New aspects of pathogenesis of type II diabetes.
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Blood Glucose↗
Biomedical subjects
M Vranic
Publications and source records attributed to M Vranic.
Portal v peripheral hyperinsulinemia and very low density lipoprotein triglyceride kinetics.
The effect of subcutaneously delivered insulin on the kinetics of rat plasma triglycerides was compared to that of intraperitoneally delivered insulin. The former route delivered insulin primarily extrahepatically and the latter, intraportally. In comparison to the intraperitoneally delivered insulin, the subcutaneously delivered insulin was associated with a higher peripheral serum insulin, lower serum glucose, lower serum FFA, lower serum triglycerides, and similar rate of triglyceride secretion. The activity of adipose tissue lipoprotein lipase was directly related to the serum insulin concentration. The pattern of serum triglycerides and lipoprotein lipase in the rats receiving subcutaneous insulin suggested that their rate of triglyceride removal exceeded that seen in the rats receiving intraperitoneal insulin. These observations indicate that the route of insulin delivery can influence the balance between the hepatic and extrahepatic effects of insulin on triglyceride kinetics.
Adipose Tissue↗
Glucoregulation in alloxan-diabetic dogs.
In order to establish whether a prolonged subnormal secretion of insulin may affect glucoregulation against hypoglycemic stimuli, the level of plasma glucose was decreased in alloxan-diabetic dogs by the infusion of either 50 micrograms/kg . min phlorizin (PHL), ie, reducing the concentration of plasma glucose without hyperinsulinemia; or with 7 mU/kg . min insulin (combined hyperinsulinemia and hypoglycemia). The concentration of glucose, immunoreactive glucagon (IRG), and insulin (IRI) and catecholamines were followed in the plasma. Hepatic glucose production (Ra) and the overall rate of glucose removal from the circulation were calculated by a tracer method. During a 200-minute infusion of PHL plasma glucose fell from 328 +/- 29 to 114 +/- 16 mg/dl, while IRG rose from a mean of 470 +/- 123 to 623 +/- 200 pg/mL, however this increase was significant only in 3 out of 6 dogs. There was no change in the plasma level of epinephrine. Plasma IRI decreased significantly, the IRI/IRG ratio remained low, and Ra did not increase. When the animals were treated with insulin for one week, plasma glucose was restored to normal, while plasma IRI and the IRI/IRG ratio were raised above the normal level. Under these circumstances the infusion of PHL increased plasma IRG significantly from 59 +/- 5 to 110 +/- 32 pg/mL, decreased IRI slightly, and increased Ra by an average of 50 +/- 16%. No measurable change in plasma glucose was observed indicating the restoration of nonhypoglycemic glucoregulation. In diabetic dogs during a 95-minute infusion of insulin, plasma glucose dropped from a mean of 338 +/- 5 to 74 +/- 24 mg/dL.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Hormonal and metabolic responses to intracarotid and intrajugular infusion of beta-endorphin in normal dogs.
The hormonal and metabolic responses of beta-endorphin infused cephalad into the carotid artery, or via the jugular vein, were examined in 10 normal dogs. The intracarotid administration of beta-endorphin resulted in significant increases in plasma glucagon, adrenocorticotropin, and cortisol levels. Hepatic glucose production increased only transiently and there was no significant change in glucose disappearance or plasma glucose concentrations. Infusion of beta-endorphin in the jugular vein gave rise to significant increases in glucagon and cortisol levels and to a transient increase in plasma epinephrine. Although no significant changes in glucose kinetics could be demonstrated, there was a slight transient decrease in plasma glucose concentrations. In conclusion, both intracarotid and intrajugular infusions of beta-endorphin stimulated glucagon secretion independent of circulating catecholamines, and increased cortisol release, probably through activation of the pituitary-adrenocortical axis.
Animals↗
Effect of opiate-receptor blockade on normoglycemic and hypoglycemic glucoregulation.
By use of the opiate antagonist naloxone, we have examined the hormonal and metabolic responses to opiate-receptor blockade under basal conditions and during insulin-induced hypoglycemia in normal dogs. Naloxone treatment had no measurable effect on glucose concentration, turnover, and norepinephrine levels, but stimulated plasma epinephrine, glucagon, and cortisol and inhibited insulin release. Insulin (7 mU X kg-1 X min-1) decreased plasma glucose to 42 +/- 4 mg/dl due to an initial decrease in glucose production and an increase in glucose disappearance. Glucose production then increased, and plasma glucose plateaued. After 50 min of insulin infusion, epinephrine levels increased 26-fold (P less than 0.05), norepinephrine and glucagon 3-fold (P less than 0.02), and cortisol 4-fold (P less than 0.01). Similarly, plasma beta-endorphin and adrenocorticotropin (ACTH) were elevated (6-fold, P less than 0.01, and 16-fold, P less than 0.05, respectively). When naloxone was given during insulin-induced hypoglycemia, there was earlier release of epinephrine, glucagon, beta-endorphin, ACTH, and cortisol as well as a greater release of glucagon (P less than 0.001) and cortisol (P less than 0.0001). This resulted in a greater increase in glucose production (P less than 0.01), thus lessening the insulin-induced hypoglycemic excursion. In conclusion, in the dog, endogenous opiates may play a small role in the regulation of basal insulin and glucagon release and can inhibit the pituitary-adrenal axis under basal conditions and during hypoglycemia. Thus increased glucose production in response to insulin-induced hypoglycemia is consistent with the excessive response of counterregulatory hormones during opiate-receptor blockade.
Adrenocorticotropic Hormone↗
Triglyceride kinetics: effects of dietary glucose, sucrose, or fructose alone or with hyperinsulinemia.
The effects of different dietary sugars, with or without exogenously induced hyperinsulinemia, on rat plasma triglyceride kinetics have been studied. Glucose, sucrose, or fructose were supplied as 10% drinking solutions. The sugar-supplemented groups were each divided into subgroups, one receiving 6 U of insulin per day for 2 wk from intraperitoneally implanted minipumps and the other receiving none. The same degree of hyperglycemia and of endogenous hyperinsulinemia was seen in each sugar-supplemented group. Infusing exogenous insulin restored normoglycemia and produced more pronounced but equal hyperinsulinemia in each subgroup. In those rats that received no exogenous insulin, triglyceride production increased 18% in the sucrose-supplemented group and 20% in the fructose supplemented subgroups, but not at all in the glucose-supplemented subgroup. This 20% increase in triglyceride production in the fructose-supplemented subgroup was accompanied by a six times greater (120%) increase in triglyceride concentration. This suggested that dietary fructose not only increased triglyceride production, but also impaired triglyceride removal. Exogenously induced hyperinsulinemia further increased triglyceride production in those rats receiving dietary fructose, either as the monosaccharide or as sucrose, but not in those receiving only glucose. Thus, in the presence of fructose, but not glucose, insulin stimulates triglyceride production. As exogenous insulin returned the triglyceride concentrations to normal in the fructose-supplemented rats, it also appeared to overcome any fructose-associated impairment of triglyceride removal.
Animals↗
Glucoregulatory role of cortisol and epinephrine interactions studied in adrenalectomized dogs.
The importance of basal cortisol (H) and epinephrine (E) levels on glucoregulation, and the effects of E, given to simulate moderate to severe stress (5 times basal rate of infusion), were examined in seven conscious adrenalectomized dogs. Although plasma glucagon (IRG) increased by 47%, insulin (IRI) decreased by 36%, norepinephrine (NE) increased by 103%, and FFA decreased by 26%, glucose concentration and kinetics remained normal after adrenalectomy. A 4-h infusion of H reestablished basal cortisol levels and returned IRG to its basal preadrenalectomy level with no change in IRI, NE, and FFA levels. Glucose production and metabolic clearance decreased concomitantly by 20%, maintaining euglycemia. A 90-min infusion of basal E caused only a transient increase in IRG. The simultaneous infusion of H with E prevented this increase in IRG and returned IRI to preadrenalectomy levels in the absence of any change in NE or glucose. A subsequent infusion of five times basal E, alone, raised circulating E levels and caused a transient decrease in plasma NE, but no change in IRI. There was a similar hyperglycemic response, as seen previously in normal dogs. The simultaneous infusion of H and E prevented the decrease in NE, but did not change the IRI and FFA responses. There was an 80% greater plasma glucose response than seen during infusion of E alone. In conclusion, what E and H lack after adrenalectomy is compensated for by an increase in IRG and a decrease in IRI, and normal glucose concentrations and kinetics are maintained. It appeared that normoglucagonemia required basal H release, whereas normoinsulinemia required both basal H and E secretion.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenalectomy↗
Glucose turnover in response to exercise during high- and low-FIO2 breathing in man.
The purpose of this study was to assess whether breathing high or low concentrations of O2 could affect glucose turnover during exercise in man. Ten healthy subjects performed two constant work-rate exercise tests, one when the fraction of inspired O2 (FIO2) was 0.15 and the other at the same work rate but when the FIO2 was 0.80. The work rate for each subject was chosen so that blood lactate would be elevated during hypoxia, but would be lower during hyperoxia. Glucose appearance (Ra) and disappearance (Rd) were measured using the primed, constant infusion of [3-3H]glucose. Although the work rate was the same during hypoxia and hyperoxia in each subject, hypoxic exercise was accompanied by a significantly larger rest to exercise increase in Rd (delta Rd) compared with hyperoxia by 265%. Similarly, delta Ra was greater during hypoxia than during hyperoxia by 188%. Lactate to pyruvate ratios were significantly higher during hypoxic exercise suggesting a shift in the cell redox to a more reduced state. Insulin and glucagon were not affected by the FIO2, but both epinephrine and norepinephrine were increased during hypoxic exercise, which may explain the increase in Ra. The regulation of blood glucose during exercise in vivo appears to be dependent on the availability of oxygen to the working muscle cells.
Adult↗
Identification of some issues and questions to be answered in comparing type I and type II diabetes.
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Blood Glucose↗
New probes to study insulin resistance in men; futile cycle and glucose turnover.
Insulin resistance has been measured in man by nonsteady state tracer methodology. Increase in overall glucose utilization and suppression of glucose production was measured when hyperglycemia was achieved either by infusing glucagon or glucose. With the first method, insulin resistance was assessed in obese man and in lean hypertriglyceridemic patients. With the second method, insulin resistance was assessed in lean mild type II diabetics. These methodologies can only assess deficiences in overall glucose utilization and glucose production, but cannot delineate the defect in glucose uptake by the liver. However, if a given metabolic event is essentially characteristic of only one organ, metabolic abnormalities specific to that organ can be detected in vivo provided there is a probe specific to that metabolic pathway. Therefore, in lean mild type II diabetics the liver glucose futile cycle was assessed by a double tracer method. Previously it was shown that liver glucose futile cycling is increased in diabetic dogs. In healthy control subjects in basal state and during glucose infusion, the futile cycle could not be detected, but it represented a major part of glucose metabolism in liver of type II diabetics. It appears, therefore, that most of the glucose taken up by the liver during the glucose challenge in diabetics reenters the blood stream without being oxidized or polymerized. On the basis of these studies, it was concluded that excessive hyperglycemia in the diabetics during glucose infusion is due to a decrease in irreversible glucose uptake (impaired phosphorylation and futile cycling) and to a decrease in suppression of glucose production. The relative contribution of the liver and periphery to hyperglycemia seems to be almost equivalent. The mechanism behind the increased glucose cycle activity is not clear. It may be due to a relative decrease of glycogen synthase or increase in glucose-6-phosphatase or both. These observations in mild lean type II diabetics may have implications also in some other types of diabetes, since we have observed that futile cycling is even more marked in obese type II diabetics and that it could account in part for the diabetogenic effect of growth hormone in acromegalics.
Blood Glucose↗
Glucoregulation in dogs treated with methyl-prednisolone.
In nonanesthetized dogs treated with 3 mg/kg . d methyl-prednisolone (MP) for four days the infusion of phlorizin decreases plasma glucose only transiently. The basal level is restored by an increase in hepatic glucose production. The concentration of plasma glucagon (IRG) is raised only about 26%, compared to the increase of 150% observed previously in untreated dogs. In insulin-induced hypoglycemia, hepatic glucose production increases and both the concentrations of epinephrine and IRG in the plasma are elevated significantly. Recovery from hypoglycemia after the cessation of the infusion is significantly faster than observed previously in normal dogs. The following conclusions were reached: In MP-treated dogs during the infusion of phlorizin (in nonhypoglycemic glucoregulation) normoglycemia is restored faster, and by a much smaller increment in plasma glucagon concentration than previously observed in normal dogs. Regulation in overt hypoglycemia too operates more efficiently. In nonhypoglycemic glucoregulation a small change in plasma glucose concentration appears to be the primary stimulus that releases glucagon to the extent necessary to achieve the appropriate increase in hepatic glucose production in a given endocrine milieu.
Animals↗
Diabetes and exercise.
The abnormal metabolic responses to exercise in insulin-dependent diabetes are in great part related to abnormal circulating plasma insulin concentrations. Exercising during relative insulin deprivation results in an increase in glycemia and ketosis. Exercise during insulin excess results in inhibition of hepatic glucose production and accelerated muscle glucose utilization and results in hypoglycemia. These responses can be significantly improved when insulin is administered more appropriately, as is the case with insulin infusion pumps. Self blood glucose monitoring before, during, and after exercise can provide important information that can be used to optimize the metabolic response to exercise in individual patients. A better understanding of the metabolic response to exercise in patients with diabetes will serve as the basis for developing specific recommendations to enable these individuals to have the freedom to take part in all forms of exercise with minimal restriction. However, the demonstration that exercise will have a long-term beneficial effect on the metabolic control of diabetes or prevent the development of the complications of diabetes remains to be established.
Diabetes Mellitus, Type 1↗
Effect of hematocrit reduction on hormonal and metabolic responses to exercise.
We wished to determine the effect of a 25% hematocrit reduction on glucoregulatory hormone release and glucose fluxes during exercise. In five anemic dogs, plasma glucose fell by 21 mg/dl and in five controls by 7 mg/dl by the end of the 90-min exercise period. After 50 min of exercise, hepatic glucose production (Ra) and glucose metabolic clearance rate (MCR) began to rise disproportionately in anemics compared with controls. By the end of exercise, the increase in Ra was almost threefold higher (delta 15.1 +/- 3.4 vs. delta 5.2 +/- 1.3 mg X kg-1 X min-1) and MCR nearly fourfold (delta 24.6 +/- 8.8 vs. delta 6.5 +/- 1.3 ml X kg-1 X min-1). Exercise with anemia, in relation to controls resulted in elevated levels of glucagon [immunoreactive glucagon (IRG) delta 1,283 +/- 507 vs delta 514 +/- 99 pg/ml], norepinephrine (delta 1,592 +/- 280 vs. delta 590 +/- 155 pg/ml), epinephrine (delta 2,293 +/- 994 vs. delta 385 +/- 186 pg/ml), cortisol (delta 6.7 +/- 2.2 vs. delta 2.1 +/- 1.0 micrograms/dl) and lactate (delta 12.1 +/- 2.2 vs. delta 4.2 +/- 1.8 mg/dl) after 90 min. Immunoreactive insulin and free fatty acids were similar in both groups. In conclusion, exercise with a 25% hematocrit reduction results in 1) elevated lactate, norepinephrine, epinephrine, cortisol, and IRG levels, 2) an increased Ra which is likely related to the increased counterregulatory response, and 3) we speculate that a near fourfold increase in MCR is related to metabolic changes due to hypoxia in working muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
Anemia↗
Important role of glucagon during exercise in diabetic dogs.
To define the role of immunoreactive glucagon (IRG) during exercise in diabetes, 12 insulin-deprived alloxan-diabetic (A-D) dogs were run for 90 min (100 m/min, 12 degrees) with or without somatostatin (St 0.5 microgram . kg-1 . min-1). Compared with normal dogs, A-D dogs were characterized by similar hepatic glucose production (Ra), lower glucose metabolic clearance, and higher plasma glucose and free fatty acid levels during rest and exercise. In A-D dogs IRG was greater at rest and exhibited a threefold greater exercise increment than controls, whereas immunoreactive insulin (IRI) was reduced by 68% at rest but had similar values to controls during exercise. Basal norepinephrine, epinephrine, cortisol, and lactate levels were similar in normal and A-D dogs. However, exercise increments in norepinephrine, cortisol, and lactate were higher in A-D dogs. When St was infused during exercise in the A-D dogs, IRG was suppressed by 432 +/- 146 pg/ml below basal and far below the exercise response in A-D controls (delta = 645 +/- 153 pg/ml). IRI was reduced by 1.8 +/- 0.2 microU/ml with St. With IRG suppression the increase in Ra seen in exercising A-D controls (delta = 4.8 +/- 1.6 mg . kg-1 . min-1) was virtually abolished, and glycemia fell by 104 to 133 +/- 37 mg/dl. Owing to this decrease in glycemia, the increase in glucose disappearance was attenuated. Despite the large fall in glucose during IRG suppression, counterregulatory increases were not excessive compared with A-D controls. In fact, as glucose levels approached euglycemia, the increments in norepinephrine and cortisol were reduced to levels similar to those seen in normal exercising dogs. In conclusion, IRG suppression during exercise in A-D dogs almost completely obviated the increase in Ra, resulting in a large decrease in plasma glucose. Despite this large fall in glucose, there was no excess counterregulation, since glucose concentrations never reached the hypoglycemic range.
Animals↗
Role of beta-adrenergic mechanisms during exercise in poorly controlled diabetes.
To examine the beta-adrenergic effects of the catecholamines in poorly controlled diabetes, we have studied insulin-deprived alloxan-diabetic (A-D) dogs during 90 min of moderate exercise (100 m/min, 10-12 degrees) alone (C) or with propranolol (5 micrograms . kg-1 . min-1) (P) or combined P and somatostatin infusion (0.5 microgram . kg-1 . min-1) (P + St). In P, in contrast to C, immunoreactive glucagon (IRG) rose only after 50 min of exercise. However, hepatic glucose production (Ra) rose normally. In P + St, IRG fell 50% below basal, and the Ra response to exercise was abolished. Interestingly, in P and P + St, glucose metabolic clearance rate (MCR) rose by 400% above the inadequate MCR response to exercise in C, despite 30% lower insulin levels. Compared with C, free fatty acids (FFA) and lactate were sharply reduced during P and P + St. Plasma glucose (G) did not change in C, but due to elevated glucose uptake, G fell over 120 mg/dl in P, and due to diminished Ra, G fell 170 mg/dl in P + St. Norepinephrine was similar in all groups. Epinephrine and cortisol were higher in P + St by 90 min of exercise, perhaps as a result of hypoglycemia. In summary, during exercise in poorly controlled A-D dogs, beta-blockade does not appear to affect Ra; beta-blockade leads to diminished mobilization of extrahepatic substrate as evidenced by reduced FFA and lactate levels; beta-blockade increases MCR to levels seen in normal dogs during exercise alone.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Changes in very low density lipoprotein particle size and production in response to sucrose feeding and hyperinsulinemia.
The effects of chronic (2 weeks) hyperinsulinemia on the production of very low density lipoprotein (VLDL) triglyceride and on VLDL particle size were examined. Hyperinsulinemia was induced by a constant sc infusion of 6 U porcine insulin/day from an osmotic minipump. To avoid profound hypoglycemia, these rats received chow plus 10% sucrose in their drinking water. Therefore, two control groups were examined; one receiving chow plus the same amount of sucrose (high carbohydrate control) and the other receiving chow only (chow control). The constant infusion model was compared to a previously reported model of hyperinsulinemia. In that model, NPH insulin was injected for 2 weeks twice daily in incrementally increasing doses (final dose, 6 U/day) into rats that were also fed chow and given 10% sucrose drinking water. Results with the injection model were similar to those previously reported: an increase in triglyceride production in face of a decrease in FFA, a minimal decrease in serum triglyceride, and some decrease in serum glucose. The infusion model produced the same increase in triglyceride production and decrease in fatty acid concentration. However, it differed in producing an increase in serum triglyceride and no change in serum glucose. The former suggested that in the infusion model triglyceride removal was not stimulated as much as in the injection model. Since there was no hypoglycemia in the infusion model, it was unlikely that VLDL changes were caused by an increase in counter regulatory hormones. VLDL particle size was increased in the high carbohydrate controls. This indicated that changes in sucrose supplementation led to the production of more triglyceride-filled VLDL particles. Hyperinsulinemia was not accompanied by any further increase in particle size. Thus, the hyperinsulinemia-induced increase in VLDL-triglyceride production was accompanied by an equivalent increase in VLDL particle production.
Animals↗
Biosynthesis of glucagon (IRG3500) in canine gastric mucosa.
The canine gastric mucosa has previously been shown to contain considerable amounts of a polypeptide with the immunologic and physicochemical characteristics and biologic activity of glucagon (IRG3500). Using mucosal pieces that remained viable for at least 8 h, we have demonstrated that IRG3500 is synthesized in this extrapancreatic tissue. Gel filtration and electrophoresis of extracts of mucosal pieces incubated with 3H-tryptophan, 3H-leucine, or 35S-methionine revealed small amounts of labeled, newly synthesized gastric IRG3500. No labeling of gastric IRG3500 was observed when the mucosa was incubated with 3H-proline, an amino acid not found in glucagon, in the presence of cycloheximide, or in isolated rat hepatocytes. Small amounts of newly synthesized IRG3500 were specifically immunoprecipitated by C-terminally directed glucagon antiserum gamma globulins. The rate of gastric IRG3500 biosynthesis in vitro was apparently unchanged in mucosal pieces from pancreatectomized dogs and unaffected by increased glucose or glucose lack during incubations. Thus we have provided evidence that a hormone of the endocrine pancreas can be synthesized in extrapancreatic tissues.
Amino Acids↗
Beta-endorphin modulation of the glucoregulatory effects of repeated epinephrine infusion in normal dogs.
Successive epinephrine infusions were used as a partial model to examine hormonal and metabolic responses to repeated stress stimuli. As both the endogenous opiates and epinephrine are released in response to stress, we have also studied interactions between epinephrine and B-endorphin. Epinephrine (0.1 microgram/kg . min) was infused for 60 min, followed by a 60-min recovery, in nine normal, conscious dogs. In a similar study, B-endorphin (0.06 microgram/kg . min) was given 30 min before epinephrine, then continuously infused throughout the study (N = 4 dogs). When epinephrine was infused, levels rose to 600-800 pg/ml. The changes in glucagon, B-endorphin, FFA, and hepatic glucose production were similar during both epinephrine infusions, but there was a diminished insulin response, a greater decrease in glucose metabolic clearance, and a greater increase in plasma glucose with the second epinephrine infusion. When B-endorphin was given, plasma levels increased to 5.3 ng/ml. Compared with the infusion of epinephrine alone, there was a much greater rise in plasma glucose due to greater suppression of glucose metabolic clearance. With the second epinephrine infusion, however, the changes in glucose concentration were not substantially different from those seen during the second infusion of epinephrine alone, as both hepatic glucose production and glucose metabolic clearance were suppressed. B-endorphin diminished the insulin and glucagon responses during the first epinephrine infusion and abolished them during the second, but did not alter the FFA, ACTH, or cortisol responses to epinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenocorticotropic Hormone↗