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Biomedical subjects

G Hetenyi

Publications and source records attributed to G Hetenyi.

At least 19 recordsLinked to original sources
PubMed1997

An historical review of rheumatoid arthritis treatment: 1948 to 1952.

OBJECTIVES: The early responses by practicing physicians to the discovery of the effect of cortisone (compound E) and adrenocorticotropic hormone (ACTH) on acute rheumatoid arthritis in 1948 and their reactions to the drugs' scarcity have been reviewed. METHODS: Review of the relevant literature in American, British, and European medical journals and some newspapers. RESULTS: Whereas the effect of the compound E and ACTH was stunning, their scarcity made them unavailable to most physicians. Nevertheless, practicing physicians took a lively interest in the new therapy, as witnessed by the large number of letters with comments and questions to professional journals from all over the world. As expected, most of these were about attempts to find a substitute for cortisone or a way to release it endogenously to a sufficient degree. A few alternative therapies were suggested too, some quite unorthodox. A lively interest was shown by the general public. CONCLUSIONS: No alternative therapy recommended to treat acute rheumatoid arthritis in lieu of cortisone proved to be effective. The era of scarcity was ended by the discovery of a more efficient method to manufacture cortisone.

Adrenocorticotropic Hormone↗
PubMed1991

Effect of stress on glucoregulation in physiology and diabetes.

To examine the glucoregulatory responses to stress and their impact on diabetes, we used the following models of stress: A) Hypoglycemia; B) Epinephrine infusion; C) intracerebroventricular (ICV) injection of carbachol, an analog of acetylcholine. A) Hypoglycemia induces release of all counterregulatory hormones. During acute hypoglycemia, glucose production increases initially mainly due to glucagon release but eventually also due to a very large increment in catecholamines. In newborn dogs, neither epinephrine nor glucagon respond to a decrease in plasma glucose. This lack of a safeguard against hypoglycemia may indicate that the brain in pups is less dependent on a normal supply of glucose as a fuel, than in adult dogs. Counterregulation is enhanced when the effects of endogenous opiates are blocked by naloxone, indicating that endogenous opiates play a regulatory role during hypoglycemia. However, beta-endorphins which can be released with epinephrine during various stress situations, potentiate the peripheral effect of epinephrine. Glucoregulatory responses, even to slight changes in plasma glucose, are greatly enhanced during glucocorticoid treatment. This apparently reflects the greater sensitivity of the liver to glucagon. In diabetic dogs, similar to human diabetics, the glucagon response is abolished and the response of the catecholamines is partially decreased. On the basis of histological studies, we proposed that the deficient glucagon response in diabetes could be related to an increase in the somatostatin-glucagon ratio in the diabetic pancreas. This ratio is further augmented when normoglycemia is maintained with insulin. In response to a decrease in plasma glucose, there is a biphasic increment in glucose production in normal dogs, which is missing in diabetes. When normoglycemia is restored in diabetic dogs with phlorizin treatment, the second but not the first increment in glucose production is restored. We postulated, therefore, that the toxic effect of hyperglycemia, in addition to the lack of glucagon response, is the main reason why in diabetes, glucose production cannot respond promptly to a decrease in plasma glucose. The low rate of metabolic clearance of glucose seen in diabetes in the post-absorptive state, also reflects, at least in part, the toxic effect of glucose, because with acute normalization of glucose with phlorizin, metabolic glucose clearance substantially improves. Hyperglycemia is the main reason for the decreased number of glucose transporters in diabetic muscle. B) Epinephrine infusion in normal dogs mimics some effects of stress, in that it increases glucose production, inhibits metabolic glucose clearance and increases lipolysis. These metabolic effects of epinephrine are independent of glucagon release.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Distribution and kinetics of glucose in rats analyzed by noncompartmental and compartmental analysis.

The steady-state kinetics and distribution of glucose were assessed using noncompartmental and various two-compartment models in rats that were infused with insulin (+/- euglycemic clamping), methylprednisolone (MP), or phlorizin (PHL) as well as rats injected with protamine-zinc-insulin (PZI) or rendered diabetic. Decreases in clearance of glucose (PCR) were greatest with insulin infusion, followed by PHL, MP, and PZI treatments. PCR decreased in diabetes to 25% of normal. With hyperinsulinemia and euglycemia, turnover rates were 1.18 times the rate of glucose infusion. In normal rats the ratio of the contents of the two compartments was 0.6-0.8 (depending on the model). Significant increases, of between 2.8 and 5.2, were observed with insulin infusion and between 0.8 and 1.8 with PHL, again depending on the model. Because PHL-induced changes in PCR are renal, these data suggest that variations in glucose distribution depend on changes in PCR as well as insulin. The intercompartmental rate constant decreased, and the noncompartmental volume of distribution increased to reflect the above changes. In non-steady-state studies, glucose release increased in response to insulin but not to PHL in contrast to other species.

Animals↗
PubMed1989

Phlorizin-induced normoglycemia partially restores glucoregulation in diabetic dogs.

The plasma concentration of glucagon (IRG), catecholamines, and hepatic glucose production (Ra) were followed in insulin-induced hypoglycemia in dogs before (normal) and at 14-21 and again at 89-119 days after the injection of alloxan (diabetic). Some diabetic dogs were also tested when euglycemia was restored by phlorizin. In the normal state plasma IRG and epinephrine were raised by a factor of 3 and 15, respectively. Ra increased in two phases, an early peak (350% basal) was followed by a plataeu at about twice basal. In diabetes, irrespective of its duration, plasma IRG was decreased in hypoglycemia, and the rise in plasma epinephrine was significantly reduced. Ra remained unchanged. In phlorizin-treated euglycemic diabetic dogs plasma IRG fell, and the response in plasma epinephrine remained blunted. There was no early rise in Ra, but the same elevated plateau was reached at the same time as in normal animals. In conclusion, the following is observed in diabetic dogs. 1) The sensitivity of alpha-cells to insulin is maintained, but that to hypoglycemia is lost. The concentration of plasma catecholamines is raised less than in normals. With no increase in plasma glucagon this rise is not sufficient to increase Ra. 2) Restoration of euglycemia with phlorizin does not restore normal IRG and epinephrine responses to hypoglycemia but restores the delayed increase of Ra. Thus the restoration of euglycemia in severely diabetic dogs partially restores the responses of the liver, but not of the alpha-cell or sympathetic discharge, to hypoglycemia.

Animals↗
PubMed1988

Gluconeogenesis from glycine and serine in fasted normal and diabetic rats.

1. Non-anaesthetized normal and diabetic rats were fasted for 1 day, and [U-14C]glycine, or [U-14C]serine, or [U-14C]- plus [3-3H]-glucose was injected intra-arterially. The rates of synthesis de novo/irreversible disposal for glycine, serine and glucose, as well as the contribution of carbon atoms by the amino acids to plasma glucose, were calculated from the integrals of the specific-radioactivity-versus-time curves in plasma. 2. The concentrations of both glycine and serine in blood plasma were lower in diabetic than in fasted normal animals. 3. The rates of synthesis de novo/irreversible disposal of both amino acids tended to be lower in diabetic animals, but the decrease was statistically significant only for serine (14.3 compared with 10.5 mumol/min per kg). 4. Of the carbon atoms of plasma glucose, 2.9% arose from glycine in both fasted normal and diabetic rats, whereas 4.46% of glucose carbon originated from serine in fasted normal and 6.77% in diabetic rats. 5. As judged by their specific radioactivities, plasma serine and glycine exchange carbon atoms rapidly and extensively. 6. It was concluded that the turnover of glycine remains essentially unchanged, whereas that of serine is decreased in diabetic as compared with fasted normal rats. The plasma concentration of both amino acids was lower in diabetic rats. Both glycine and serine are glucogenic. In diabetic rats the contribution of carbon atoms from glycine to glucose increases in direct proportion to the increased glucose turnover, whereas the contribution by serine becomes also proportionally higher.

Animals↗
PubMed1988

Glucose and lactate turnover and gluconeogenesis in chronic metabolic acidosis and alkalosis in normal and diabetic dogs.

The turnover rate of glucose, the irreversible disposal rate of lactate, and the rate of gluconeogenesis from lactate were calculated by tracer methods in four normal and four alloxan-diabetic dogs under control conditions as well as in chronic, stable metabolic acidosis and alkalosis. Acidosis was produced by feeding dogs 0.8-1 g.kg-1.day-1NH4Cl over 1 week, alkalosis was produced by feeding dogs a chloride-free diet and injections of furosemide. Mean plasma pH in the three states were 7.28 +/- 0.013, 7.40 +/- 0.024, and 7.51 +/- 0.015 in normal dogs, and 7.22 +/- 0.025, 7.42 +/- 0.009, and 7.49 +/- 0.002 in the diabetic dogs. Respective mean plasma bicarbonate levels were 14.6 +/- 0.88, 22.0 +/- 0.80, and 32.4 +/- 1.88 mequiv. in normal dogs, and 12.3 +/- 1.30, 22.6 +/- 0.66, and 35.0 +/- 1.14 mequiv. in diabetic animals. In normal dogs shifts in acid-base balance had no effect on the level of plasma glucose or the turnover rate of glucose. In diabetic dogs plasma glucose level was significantly elevated by alkalosis. Plasma lactate was positively correlated with plasma pH (r = 0.69, p less than 0.01) and was in general higher in diabetic than in normal animals. The increment in concentration was due to a decreased clearance of lactate from the plasma. The irreversible disposal rate was not changed by the acid-base status. Whereas a larger fraction of lactate removed from the plasma appeared in glucose in diabetic animals, this fraction was not changed significantly by shifts in the acid-base status.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis↗
PubMed1987

Gluconeogenesis from acetone in diabetic rats.

Previous investigations have demonstrated that acetone is a true, if minor precursor of glucose in vivo. In diabetic rats 1.30% of the carbon atoms of circulating glucose arises from acetone, whereas 0.67% does in normal 3-day fasted animals. Calculated from these fractions and the turnover rate of glucose, 48 micrograms/kg. min acetone-carbon is converted to glucose-carbon in diabetic and 16 micrograms/kg. min in normal rats. In both groups of rats the labelling of plasma lactate was stronger than that of glucose. In view of these results we conclude that: the transfer of C-atoms from acetone to glucose increases in diabetes; acetone remains a minor source of glucose even in ketonemic diabetic rats.

Acetone↗
PubMed1986

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↗
PubMed1986

The effect of insulin-induced hypoglycaemia on the secretion of glucagon and hepatic glucose production in pancreatectomized dogs.

The concentration of plasma glucose in insulin deprived pancreatectomized dogs was decreased from the basal 385 +/- 44 to 65 +/- 12 mg/dL by the infusion of 7 mU X kg-1 X min-1 insulin. During the infusion, the plasma concentration of immunoreactive glucagon (IRG) did not change and hepatic glucose production was decreased. This is in contrast to earlier findings in alloxan diabetic dogs in which plasma IRG decreased in hypoglycaemia. The hypothesis is put forward that, in contrast to pancreatic alpha cells in which the effect of insulin prevails, neither insulin nor a decrease in the ambient concentration of glucose exerts any effect on the secretion of glucagon from extrapancreatic alpha cells.

Animals↗
PubMed1985

Gluconeogenesis from acetone in starved rats.

To non-anaesthetized rats starved for 3 days, [U-14C]acetone, NaH14CO3, L-[U-14C]lactate, [2-14C]acetate or D-[U-14C]- plus D-[3-3H]-glucose was injected intravenously. From the change in the plasma concentration of labelled acetone versus time after the injection, the metabolic clearance rate of acetone was calculated as 2.25 ml/min per kg body wt., and its rate of turnover as 0.74 mumol/min per kg. The extent and time course of the labelling of plasma glucose, lactate, urea and acetoacetate were followed and compared with those observed after the injection of labelled lactate, acetate and NaHCO3. The labelling of plasma lactate was rapid and extensive. Some 1.37% of the 14C atoms of circulating glucose originated from plasma acetone, compared with 44% originating from lactate. By deconvolution of the Unit Impulse Response Function of glucose, it was shown that the flux of C atoms from acetone to glucose reached a peak at about 100 min after injection of labelled acetone. In comparable experiments the transfer from lactate reached a peak at 14 min after the injection of labelled lactate. It was concluded that acetone is converted into lactate to a degree sufficient to account for the labelling of plasma glucose and is thus a true, albeit minor, substrate of glucose synthesis in starved rats.

Acetoacetates↗
PubMed1985

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↗
PubMed1985

HL-60 human leukaemic cell line colonies in agar capillaries: comparison of their reactivity to hormones, cytostatics and selective inhibitors of proliferation.

Colonies of the HL-60 human leukaemic promyelocytic cell line developing in semisolid agar gel capillaries were established. The endogenous inhibitory fraction GI-3, specific for myeloid cells, hydrocortisone and adriamycin decreased colony number in a dose dependent manner. ED50 values amounted to 220, 10(-1) and 4.5 X 10(-3), micrograms/ml respectively. If administered in combination, the endogenous inhibitor, steroid hormone and cytostatic agent exhibited a marked synergism. They affected HL-60 cells additively, and in some cases, a slight potentiation occurred. The experiments demonstrate the possibility of augmenting the inhibitory activity of cytostatics and hormones on leukaemic cells by endogenous inhibitors without an increase in drug toxicity.

Animals↗
PubMed1984

Gluconeogenesis from threonine in normal and diabetic rats.

L-[U-14C]Threonine was infused at a steady rate to non-anaesthetized rats starved for 1 or 3 days and to diabetic rats starved for 1 day. The rates of turnover of threonine, calculated from the equilibrium specific radioactivity (SA) of plasma threonine, were 5.79 +/- 1.00, 11.67 +/- 1.43 and 13.35 +/- 1.85 mumol/min per kg body wt. in 1-day-starved, 3-day-starved and diabetic rats respectively. The calculated turnover rate of threonine agreed well with the rate expected from the rate of protein turnover reported in the literature. The equilibrium SA of plasma alanine was 5.1-9.8% of that of threonine in the three groups of rats. The equilibrium SA of glucose was 1.42 and 2.90% of that of threonine in 1-day- and 3-day-starved rats respectively. From the non-equilibrium SA of glucose, it is estimated that a higher percentage of 14C atoms is transferred from threonine to glucose in diabetic than in non-diabetic rats. In spite of increases in gluconeogenesis from threonine in long-starved or diabetic rats, we conclude that threonine remains a minor contributor to plasma glucose. Since it is an essential amino acid, its turnover and contribution to the formation of plasma glucose is an index of catabolism and gluconeogenesis from tissue protein.

Alanine↗
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↗