Staub-Traugott Effect Research Articles

Improved tolerance to sequential glucose loading (Staub-Traugott effect): size and mechanisms

Improved glucose tolerance to sequential glucose loading (Staub-Traugott effect) is an important determinant of day-to-day glycemic exposure. Its mechanisms have not been clearly established. We recruited 17 healthy volunteers to receive two sequential oral glucose tolerance tests (OGTTs), at time 0 min and 180 min (Study I). The protocol was repeated on a separate day (Study II) except that plasma glucose was clamped at 8.3 mmol/l between 60 and 180 min. beta-Cell function was analyzed by mathematical modeling of C-peptide concentrations. In a subgroup, glucose kinetics were measured by a triple-tracer technique (infusion of [6,6-(2)H(2)]glucose and labeling of the 2 glucose loads with [1-(2)H]glucose and [U-(13)C]glucose). In both Studies I and II, the plasma glucose response to the second OGTT equaled 84 +/- 2% (P = 0.003) of the response to the first OGTT. Absolute insulin secretion was lower (37.8 +/- 4.3 vs. 42.8 +/- 5.1 nmol/m(2), P = 0.02), but glucose potentiation (i.e., higher secretion at the same glycemia) was stronger (1.08 +/- 0.02- vs. 0.92 +/- 0.02-fold, P = 0.006), the increment being higher in Study II (+36 +/- 5%) than Study I (+19 +/- 6%, P < 0.05). In pooled data, a higher glucose area during the first OGTT was associated with a higher potentiation during the second OGTT (rho=0.60, P = 0.002). Neither insulin clearance nor glucose clearance differed between loads, and appearance of glucose over 3 h totalled 60 +/- 6 g for the first load and 52 +/- 5 g for the second load (P = not significant). Fasting endogenous glucose production [13.3 +/- 0.6 micromol x min(-1) x kg fat-free mass (FFM)(-1)] averaged 6.0 +/- 3.8 micromol x min(-1) x kg FFM(-1) between 0 and 180 min and 1.7 +/- 2.6 between 180 and 360 min (P < 0.03). Glucose potentiation and stronger suppression of endogenous glucose release are the main mechanisms underlying the Staub-Traugott effect.

Effect of Added Fat on the Plasma Glucose and Insulin Response to Ingested Potato Given in Various Combinations as Two Meals in Normal Individuals

In normal subjects, ingestion of fat with potato in a morning meal resulted in a decrease in the glucose response. Therefore, we wished to determine whether a fat-induced decrease in blood glucose also would be observed after a second identical meal. In addition, we were interested in determining if fat ingestion with a morning meal would have an effect on the blood glucose and insulin responses to a second meal not containing fat. Nine healthy male subjects ingested two meals consisting of an amount of potato containing 50 g carbohydrate, either alone or with 50 g fat as butter. The meals were served in four combinations as follows: 1) potato for the first meal, potato for the second meal; 2) potato for the first meal, potato with fat for the second meal; 3) potato with fat for the first meal, potato for the second meal; and 4) potato with fat for the first meal, potato with fat for the second meal. Meals were ingested at 8:00 A.M. and noon. Plasma glucose and C-peptide, serum insulin, triglyceride, and free fatty acid (FFA) concentrations were determined over an 8-h period. The integrated area responses to the meals were quantified over the subsequent 4-h period using the fasting value or the noon value as baseline for the first and second meals, respectively. When the first meal contained potato only, the glucose area response to the second meal was significantly less when the second meal contained fat. However, fat ingestion had no effect on the glucose area response to the second meal when fat was present in the first meal. The insulin area responses to the first and second meals were similar after ingestion of potato or potato with fat. However, the insulin response to the second meal always was less than that to the first meal. The C-peptide area responses after ingestion of the second meal also were all higher than those after the first meal. The triglyceride area responses were slightly negative after ingestion of potato alone in the first meal. When fat was ingested, they were positive. When the first meal contained fat but the second meal did not, there was a rise in triglyceride concentration after the second meal as well as after the first meal. That is, a rise occurred without ingestion of fat with the second meal. If fat was present in the second meal the rise was even greater. The FFA area responses were similar to the triglyceride area responses. When fat was ingested with carbohydrate in either the first or second meal, the glucose area response was decreased. However, when both meals contained fat, a decrease in the glucose area response did not occur with the second meal. The glucose area responses all were greater after the second meal compared with those after the first meal, i.e., the opposite of a Staub-Traugott effect was observed. The insulin area responses to the first and second meals were similar whether fat was ingested or not.

Potentiation of glucose-stimulated insulin release by tolazamide and paradoxical absence of glucose facilitation (Staub effect) in non-insulin-dependent diabetes

Acceleration of glucose tolerance after repetitive intravenous glucose loads (Staub-Traugott effect) has not previously been tested in non-insulin-dependent diabetes (NIDDM). Six overt, untreated subjects were administered three hourly IV glucose tolerance tests (GTT). The glucose disappearance rate (K) changed very little between loads, indicating a suppressed Staub effect. However, insulin levels increased with each load. The characterstic loss of early phase insulin release after the first intravenous glucose injection was recovered with the third injection. After four months of tolazamide treatment the fasting plasma glucose fell from 180 ± 19 to 134 ± 13 mg/dL. Despite dramatic potentiation of glucose-stimulated insulin release and further improvement of early phase insulin release, K values again failed to progressively rise. This paradox occurred even in three additional subjects tested after two years of tolazamide treatment, suggesting that tolazamide may not ameliorate the postreceptor defects that impede the expression of the Staub effect. The applicability of the glucose facilitatory effect to the treatment of NIDDM might be limited to subjects in whom adjunctive measures have reestablished effective tissue responsiveness to endogenous insulin.

Potentiation of 14C-glucose oxidation by priming glucose loads: Effect of starvation

The mechanism of the Staub-Traugott effect or facilitated glucose disposal after successive glucose loads has remained elusive. In earlier publications, we have shown it can be independent of circulating hormone and free fatty acid levels. We have also proposed that it might partially depend on the rapid induction of glycogytic pathways, which are known to be depressed by prolonged fast. Mature rats were given 1.75 gm/kg glucose doses intravenously at 60-minute intervals. Respiratory CO 2 was collected at 15-minute intervals over a 120-minute period following administration of the carrier glucose plus 6 μCi 100 gm rat weight of 14C- d-glucose, given either as the first, second, or third challenge. In rats fasted 14 hours there was potentiation of labeled CO 2 recovered after each successive load. After three days of starvation, both relative 14C-glucose oxidation to 14CO 2 as well as absolute 14CO 2 increments after each load were lower. The changes in relative oxidation of an intravenous glucose load might partly account for the facilitated disposal of blood glucose seen in the second and third hours in overnight-fasted rats (Staub-Traugott effect). However, although rats fasted for three days had suppressed the Staub effect, the increments in oxidation were attenuated but still present, suggesting that alterations of other pathways must participate in the disappearance of this effect after fasting.

The Staub-Traugott effect. Evidence for multifactorial regulation of a physiological function

Previous exposure to large amounts of glucose facilitates the disposal of a subsequent load of the sugar (priming or Staub-Traugott effect). We have investigated whether, in man, the classical effect can also be induced by more physiological loads of glucose and whether a priming effect is accompanied by augmented insulin release. To facilitate interpretation of results, a second exposure to glucose was imposed at a time point following the first exposure when the subjects were again euglycaemic. Initial infusion of glucose significantly diminished the hyperglycaemia seen after the subsequent ingestion of 1.75 g/kg of glucose. The corresponding incremental insulin response was diminished while the integrated absolute levels of the hormone were unaffected by prior i.v. glucose. Initial ingestion of 0.5 g/kg of glucose slightly reduced the glycaemic but did not affect the insulin response to a second oral load. Initial ingestion of the same oral glucose load clearly facilitated the disposal of 12.5 g of glucose subsequently injected i.v. Again, this effect of priming with glucose was not accompanied by any priming effect on insulin levels. The lack of enhancement of peripherally measured insulin secretion seemed, if anything, to overestimate B-cell secretory rates since the ratio of insulin to C-peptide was increased (from 37 to 89) after priming with glucose, suggesting that the hepatic clearance of insulin was decreased during the second glucose challenge. It is concluded that (1) facilitation of glucose disposal by previous glucose administration can be induced by amounts of glucose equivalent to those associated with meal intake, (2) enhancement of insulin release is not an obligatory component of the facilitated glucose disposal, (3) decreased hepatic clearance of insulin may accompany the Staub-Traugott effect.

Preservation of glucose tolerance and insulin secretory response to repeated glucose loads by the feeding of minimal glucose during prolonged fasting

The facilitation of glucose disposal (Staub-Traugott effect) and potentiation of serum insulin (IRI) concentration normally occurring after closely spaced intravenous glucose loads, are known to disappear after prolonged starvation. To study the effects of minimal amounts of glucose during fasting upon the insulin response and disposal of repeated intravenous glucose tolerance tests, obese volunteers were fasted for a mean of 25 ± 2 days, while receiving either 8 or 16 gm of oral glucose every 6 hr, and compared to totally fasted subjects without glucose supplementation. Weight loss rate and the fall in basal IRI and glucose levels were similar to those of totally fasted subjects. However, the Staub-Traugott effect and insulin secretory dynamics after stimulation by repetitive intravenous glucose loading were preserved by this glucose modified fast, while baseline serum glucagon levels (IRG) were significantly lower, and the basal IRI/IRG ratios were thus unchanged from the fed state. IRG and free fatty acid suppression were similar in the fed and glucose modified fasted states. Lactic acid levels increased as expected after the repeated glucose injections in the fed state, but failed to do so after the prolonged modified fast until the second and third repetitive glucose loads, in which a significant rise coincided with accelerated glucose disposal. It is suggested that minimal amounts of carbohydrate during fasting preserve the insulin potentiating action of glucose, preferentially sparing a delayed releasable pool of insulin, while protecting the glucose utilization mechanisms, including increased glycolysis, responsible for the Staub-Traugott effect.

The Staub-Traugott phenomenon III. Effects of starvation1–2

Improved tolerance with closely spaced successive glucose loads is known as the Straub-Traugott effect. Results of previous studies from this laboratory suggest that this phenomenon is not dependent upon changes in circulating growth hormone or insulin, but may depend on nutrient induction of essential glycogenic and glycolytic enzymes. To test this thesis, three, hourly spaced, intravenous glucose tolerance tests were administered to obese subjects before and at the conclusion of a prolonged fast. While a clear Staub-Traugott effect was shown in the fed state, this effect was conspicuously absent after long-term caloric deprivation. Compared to the findings before fasting, insulin levels after prolonged caloric deficit were similar during the initial intravenous glucose challenge but failed to elicit incremental insulin rise with successive glucose loads, in keeping with earlier suggestions that distinct mechanisms mediate the insulin-initiating and potentiating actions of glucose. After starvation there was greater suppression of plasma free fatty acids and immunoreactive glucagon levels. Initial intravenous glucose tolerance after fasting was either frankly improved or unchanged in all but one of the subjects studied. Absence of the Staub-Traugott effect after fasting, however, would appear to reflect a failure of nutrient induction of improved glucose metabolism as alterations in glucoregulatory hormones and free fatty acids do not consistently explain the presence or absence of this phenomenon in the different metabolic states so far studied.

Improved tolerance to successive glucose loads in acromegaly

The mechanism of the Staub-Traugott effect, or facilitated glucose disposal with closely timed successive glucose loads, remains poorly understood. Progressive suppression of growth hormone has been suggested as an explanation. To test this hypothesis, three successive intravenous glucose loads were administered to seven active acromegalic patients and six healthy controls. All subjects showed a clear Staub-Traugott effect despite failure of hyperglycemia to suppress abnormally high growth hormone levels in the acromegalics. Except for higher basal and incremental insulin release in the acromegalic patients, patterns of insulin secretion and suppression of free fatty acids were not substantially different from controls. These studies clearly suggest that hyperglycemia-induced suppression of growth hormone is not the cause of the Staub-Traugott effect.

Absence of facilitated glucose disposal (Staub-Traugott effect) in subjects with hypopituitarism

Improved glucose tolerance follows glucose challenges given in rapid succession, the Staub-Traugott effect. The cause for this facilitated glucose disposal is not clear. Augmented insulin release, prior “insulinization” of cells, and suppression of a pituitary factor or free fatty acids (FFA) are previously suggested mechanisms. For information bearing on the role of the pituitary in this phenomenon, study of the Staub effect was undertaken in hypopituitary patients receiving replacement thyroid, cortisone, and sex-steroid therapy and in normal untreated controls. All subjects received three intravenous injections of glucose (0.5 g/kg) at hourly intervals. Plasma glucose, FFA, and insulin were measured. Whereas a definite Staub effect was seen in each control subject, this phenomenon was conspicuously absent in seven hypopituitary patients similarly studied. Patterns of peripheral insulin response were similar for both groups: FFA levels fell more slowly in the hypopituitary subjects. Normal pituitary function appears to be required for the Staub effect. Incremental peripheral insulin levels do not explain the effect. Subnormal suppression of free fatty acids and impaired induction of key glycolytic and glycogenic enzymes are alternative explanations for the absence of the Staub effect in hypopituitary subjects.

The relation between free fatty acid levels and tolerance for glucose in a triple glucose tolerance test

The improved glucose tolerance observed in a multiple glucose tolerance test (Staub-Traugott effect) has been observed in dogs with concomitant measurement of immunoreactive insulin (IRI) and plasma free fatty acid (FFA). It was possible to reduce and in one experiment eliminate the improved glucose tolerance observed in the Staub-Traugott procedure. This was done in successive experiments in which the glucose challenge dose was 1 × BW 0 period; 7 grams: (1) by injecting octanoate (0.1 mmoles/kg each hour) at the same time as the glucose; (2) by supplementing the injections with the infusion of octanoate (0.1 mmoles/kg/15 mins) during the second and third hours; (3) by repeating this last procedure after a seven day fast. Similar experiments were carried out with a larger glucose challenge dose (1 g/kg). Glucose tolerance appeared to depend as strongly on FFA levels as it did on IRI levels, and improvement in glucose tolerance occurred only when there was an associated reduction in FFA for a given glucose challenge. A measure of the Staub-Traugott effect was defined in terms of the different glucose utilizations during a multiple glucose tolerance test. An increase in the mean FFA levels achieved before or during a multiple glucose tolerance test lessened or eliminated the Staub-Traugott effect.

Improved glucose disappearance following repeated glucose administration. Serum insulin growth hormone and free fatty acid levels during the Staub-Traugott effect.

The Staub-Traugott effect, the phenomenon of improved tolerance to repeated glucose administration, was investigated in fifteen healthy volunteers. Two glucose loads were administered intravenously forty-six minutes apart. Blood samples were taken periodically after each glucose infusion. The second glucose load was given immediately after the first sampling period. The glucose disappearance rate (K) improved after the second infusion from 2.04 ± 0.23 to 2.87 ±0.16 (p &amp;lt; 0.001). Serum immunoreactive insulin levels rose promptly after the glucose infusions, but while a decrease was noted following the first peak, the levels remained persistently elevated after the second glucose load. Growth hormone levels decreased and were slightly lower yet six to nine minutes after completion of the infusions. A striking reduction of free fatty acid levels followed the first glucose load; values fell to 50 per cent of the fasting levels prior to, and decreased even further following, the second infusion. Thus, the improved K of the second glucose tolerance test was associated with already diminished serum free fatty acid levels.

PITUITARY FUNCTION IN ADIPOSO GENITAL DYSTROPHY (FRÖHLICH)11

SINCE THE syndrome of dystrophia adioposogenitalis was first described by Frohlich (1)in 1901, its pathogenesis was generally assumed to be inherent in some aberration of the pituitarygland. As early as 1909, objections to the pituitary origin of the disease were heard (2). Pathologic reports have demonstrated lesions of the hypophysis, of neighboring cephalic structures suchasthe infundibulum or infundibulo-hypothalamic region and indeed cases with no demonstrable organicdisease. In the light of more recent knowledge a wider approach to the pathogenesis of Frohlich'ssyndrome becomes possible. A series of children displaying a typical pic ture of the disease were studied from the point of view of (a) fat metabolism hormone concentration of the blood; (b) carbohydrate metabolism as reflected not alone in the dextrose tolerance test but in their sensitivity to insulin, their hyperglycemic re sponse to epinephrin and their response to the Staub-Traugott effect; (c) sensitivity to the induction of ketonemia o...