Showing papers on "Insulin published in 1981"

The Effect of Insulin on the Disposal of Intravenous Glucose: Results from Indirect Calorimetry and Hepatic and Femoral Venous Catheterization

Abstract: The effect of insulin on the disposal of intravenous glucose was examined employing the euglycemic insulin clamp technique in 24 normal subjects. When the plasma insulin concentration was raised by approximately 100 μU/ml, total glucose metabolism rose to 6.63 ± 0.38 mg/kg · min. Basal splanchnic (hepatic venous catheter technique) glucose production, 2.00 increased only slightly. These results suggest that the ability of higher doses of insulin to further stimulate glucose metabolism is primarily the result of increased glucose storage by peripheral tissues, most likely muscle. 0.15 ± mg/kg · min, reverted to a small net glucose uptake which averaged 0.33 mg/kg · min over the ensuing 2 h. This represented only 5% of the total glucose metabolized. In contrast, leg (femoral venous catheterization) glucose uptake rose from 1.18 ± 0.14 to 8.40 ± 1.06 mg/kg of leg wt. per min. If all muscles in the body respond similarly to those in the leg, muscle would account for 85% of the total glucose metabolism. To determine the relative contributions of glucose oxidation versus glucose storage by peripheral tissues following hyperinsulinemia, we performed euglycemic insulin clamp studies in combination with indirect calorimetry. Basal glucose oxidation, 1.21 ± 0.10 mg/kg min, rose to 2.28 ± 0.16 (P

Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose.

Abstract: The quantitative contributions of pancreatic responsiveness and insulin sensitivity to glucose tolerance were measured using the "minimal modeling technique" in 18 lean and obese subjects (88-206% ideal body wt). The individual contributions of insulin secretion and action were measured by interpreting the dynamics of plasma glucose and insulin during the intravenous glucose tolerance test in terms of two mathematical models. One, the insulin kinetics model, yields parameters of first-phase (phi 1) and second-phase (phi 2) responsivity of the beta-cells to glucose. The other glucose kinetics model yields the insulin sensitivity parameters, SI. Lean and obese subjects were subdivided into good (KG greater than 1.5) and lower (KG less than 1.5) glucose tolerance groups. The etiology of lower glucose tolerance was entirely different in lean and obese subjects. Lean, lower tolerance was related to pancreatic insufficiency (phi 2 77% lower than in good tolerance controls [P less than 0.03]), but insulin sensitivity was normal (P greater than 0.5). In contrast, obese lower tolerance was entirely due to insulin resistance (SI diminished 60% [P less than 0.01]); pancreatic responsiveness was not different from lean, good tolerance controls (phi 1: P greater than 0.06; phi 2: P greater than 0.40). Subjects (regardless of weight) could be segregated into good and lower tolerance by the product of second-phase beta-cell responsivity and insulin sensitivity (phi 2 . SI). Thus, these two factors were primarily responsible for overall determination of glucose tolerance. The effect of phi 1 was to modulate the KG value within those groups whose overall tolerance was determined by phi 2 . SI. This phi 1 modulating influence was more pronounced among insulin sensitive (phi 1 vs. KG, r = 0.79) than insulin resistant (obese, low tolerance; phi 1 vs. KG, r = 0.91) subjects. This study demonstrates the feasibility of the minimal model technique to determine the etiology of impaired glucose tolerance.

Effect of Insulin and Glucose Infusions on Sympathetic Nervous System Activity in Normal Man

Abstract: Recent studies indicate a link between carbohydrate intake and the functional state of the sympathetic nervous system. Fasting or carbohydrate restriction decreases sympathetic activity, while glucose ingestion or dietary supplementation with sucrose increases sympathetic nerve activity. To examine the potential contributions of hyperglycemia and hyperinsulinemia to sympathetic stimulation, sympathetic activity was assessed by measurement of plasma norepinephrine (NE) levels and concomitant cardiovascular indices in nonobese young men during glucose and insulin infusions using glucose clamp techniques. In the insulin infusion studies (euglycemic glucose clamp), insulin was administered at 2 mU/kg/min and 5 mU/kg/min for 2 h while blood glucose was maintained at basal levels by a variable rate of glucose infusion. In the hyperglycemic studies, blood glucose was raised 125 mg/dl above basal and maintained at that level for 2h. In response to both insulin infusions, plasma NE rose progressively over the course of the study, increasing 50% with the 2-mU infusion (from mean basal value of 240 ± 34 pg/ml to 360 ± 41 at 150 min, P

Dose-response characteristics for effects of insulin on production and utilization of glucose in man

Abstract: To determine the dose-response characteristics for the effects of insulin on glucose production, glucose utilization, and overall glucose metabolism in normal man, 15 healthy subjects were infused with insulin for 8 h at sequential rates ranging from 0.2 to 5.0 mU.kg-1.min-1; each rate was used for 2 h. Glucose production and utilization were measured isotopically ([3-3H]glucose). Tissue insulin receptor occupancy was estimated from erythrocyte insulin binding. Glucose production was completely suppressed at plasma insulin concentrations of approximately 60 microunits/ml. Maximal glucose utilization (10-11 mg.kg-1.min-1) occurred at insulin concentrations of 200-700 microunits/ml. The concentration of insulin causing half-maximal glucose utilization (55 + 7 microunits/ml) was significantly greater than that required for half-maximal suppression of glucose production (29 +/- 2 microunits/ml, P less than 0.01). Maximal effects of insulin on glucose production and utilization occurred at plasma insulin concentrations causing 11 and 49% insulin receptor occupancy, respectively. The above dose-response relationships indicate that in man 1) glucose production is more sensitive to changes in plasma insulin concentration than is glucose utilization; 2) both hepatic and peripheral tissues may contain "spare" insulin receptors; and 3) relatively minor changes in plasma insulin concentration or insulin receptor function can cause appreciable alterations in glucose metabolism.

Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus.

Abstract: We have assessed the mechanisms involved in the pathogenesis of the insulin resistance associated with impaired glucose tolerance and Type II diabetes mellitus by exploring, by means of the euglycemic glucose-clamp technique, the in vivo dose-response relationship between serum insulin and the overall rate of glucose disposal in 14 control subjects; 8 subjects with impaired glucose tolerance, and 23 subjects with Type II diabetes. Each subject had at least three studies performed on separate days at insulin infusion rates of 40, 120, 240, 1,200, or 1,800 mU/M2 per min. In the subjects with impaired glucose tolerance, the dose-response curve was shifted to the right (half-maximally effective insulin level 240 vs. 135 microunits/ml for controls), but the maximal rate of glucose disposal remained normal. In patients with Type II diabetes mellitus, the dose-response curve was also shifted to the right, but in addition, there was a posal. This pattern was seen both in the 13 nonobese and the 10 obese diabetic subjects. Among these patients, an inverse linear relationship exists (r = -0.72) so that the higher the fasting glucose level, the lower the maximal glucose disposal rate. Basal rates of hepatic glucose output were 74 +/- 4, 82 +/- 7, 139 +/- 24, and 125 +/- 16 mg/M2 per min for the control subjects, subjects with impaired glucose tolerance, nonobese Type II diabetic subjects, and obese Type II diabetic subjects, respectively. Higher serum insulin levels were required to suppress hepatic glucose output in the subjects with impaired glucose tolerance and Type II diabetics, compared with controls, but hepatic glucose output could be totally suppressed in each study group. We conclude that the mechanisms of insulin resistance in patients with impaired glucose tolerance and in patients with Type II noninsulin-dependent diabetes are complex, and result from heterogeneous causes. (a) In the patients with the mildest disorders of carbohydrate homeostasis (patients with impaired glucose tolerance) the insulin resistance can be accounted for solely on the basis of decreased insulin receptors. (b) In patients with fasting hyperglycemia, insulin resistance is due to both decreased insulin receptors and postreceptor defect in the glucose mechanisms. (c) As the hyperglycemia worsens, the postreceptor defect in peripheral glucose disposal emerges and progressively increases. And (d) no postreceptor defect was detected in any of the patient groups when insulin's ability to suppress hepatic glucose output was measured.

The effect of insulin on renal sodium metabolism. A review with clinical implications.

Abstract: Data are discussed which demonstrate that insulin plays an important role in sodium metabolism. The primary action of insulin on sodium balance is exerted on the kidney. Increases in plasma insulin concentration within the physiological range stimulate sodium reabsorption by the distal nephron segments and this effect is independent of changes in circulating metabolites or other hormones. Several clinical situations are reviewed: sodium wasting in poorly controlled diabetics, natriuresis of starvation, anti-natriuresis of refeeding and hypertension of obesity, in which insulin-mediated changes in sodium balance have been shown to play an important pathophysiological role.

Insulin resistance in uremia.

Abstract: Tissue sensitivity to insulin was examined with the euglycemic insulin clamp technique in 17 chronically uremic and 36 control subjects. The plasma insulin concentration was raised by approximately 100 microU/ml and the plasma glucose concentration was maintained at the basal level with a variable glucose infusion. Under these steady-state conditions of euglycemia, the glucose infusion rate is a measure of the amount of glucose taken up by the entire body. In uremic subjects insulin-mediated glucose metabolism was reduced by 47% compared with controls (3.71 +/- 0.20 vs. 7.38 +/- 0.26 mg/kg . min; P less than 0.001). Basal hepatic glucose production (measured with [3H]-3-glucose) was normal in uremic subjects (2.17 +/- 0.04 mg/kg . min) and suppressed normally by 94 +/- 2% following insulin administration. In six uremic and six control subjects, net splanchnic glucose balance was also measured directly by the hepatic venous catheterization technique. In the postabsorptive state splanchnic glucose production was similar in uremics (1.57 +/- 0.03 mg/kg . min) and controls (1.79 +/- 0.20 mg/kg . min). After 90 min of sustained hyperinsulinemia, splanchnic glucose balance reverted to a net uptake which was similar in uremics (0.42 +/- 0.11 mg/kg . min) and controls (0.53 +/- 0.12 mg/kg . min). In contrast, glucose uptake by the leg was reduced by 60% in the uremic group (21 +/- 1 vs. 52 +/- 8 mumol/min . kg of leg wt; P less than 0.005) and this decrease closely paralleled the decrease in total glucose metabolism by the entire body. These results indicate that: (a) suppression of hepatic glucose production by physiologic hyperinsulinemia is not impaired by uremia, (b) insulin-mediated glucose uptake by the liver is normal in uremic subjects, and (c) tissue insensitivity to insulin is the primary cause of insulin resistance in uremia.

Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man

Abstract: Comparisons were made between the artery and a heated superficial hand vein (HSHV) for the measurements of amino acids, lactate, glycerol, free fatty acids, insulin and glucagon and the measurements of glucose and alanine kinetics in man. Normal subjects (n = 8) were studied after an overnight fast (12–14 hr). U-14C-alanine and 3, 3H glucose were administered by a constant infusion and blood was sampled from catheters placed in a radial artery and a superficial dorsal vein of a heated hand (68°C environment), during a control period and a period of a steady state hyperaminoacidemia achieved by a constant infusion of an L-amino acid solution. The blood concentrations of all substrates and hormones measured and the concentrations of cold and radioactive glucose and alanine were comparable in the two vessels during both study periods. In contrast, measurements obtained in a deep forearm vein (DV) showed the concentrations of plasma glucose to be lower (3% in the control period and 5% during the experimental period) and those of plasma alanine to be higher (13% and 5% during control and experimental periods respectively) than the artery or the HSHV. The difference in glucose specific activity between the artery or the HSHV and the DV were however slight but non-significant, while plasma alanine specific activity was significantly lower in the DV as compared to the artery or the HSHV (32% in the control period versus 14% in the experimental period) suggesting a process of exchange of alanine and glucose occuring during the transit of blood across the forearm. As a result blood samples obtained from a DV will overestimate the derived total body glucose and alanine turnover rates. Thus the heated superficial hand vein can adequately replace the artery for the measurements of whole blood amino acids, lactate and glycerol and for plasma FFA, insulin and glucagon; its use can obviate the risks associated with arterial catheterization and can be a suitable site for the measurements of total body glucose and alanine kinetics in man.

Synergistic interaction between exercise and insulin on peripheral glucose uptake.

Abstract: The interaction of exercise and insulin on glucose metabolism was examined in 10 healthy volunteers. Four study protocols were used: study 1: plasma insulin was raised by approximately 100 microunits/ml while plasma glucose was maintained at basal levels for 2 h (insulin clamp). Study 2: subjects performed 30 min of bicycle exercise at 40% of VO2 max. Study 3: an insulin clamp was performed as per study 1. Following 60 min of sustained hyperinsulinemia, however, subjects exercised for 30 min as per study 2. Study 4: subjects were studied as per study 3 except that catheters were inserted into the femoral artery and vein to quantitate leg glucose uptake. During the 60-90 min period of hyperinsulinemia (study 1), glucose uptake averaged 8.73 +/- 0.10 mg/kg per min. With exercise alone (study 2), the increment in peripheral glucose uptake was 1.43 +/- 0.30 mg/kg per min. When hyperinsulinemia and exercise were combined (study 3), glucose uptake averaged 15.06 +/- 0.98 mg/kg per min (P less than 0.01) and this was significantly (P less than 0.001) greater than the sum of glucose uptake when exercise and the insulin clamp were performed separately. The magnitude of rise in glucose uptake correlated closely with the increase in leg blood flow (r = 0.935, P less than 0.001), suggesting that the synergism is the result of increased blood flow and increased capillary surface area to exercising muscle. More than 85% of total body glucose metabolism during studies 1 and 3 was accounted for by skeletal muscle uptake. These results demonstrate that (a) insulin and exercise act synergistically to enhance glucose disposal in man, and (b) muscle is the primary tissue responsible for the increase in glucose metabolism following hyperinsulinemia and exercise.

Abnormal plasma glucose and insulin responses in heterozygous lean (ob/+) mice.

Abstract: To investigate the effect of the ob gene in the heterozygous condition, plasma glucose and insulin responses of adult heterozygous lean (ob/+) mice were compared with mice of the homozygous lean (+/+) and homozygous obese (ob/ob) genotypes. The ob/+ mice consumed 24% more food than +/+ mice although body weights were similar. Plasma glucose and insulin concentrations were respectively 16% and 176% higher in ob/+ mice than +/+ mice in the freely fed state, and 44% and 88% higher during glucose tolerance tests. In 24 hour fasted ob/+ mice, plasma glucose concentrations were 23% higher than +/+ mice but plasma insulin concentrations were not significantly different. Arginine produced a greater insulin response (172%) and a greater fall in glycaemia (200%) in ob/+ mice. A significant difference in the hypoglycaemic effect of insulin in ob/+ and +/+ mice was not observed. These results demonstrate an effect of the ob gene on glucose homeostasis in heterozygous lean (ob/+) mice. The abnormalities were qualitatively similar but considerably less severe than those in ob/ob mice, suggesting that ob/+ mice might prove useful to study factors predisposing to inappropriate hyperglycaemia.

Insulin synthesis in a clonal cell line of simian virus 40-transformed hamster pancreatic beta cells

Abstract: A clonal hamster beta cell line (HIT) was established by simian virus 40 transformation of Syrian hamster pancreatic islet cells. Cytoplasmic insulin was detected in all cells by indirect fluorescent antibody staining, and membrane-bound secretory granules were observed ultrastructurally. Acidified-ethanol extracts of HIT cell cultures contained hamster insulin as determined by radioimmunoassay, radioreceptor assay, and bioassay. One subclone at passage 39 contained 2.6 micrograms of insulin per mg of cell protein. [3H]Leucine-labeled HIT insulin and proinsulin were identical to islet-derived proteins when compared by NaDodSO4/polyacrylamide gel electrophoresis of immunoprecipitates. HIT cell insulin secretion was stimulated by glucose, glucagon, and 3-isobutyl-1-methylxanthine. Insulin secretion at optimal glucose concentration (7.5 mM) was 2.4 milliunits per 10(6) cells per hr. Somatostatin and dexamethasone markedly inhibited HIT insulin secretion. The HIT cell line represents a unique in vitro system for studying beta cell metabolism and insulin biosynthesis.

Glucose Intolerance and Aging

Abstract: Glucose tolerance is known to decrease with advancing age. This decline begins in the third or fourth decade of life and is progressive throughout the entire adult life span. The primary cause of this age-related impairment in glucose metabolism results from tissue unresponsiveness to insulin. The plasma insulin response to glucose shows little change with age. Several factors, including decreased physical activity and decreased lean body mass, probably contribute to the insulin resistance. The aging process per se, however, appears to have its own deleterious effect on tissue sensitivity to insulin.

Assessment of Insulin Resistance with the Insulin Suppression Test and the Euglycemic Clamp

Abstract: Insulin resistance was quantified with two different methods in 30 subjects with varying degrees of glucose tolerance. One method, the insulin suppression test, is performed by continuously infusing epinephrine, propranolol, insulin, and glucose. Epinephrine and propranolol suppress endogenous insulin release, and steady-state plasma levels of exogenous insulin and glucose are reached in all individuals. Because the steady-state insulin level is the same in all subjects, the height of the steady-state plasma glucose level provides a direct estimate of insulin resistance. The other method, the euglycemic clamp technique, produces a steady-state level of exogenous hyperinsulinemia by means of a primed and continuous insulin infusion. Glucose is also infused at a rate sufficient to prevent an insulin-induced fall in glucose concentration, and the amount of glucose required to maintain the basal plasma glucose level provides the estimate of insulin resistance. The results indicated that estimates of insulin resistance generated by the two methods were highly correlated (r = 0.93). Furthermore, both methods of assessing insulin resistance indicated that the greater the degree of glucose intolerance, the more severe the insulin resistance. These results serve to further emphasize the importance of insulin resistance in the pathogenesis of hyperglycemia in type II diabetes.

Responses of Neonatal Rat Islets to Streptozotocin: Limited B-Cell Regeneration and Hyperglycemia

Abstract: Streptozotocin (SZ) was given to 2-day-old neonatal rats, and, during their subsequent development, the interrelationships between plasma glucose, plasma insulin, pancreatic islet morphology, and hormone content were examined. At 4 days of age, a peak of hyperglycemia was observed (SZ, 349 ± 8 mg/dl versus control (C), 127 ± 2) that was associated with a marked reduction of B-cell numbers (SZ, 26.5 ± 2.6% B-cell per islet versus C, 72.8 ± 0.8%). By 10 days of age the SZ animals became normoglycemic with partial recovery of the B-cell number (SZ, 39.6 ± 2.1% versus C, 64.0 ± 2.6%). By 6 weeks hyperglycemia returned (SZ, 345 ± 5.2 mg/dl versus C, 171 ± 6.2) with B-cell number of the SZ being 72% of the C (SZ, 48.8 ± 2.4% versus C, 67.5 ± 1.5%). This hyperglycemia and reduced B-cell number persisted to at least 13 wk age. Despite a marked reduction of pancreatic insulin content observed during development, there was little effect upon glucagon or somatostatin content. At 6 wk of age, the plasma insulin concentration was only 30% of C, which suggests an insulin secretory defect beyond that which could be accounted for by the modest B-cell reduction. The present study indicates that even though active regeneration of B-celle occurred after early injury, the capacity for ultimate normalization was limited. The resultant moderate reduction in B-cell number may be associated with a functional defect in glucose-stimulated insulin secretion.

Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells.

Abstract: The role of insulin in the regulation of basal and gonadotropin-releasing hormone (GnRH)-stimulated release of LH and FSH was investigated in vitro using primary cultures of rat anterior pituitary cells from adult ovariectomized rats. Anterior pituitary cells were incubated for 2 days in the presence or absence of insulin in a serum-free medium. At the end of the insulin treatment, the cells were washed and reincubated in the presence or absence of GnRH, and the LH and FSH released into the medium were measured by RIA. Treatment with insulin (1.0 microgram/ml) for 2 days resulted in significant increases in both the basal and the maximal release of LH and FSH, as well as a 3.2- and 6.3-fold decrease in the ED50 values for GnRH in terms of LH and FSH release, respectively. Treatment with increasing concentrations (0.1-10,000 ng/ml) of insulin, led to a dose-dependent increase in the GnRH (3 X 10(-10) M)-stimulated release of both LH and FSH. This effect of insulin was significant (P less than 0.05) at a physiological concentration of 1 ng/ml (24 microU/ml) with an ED50 value of 40 ng/ml. Increasing duration of exposure to insulin resulted in time-dependent increases in the GnRH (3 X 10(-10) M)-stimulated release of LH, becoming significant at 24 h with maximal enhancement observed by 48 h. The effect of insulin was specific; epidermal or fibroblast growth factor did not enhance LH release. The augmenting effect of insulin was not associated with cellular proliferation or an overall change in protein or LH synthesis. Furthermore, the effect of insulin was independent of the ambient glucose concentration. Insulin was, however, without effect on gonadotrophs cultured in a serum-supplemented medium. Our findings suggest that the gonadotroph constitutes a target cell of insulin and that insulin may act directly on the anterior pituitary in the regulation of gonadotropin release.

Lilly Lecture 1980: Insulin Resistance and Insulin Action: An In Vitro and In Vivo Perspective

Abstract: Insulin is produced in the pancreatic B-cell as the primary biosynthetic product pre-proinsulin. This peptide is rapidly converted to proinsulin (MW ~ 9000) which is, in turn, converted to insulin (MW ~ 6000) plus C-peptide (MW ~ 3000) by specific proteolytic steps within the B-cell secretory granule. The normal secretory products are, therefore, insulin, an equimolar amount of C-peptide, and a small amount (~5%) of unconverted proinsulin. After a brief circulation time (t1/2 6-10 min) the hormone interacts with target tissues to exert its biologic effects. One of insulin's major biologic effects is to promote overall glucose metabolism, and abnormalities of this aspect of insulin action can lead to a number of important clinical and pathophysiologic states. Insulin resistance exists when a given, known quantity of insulin produces less than the normal expected biologic effect. Since insulin travels from the B-cell, through the circulation, to the target tissue, events at any one of these loci can influence the ultimate action of the hormone. Therefore, it is useful to categorize insulin resistance according to known etiologic mechanisms, and such a classification is presented in Table 1. Insulin resistance can be due to three general categories of causes: (1) an abnormal B-cell secretory product, (2) circulating insulin antagonists, or (3) a target tissue defect in insulin action. Within each of these categories, subclassifications exist.

DNA synthesis in primary cultures of adult rat hepatocytes in a defined medium: effects of epidermal growth factor, insulin, glucagon, and cyclic-AMP.

Abstract: Epidermal growth factor (EGF) especially in combination with insulin and glucagon, has been shown to stimulate DNA synthesis in liver cells, both in the whole animal and in cell cultures. As a further development we have found that in primary monolayer cultures of freshly isolated adult rat liver parenchymal cells, in which contamination with nonparenchymal cells was negligible, DNA synthesis was substantially stimulated by these substances. In control cultures, incorporation of [3H]thymidine into DNA and labeling of nuclei in autoradiographs was low. The stimulation by EGF was enhanced by insulin and glucagon, whereas these hormones by themselves exhibited only limited activity. These observations were made in cultures of hepatocytes that were never exposed to serum, even during cell isolation and plating. Hence for stimulation of DNA synthesis under these conditions neither serum factors nor interactions with other types of cells or their products were required. The effects of glucagon were reproduced by substances that elevate intracellular concentration of cyclic-AMP, including cholera toxin, isoproterenol, and methylisobutylxanthine. These various substances, especially EGF, glucagon, or cyclic-AMP, altered the morphological characteristics of the cultures during early stages, promoting cellular spreading and aggregation.

Brief, Irregular Oscillations of Basal Plasma Insulin and Glucose Concentrations in Diabetic Man

Abstract: The basal plasma insulin and glucose concentrations of 12 diet-treated maturity-onset diabetics were measured at minute intervals for 2 h. Brief, irregular oscillations (mean period 8.8 min) in plasma insulin were superimposed on longer term fluctuations (greater than 30 min). Time series analysis demonstrated a synchronous plasma glucose oscillation (mean amplitude 0.03 mmol/L) associated with short insulin cycles. The glucose changes seen in diabetic subjects were similar to the short plasma insulin cycles (less than 10 min) observed in normal subjects. In contrast, the longer plasma insulin cycles (greater than 10 min) of normal subjects were associated with a plasma glucose oscillation that rose before the end of the cycle. The demonstration of insulin oscillations independent of preceding plasma glucose changes in both normal and diabetic subjects suggests a pancreatic oscillating mechanism of "pacemaker". The associated glucose changes may reflect the entrainment, by the insulin cycles, of glucose production or utilization.

Islet Secretion in a New Experimental Model for Non-insulin-dependent Diabetes

Abstract: An animal model of diabetes mellitus has been developed in which neonatal rats are injected with streptozotocin at 2 days of age. After transient hyperglycemia followed by near normal glycemia, these animals develop nonketotic diabetes at about 6 wk of age that does not require insulin treatment. Secretion form the endocrine pancreas of 6-15-wk-old rats was evaluated with the isolated, perfused pancreas technique. Insulin secretion responded very poorly to high perfusate glucose concentrations, but in the presence of theophylline this meager response was enhanced. In contrast, arginine elicited an insulin response comparable to that of the control rats. Isoproterenol stimulated insulin secretion more in the diabetic model than in the controls, and tolbutamide failed to evoke insulin secretion. Glucagon secretion in response to arginine and isoproterenol was similar in both groups, but was suppressed less efficiently be glucose in the model than in controls. Evidence for enhanced basal secretion of somatostatin was also found. Thus, these hyperglycemic rats have a selective defect in glucose-stimulated insulin secretion with preservation of responses to other agents. In addition, abnormalities in the secretion of glucagon and somatostatin have been found.

Pancreatic islet-acinar cell interaction: amylase messenger RNA levels ar determined by insulin

Abstract: Pancreatic amylase messenger RNA progressively decreases in rats rendered diabetic with streptozotocin. Insulin reverses this effect, inducing a selective decrease in amylase messenger RNA in the pancreas. Parotid amylase messenger RNA is not significantly affected by either diabetes or insulin.

Synergistic Interactions among Antiinsulin Hormones in the Pathogenesis of Stress Hyperglycemia in Humans

Abstract: We infused epinephrine, glucagon, and cortisol in combination into health y overnight-fasted subjects in doses designed to simulate changes in severe stress. Whenall three hormones were infused simultaneously, glucose levels rose above 200 mg/dl in spite of a 100–200% increase in plasma insulin. In contrast, infusion of each hormone individually produced eithera mild (<120 mg/dl) or a transient elevation in the plasma glucoseconcentration. With the combined hormone infusion,the increment in plasmaglucose was 3-fold greater than the sum of the responses to the individual hormones (< 0.001). The marked hyperglycemia in this setting is a resultof ongoing glucose overproduction which is stimulated by epinephrine and glucagon and sustained by cortisol. Furthermore, epinephrine(and possibly cortisol) inhibited glucose disposal despite concomitant hyperinsulinemia. In contrast to their effects on glucoseregulation, the simultaneous infusion of epinephrine, glucagon, and cortisol failed to cause hyperketonemia. W...

A method for the simultaneous measurement of insulin release and B cell membrane potential in single mouse islets of Langerhans.

Abstract: A method has been developed for the simultaneous measurement of insulin release and electrical activity in single micro-dissected mouse islets of Langerhans. The effects of D-glucose have been studied in individual islets. Each islet was exposed to 0, 5.6, 11.1, 16.7, 22.2, 27.8 and 33.3 mmol/l glucose in a stepwise fashion. The minimum glucose concentration required to elicit spike activity is lower than that required to stimulate insulin release above basal levels and the maximum spike frequency occurs at a lower glucose concentration than does maximum insulin release. Following a reduction in glucose from 27.8 (or 33.3) to 5.6 mmol/l, membrane potentials returned to resting values within 2 min whereas insulin returned to basal values after 20 min. Increasing glucose from 5.6 to 27.8 mmol/l induced spike activity within 10 s; the insulin response was detected within 40 s. Thus, it is possible to use the single mouse islet for simultaneous measurements of insulin release and electrical activity.

Relationship Between Insulin Resistance, Insulin Secretion, Very Low Density Lipoprotein Kinetics, and Plasma Triglyceride Levels in Normotriglyceridemic Man

Abstract: We have previously postulated that resistance to insulin-mediated glucose uptake was the basic metabolic abnormality in patients with endogenous hypertriglyceridemia. In this situation, glucose tolerance would tend to deteriorate, and could only be maintained by the increased secretion of insulin. Although the ensuing hyperinsulinemia might prevent the development of glucose intolerance, we suggested that it would also lead to increased hepatic very low density (VLDL) triglyceride (TG) synthesis and secretion. In the current study we have quantified these four metabolic variables in 16 nonobese human subjects with plasma TG concentrations insulin response to food VLDL-TG secretion rate plasma TG concentration. These data indicate that nonobese subjects with normal TG levels have the same relationship between degree of insulin sensitivity, insulin response to food, VLDL-TG secretion, and TG concentration previously described in patients with endogenous hypertriglyceridemia.

Extrarenal potassium homeostasis

Abstract: Normal potassium homeostasis is regulated by both renal and extrarenal mechanisms. Although chronic potassium balance is primarily regulated by the kidneys, acute potassium tolerance is largely determined by extrarenal tissues. During the first 4-6 h following an acute potassium load, only about 50% of the potassium is excreted by the kidneys. Of the remaining 50% that is retained, over 80% is translocated into cells, and this provides the primary defense against hyperkalemia. Potassium uptake by both liver and muscle and intestinal secretion of potassium are the most important mechanisms of extrarenal potassium disposal. Several hormones, including insulin and epinephrine, have been shown to play an important role in the maintenance of normal extrarenal potassium metabolism. These hormones function by enhancing potassium uptake by liver and muscle. There is also evidence that aldosterone is necessary in the maintenance of normal extrarenal potassium tolerance. Although the major extrarenal site of action of aldosterone has not yet been clearly defined, gastrointestinal potassium secretion and muscle transport of potassium are both affected by the hormone. Evidence exists that glucocorticoids may also have an effect on extrarenal potassium homeostasis. In addition to this hormonal regulation, cellular shifts of potassium are influenced by changes in acid-base balance. Extrarenal potassium tolerance is impaired in chronic renal insufficiency. These uremia-related changes are discussed in the context of our present understanding of normal extrarenal potassium metabolism.