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Original Studies |
Departments of Medicine, Molecular Physiology, and Biophysics, Vanderbilt University School of Medicine and Nashville Veterans Affairs Medical Center, Nashville, Tennessee 37232
Address all correspondence and requests for reprints to: Stephen N. Davis, M.D., Division of Diabetes and Endocrinology, Vanderbilt University School of Medicine, 712 Medical Research Building II, Nashville, Tennessee 37232-6303. E-mail: steve.davis{at}mcmail.vanderbilt.edu
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Abstract |
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Introduction |
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The acute physiologic effects of an episode of prior hypoglycemia on metabolism during subsequent same-day hypoglycemia in normal man have not been determined. The metabolic actions of catecholamines, cortisol, and GH are prolonged and produce a milieu of insulin resistance (8, 9, 10). Therefore, although levels of neuroendocrine hormones are important determinants of the counterregulatory response, it is their metabolic end points that maintain homeostasis. Thus, two additional unanswered questions need to be addressed: 1) to what extent is metabolism altered by prior same-day hypoglycemia, and 2) will an altered metabolic environment modulate actions of counterregulatory hormones during a subsequent, near-term episode of hypoglycemia?
Therefore, the aims of this study were to determine whether 2 h of moderate hypoglycemia (50 mg/dL) could diminish neuroendocrine and symptomatic responses to subsequent hypoglycemia induced 2 h later, and to determine how same-day prior hypoglycemia alters intermediary metabolism during subsequent near-term hypoglycemia in normal man.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We studied 24 healthy volunteers (12 male and 12 female) aged 29 ± 2 yr with a body mass index of 22 ± 1 kg/m2 and glycosylated hemoglobin (hemoglobin A1c) of 4.5 ± 0.1% (normal range, 4–6.5%). None were taking medication or had a family history of diabetes. Each subject had a normal blood count, plasma electrolytes, and liver and renal function. All gave written informed consent. Studies were approved by the Vanderbilt University human subjects Institutional Review Board. The subjects were asked to avoid any exercise and consume their usual weight-maintaining diet for 3 days before each study. Each subject was admitted to the Vanderbilt Clinical Research Center at 1700 h on the evening before an experiment. All subjects were studied after an overnight 10-h fast.
Glucose clamp studies
A total of 16 subjects attended for two separate randomized experiments (repeat hypoglycemia and repeat euglycemia studies) separated by at least 2 months. Subjects were blinded as to the order of the two glucose clamp studies. A total of 8 additional subjects participated in a single 1-day study (morning euglycemia, afternoon hypoglycemia). On the morning of each study, after an overnight fast, two iv cannulae were inserted under 1% lidocaine local anesthesia. One cannula was placed in a retrograde fashion into a vein on the back of the hand. This hand was placed in a heated box (55-60 C) so that arterialized blood could be obtained (11). The other cannula was placed in the contralateral arm so that 20% glucose could be infused via a variable rate volumetric infusion pump (Imed, San Diego, CA).
Repeat hypoglycemia experiments
After insertion of venous cannulae, a period of 90 min was allowed to elapse followed by a 30-min basal control period and a 120-min hyperinsulinemic-hypoglycemic experimental period. At time zero, a primed continuous infusion of insulin (12) was administered at a rate of 9 pmol/kg·min for 120 min. Plasma glucose levels were measured every 5 min, and a variable infusion of 20% dextrose was adjusted so that plasma glucose levels were held constant at 2.9 ± 0.1 mmol/L (13). Potassium chloride was infused at a rate of 5 mmol/h during each study. After completion of the initial 2-h test period, the insulin infusion was discontinued and plasma glucose was rapidly restored to euglycemia with 20% dextrose. Plasma glucose was maintained at euglycemia for a further 2 h by initially adjusting an exogenous glucose infusion. However, by 100 min, the exogenous glucose infusion was discontinued as subjects could maintain euglycemia without external glucose support. Two hours after cessation of the morning experiment, insulin was restarted and a second hyperinsulinemic-hypoglycemic clamp, identical with the morning clamp, was performed.
Repeat euglycemia experiments
These experiments followed a similar format to the previously described hypoglycemia experiments, with the exception that identical morning and afternoon hyperinsulinemic (9 pmol/kg·min) euglycemic (5.0 mmol/L) clamps were performed (14). An exogenous glucose infusion was required to maintain euglycemia during the entire 2-h interval between morning and afternoon glucose clamp studies.
Morning euglycemia, afternoon hypoglycemia experiments
These experiments also followed a similar format to the above experiments, with the exception that the morning study consisted of a 2-h hyperinsulinemic (9 pmol/kg·min) euglycemic (5.0 mmol/L) clamp, followed 2 h later by an afternoon 2-h hyperinsulinemic (9 pmol/kg·min) hypoglycemic (2.9 mmol/L) clamp. As described above, an exogenous glucose infusion was used to maintain euglycemia during the 2-h interval between morning and afternoon glucose clamp studies.
Indirect calorimetry
Air flow, O2, and CO2 concentrations in expired gases were measured by a computerized open-circuit system (Medical Graphics Corp., Yorba Linda, CA). Rates of fat and carbohydrate oxidation and energy expenditure before and during the final 30 min of glucose clamp studies were calculated from rates of measured VO2 and VCO2 as described by Frayn (15). Rates of nonoxidative glucose disposal were calculated by subtracting the amount of glucose disappearance as measured by indirect calorimetry from the total glucose infusion rate required to maintain euglycemia (16).
Analytical methods
The collection and processing of blood samples have been described elsewhere (17). Plasma glucose concentrations were measured in triplicate using the glucose oxidase method with a glucose analyzer (Beckman Coulter, Inc., Fullerton, CA). Glucagon was measured according to a modification of the method of Aguilar-Parada et al. (18) with an interassay coefficient of variation (CV) of 12%. Insulin was measured as previously described (19) with an interassay CV of 9%. Catecholamines were determined by high-performance liquid chromatography (20) with an interassay of 12% for epinephrine and 8% for norepinephrine. We made two modifications to the procedure for catecholamine determination: 1) we used a five-point rather than a one-point standard calibration curve; and 2) we spiked the initial and final samples of plasma with known amounts of epinephrine and norepinephrine so accurate identification of the relevant respective catecholamine peaks could be made. Cortisol was assayed using the Clinical Assays Gamma Coat RIA kit with an interassay CV of 6%. GH was determined by RIA (21) with a CV of 8.6%. Pancreatic polypeptide was measured by RIA using the method of Hagopian et al. (22) with an interassay CV of 8%. Lactate, glycerol, alanine, and ß-hydroxybutyrate were measured in deproteinized whole blood using the method of Lloyd et al. (23). Nonesterified fatty acids (FFA) were measured using the WAKO kit (Wako Pure Chemical Industries Ltd., Richmond, VA) adopted for use on a centrifugal analyzer (24).
Blood for hormones and intermediary metabolites was drawn twice during the control period and every 15 min during the experimental period. Cardiovascular parameters (pulse, systolic, diastolic, and mean arterial pressure) were measured noninvasively by a Dinamap (Critikon, Tampa, FL) every 10 min throughout each 210-min study. Gas exchange measurements were performed during the control period and during the final 30 min of each glucose clamp.
Hypoglycemic symptoms were quantified using a previously validated semiquantitative questionnaire (25). Each individual was asked to rate his/her experience of the symptoms twice during the control period and every 15 min during experimental periods. Symptoms measured included tiredness, confusion, hunger, dizziness, difficulty thinking, blurred vision, sweaty, tremor, agitation, hot/thirsty, and pounding heart. The ratings of the first six symptoms were summed to get a neuroglycopenic score whereas the ratings from the last five symptoms provide an autonomic symptom score.
Materials
Human regular insulin was purchased from Eli Lilly & Co. (Indianapolis, IN). The insulin infusion solution was prepared with normal saline and contained 3% (vol/vol) of the subjects’ own plasma.
Statistical analysis
Data are expressed as mean ± SE unless otherwise stated, and analyzed using standard, parametric, two-way ANOVA with repeated measures design. This was coupled with Student’s t test to delineate at which time statistical significance was reached. A value of less than 0.05 indicated significant difference.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Insulin levels increased from 36 ± 6 to 492 ± 60
pmol/L by the final 30 min of hypoglycemia in the morning and by
similar amounts (48 ± 12 to 528 ± 66 pmol/L) during
afternoon hypoglycemia. Insulin levels were significantly increased
(P < 0.05) at the start of afternoon hypoglycemia
following morning hypoglycemia (Fig. 1
).
Plasma glucose levels were also significantly increased at the start of
hypoglycemia following morning hypoglycemia (5.7 ± 0.1
vs. 5.1 ± 0.1 mmol/L; P < 0.01).
Plasma glucose levels were maintained at 5.1 ± 0.1 mmol/L during
morning euglycemia and at 2.9 ± 0.1 mmol/L during all morning and
afternoon hypoglycemia studies.
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Epinephrine levels increased from basal values of 0.13 ±
0.03 to 3.7 ± 0.4 nmol/L by the final 30 min of morning
hypoglycemia. Despite equivalent hypoglycemia, epinephrine levels
during the afternoon following morning hypoglycemia (2.0 ± 0.3
nmol/L) were significantly blunted (P < 0.01) compared
with morning values (Fig. 2). Morning
euglycemia had no effect on epinephrine responses during
afternoon hypoglycemia 0.1 ± 0.03 to 3.6 ± 0.3 nmol/L).
Plasma norepinephrine levels (Fig. 2) increased significantly during
morning hypoglycemia (1.3 ± 0.3 to 2.1 ± 0.3 nmol/L;
P < 0.01) and during afternoon hypoglycemia following
morning euglycemia (1.2 ± 0.2 to 1.8 ± 0.2 nmol/L;
P < 0.05). Following morning hypoglycemia,
norepinephrine levels remained similar to baseline (1.4 ± 0.3 to
1.7 ± 0.3 nmol/L) during afternoon hypoglycemia. Pancreatic
polypeptide responses (Fig. 2) were also significantly greater
(P < 0.01) during morning (20 ± 3 to 165 ±
19 pmol/L) compared with afternoon hypoglycemia (27 ± 6 to
88 ± 14 pmol/L). Morning euglycemia had no effect on pancreatic
polypeptide responses during afternoon hypoglycemia (18 ± 4 to
149 ± 26 pmol/L).
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). Morning hypoglycemia resulted in
significantly blunted (P < 0.01) glucagon responses
during afternoon hypoglycemia (51 ± 4 to 73 ± 7 ng/L).
Plasma cortisol levels increased from 303 ± 56 to 800 ± 56
nmol/L in the morning and from 262 ± 83 to 826 ± 98 nmol/L
during afternoon hypoglycemia following morning euglycemia. These
values were significantly greater (P < 0.05) than the
response in the afternoon following morning hypoglycemia (442 ±
112 to 662 ± 83 nmol/L). GH levels (Fig. 3) increased from 3
± 1 to 40 ± 4 µg/L during morning hypoglycemia and from 2
± 1 to 36 ± 3 µg/L during afternoon hypoglycemia following
morning euglycemia, which were also significantly greater
(P < 0.05) than the response following morning
hypoglycemia (6 ± 2 to 32 ± 4 µg/L). Basal levels of
epinephrine, norepinephrine, glucagon, and pancreatic polypeptide were
similar at the start of morning and afternoon hypoglycemia. Cortisol
and GH levels were increased (P < 0.05) at the start
of afternoon compared with morning hypoglycemia. Thus, 2 h of
interval euglycemia was sufficient for the majority of
counterregulatory hormones to return to usual postabsorptive
values.
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Intermediary metabolism at the start of afternoon experiments was significantly affected by morning hypoglycemia. Despite the significantly elevated insulin and glucose values, plasma FFA (720 ± 70 vs. 555 ± 90 µmol/L), blood glycerol (95 ± 10 vs. 50 ± 7 µmol/L), and ß-hydroxybutyrate levels (110 ± 30 vs. 56 ± 20 µmol/L) were significantly increased (P < 0.05) at the start of afternoon following morning hypoglycemia, respectively. Similarly, blood lactate was also significantly increased at the start of afternoon hypoglycemia compared with morning studies (1170 ± 140 vs. 590 ± 50 µmol/L; P < 0.01).
Steady state values of intermediary metabolites were similar during the
final 30 min of morning and afternoon hypoglycemia. However, following
morning hypoglycemia incremental from baseline metabolic responses
during afternoon hypoglycemia were significantly reduced. Thus, there
were greater reductions (P < 0.05) of FFA (
468 ± 25 vs. 362 ± 30 µmol/L), glycerol
(-32 ± 4 vs. +8 ± 3 µmol/L), and
ß-hydroxybutyrate ( 85 ± 9 vs. 43 ± 5
µmol/L) during afternoon hypoglycemia following morning hypoglycemia.
Similarly, the increase in blood lactate was attenuated in the
afternoon following morning hypoglycemia (540 ± 60 vs.
820 ± 70 µmol/L; P < 0.05). Following morning
euglycemia, blood lactate responses during hypoglycemia were preserved
but glycerol, ß-hydroxybutyrate, and FFA levels were attenuated
compared with morning hypoglycemia values (Table 1). Despite reduced neuroendocrine
responses, glucose infusion rates required to maintain hypoglycemia
were lower (P < 0.05) during the final 30 min of
afternoon hypoglycemia following morning hypoglycemia (3.5 ± 1.4
vs. 8.0 ± 1.7 µmol/kg·min), respectively (Table 2). Following morning euglycemia, and
despite preserved neuroendocrine responses, glucose infusion rates were
significantly increased (P < 0.01) during afternoon
hypoglycemia (21.5 ± 5.5 µmol/kg·min).
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Respiratory quotient (RQ) was significantly increased at the start of afternoon hypoglycemia following morning hypoglycemia (0.86 ± 0.02 vs. 0.83 ± 0.01; P < 0.05). RQ increased significantly during morning hypoglycemia (0.83 ± 0.01 to 0.91 ± 0.02; P < 0.01) but remained similar to baseline during subsequent afternoon hypoglycemia (0.86 ± 0.02 to 0.89 ± 0.03). Consistent with the changes in RQ, glucose oxidation increased by a greater amount (P < 0.01) during morning hypoglycemia (8.8 ± 1.1 to 15.4 ± 2.2 µmol/kg·min) compared with subsequent afternoon hypoglycemia (11.6 ± 1.1 to 14.3 ± 1.7 µmol/kg·min). Lipid disappearance declined to similar levels during morning and afternoon hypoglycemia. Following morning euglycemia, RQ was significantly increased at the start of afternoon hypoglycemia (0.92 ± 0.04 vs. 0.86 ± 0.02; P < 0.05). RQ increased significantly during afternoon hypoglycemia following morning euglycemia (0.92 ± 0.04 vs. 0.98 ± 0.03; P < 0.05). Consistent with changes in RQ, glucose oxidation increased significantly during afternoon hypoglycemia following morning euglycemia (12.3 ± 2.8 to 17.6 ± 2.1 µmol/kg·min; P < 0.05).
Hypoglycemic symptom scores
Symptom scores were similar at the start of morning and afternoon studies (16 ± 1 vs. 17 ± 2, respectively). Incremental hypoglycemic symptom scores were significantly reduced during afternoon hypoglycemia compared with morning hypoglycemia and euglycemia(+10 ± 1 vs. +24 ± 4, respectively; P < 0.01). Increases in hypoglycemic symptom scores (+20 ± 3) were unaffected by morning euglycemia. Although increases in autonomic symptom scores were reduced during afternoon compared with morning hypoglycemia (+7 ± 1 vs. +12 ± 2; P < 0.05), the greatest blunting was observed in neuroglycopenic symptoms (+3 ± 1 vs. +12 ± 2; P < 0.01).
Cardiovascular responses during hypoglycemia
Heart rate and systolic and diastolic blood pressure were similar at the start of morning and afternoon hypoglycemia studies. Heart rate increased similarly during morning (59 ± 4 to 65 ± 4 beats/min) and afternoon studies (59 ± 4 to 70 ± 5 beats/min). Systolic blood pressure increased similarly during morning (108 ± 4 to 113 ± 3 mm Hg) and afternoon (105 ± 5 to 109 ± 5 mm Hg) and diastolic blood pressure decreased by similar levels during morning (62 ± 3 to 52 ± 2 mm Hg) and afternoon (59 ± 3 to 52 ± 3 mm Hg) studies.
Hyperinsulinemic euglycemic experiments
Plasma glucose (5.2 ± 0.1 vs. 5.2 ± 0.1 mmol/L) and insulin (30 ± 6 vs. 30 ± 9 pmol/L) levels were identical at the start of morning and afternoon euglycemic studies respectively. Steady state plasma glucose values (5.1 ± 0.1 vs. 5.2 ± 0.1 mmol/L) and insulinemia (495 ± 48 vs. 490 ± 42 pmol/L) were similar during morning and afternoon experiments respectively. Plasma glucagon levels also declined similarly during morning (41 ± 2 to 33 ± 2 ng/L) and afternoon (37 ± 3 to 31 ± 2 ng/L). In marked contrast to morning hypoglycemia studies, morning euglycemia improved insulin sensitivity during afternoon studies. Despite equivalent glycemia, glucagon, and insulin levels, glucose infusion rates required to maintain euglycemia were significantly increased in the afternoon (60.2 ± 5.8 vs. 43.2 ± 6.6 µmol/kg·min; P < 0.05). Blood glycerol and lactate levels were similar during morning and afternoon euglycemic studies. FFA were significantly (P < 0.01) reduced at the start of afternoon (260 ± 72 µmol/L) compared with morning studies (506 ± 50 µmol/L). Indirect calorimetric values were similar during morning and afternoon experiments as follows: RQ, 0.92 ± 2 vs. 0.94 ± 3; glucose disappearance, 17.6 ± 1.7 vs. 18.4 ± 2.2 µmol/kg·min; and lipid disappearance, 0.3 ± 0.1 vs. 0.2 ± 0.1 mg/kg·min, respectively. Nonoxidative rates of glucose disposal (total glucose infusion rates minus glucose disappearance rates from indirect calorimetry) were significantly increased in the afternoon compared with morning euglycemic studies (41.8 ± 5.0 vs. 24.8 ± 3.8 µmol/kg·min; P < 0.01).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The integrated physiologic effects of a prior episode of hypoglycemia on subsequent same-day hypoglycemia are undetermined. Previous studies have focused on neuroendocrine, cognitive, and symptomatic sequelae of repeated short-term hypoglycemia and provided somewhat conflicting data (1, 2, 3, 4, 5, 6, 7). Heller and Cryer (4) determined that an episode of hypoglycemia in normal individuals had minimal effects on counterregulatory responses to hypoglycemia induced 24 h later. Moriarty et al. (26) reported that neuroendocrine responses to moderate hypoglycemia were unaffected by 1 h of immediate prior hypoglycemia. Similarly, Kerr et al. (27) reported that over a 2-h period, two short episodes of intermittent hypoglycemia had no effect on counterregulatory responses. In contrast, Davis et al. (3, 6) have reported that some neuroendocrine responses (glucagon, GH, and cortisol) to a second episode of hypoglycemia were blunted by prior hypoglycemia induced 60 min earlier. Veneman et al. (5), in contrast, demonstrated that one episode of prolonged nocturnal hypoglycemia was sufficient to blunt all major neuroendocrine responses to subsequent morning hypoglycemia. Thus, previous studies have reported a range of differing effects of prior hypoglycemia on subsequent near-term counterregulatory responses. Our present results demonstrate a substantial, comprehensive blunting of all major counterregulatory responses in the afternoon by morning hypoglycemia. Control experiments determined that morning euglycemia had no effect on modulating neuroendocrine responses during afternoon hypoglycemia. Therefore, we believe that the observed blunting of counterregulatory responses in the afternoon were due to morning hypoglycemia rather than any circadian effects on neuroendocrine release. Thus, our results are conceptually similar to those described by Veneman et al. (5). The percentage blunting of afternoon neuroendocrine responses in this present study ranged from 33 to 55%. Parenthetically, this magnitude of blunting is similar to our previous findings observed after two episodes of antecedent hypoglycemia on next day counterregulatory responses (28).
The above previous studies have employed substantially differing experimental designs. Collective analysis of the studies reveals that time seems to play an important role in modulating the effects of antecedent hypoglycemia on subsequent counterregulatory responses. Thus, continuous sequential episodes of antecedent hypoglycemia induced over a period of 2 h are unable to modify counterregulatory responses (26, 27). However, when a period of euglycemia is allowed to supervene, the positive stimulus of hypoglycemia is alleviated and negative signals for down regulation of subsequent neuroendocrine responses are established. The differences in the results of the present study and those of Davis et al. (3, 6) are intriguing. Davis et al. (3, 6) observed no blunting of epinephrine or norepinephrine responses during two episodes of hypoglycemia induced over a 330-min period. The studies of Davis et al. (3, 6) used a 1-h euglycemic period between two episodes of hypoglycemia but maintained continuous hyperinsulinemia throughout the 330-min experiments. Therefore, we would speculate that either 1 h is insufficient for the negative modulation of the sympathetic nervous system by prior hypoglycemia to be manifest and/or continuous hyperinsulinemia may provide a tonic stimulus to the sympathetic nervous system (29) that could offset the negative signal of prior hypoglycemia.
Previous studies have documented that hypoglycemia results in a state of insulin resistance (8, 9, 10). Multiple mechanisms contribute to this insulin-resistant state with catecholamines, cortisol, and GH implicated in the pathogenesis of this phenomenon (8, 9, 10). To date, the acute effects of posthypoglycemic insulin resistance on counterregulatory responses to same-day hypoglycemia have not been determined. At the conclusion of morning hypoglycemia, exogenous insulin was discontinued and the glucose infusion used to maintain the desired hypoglycemic level was increased so that each subject was rapidly restored to euglycemia. However, over a period of 90–100 min, the glucose infusion was gradually discontinued so that by the start of afternoon hypoglycemia subjects required no exogenous glucose to maintain their plasma glucose. This was in marked contrast to hyperinsulinemic euglycemic control experiments where substantial amounts of glucose (7.7 ± 2.2 to 10.5 ± 2.8 µmol/kg·min) were required at the start of afternoon experiments to maintain plasma glucose at euglycemia. Thus, following morning hypoglycemia, despite the absence of exogenous insulin for 2 h and exogenous glucose for 20–30 min, plasma glucose and insulin levels were significantly increased relative to the morning indicating an insulinresistant state. Consistent with these findings, plasma FFA, glycerol, and ß-hydroxybutyrate levels were also increased in the afternoon following morning hypoglycemia indicating increased lipolytic activity (and FFA flux to the liver). Blood lactate levels in the afternoon were also increased following morning hypoglycemia presumably reflecting prolonged catecholamine effects from the morning. Paradoxically, despite blunted neuroendocrine responses, glucose infusion rates and the amount of glucose oxidized during afternoon hypoglycemia were significantly reduced following morning hypoglycemia. Thus, in the short-term, the posthypoglycemic insulin-resistant state was able to compensate via metabolic mechanisms for deficient neuroendocrine responses. This has not been previously reported and may have clinical implications. If similar mechanisms operate in patients with diabetes then the development (or worsening) of insulin resistance after an episode of hypoglycemia may provide a partial defense against subsequent hypoglycemia occurring soon after.
The effects of hyperinsulinemia and time on metabolic responses can be determined from the morning hyperinsulinemic euglycemic control studies. In marked contrast to the morning hypoglycemia studies, morning euglycemia substantially increased whole body insulin sensitivity during afternoon studies. Rates of glucose infusion were significantly increased, whereas glycerol and FFA levels were reduced during afternoon hypoglycemia following morning euglycemia (despite preserved neuroendocrine responses) indicating increased insulin sensitivity at the level of skeletal muscle and adipocyte. The contributing mechanisms to this finding seemed to be reduced FFA levels (30) and increased nonoxidative (i.e. glycogen synthesis) glucose metabolism.
Hypoglycemic symptoms were significantly reduced in the afternoon following morning hypoglycemia. Although autonomic symptoms were blunted, the majority of the reduced symptom scores were due to diminished neuroglycopenic symptoms. Thus, similar to the neuroendocrine responses, blunted hypoglycemic symptoms can be manifested only 2 h following antecedent hypoglycemia. Recent studies have provided some insight into the mechanisms responsible for diminished neuroendocrine and symptomatic responses following antecedent hypoglycemia. These include antecedent increases in plasma cortisol (31), relatively elevated brain glucose uptake during hypoglycemia (32, 33), and increases in ketone bodies and lactate (34). In this present study, blood ß-hydroxybutyrate and lactate levels were 2-fold higher at the start of afternoon compared with morning hypoglycemia. These levels are considerably lower than the concentrations of lactate and ketone bodies that have been previously demonstrated to reduce neuroendocrine responses during hypoglycemia (34). Nevertheless, we cannot exclude the possibility that these elevated metabolite levels may have contributed to the blunted neuroendocrine and symptomatic responses occurring during hypoglycemia.
In summary, these present results demonstrate that in overnight fasted normal man: 1) a single prolonged episode of moderate hypoglycemia in the morning can significantly blunt neuroendocrine, metabolic and symptom responses to subsequent hypoglycemia induced 2 h later; and 2) prior hypoglycemia induces a state of insulin resistance that in the short-term can partially compensate for diminished neuroendocrine responses by limiting glucose use during subsequent hypoglycemia.
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Acknowledgments |
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Footnotes |
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Received January 19, 2000.
Revised January 8, 2001.
Accepted January 12, 2001.
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References |
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