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Department of Medicine, Vanderbilt University School of Medicine and 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.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As a first step in attempting to solve this puzzle, we recently sought to determine whether a sexual dimorphism exists in counterregulatory responses to hypoglycemia in type 1 DM. Similar to healthy controls, women with type 1 DM have significantly reduced sympathetic nervous system (SNS) responses to hypoglycemia (7). Thus, another mechanism must be present to explain why, despite markedly reduced epinephrine and endogenous glucose production responses, women with type 1 DM experience a similar prevalence of hypoglycemia compared to their male counterparts.
Intensively treated type 1 DM patients develop syndromes of deficient counterregulatory responses that predispose these individuals to increased hypoglycemia (8). The mechanisms responsible for the pathogenesis of these syndromes are not fully elucidated. However, recent studies have demonstrated the central importance of antecedent hypoglycemia in causing blunted autonomic nervous system (ANS) hypoglycemic counterregulatory responses (9, 10, 11, 12, 13, 14, 15). Clearly, any factors that modify (either by increasing or decreasing) the effects of antecedent hypoglycemia on subsequent counterregulatory responses would have a dramatic impact on the prevalence of hypoglycemia in type 1 DM. Thus, if women were more resistant to the blunting effects of antecedent hypoglycemia, the usually greater SNS counterregulatory responses in men would be neutralized, and the counterregulatory sexual dimorphism would disappear. Therefore, the aim of this study was to test the hypothesis that antecedent hypoglycemia produces less blunting of subsequent counterregulatory responses in women relative to men. The glucose clamp technique (16) was used to determine the effects of a spectrum of differing antecedent hypoglycemia, ranging from mild (plasma glucose, 3.9 mmol/L) to moderate (plasma glucose, 2.9 mmol/L) on subsequent counterregulatory responses in two groups of healthy men and women.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We studied seven healthy females [age, 27 ± 2 yr; body mass index, 22.4 ± 0.5 kg/m2; hemoglobin A1c, 5.0 ± 0.1% (normal range, 4–6.5%)] and eight healthy males (age, 24 ± 2 yr; body mass index, 22.9 ± 0.6 kg/m2; hemoglobin A1c, 4.9 ± 0.1%). None was taking medication or had a family history of diabetes. Each subject had 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 follow 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. Data from the male volunteers have been published in a related report (17).
Glucose clamp studies
Subjects attended four separate 2-day experiments separated by at least 2 months. The order of the four experiments was randomized and performed in a single blind fashion. Studies in women were performed in the follicular phase of a menstrual cycle. On the morning of the first day of each study, after an overnight fast, two iv cannulas 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 (18). 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).
Antecedent euglycemia experiments (Fig. 1
)
On the morning of day 1, after the insertion of venous cannulas, a period of 90 min was allowed to elapse, followed by a 30-min baseline period and a 120-min hyperinsulinemic-euglycemic experimental period. At time zero, a primed continuous infusion of insulin (19) 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 (16). Potassium chloride (20 mmol/L) was added to the glucose infusate in each study. After completion of the initial 2-h test period, each subject received a small snack (15 g carbohydrate in the form of fruit juice), and plasma glucose was maintained at euglycemia for 2 h. At that point, insulin was restarted, and a second hyperinsulinemic-euglycemic clamp, identical to that used in the morning’s study, was performed. At completion of the second glucose clamp, subjects consumed a large meal and a bedtime snack and remained in the Clinical Research Center.
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These experiments followed a format similar to that of the previously described euglycemia experiments with the exception that on day 1, identical 120-min morning and afternoon hyperinsulinemic-hypoglycemic clamps of 3.9 ± 0.1, 3.3 ± 0.1, or 2.9 ± 0.1 mmol/L were performed. At the completion of the day 1 morning hypoglycemic experiments, subjects received a 15-g carbohydrate snack, and plasma glucose was rapidly restored to normal by use of an exogenous 20% glucose infusion. Plasma glucose was maintained at euglycemia for 2 h before the afternoon hypoglycemic clamp experiments were performed.
Day 2 experiments
Day 2 experiments involved standardized clamped hypoglycemia to
assess the effects of day 1 glycemia on subsequent hypoglycemic
counterregulatory responses. After a 10-h overnight fast, a third
glucose clamp study was performed. The timing of the experiment was
identical to that of the previous morning. To measure glucose kinetics,
a primed (18 µCi) constant infusion (0.18 µCi/min) of
[3-3H]glucose was started at -120 min
and continued throughout the 240-min experiment. At time zero, a primed
constant infusion of insulin at a rate of 9 pmol/kg·min was started,
and the rate of fall of plasma glucose and the hypoglycemic plateau
(
2.9 mmol/L) were controlled by a modification of the glucose clamp
technique (20).
Rates of glucose appearance (Ra), endogenous glucose production (EGP), and glucose utilization (Rd) were calculated according to the methods of Wall et al. (21). EGP was calculated by determining the total Ra (this comprises both endogenous glucose production and exogenous glucose infused to maintain the desired hypoglycemia) and subtracting from it the amount of glucose infused. It is now recognized that this approach is not fully quantitative, as underestimates of total Ra and Rd can be obtained. The use of a highly purified tracer and taking measurements under steady state conditions (i.e. constant specific activity) in the presence of a low glucose flux minimize the major problems. Note that isotopic determinations of glucose turnover were only quantified on day 2, as it is unclear whether tracer infused on day 1 would be stored in glycogen and then released in unknown amounts during day 2.
Direct measurement of muscle sympathetic nerve activity
Microneurographic activity was recorded from the peroneal nerve at the level of the fibular head (22). The approximate location of this nerve was determined by transdermal electrical stimulation (10–60 V, 0.01-ms duration). This stimulation produced painless muscle contraction of the foot. After this, a reference tungsten electrode with a shaft diameter of 200 µm was placed sc. A similar electrode, with an uninsulated tip (1–5 µm), was inserted into the nerve and used for recording muscle sympathetic nerve activity (MSNA). A recording of MSNA was considered adequate when 1) electrical stimulation produced muscle twitches but not paresthesia; 2) stretching of the tendons in the foot evoked proprioceptive afferent signals, whereas cutaneous stimulation by slight stroking of the skin did not; 3) nerve activity increased during phase II of the Valsalva maneuver (hypotensive phase) and was suppressed during phase IV (blood pressure overshoot); and 4) nerve activity increased in response to held expiration.
Two types of sympathetic fibers (skin and muscle) can be identified from recordings of peripheral nerves. MSNA was recorded in the present studies, as this has been demonstrated to reflect increased sympathetic activity during insulin-induced hypoglycemia (23), 2-deoxyglucose-induced neuroglycopenia (24), and hyperinsulinemic euglycemia in normal humans (25).
Sympathetic nerve activity is expressed as bursts per minute. Measurements of MSNA were made from the original tracings using a digitizer tablet (HIPAD, Houston Instruments, Austin, TX) coupled to SigmaScan software (Jandel Scientific, Modena, CA) in a microcomputer.
Analytical methods
The collection and processing of blood samples were described previously (26). 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 the method of Aguilar-Parada et al. (27) with an interassay coefficient of variance (CV) of 15%. Insulin was measured as described previously (28) with an interassay CV of 11%. Catecholamines were determined by high pressure liquid chromatography (29) with an interassay CV of 12% for epinephrine and 12% 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 that accurate identification of the relevant respective catecholamine peaks could be made. Cortisol was assayed using the Clinical Assays Gamma Coat RIA kit (Diagnostic Products, Los Angeles, CA) with an interassay CV of 6%. GH was determined by RIA (30) with a CV of 8%. Pancreatic polypeptide was measured by RIA using the method of Hagopian et al. (31) with an interassay CV of 8%. Lactate, glycerol, alanine, and 3-hydroxybutyrate were measured in deproteinized whole blood, using the method of Lloyd et al. (32). Nonesterified fatty acids (NEFA) were measured using the WAKO kit (Richmond, VA) adopted for use on a centrifugal analyzer (33).
Blood samples for glucose flux were taken every 10 min throughout the baseline period and every 15 min during the 120-min experimental period. Blood for determinations of counterregulatory hormones and intermediary metabolites was drawn twice during the 30-min baseline period and every 15 min during the experimental period. Cardiovascular parameters (pulse and systolic, diastolic, and mean arterial pressures) were measured noninvasively with a Dinamap (Critikon, Tampa, FL) every 10 min throughout each 300-min study. MSNA was measured continuously throughout each 300-min study. Hypoglycemic symptoms were quantified using a previously validated semiquantitative questionnaire (34). 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, sweating, tremor, agitation, feelings of heat/thirst, and pounding heart. The ratings of the first six symptoms were summed to get a neuroglycopenic score, and the ratings from the last five symptoms provide an autonomic symptom score. Neuroendocrine, MSNA, glucose kinetics, intermediary metabolites, hypoglycemic symptoms, and cardiovascular results are only presented from day 2 morning studies. In this way the effects of differing day 1 glycemia on a subsequent standardized hypoglycemic challenge are evident.
Materials
High pressure liquid chromatography-purified [3-3H]glucose (New England Nuclear, Boston, MA) was used as the glucose tracer (11.5 mCi/mmol·L). 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 subject’s own plasma.
Statistical analysis
Data are expressed as the mean ± SE unless otherwise stated and were analyzed using standard, parametric, two-way ANOVA with a repeated measure design. This was coupled with Duncan’s post-hoc test to delineate at which time statistical significance was reached. P < 0.05 indicated significant difference.
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Results |
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Steady state insulin levels were similar in females (515 ± 60 pmol/L) and males (605 ± 50 pmol/L) during day 1 morning and afternoon experiments. Plasma glucose levels reached steady state by 30 min and were maintained at the desired target glycemia (5.1 ± 0.1, 3.9 ± 0.1, 3.3 ± 0.1, and 2.9 ± mmol/L) for the remainder of the morning and afternoon experimental protocols.
Insulin, glucose, and counterregulatory hormone levels from day 2 morning studies
Insulin infusions resulted in similar steady state levels by 20
min in all groups. During the final 45 min of each experiment,
peripheral insulin levels were stable at 520 ± 55 pmol/L in
females and 588 ± 36 pmol/L in males. Plasma glucose levels fell
at an equivalent rate (0.06 mmol/min) in all studies and reached a
similar hypoglycemic plateau of 2.-9 ± 0.1
mmol/L (Fig. 2).
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and 4)
and reached a steady state by the final 30 min of hypoglycemia. In
women, antecedent hypoglycemia produced only limited blunting of day 2
neuroendocrine responses. Counterregulatory hormone responses were no
different after antecedent hypoglycemia of 3.9 or 3.3 mmol/L
compared to 5.1 ± 0.1 mmol/L (euglycemia). Some, but
not all, counterregulatory hormone responses were blunted
(P < 0.05) after antecedent hypoglycemia of 2.9
mmol/L (Table 1). Compared to antecedent
euglycemia, epinephrine, glucagon, cortisol, and pancreatic polypeptide
responses were significantly reduced (25 ± 5% to 33 ±
6%). Norepinephrine and GH responses were unaffected by any antecedent
hypoglycemia.
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and Table 1). Whereas antecedent hypoglycemia of 3.3 ± 0.1 and 2.9 ±
0.1 mmol/L resulted in reductions of responses in epinephrine (40
± 7% and 56 ± 6%), norepinephrine (25 ± 4% and 23
± 5%), glucagon (45 ± 6% and 56 ± 7%), GH (37 ±
4% and 37 ± 6%), and pancreatic polypeptide (38 ± 7% and
34 ± 5%), respectively. Muscle sympathetic nerve activity
In women, incremental increases in MSNA (Table 1) were similar
after antecedent euglycemia (±6 ± 2 bursts/min) or hypoglycemia
of 3.9 ± 0.1 mmol/L (±8 ± 2 bursts/min), 3.3 ± 0.1
mmol/L (±9 ± 2 bursts/min), and 2.9 ± 0.1 mmol/L (±
5 ± 2 bursts/min.). In men, MSNA responses were significantly
blunted (P < 0.01) by all levels of antecedent
hypoglycemia (Table 1). MSNA increased by 18 ± 4 bursts/min after
day 1 euglycemia, but by only 5 ± 2 bursts/min after day 1
3.9 ± 0.1 mmol/L, 8 ± 3 bursts/min after day 1 3.3 mmol/L,
and 6 ± 2 bursts/min after day 1 2.9 ± 0.1 mmol/L.
Glucose kinetics
Glucose specific activity (disintegrations per min/mmol) was in a
steady state during the control period and the final 30 min of each day
2 insulin infusion period (Table 2). In
women, EGP was 7.2 ± 2.2 µmol/kg·min. following day 1
euglycemia and 6.4 ± 1.7, 7.5 ± 2.0 and 6.6 ± 2.2
µmol/kg/min after day 1 hypoglycemia of 3.9, 3.3, and 2.9 mmol/L,
respectively. In men, EGP was significantly blunted (P
< 0.05) compared to day 1 euglycemia (10.3 ± 0.6
µmol/kg·min) after antecedent hypoglycemia of 3.3 ± 0.1
mmol/L (8.1 ± 1.1 µmol/kg·min) and 2.9 ± 0.1 mmol/L
(6.2 ± 1.7 µmol/kg·min). Exogenous glucose infusion rates
used to maintain the desired hypoglycemia during day 2 studies are
displayed in Table 2. Glucose disappearance rates were similar in men
and women during all day 2 studies.
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Day 2 heart rate, systolic, diastolic, and mean arterial pressure
responses were unaffected by differing day 1 glycemia (Table 3). Systolic and mean arterial blood
pressure were, however, consistently elevated in men compared to women
in all day 2 studies.
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In women, differing day 1 glycemia had limited effects on day 2
intermediary metabolite responses. Blood alanine, lactate, and
ß-hydroxybutyrate levels were no different after day 1 euglycemia or
any of the three hypoglycemic levels (Table 4). Day 1 hypoglycemia of 2.9 mmol/L
resulted in significant reductions in day 2 levels of blood glycerol
and plasma NEFA. In men, incremental blood lactate and glycerol
responses were blunted by all levels of day 1 hypoglycemia (Table 4).
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Total symptom scores in women increased 14 ± 2, 13 ± 2, and 11 ± 2 after day 1 euglycemia and hypoglycemia of 3.9 and 3.3 mmol/L, respectively. Neuroglycopenic symptoms increased 8 ± 2, 8 ± 1, and 6 ± 1, and autonomic symptom scores increased 6 ± 1, 5 ± 1, and 5 ± 1 after day 1 euglycemia, hypoglycemia of 3.9 and 3.3 mmol/L, respectively. Day 1 hypoglycemia of 2.9 ± 0.1 mmol/L resulted in significant blunting of day 2 symptom scores (7 ± 2). Both neuroglycopenic (5 ± 1) and autonomic symptom scores (2 ± 1) were significantly reduced after day 1 hypoglycemia of 2.9 mmol/L.
In men, after day 1 euglycemia, day 2 total hypoglycemia symptoms scores increased 15 ± 3 (neuroglycopenic symptoms, 9 ± 2; autonomic symptoms, 6 ± 2). Antecedent hypoglycemia of 2.9 mmol/L significantly blunted (P < 0.01) day 2 symptom scores (8 ± 1). Neuroglycopenic symptoms were significantly blunted (P < 0.01) compared to the control (3 ± 1 vs. 9 ± 2), whereas autonomic symptoms changed very little compared to antecedent euglycemia (5 ± 1 vs. 6 ± 2). Thus, antecedent hypoglycemia of 2.9 mmol/L had a differential effect on reducing the composition of symptom scores in men and women. Antecedent hypoglycemia of 2.9 mmol/L had a greater effect in reducing autonomic symptom scores (66 ± 12% decrease) in women and neuroglycopenic symptom scores (66 ± 10% decrease) in men.
Comparison of counterregulatory results from men and women
After antecedent euglycemia, day 2 neuroendocrine, EGP, and MSNA
responses were significantly increased in men relative to women. The
comparative effects of differing day 1 hypoglycemia on day 2
counterregulatory responses are displayed in Tables 1 and 2. With the
exception of glucagon, antecedent hypoglycemia removed the usual large
gender-related differences in hypoglycemic counterregulatory responses
(Tables 1 and 2). This occurred because women were resistant to the
blunting effects of antecedent hypoglycemia. When expressed in terms of
the percent change from the control value (antecedent euglycemia),
counterregulatory responses in women were reduced 3 ± 2%, 5
± 2%, and 25 ± 4% after day 1 hypoglycemia of 3.9, 3.3, and
2.9 mmol/L, respectively. In men, there were greater overall percent
reductions in day 2 counterregulatory responses (P <
0.01) after all day 1 hypoglycemic levels. Day 2 responses were reduced
30 ± 6%, 39 ± 5%, and 52 ± 6% after day 1
hypoglycemia of 3.9, 3.3, and 2.9 mmol/L, respectively.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We recently demonstrated in healthy male subjects that the depth of antecedent hypoglycemia is important in determining the magnitude of subsequent counterregulatory failure (17). In men, two episodes of mild day 1 hypoglycemia (3.9 ± 0.1 mmol/L) produced a significant overall reduction of 30 ± 6% during day 2 neuroendocrine, ANS, and metabolic counterregulatory responses. Day 1 hypoglycemia of 3.3 ± 0.1 and 2.9 ± 0.1 mmol/L produced greater overall reductions of 39 ± 5% and 52 ± 6% in the day 2 counterregulatory response, respectively. In this article we report the effects of differing levels of antecedent hypoglycemia on subsequent counterregulatory responses in a group of normal women. The subjects were studied under identical experimental conditions and over a similar time frame. The glucose clamp technique was used so that the critical confounding variables of glycemia and insulinemia (35, 36, 37) could be controlled. Insulin levels were similar during all day 1 and day 2 experiments. Similarly, glycemic targets on both days of the studies were strictly adhered to and did not differ between men and women.
Day 2 counterregulatory responses in women were remarkably resistant to the effects of antecedent hypoglycemia. Day 2 ANS (epinephrine, pancreatic polypeptide, and MSNA) responses in women were similar after day 1 euglycemia or hypoglycemia of 3.9 ± 0.1 and 3.3 ± 0.1 mmol/L. In fact, in women, it was only day 1 hypoglycemia of 2.9 ± 0.1 mmol/L that produced any significant reduction in day 2 ANS responses (epinephrine and pancreatic polypeptide responses were reduced 25 ± 5% and 28 ± 6%, respectively). Basal MSNA values were similar at the start of day 2 studies in men and women. Therefore, it was MSNA responses rather than basal sympathetic tone that were affected by day 1 hypoglycemia in men and women. The question of whether basal MSNA values differ in healthy males and females is somewhat controversial. Two reports have observed significant reductions in basal MSNA in women (39, 40). Although a subsequent study from one of the same laboratories found no clear gender-related difference in a group of pre- and postmenopausal women and age-matched men (41). Furthermore, even in the report by Jones et al. that described a gender difference, there was clear overlap in basal MSNA in 22 of the 28 men and women studied (39).
Day 2 neuroendocrine (glucagon, GH, and cortisol) and ANS responses in women followed a remarkably similar pattern. Neuroendocrine responses were similar after day 1 euglycemia and hypoglycemia of 3.9 ± 0.1 and 3.3 ± 0.1 mmol/L. Again, it was only after day 1 hypoglycemia of 2.9 ± 0.1 mmol/L that there were any significant reduction in day 2 glucagon (33 ± 6% decrease) and cortisol (30 ± 5% decrease) responses. GH responses tended to decrease (15 ± 6% decrease), but were not significantly reduced by any day 1 hypoglycemia. Commensurate with neuroendocrine and sympathetic nervous system (SNS) data, day 2 metabolic responses in women were also relatively unaffected by differing levels of day 1 hypoglycemia. Endogenous glucose production, a critical homeostatic counterregulatory mechanism, was unaffected by any antecedent hypoglycemia. We point out that in the experimental model of hypoglycemia used in this study there are limited changes in glucose flux. In fact, during day 2 protocols, glucose disappearance did not increase from basal levels. Consequently, during these conditions of low glucose turnover, a constant infusion of tritiated glucose was able to achieve very stable plasma glucose specific activities. Therefore, as demonstrated by Norwich (42), conditions of stable plasma glucose and glucose infusion rates provide reliable estimates of whole body glucose kinetics.
Blood lactate [a substantive precursor for gluconeogenesis (43) and an alternative fuel for brain metabolism (44)] remained unblunted by prior hypoglycemia. Lipolytic responses, important for producing substrate (glycerol), and energy (NEFA) for gluconeogenesis (43) and reducing glucose uptake by substrate competition (NEFA) in muscle (45) were also unaffected by day 1 hypoglycemia of 3.9 and 3.3 mmol. However, consistent with blunted SNS and neuroendocrine responses, glycerol and NEFA levels were reduced after day 1 hypoglycemia of 2.9 ± 0.1 mmol/L.
The results in normal women were remarkably different from the effects of antecedent hypoglycemia in men. Compared to women, where prior hypoglycemia had limited effects on subsequent counterregulatory responses, day 1 hypoglycemia in men produced dramatic blunting of subsequent neuroendocrine, ANS, and metabolic responses. Illustrating this fact, minimal day1 hypoglycemia of 3.9 mmol/L in men and significantly deeper hypoglycemia of 2.9 mmol/L in women produced equivalent counterregulatory failure. Interestingly, with the exception of glucagon, two episodes of mild hypoglycemia in men and women were enough to completely remove the usual substantial sexual dimorphism present in gender-related counterregulatory responses to hypoglycemia. Glucagon responses to hypoglycemia are generally lost after about 5 yr of type 1 DM (46). Thus, type 1 DM patients become reliant on adequate sympathoadrenal responses for defense against hypoglycemia (47). Therefore, the finding that sympathoadrenal counterregulatory responses are equal in men and women after antecedent hypoglycemia carries the greatest potential clinical relevance. Nevertheless, we stress that one should be guarded in directly applying the results of this study to all patients with type 1 DM. Neuroendocrine and ANS responses to hypoglycemia in type 1 diabetic patients decline with disease duration and tight metabolic control. Therefore, additional studies are required to determine whether a similar sexual dimorphism exists in counterregulatory responses to antecedent hypoglycemia in type 1 DM.
Although there is general agreement that antecedent hypoglycemia can blunt subsequent counterregulatory responses, the extent of the diminished responses appears to be somewhat experimental model dependent (9, 10, 11, 12, 13, 14, 17). In the present study we used a concentrated model of antecedent hypoglycemia that provides 4 h of hypoglycemia split between two separate episodes. This model provides a large experimental signal in men (50% reduction in counterregulatory responses). Therefore, the lack of a response in women cannot be due to a small antecedent hypoglycemic signal. Similarly, plasma glycemia were equivalent in both groups during experiments and thus also cannot be the cause of the differing day 2 results in men and women.
In summary, these results demonstrate that in normal humans antecedent hypoglycemia produces differing effects on subsequent counterregulatory responses in men and women. Antecedent hypoglycemia of 3.9 ± 0.1 and 3.3 ± 0.1 in women produced virtually no reduction in subsequent counterregulatory responses. Only deeper hypoglycemia of 2.9 ± 0.1 significantly reduced (25 ± 6%) subsequent counterregulatory responses. In contrast, identical antecedent hypoglycemia of 3.9, 3.3, and 2.9 ± 0.1 mmol/L in men produced significant reductions in subsequent counterregulatory responses of 30 ± 6%, 39 ± 6%, and 52 ± 6%, respectively. The end result of the differential gender effects of antecedent hypoglycemia was to overcome the usual increased (50%) SNS counterregulatory responses to hypoglycemia found in men. We conclude that 1) antecedent hypoglycemia produces less blunting of counterregulatory responses to subsequent hypoglycemia in women relative to men; 2) two episodes of antecedent hypoglycemia can overcome the greater SNS response to hypoglycemia usually found in men; and 3) further studies are required in type 1 DM patients to determine whether the reduced susceptibility of women to the blunting effects of antecedent hypoglycemia is a mechanism explaining why despite inherently reduced SNS counterregulatory responses, females with type 1 DM have a similar prevalence of hypoglycemia as men.
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Acknowledgments |
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Footnotes |
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Received October 21, 1999.
Revised March 1, 2000.
Accepted March 11, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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