Geza Hetenyi

Glucoregulatory responses in normal and diabetic dogs recorded by a new tracer method

Abstract A modification of the primed tracer infusion technique has been developed that permits the calculation of the rates of glucose production (Ra) and utilization (Rd) as continuous functions of time. A correction for the recycling of label into newly released glucose is also introduced. In normal dogs insulin (0.06 IU/kg i.v.) appreciably decreased Ra and increased Rd within 4 min during which time the glucose concentration in the plasma fell by only about 2–4 mg 100 ml . In normal dogs the intravenous injection of 0.18–0.29 g/kg glucose decreased Ra and abruptly increased Rd. The changes in Ra and Rd with respect to time followed oscillations typical of underdamped harmonic motion. In diabetic dogs the decrease of Ra was less or absent and the restoration of the basal plasma glucose level was largely due to an increase of Rd. These experiments allowed the estimation of the “pool fraction” which averaged 65 per cent of the total glucose pool in normal and 86 per cent in diabetic dogs.

Glucose Dynamics in Normal Subjects and Diabetic Patients before and after a Glucose Load

The method of successive measured injections of tracer using uniformly labeled C-14-glucose as tracer was applied to determine the pool size, apparent distribution space and the rates of endogenous glucose production and utilization in the fasting state and at twenty to 110 minutes after the intravenous injection of a 0.3 gm./kg. glucose load in six nondiabetic and sixteen diabetic subjects. The amount of intermixing glucose (“pool”) and the endogenous glucose production in the fasting state were higher in diabetics than in normals. The rate of glucose production decreased after the intravenous injection of the glucose in normals and nonketotic diabetics, but not in three out of four ketotic diabetics. The average rate of glucose utilization in the fasting state was found to be slightly higher in diabetics than in normals, but it increased to a lesser extent following the injection of glucose. This smaller increase and larger glucose pool are the main causes of decreased glucose tolerance in diabetics. The exponential slope of the concentration of glucose in the plasma after an intravenous injection of glucose (usually referred to as ‘K’) was not found to be correlated significantly with the rate of glucose utilization.

Effects of infusion of octanoate on glucose concentration in plasma and the rates of glucose production and utilization in dogs

The effects of intravenously administeredsodium octanoate, an 8-carbon saturated fatty acid, on glucose turnover were investigated in 16 healthy dogs by 2 isotope dilution technics: the method of successive measured injections of glucose-U-C 14 (14 dogs) and the procedure of priming injection-continuous infusion (2 dogs). The results obtained with both technics were similar. Intravenous administration of octanoate, with or without albumin, in amounts which produced a mean maximal increase of 4.3 mEq./L. in plasma FFA levels decreased significantly plasma glucose concentration by an average of 25 mg./100 ml., and decreased also the rates of plasma glucose appearance (production) and disappearance (utilization) by approximately 30 and 24 per cent of control values, respectively. Furthermore, the intermixing glucose mass was decreased significantly by about 34 per cent of control values during infusion of octanoate in saline. The apparent distribution space of glucose was not altered. The effect on glucose production, primarily the hepatic release of glucose, occurred within 3 minutes of starting the octanoate infusion and was quantitatively greater than the effect on glucose utilization by tissues accounting thereby for the decrements in the intermixing mass and plasma concentration of glucose. The possible mechanisms by which octanoate alters glucose turnover are discussed. Finally, intravenously administered octanoate produced no changes in plasma cholesterol and triglyceride concentrations.

Effect of Adrenal Steroids on Glucose Kinetics in Normal and Diabetic Dogs

The rates of endogenous glucose production, utilization, the amount of the intermixing glucose (“pool”) and the apparent distribution space were measured in conscious, trained normal and depancreatized dogs by the method of successive measured injections of tracer. During the intravenous infusion of hydrocortisone or methylprednisolone both the rates of glucose production and utilization fell in normal dogs. Since the same effect was obtained during the infusion of hydrocortisone in depancreatized dogs this effect of adrenal steroids does not seem to be due to an extra release of insulin. In normal dogs, daily injections of 4 mg. per kilogram of methylprednisolone for one week significantly increased the rates of glucose production and utilization and also the amount of intermixing glucose and the apparent glucose space, without any significant change in the concentration of glucose in the blood plasma. Prolongation of methylprednisolone treatment for a second week caused a further increase in all four parameters again with no change in plasma glucose level. The intravenous infusion of glucose was found to diminish the rate of endogenous glucose production to the same degree before as after one week of methylprednisolone treatment. In diabetic dogs deprived of insulin, two daily injections of methylprednisolone increased the rate of glucose production and the plasma concentration but not the apparent distribution space of glucose. These experiments indicate that in dogs the homeostasis of plasma glucose level is maintained in spite of markedly increased gluconeo genesis if pancreatic function is unimpaired.

Mitochondrial myelin-like figures: A non-specific reactive process of mitochondrial phospholipid membranes to several stimuli

SummarySmall concentric arrays resembling myelin figures were found in the liver cell mitochondria of fasted rats, of fasted rats given insulin and glucose, and of untreated fed rats. In addition to myelin-like figures, interdigitation of the membranes of adjacent mitochondria were common and often formed chains of mitochondria. Fusion between the outer membranes of mitochondria and protrusions of part of one mitochondrion into another were also found. Since mitochondrial myelin-like figures were even occasionally observed in control fed animals and since identical structures have been described in a number of unrelated conditions, it is concluded that they are not aetiologically specific. The myelin-like figures are considered to represent a form of focal mitochondrial phospholipid membrane degeneration under various stimuli.

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)

Absolute Rates of Glucose Production, Accumulation, and Utilization in the Dog at Pancreatectomy and Thereafter

1. The method of successive measured injections of tracer has been used to determine absolute rates of glucose appearance (production), accumulation, disappearance, excretion and utilization in six fasting bitches at times before and after total pancreatectomy. 2. The rate of glucose utilization underwent a great reduction within minutes following pancreatectomy. 3. In contrast, the rate of glucose production did not change greatly at this time. 4. As a consequence, there was a rapid accumulation of glucose in the dog when measured in terms of the amount which intermixed with the injected tracer, and as seen less directly by a rise in the concentration of glucose in the blood plasma. 5. The increase in blood glucose level following pancreatectomy was accompanied by a restoration in the average rate of glucose utilization to about two thirds of its value before pancreatectomy, and by glycosuria. 6. Both the rate of production and that of utilization increased moderately during the first one or two days following total pancreatectomy. Thereafter they decreased progressively and ketonuria became severe. 7. No effect of general anesthesia (Nembutal) was noted on the above patterns of change in glucose rates.

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.

Intestinal glucose formation

Abstract A low percentage of the carbon atoms from alaline and glycine, but not from lactate appears in glucose recovered from the incubation medium of everted intestinal sacs.