circulation accounts for 55 and 69% of their metabolic clerance rates, while the renal contribution to the peripheral metabolism of insulin was smaller, averaging 33%. This difference is due to the fact that insulin, but not the other two polypeptides, is metabolized to a significant extent by the liver. These results define the renal handling of proinsulin, insulin, and C-peptide in the rat and indicate that in this species the kidney represents a major site for insulin metabolism and is the main organ responsible for the degradation of proinsulin and C-peptide.

Plasma triglyceride transport kinetics in diabetes mellitus.

Abstract: Plasma endogenous triglyceride transport has been measured in 74 adult patients with different types of diabetes and compared to similar data obtained in 35 healthy normoglyceridemic control subjects. The diabetic material was divided into subgroups by a number of criteria including ketoacidosis, insulin-dependence, relative body weight, control of blood glucose, and severity of hypertriglyceridemia. In ketoacidosis, a marked elevation of plasma triglyceride production rate was the rule, and this probably accounted for the moderate hypertriglyceridemia even though the fractional transport was simultaneously lowered. In uncontrolled but nonketotic juvenile-type diabetes the mean plasma triglyceride turnover rate and concentration were both significantly increased while the fractional turnover was in most cases within normal range. When the disease was brought into good control by insulin the production rate decreased but not completely in line with blood glucose. Patients with adult-onset-type diabetes showed also an increase of triglyceride turnover rate, and the magnitude of hypertriglyceridemia was consistent with this increment so that most patients were “on line” of the enzyme kinetic Michaelis curves extrapolated from the normal material. On the other hand, of nonketotic diabetics with severe hyperglyceridemia (more than 4.0 mM) some had an increased turnover rate, while others were characterized by a normal production rate. Therefore, it is probable that one minor group of diabetics has a true removal defect, while in other forms of diabetes, the hypertriglyceridemia, if present, is primarily due to enhanced hepatic secretion of triglycerides into plasma. The exogenous fat tolerance was tested in 15 uncontrolled diabetics and 10 control subjects with intravenous intralipid emulsion. The fractional disappearance rate was either normal or decreased in diabetes but, when compared at similar basal plasma triglyceride concentration, there was no difference in the elimination of exogenous particulate fat between diabetics and nondiabetics. The different mechanisms of hypertriglyceridemia associated with diabetes are discussed on the basis of the results obtained in this study. In this connection a new concept on the regulation of removal kinetics by plasma triglyceride production rate is suggested.

Diurnal Variation in Glucose Tolerance and in Insulin Secretion in Man

Abstract: The changes in blood glucose and plasma free fatty acid (FFA), insulin, and human growth hormone (HGH) concentrations in response to oral and intravenous glucose and intravenous insulin were measured at 7 a.m. and 7 p.m., on both occasions after a ten hour fast, in thirteen normal males and two juvenile diabetics. Basal concentration of plasma FFA was lower and that of plasma insulin higher in the morning than in the evening. Blood glucose and plasma HGH levels did not differ at these times. In the normal subjects, glucose tolerance was diminished and plasma insulin response was delayed in the evening. The delay was significantly less with intravenous glucose than with oral glucose. When compared with the usually accepted criteria for diagnosis of diabetes mellitus, the normal subjects responded in the evening as mild diabetics. Two juvenile-onset diabetics, who had virtually no increase in plasma insulin concentrations after ingestion or injection of glucose, showed no diurnal variation in glucose tolerance. No diurnal variation was seen in the blood glucose response to intravenously injected insulin or in the plasma clearance rate of insulin; these findings suggest that impairment in glucose tolerance in the evening is due to diminished early insulin response to glucose, rather than to abnormal handling of glucose or insulin. The effect of tolbutamide, phentolamine, and theophylline on the diurnal variation of glucose tolerance was studied. In four subjects, intravenous injection of tolbutamide induced a greater insulin response and a greater fall in the blood glucose concentration in the morning than in the evening. The disappearance rate of intravenously injected glucose and both early and delayed insulin responses to the glucose were enhanced to a much greater degree in the morning than in the evening by the simultaneous intravenous injection of tolbutamide. Intravenous infusion of phentolamine, an alpha-adrenergic blocking agent, in five subjects failed to influence responses to intravenous injection of glucose. Intravenous infusion of theophylline, which inhibits cyclic 3′5′-adenosine monophosphate phosphodiesterase activity, in five subjects potentiated the plasma insulin response to intravenous glucose in the evening but not in the morning; the substance did not influence the disappearance rate of glucose.

Guanosine 3′:5′-Cyclic Monophosphate and the Action of Insulin and Acetylcholine

Abstract: Low concentrations of insulin (120 μunits/ml) and of carbamylcholine (1 μM) increase cyclic GMP content in isolated fat cells by 350%. The maximal amount of cyclic GMP, achieved within 2 min after addition of insulin or carbamylcholine, falls rapidly for insulin and much more slowly for carbamylcholine. 10 pM Acetylcholine can also augment the content of fat-cell cyclic GMP, but by 5 min (37°) the amount falls to that of unstimulated cells. Atropine abolishes the effects of carbamylcholine and acetylcholine but does not modify that of insulin, indicating that the ability of insulin to regulate cyclic GMP levels is not mediated by cholinergic receptors. Insulin and carbamylcholine increase the concentration of cyclic GMP in rat-liver slices by 400%; the effects of both agents occur rapidly and are relatively transient. Insulin does not alter cyclic GMP concentrations in purified human peripheral lymphocytes or in rat-spleen lymphocytes, cells which possess few insulin receptors and which are insensitive to the metabolic effects of the hormone. Carbamylcholine, however, causes a substantial increase in the cyclic GMP content of these lymphocytes. The data support the view that close and reciprocal relationships may exist between the concentrations and actions of cyclic AMP and cyclic GMP, as well as between the enzymes responsible for biosynthesis and degradation of these nucleotides.

Adrenergic Receptors and the Secretion of Glucagon and Insulin from the Isolated, Perfused Canine Pancreas

Abstract: During perfusion with a glucose concentration of 150 mg/100 ml, infusions of l-epinephrine, l-norepinephrine, and d-l-isoproterenol at physiological concentrations of 2 ng/ml for 9 min stimulated secretion of glucagon in a monophasic response pattern, in contrast to the biphasic response normally encountered after glucagon releasing stimuli as previously reported from our laboratory (1971. J. Clin. Invest.50: 2123). Glucagon was stimulated in spite of a glucose concentration which in itself effectively inhibits glucagon release. Release of insulin was strongly inhibited after epinephrine and norepinephrine, and strongly stimulated after isoproterenol. During perfusion with a glucose concentration of 25 mg/100 ml, secretion of glucagon was greatly accentuated by the catechols investigated. Secretion of insulin remained unchanged after epinephrine and norepinephrine, but was stimulated by isoproterenol. The catechol induced glucagon release was suppressed or abolished when the beta-blocking agent propanolol was simultaneously infused at a concentration of 1 muM, while the inhibition of insulin became further accentuated. The catechol induced glucagon release remained unchanged when alpha blockade was performed using either phentolamine (1 muM) or dibenzyline (10 mug/ml), while the inhibition of insulin was converted to a stimulation. Evidence is thus presented that both the alpha cells and the bet cells are under the influence of adrenergic substances, the stimulation of glucagon release being mediated through a beta receptor and the inhibition of insulin release being mediated through an alpha receptor.

Euglycaemic Diabetic Ketoacidosis

Abstract: Of a series of 211 episodes of diabetic metabolic decompensation 37 had severe euglycaemic ketoacidosis (a blood sugar level of less than 300 mg/100 ml and a plasma bicarbonate of 10 mEq/1. or less). All were young insulin-dependent diabetics, only one being previously undiagnosed. Vomiting was a common factor, and in all carbohydrate reduction occurred with continued or increased daily insulin dose. Treatment comprised fluid and electrolyte replacement and large doses of insulin covered by adequate carbohydrate, many receiving 10% dextrose. Alkali was either withheld or given sparingly and the therapy was monitored by serial estimations of plasma bicarbonate. All the patients survived.

Abnormal Pancreatic Alpha-Cell Function in Bacterial Infections

Abstract: To determine the effect of infection on pancreatic alpha-cell function, plasma glucagon was measured in 22 nondiabetic patients hospitalized with bacterial infection. Glucagon averaged 409 ± 129 pg per milliliter(mean ± S.E.M.) in six patients with severe infection and 185 ± 31 pg per milliliter in 11 with moderate infection, values significantly greater than the mean fasting concentration of 75 ± 4 pg per milliliter found in healthy subjects. The elevated value in all groups returned to normal with recovery. Experimental pneumonococcal pneumonia in dogs was also associated with hyperglucagonemia. Hyperglucagonemia induced in alloxan-diabetic dogs by zinc glucagon given in addition to their usual insulin produced hyperglycemia, glycosuria and an increase in urine volume and urea excretion. Thus, in man and in dogs, infection appears to be accompanied by hyperglucagonemia. In diabetic dogs the glucagon elevation can cause worsening of the diabetic state. This effect may explain infection-induced d...

The Glucose Receptor A DEFECTIVE MECHANISM IN DIABETES MELLITUS DISTINCT FROM THE BETA ADRENERGIC RECEPTOR

Abstract: Acute serum insulin responses in 10 normal subjects after rapid intravenous injection of glucose (5 g) or isoproterenol (2 mug) were of similar magnitude and timing (glucose: 431+/-349%; mean Delta3-5' insulin (IRI)+/-SD, per cent basal and isoproterenol: 359+/-216%; mean Delta2-4' IRI+/-SD, per cent basal). To elucidate the relationship of glucose-induced insulin secretion to pancreatic beta adrenergic receptors and the implications of this relationship with regards to abnormal insulin secretion in diabetes mellitus, two questions were studied. (a) To determine whether glucose-induced insulin secretion is dependent upon beta adrenergic activity, the effect of beta adrenergic blockade with intravenous propranolol (0.08 mg/min) upon acute insulin responses to isoproterenol and glucose were compared in normal subjects. (b) To determine whether acute insulin responses to beta adrenergic stimulation were intact in diabetes mellitus, the effect of isoproterenol upon serum insulin levels was studied in diabetic subjects. Beta adrenergic blockade in the normal subjects obliterated acute insulin responses to isoproterenol (before: 361+/-270%, during: - 31+/-15%; n = 6, P < 0.001) but did not significantly affect responses to glucose (before; 311+/-270%; during: 284+/-206%; n = 5). The mean acute insulin response after isoproterenol in the diabetic group was significantly elevated over basal levels (152+/-74%; n = 10, P < 0.001) but the response after glucose was not (- 11+/-11%). These data suggest that insulin responses to glucose in normal subjects are mediated by specific pancreatic glucose receptors which are independent from beta adrenergic receptors and that abnormal glucose-induced insulin secretion in diabetics is due to defects within glucose receptors and not beta adrenergic receptors as has been previously hypothesized.

Relationship between fasting plasma insulin level and resistance to insulin-mediated glucose uptake in normal and diabetic subjects

Abstract: We have previously shown that a significant inverse correlation exists between the height of the plasma insulin concentration and the efficiency of glucose uptake in the fasting state. Subsequently, we devised an infusion technic that provides a more specific measure of cellular resistance to insulin mediated glucose uptake. We have used this technic to study the relationship between fasting plasma insulin level and resistance to insulin mediated glucose uptake in twenty-two patients with normal oral glucose tolerance, fourteen patients with impaired glucose tolerance, and fourteen patients classified as having chemical diabetes mellitus. The results indicate a highly significant positive correlation between the degree of insulin resistance and fasting plasma insulin concentration (r = .69, p

Stimulation of Insulin Secretion by Long-Chain Free Fatty Acids. A DIRECT PANCREATIC EFFECT

Abstract: A continuous-flow centrifuge was used to infuse sodium salts of oleic, linoleic, lauric, or palmitic acid into the pancreatic artery of anesthetized dogs. In these regional perfusion studies there was no increase in FFA levels in the general circulation. Elevation of pancreatic FFA levels produced an immediate increase in pancreatic venous immunoreactive insulin (IRI). After 10 min of FFA infusion. IRI levels declined somewhat from the initial peak response but soon rose again to high levels which were then sustained until the infusion was terminated. All four long-chain FFA tested produced a similar biphasic IRI response. Clearcut increases in IRI were associated with absolute FFA levels (measured in pancreaticoduodenal venous plasma) as low as 0.6-0.8 μeq/ml and with increments over basal levels of as little as 0.4-0.5 μeq/ml. At higher levels of FFA, absolute IRI levels in the pancreatic venous effluent exceeded 1,000 μU/ml in some experiments and 5- to 10-fold increases over basal values were observed. These studies indicate that long-chain FFA, in physiological concentrations, can markedly stimulate insulin secretion by a direct effect on the pancreas. The results lend support to the concept of insulin as a hormone that is importantly involved in regulating the metabolism of all three principal classes of metabolic substrates and whose release is in turn regulated by all of them. The relative importance and precise nature of its physiologic role in the regulation of lipolysis, lipid deposition, and ketone body formation remains to be established.

A comparative study on the metabolism of human insulin and porcine proinsulin in man.

Abstract: SUMMARY 1. The metabolism of unlabelled monocomponent human insulin and porcine proinsulin was studied in ten normal subjects (five males and five females) by using a priming dose-constant-infusion technique. In each subject, the metabolic clearance rate (MCR) was measured at four separate steady-state hormone concentrations averaging 16-21 6 punitslml (insulin) and 4-2-42.8 ng/ml (proinsulin). 2. For insulin the MCR fell progressively from 34 ml kg-' min-' at a mean fasting insulin concentration of 3.8 punitslml to 11.4 ml kg-' min-' at the highest concentration achieved (280 punits/ml); for proinsulin MCR averaged 3.7 ml kg - ' min-' at a mean plasma concentration of 4.2 ng/ml and fell to 2.71 ml kg-' min-' at 10.7 ng/ml, remaining constant thereafter at concentrations up to 71 ng/ml. 3. The half-disappearance time (T+) from the plasma, after the end of the infusion, averaged 4.3 min for insulin and 25.6 min for proinsulin. 4. The apparent distribution space (DS) was similar for both hormones (83 ml/kg of insulin and 98.9 ml/kg of proinsulin). 5. There was a direct correlation between T+ and DS for both hormones. 6. Although the higher MCR of insulin was reflected in its shorter T+, there was, for each hormone, no relationship between MCR and T+. 7. The biological potency of porcine proinsulin, as judged by its effect on plasma glucose, was approximately 5% of that of insulin. 8. The responses of serum growth hormone and cortisol were shown to be directly related to the degree of hypoglycaemia induced.

Influence of an -amylase inhibitor (BAY d 7791) on blood glucose, serum insulin and NEFA in starch loading tests in rats, dogs and man.

Abstract: An a-amylase inhibitor isolated from wheat was used in experiments involving rats, dogs and healthy volunteers. The hyperglycaemia and hyperinsulinaemia resulting from starch loading could be reduced dose dependently by the inhibitor. Its inhibitory effect is specific and limited to α-amylase. In loading tests with cooked starch the effect on blood sugar is markedly diminished.