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Biomedical subjects

M Vranic

Publications and source records attributed to M Vranic.

At least 127 records · Page 7Linked to original sources
PubMed1984

Hyperinsulinemia and in vivo very-low-density lipoprotein-triglyceride kinetics.

The effect of hyperinsulinemia (2 wk of twice daily NPH insulin) on the kinetics of very-low-density lipoprotein (VLDL)-triglyceride (TG) was studied in rats. To avoid profound hypoglycemia the rats were allowed sucrose ad libitum. Two control groups were needed: chow only and ad libitum sucrose-supplemented (high-CHO). The insulin-treated rats had 15 times higher IRI and 50% lower plasma glucose levels than either control group. Their TG production exceeded and their TG concentrations were less than those of either control group. This indicated that their TG removal was increased even more than their TG production. This increase in TG production occurred despite lower plasma free fatty acid (FFA) levels, suggesting that a greater proportion of TG fatty acids came from a source other than FFA. Compared with chow controls, high-CHO controls had the same peripheral IRI, a slight increase in TG production, and an increase in TG concentration. The differences between the effects of CHO supplementation alone or together with injected insulin may relate to the IRI and/or the route of access of insulin (peripheral vs. portal). The present studies indicate that hyperinsulinemia, either directly or indirectly, accelerates triglyceride turnover.

Animals↗
PubMed1984

Catecholamine responses and their interactions with other glucoregulatory hormones.

We have investigated catecholamine-glucagon-insulin interactions using three stress models: 1) hypoglycemia; 2) exercise; and 3) epinephrine infusion. Phlorizin caused mild hypoglycemia with hypoinsulinemia. Plasma glucagon increased as did hepatic glucose production. Catecholamines did not increase. Insulin caused severe hypoglycemia. Metabolic counterregulation was due mainly to the 40-fold increase in epinephrine. Glucagon played a role only in the recovery from insulin-induced hypoglycemia, which could reflect increased hepatic sensitivity to glucagon with declining plasma insulin. Glucagon suppression during exercise caused transient hypoglycemia due to an inadequate rise in glucose production. Exaggerated epinephrine release during hypoglycemic exercise prevented severe hypoglycemia by inhibiting glucose utilization and stimulating glucose production, with an associated increase in lactate and free fatty acid levels. Hypoglycemic exercise also caused increased cortisol release. Counterregulation was prevented by a euglycemic clamp. We conclude that, during exercise, glucagon is directly responsible for 80% of the increment of glucose production and controls glucose uptake by the muscle indirectly; thus glucagon spares muscle glycogen by increasing hepatic glucose production. Epinephrine infusion in normal dogs caused a transient increase in glucose production and a sustained inhibition of glucose clearance, resulting in hyperglycemia. Insulin rose transiently, followed by a relative inhibition of secretion. Glucagon suppression did not modify the metabolic effects of epinephrine. In alloxan-diabetic dogs, the glucagon response to epinephrine was augmented, whereas in depancreatized dogs, during subbasal insulin infusion, the hepatic response to glucagon was excessive. Glucagon suppression diminished hepatic responsiveness to epinephrine in both models. Stress-induced diabetic instability could relate to exaggerated glucagon release or to increased hepatic sensitivity to glucagon. Thus, during hypoglycemia, exercise, or epinephrine infusion, prevailing plasma insulin levels govern the relative metabolic roles of epinephrine and glucagon.

Adolescent↗
PubMed1984

Interactions between glucagon and other counterregulatory hormones during normoglycemic and hypoglycemic exercise in dogs.

Somatostatin (ST)-induced glucagon suppression results in hypoglycemia during rest and exercise. To further delineate the role of glucagon and interactions between glucagon and the catecholamines during exercise, we compensated for the counterregulatory responses to hypoglycemia with glucose replacement. Five dogs were run (100 m/min, 12 degrees) during exercise alone, exercise plus ST infusion (0.5 micrograms/kg-min), or exercise plus. ST plus glucose replacement (3.5 mg/kg-min) to maintain euglycemia. During exercise alone there was a maximum increase in immunoreactive glucagon (IRG), epinephrine (E), norepinephrine (NE), FFA, and lactate (L) of 306 +/- 147 pg/ml, 360 +/- 80 pg/ml, 443 +/- 140 pg/ml, 541 +/- 173 mu eq/liter, and 6.3 +/- 0.7 mg/dl, respectively. Immunoreactive insulin (IRI) decreased by 10.2 +/- 4 micro/ml and cortisol (C) increased only slightly (2.1 +/- 0.3 micrograms/dl). The rates of glucose production (Ra) and glucose uptake (Rd) rose markedly by 6.6 +/- 2.2 mg/kg-min and 6.2 +/- 1.5 mg/kg-min. In contrast, when ST was given during exercise, IRG fell transiently by 130 +/- 20 pg/ml, Ra rose by only 3.6 +/- 0.5 mg/kg-min, and plasma glucose decreased by 29 +/- 6 mg/dl. The decrease in IRI was no different than with exercise alone (10.2 +/- 2.0 microU/ml). As plasma glucose fell, C, FFA, and L rose excessively to peaks of 5.4 +/- 1.3 micrograms/dl, 1,166 +/- 182 mu eq/liter and 15.5 +/- 7.0 mg/dl. The peak increment in E (765 +/- 287 pg/ml) coincided with the nadir in plasma glucose and was four times greater than during normoglycemic exercise. Hypoglycemia did not affect the rise in NE. The increase in Rd was attenuated and reached a peak of only 3.7 +/- 0.8 mg/kg-min. During glucose replacement, IRG decreased by 109 +/- 30 pg/ml and the IRI response did not differ from the response to normal exercise. Ra rose minimally by 1.5 +/- 0.3 mg/kg-min. The changes in E, C, Rd, and L were restored to normal, whereas the FFA response remained excessive. In all protocols increments in Ra were directly correlated to the IRG/IRI molar ratio while no correlation could be demonstrated between epinephrine or norepinephrine and Ra. In conclusion, (a) glucagon controlled approximately 70% of the increase of Ra during exercise. This became evident when counterregulatory responses to hypoglycemia (E and C) were obviated by glucose replacement; (b) increments in Ra were strongly correlated to the IRG/IRI molar ratio but not the plasma catecholamine concentration; (c) the main role of E in hypoglycemia was to limit glucose uptake by the muscle; (d) with glucagon suppression, glucose production was deficient but a further decline of glucose was prevented through the peripheral effects of E, (e) the hypoglycemic stimulus for E secretion was facilitated by exercise; and (f) we hypothesize that an important role of glucagons during exercise could be to spare muscle glycogen by stimulating glucose production by the liver.

Animals↗
PubMed1984

The effects of an alpha-glucoside hydrolase inhibitor on glycemia and the absorption of sucrose in man determined using a tracer method.

Acarbose, an alpha-glucosidase inhibitor, lowers the glycemic excursion following the ingestion of carbohydrates, in particular, sucrose. This was confirmed with increasing doses of acarbose (0, 50, and 100 mg) and the causes investigated. The absorption of the glucose moiety of sucrose was determined from plasma tracer concentrations when overnight-fasted normal subjects received a 100-g oral sucrose load labeled with sucrose [(1-14C]glucose and a simultaneous intravenous infusion of [3-3H]glucose. As the dose of acarbose given with the sucrose load was increased from 0 to 100 mg, the percentage of the load appearing in the peripheral circulation decreased from 90% to 62%. Malabsorption was confirmed by the appearance of breath hydrogen. Simultaneously, absorption time increased from 243 to 411 min. Maximal glycemic excursions were therefore lowered from 64 to 31 mg/dl. The plasma concentrations of gastric inhibitory polypeptide and insulin decreased with the acarbose dose so that the fractional disappearance rate of glucose also decreased. However, the concentrations of glucagon-like immunoreactivity (GLI) rose, confirming the ileal appearance of malabsorbed sucrose.

Acarbose↗
PubMed1983

Glucagon suppression improves glucoregulation in moderate but not chronic severe diabetes.

To determine the effectiveness of glucagon suppression in improving glucose homeostasis in diabetes, tracer-determined glucose kinetics were measured during a 6-h somatostatin infusion in six alloxan-diabetic dogs (moderately severe diabetes) and five depancreatized dogs deprived of insulin treatment for 3 days (prolonged severe diabetes). Plasma immunoreactive glucagon (IRG) decreased 70 +/- 9% in the alloxan-diabetic and 80 +/- 4% in the depancreatized dogs. Portal vein levels of plasma immunoreactive insulin (IRI) fell (17.0 +/- 2.3 to 4 micro.5 +/- 0.4 microU/ml) as did peripheral vein IRI levels (6.7 +/- 0.9 to 4.7 +/- 0.5 microU/ml) in the alloxan-diabetic dogs. In the depancreatized dogs plasma IRI levels were undetectable. Plasma glucose concentrations fell (278 +/- 17 to 169 +/- 12 mg/dl) during IRG suppression in the alloxan-diabetic dogs due to a rapid and sustained decrease in glucose production (Ra) (6.0 + 0.9 to 3.6 + 0.3 mg X kg-1 X min-1). Glucose disappearance (Rd) decreased gradually (5.9 + 0.6 to 3.9 + 0.2 mg X kg-1 X min-1). In contrast, in the depancreatized dogs, IRG suppression did not alter glucose concentrations or kinetics. Thus, glucagon suppression decreased glycemia by decreasing Ra only in moderately severe diabetes. However, this was associated with decreased rather than improved glucose utilization. The ineffectiveness of glucagon suppression during prolonged severe diabetes could relate to the degree and duration of the metabolic derangement and/or indicate that the continuous presence of some insulin is necessary for glucagon suppression to improve glucose homeostasis.

Alloxan↗
PubMed1983

Minimal increases in glucagon levels enhance glucose production in man with partial hypoinsulinemia.

In man a small dose of somatostatin (50 micrograms/h) suppressed moderately basal insulin (5 microU/ml) and glucagon (40 pg/ml) levels. This resulted in a short-lasting hypoglycemia, which was then followed by marginal hyperglycemia throughout the experiment. The addition of a minimal dose of glucagon (0.50 ng/kg/min) to somatostatin normalized basal glucagon levels and resulted in a significant and sustained hyperglycemia. During the first 2 h, hyperglycemia was mainly due to increased glucose production, whereas later on it was maintained by decreased glucose uptake. We conclude that, in man moderately deprived of insulin, even a marginal change in glucagon level induces a long-lasting hyperglycemia.

Adult↗
PubMed1982

Exercise in diabetic man: glucose turnover and free insulin responses after glycemic normalization with intravenous insulin.

The metabolic response to moderate exercise in postabsorptive insulin-dependent diabetics receiving insulin by constant intravenous infusion was compared with that of normal controls. The diabetics were infused with insulin overnight and were normoglycemic (89 +/- 6 mg/dL, controls: 90 +/- 6 mg/dL). With exercise, glycemia remained constant in both groups. In the diabetic subjects, glucose production was 166 +/- 11 mg/min at rest, increased to 230 +/- 27 mg/min with exercise (p less than 0.05), and returned to base line during recovery. Glucose disappearance changed in a synchronous and parallel fashion. In the normal controls, insulin concentration was 0.44 +/- 0.03 ng/mL at rest and decreased significantly with exercise (p less than 0.01) while in the diabetic free insulin was fourfold higher (1.70 +/- 0.32) and did not change with exercise. Lactate increased similarly (twofold) with exercise in both groups. In summary, (i) complete normalization of glycemia, glucose turnover, and the lactate response to postabsorptive exercise can be achieved by the intravenous infusion of insulin adjusted to obtain normoglycemia before the onset of exercise; (ii) this response was obtained with an associated elevation in circulating free insulin which probably reflects the peripheral intravenous route rather than the physiologic (portal) site of insulin administration.

Adult↗
PubMed1982

State of metabolic control determines role of epinephrine-glucagon interaction in glucoregulation in diabetes.

Epinephrine (0.1 micrograms.kg-1.min-1) was infused with or without somatostatin (0.1 microgram.kg-1.min-1) in six depancreatized dogs, studied under normo- and hypoinsulinemia to determine whether the participation of glucagon in epinephrine-induced hepatic glucose overproduction is governed by the degree of metabolic control. When normoglycemia was achieved by basal intraportal insulin replacement, insulin levels remained constant during the epinephrine infusion, and there was a twofold increase in extrapancreatic immunoreactive glucagon (eIRG) and glucose production (Ra). Although eIRG increments were prevented by somatostatin, the increase in Ra was undiminished, indicating that epinephrine can act independently of glucagon as in normal animals. During subbasal intraportal insulin infusion in the depancreatized dogs, insulin levels remained 35% lower than with basal replacement, and the animals were hyperglycemic. Epinephrine induced a similar twofold increase in eIRG as during normoglycemia, and again this rise was prevented by somatostatin. There was a significantly greater, threefold increase in Ra with epinephrine when the animals were hyperglycemic. This exaggerated response to epinephrine was not seen during eIRG suppression by somatostatin, suggesting that glucagon participated in the epinephrine-induced hepatic glucose overproduction when the depancreatized dogs were in poor metabolic control, as seen previously in alloxan-diabetic dogs. However, in the depancreatized, unlike in the alloxan-diabetic dogs, epinephrine-induced glucagon release was small. Thus, hypoinsulinemia appears to sensitize the liver to eIRG during epinephrine infusion. The fact that epinephrine induces hyperglycemia both in physiology and diabetes could indicate an important role in enhancing glucose transport in insulin-insensitive tissues.

Animals↗
PubMed1982

Hyperinsulinemia and hypertriglyceridemia, a vicious cycle with atherogenic potential.

This paper reviews and integrates a number of experiments which suggest the existence of a vicious cycle. In this cycle hypertriglyceridemia can lead to insulin resistance even without concomitant obesity or non-insulin dependent diabetes. This insulin resistance may be the basis for the hyperinsulinemia response to a glucose challenge. The hyperinsulinemia can stimulate VLDL-triglyceride production. This increase in production, if it is not accompanied by an equivalent increase in removal, will result in hypertriglyceridemia. The whole cycle would accelerate VLDL-triglyceride turnover and may increase the supply of potentially atherogenic VLDL-remnants.

Animals↗
PubMed1981

Glucoregulatory and metabolic response to exercise in obese noninsulin-dependent diabetes.

The metabolic response to exercise in obese postabsorptive noninsulin-dependent diabetics was compared to that of obese nondiabetics. Exercise consisted of 45 min on a cycle ergometer at 60% maximum oxygen consumption. Six diabetic subjects were studied during oral hypoglycemic therapy and four on diet alone. The sulfonylurea therapy had no effect on the response. Glycemia was elevated at rest in both diabetic subgroups (192 +/- 24 mg/dl for diet alone, 226 +/- 36 mg/dl for sulfonylurea treatment) and a similar fall (35 and 37 mg/dl, respectively) occurred with exercise. In control subjects, glycemia was 86 +/- 4 mg/dl and did not change with exercise. In the diabetics at rest, glucose production was elevated (220 +/- 25 mg/min), whereas the metabolic clearance of glucose was suppressed. During exercise the increase in glucose utilization was similar to that in controls, but glucose production failed to increase significantly, thus accounting for the decline in plasma glucose. At rest, plasma immunoreactive insulin (IRI) was elevated to 0.90 ng/ml in the controls and decreased to 0.65 ng/ml with exercise. In the diabetics IRI was similarly elevated (0.89 ng/ml) but failed to decrease normally with exercise. Lactate, pyruvate, alanine, and free fatty acids increased similarly in diabetics and controls, whereas the increase in 3-hydroxybutyrate during recovery was less in diabetics. The sustained insulinemia, the basal overproduction of glucose, and hyperglycemia itself may all contribute to the observed differences in glucose flux during exercise in noninsulin-dependent diabetics.

Adult↗
PubMed1981

Importance of glucagon in mediating epinephrine-induced hyperglycemia in alloxan-diabetic dogs.

In normal dogs epinephrine stimulates glucose production (Ra) independently of glucagon. To investigate the role of this interaction in diabetes, epinephrine (0.1 micrograms . kg-1 . min-1) was infused for 90 min in five alloxan-diabetic dogs in the presence or absence of somatostatin (0.1 micrograms . kg-1 . min-1). In response to epinephrine, glycemia rose by 40% reflecting a near maximal (122%) increase in Ra. Plasma glucagon (IRG) rose to 953 pg/ml, whereas insulin (IRI) increased minimally. When somatostatin was infused with epinephrine to prevent the rise of IRG and IRI, there was only a marginal increase of glucose concentration (12%) and production (38%). The effect of somatostatin was reversed by infusing glucagon (10 ng . kg-1 . min-1) together with epinephrine and somatostatin into five additional alloxan-diabetic dogs. Increments in IRG, glycemia, and Ra were fully reestablished. A 100% FFA increase was observed in all three groups, indicating that the lipolytic effect of epinephrine was independent of glucagon. In conclusion, in diabetic dogs, in contrast to normal dogs, epinephrine induced a marked and prolonged increase in glucose concentration and production mostly through a stimulation of IRG secretion.

Alloxan↗
PubMed1981

Chromatographic pattern of extrapancreatic glucagon and glucagon-like immunoreactivity before and during stimulation by epinephrine and participation of glucagon in epinephrine-induced hepatic glucose overproduction.

To characterize the glucagon released in response to epineephrine in depancreatized dogs, plasma samples before and during epinephrine infusion were subjected to molecular-sieve chromatography on Bio-Gel P-30 columns. The chromatographic profile for extrapancreatic immunoreactive glucagon (eIRG) revealed two glucagon moieties of molecular weight 9,000 to 12,000. GLI of this molecular weight was released in response to epinephrine only under conditions of prevailing hyperglycemia. To determine if glucagon's participation in epinephrine-induced hepatic glucose overproduction in diabetes was dependent upon the degree of metabolic control, six conscious depancreatized dogs were infused with epinephrine or epinphrine plus somatostatin, under conditions of prevailing hyperglycemia or normoglycemia. Under normoglycemic conditions, epinephrine stimulated eIRG release, but there was a similar rise in hepatic glucose production (Ra) with or without glucagon suppression by somatostatin. Under hyperglycemic conditions, epinephrine stimulated eIRG and GLI release, and the rise in Ra was significantly greater with epinephrine than with epinephrine plus somatostatin infusion. Thus, under conditions of good metabolic control, epinephrine increased hepatic glucose production independently of glucagon, whereas with poor metabolic control, glucagon contributed to hepatic overproduction of glucose.

Animals↗