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Cited by 100Diabetes Management and ResearchPancreatic function and diabetesDiabetes Treatment and Management

Effects of differing durations of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglycemia in normal humans.

Open access
Davis, S N, Mann, S, Galassetti, P, Neill, R A, Tate, D, Ertl, A C, Costa, F·2000·Diabetes
DOI 10.2337/diabetes.49.11.1897
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Abstract

The aim of this study was to determine whether the duration of antecedent hypoglycemia regulates the magnitude of subsequent counterregulatory failure. A total of 31 lean healthy overnight-fasted individuals (16 men/15 women) were studied. There were 15 subjects (8 men/7 women) who underwent two separate 2-day randomized experiments separated by at least 2 months. On day 1, 2-h hyperinsulinemic (9 pmol x kg(-1) x min(-1)) euglycemic (5.2 +/- 0.1 mmol/l) or hypoglycemic (2.9 +/- 0.1 mmol/l) glucose clamps (prolonged hypoglycemia) were carried out in the morning and afternoon. Of the other subjects, 16 participated in a 2-day study in which day 1 consisted of morning and afternoon short-duration hypoglycemia experiments (hypoglycemic nadir of 2.9 +/- 0.1 mmol for 5 min), and 10 of these individuals underwent an additional 2-day study in which day 1 consisted of morning and afternoon intermediate-duration hypoglycemia (hypoglycemic nadir of 2.9 +/- 0.1 mmol for 30 min). The next morning (day 2) all subjects underwent an additional 2-h hyperinsulinemic-hypoglycemic clamp (2.9 +/- 0.1 mmol/l). The rate of fall of glucose (0.07 mmol/min) was carefully controlled during all hypoglycemic studies so that the glucose nadir was reached at 30 min. Despite equivalent day 2 plasma glucose and insulin levels, there were significant differences in counterregulatory physiological responses. Steady-state epinephrine, glucagon, growth hormone, cortisol, and pancreatic polypeptide levels were similarly significantly blunted (P < 0.01) by the differing duration day 1 hypoglycemia compared with day 1 euglycemia. Muscle sympathetic nerve activity and endogenous glucose production were also similarly blunted (P < 0.01) by day 1 hypoglycemia (relative to day 1 euglycemia). Day 2 hypoglycemic symptoms were significantly reduced (P < 0.01) after day 1 prolonged intermediate- but not short-duration hypoglycemia. In summary, two episodes of short-duration moderate hypoglycemia can produce significant blunting of key neuroendocrine and metabolic counterregulatory responses. Hypoglycemic symptom scores are reduced by prolonged but not short-duration prior hypoglycemia. We conclude that in healthy overnight fasted humans, 1) neuroendocrine, autonomic nervous system, and metabolic counterregulatory responses are sensitive to the blunting effects of even short-duration prior hypoglycemia, and 2) the duration of antecedent hypoglycemia results in a hierarchy of blunted physiological responses with hypoglycemic symptom awareness less vulnerable than neuroendocrine responses.

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Crossref · 10.2337/diabetes.49.11.1897

Cites

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Claims the paper makes

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  • Findingown data
    § RESULTS · p. 5

    Blood β-hydroxybutyrate levels were suppressed similarly during day 2 hypoglycemia after day 1 euglycemia and after short-duration, intermediate-duration, or prolonged hypoglycemia.

    “Blood 𝛃 -hydroxybutyrate levels were suppressed similarly after day 1 euglycemia (32 ± 8 to 10 ± 3 µmol/l), short-duration (37 ± 6 to 8 ± 2 µmol/l), intermediateduration (47 ± 18 to 11 ± 4 µmol/l), or prolonged hypoglycemia (35 ± 6 to 8 ± 2 µmol/l).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § RESULTS · p. 4

    Blood glycerol levels were significantly and similarly blunted during day 2 hypoglycemia after day 1 short-duration, intermediate-duration, or prolonged hypoglycemia.

    “Glycerol levels were significantly and similarly blunted ( P &lt; 0.01) after short-duration (54 ± 4 to 37 ± 4 µmol/l), intermediate-duration (50 ± 5 to 38 ± 4 µmol/l), or prolonged hypoglycemia (41 ± 3 to 29 ± 3 µmol/l).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § RESULTS · p. 3

    Day 2 glucagon responses were significantly blunted after short-duration, intermediate-duration, and prolonged day 1 hypoglycemia compared with day 1 euglycemia.

    “Glucagon responses were also significantly blunted ( P < 0.01) by all differing-duration day 1 hypoglycemia (Fig. 3).”
    • Also stated in: § RESULTS · p. 3 · plain
      “Glucagon levels after shortduration, intermediate-duration, and prolonged hypoglycemia increased to 138 ± 8, 140 ± 12, and 141 ± 18 ng/l, respectively. These values were considerably reduced compared with responses after euglycemia (262 ± 34 ng/l).”
    Quote in the paperSubstantial claim
  • Findingown data
    § RESULTS · p. 3

    Incremental norepinephrine responses during day 2 hypoglycemia were significantly blunted after short-duration, intermediate-duration, and prolonged day 1 hypoglycemia compared with day 1 euglycemia.

    “However, because of baseline differences, the incremental responses were similarly significantly blunted ( P < 0.05) after both short-duration, intermediate-duration, or prolonged hypoglycemia compared with day 1 euglycemia (Fig. 2).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Effects of Differing Durations of Antecedent Hypoglycemia on Counterregulatory Responses to Subsequent Hypoglycemia in Normal Humans · p. 1

    Day 2 hypoglycemic symptoms were significantly reduced after day 1 prolonged and intermediate but not short-duration hypoglycemia.

    “Day 2 hypoglycemic symptoms were significantly reduced ( P < 0.01) after day 1 prolonged intermediate- but not short-duration hypoglycemia.”
    • Also stated in: § Effects of Differing Durations of Antecedent Hypoglycemia on Counterregulatory Responses to Subsequent Hypoglycemia in Normal Humans · p. 1 · plain
      “Hypoglycemic symptom scores are reduced by prolonged but not short-duration prior hypoglycemia.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 25
  • The quote only partly states this claim. 1
  • May combine two claims. 18

  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based). The quote only partly states this claim.

    Findingown data
    § Effects of Differing Durations of Antecedent Hypoglycemia on Counterregulatory Responses to Subsequent Hypoglycemia in Normal Humans · p. 1

    Endogenous glucose production during day 2 hypoglycemia was significantly blunted after day 1 hypoglycemia compared with day 1 euglycemia.

    “Muscle sympathetic nerve activity and endogenous glucose production were also similarly blunted ( P < 0.01) by day 1 hypoglycemia (relative to day 1 euglycemia).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    The reduction in day 2 neuroendocrine responses was homogeneous and existed across all major counterregulatory hormones.

    “The reduction in day 2 neuroendocrine responses was homogeneous and existed across the spectrum of all major counterregulatory hormones.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    ANS neuroendocrine markers (epinephrine, norepinephrine, pancreatic polypeptide) and MSNA were concordant and exhibited significant blunting after short-duration or prolonged hypoglycemia.

    “ANS neuroendocrine markers (epinephrine, norepinephrine, and pancreatic polypeptide) and MSNA were concordant and exhibited significant blunting after short-duration or prolonged hypoglycemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § DISCUSSION · p. 5

    Hypoglycemic symptoms (principally autonomic) were significantly blunted by prolonged and intermediate-duration antecedent hypoglycemia but were unaffected by prior short-duration hypoglycemia.

    “Hypoglycemic symptoms (principally autonomic symptoms) were significantly blunted by prolonged and intermediate-duration hypoglycemia but were unaffected by prior short-duration hypoglycemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    Key metabolic counterregulatory responses (EGP and lipolysis) were reduced commensurately with diminished neuroendocrine and SNS activation and are significantly blunted by short-duration antecedent hypoglycemia.

    “Key metabolic counterregulatory responses (EGP and lipolysis) were also reduced commensurately with diminished neuroendocrine and SNS activation and are also therefore significantly blunted by short-duration antecedent hypoglycemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Experimental design · p. 2

    Muscle sympathetic nerve activity reflects increased sympathetic activity during insulin-induced hypoglycemia, 2-deoxyglucose-induced neuroglycopenia, and hyperinsulinemic euglycemia in normal humans.

    “MSNA was recorded in the present studies because this has been demonstrated to reflect increased sympathetic activity during insulin-induced hypoglycemia (17), 2-deoxyglucose-induced neuroglycopenia (18), and hyperinsulinemic euglycemia in normal humans (19).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] 17. Fagius J, Niklasson F, Berne C: Sympathetic outflow in human muscle nerves increases during hypoglycemia. Diabetes 35:1126-1129, 1986

      Not checked in the free run.

    • cites [18] 18. Fagius J, Berne C: Changes of sympathetic nerve activity induced by 2 deoxyD-glucose infusion in humans. Am J Physiol 256:E714-E720, 1989

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    • cites [19] 19. Anderson E, Hoffman P , Balon T, Sinkey K, Mark A: Hyperinsulinemia produces

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    Premisecitation
    § Effects of Differing Durations of Antecedent Hypoglycemia on Counterregulatory Responses to Subsequent Hypoglycemia in Normal Humans · p. 1

    Four episodes of only 60 min of moderate hypoglycemia on consecutive days can diminish neuroendocrine responses to subsequent hypoglycemia.

    “Widom and Simonson (2) have demonstrated that four episodes of only 60 min of moderate hypoglycemia on consecutive days could diminish neuroendocrine responses to subsequent hypoglycemia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] 2. Widom B, Simonson D: Intermittent hypoglycemia impairs glucose counterregulation. Diabetes 41:1597-1602, 1992

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    Premisecitation
    § Effects of Differing Durations of Antecedent Hypoglycemia on Counterregulatory Responses to Subsequent Hypoglycemia in Normal Humans · p. 1

    Hypoglycemia of 30 min in the morning and 2 h in the afternoon produces a similar magnitude of counterregulatory failure.

    “Heller and Cryer (4) have demonstrated a similar magnitude of counterregulatory failure after hypoglycemia of 30 min in the morning and 2 h in the afternoon.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] 4. Heller S, Cryer PE: Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after one episode of hypoglycemia in nondiabetic humans. Diabetes 40:223-226, 1991

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    Study design and conductnone given
    § Experimental design · p. 2

    Studies in women were performed in the follicular phase of the menstrual cycle.

    “Studies in women were performed in the follicular phase of a menstrual cycle.”
    Quote in the paperNot a substantial claim

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    Study design and conductcitation
    § Experimental design · p. 2

    Hypoglycemic symptoms were quantified using a previously validated semiquantitative questionnaire.

    “Hypoglycemic symptoms were quantified using a previously validated semiquantitative questionnaire (28).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] 28. Cox D, Cryer P , Gonder-Frederick L, Clarke W, Antain B: Perceived symptoms in the recognition of hypoglycemia. Diabetes Care 16:519-527, 1993

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data
    § Effects of Differing Durations of Antecedent Hypoglycemia on Counterregulatory Responses to Subsequent Hypoglycemia in Normal Humans · p. 1

    The rate of fall of glucose was controlled to be equivalent across all hypoglycemic studies, with the glucose nadir reached at 30 min.

    “The rate of fall of glucose (0.07 mmol/min) was carefully controlled during all hypoglycemic studies so that the glucose nadir was reached at 30 min.”
    • Also stated in: § Experimental design · p. 2 · plain
      “The rate of fall of plasma glucose was equated in all studies by adjusting an exogenous infusion of glucose via a feedback algorithm based on 5-min bedside glucose values.”
    • Also stated in: § Experimental design · p. 2 · plain
      “The exogenous glucose infusion was adjusted to ensure that plasma glucose fell at a rate of 0.35 ± 0.01 mmol/l every 5 min.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning
    § Experimental design · p. 2

    The glucose kinetic method used may underestimate total glucose appearance and utilization, but use of a highly purified tracer and steady-state measurements minimizes major problems.

    “It is now recognized that this approach is not fully quantitative because underestimates of total R a and R d can be obtained. The use of a highly purified tracer and the taking of measurements under steady-state conditions (i.e., constant specific activity) in the presence of a low glucose flux minimizes the major problems.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data
    § Effects of Differing Durations of Antecedent Hypoglycemia on Counterregulatory Responses to Subsequent Hypoglycemia in Normal Humans · p. 1

    The prolonged antecedent euglycemia and hypoglycemia experiments were randomized and separated by at least 2 months.

    “There were 15 subjects (8 men/7 women) who underwent two separate 2day randomized experiments separated by at least 2 months.”
    • Also stated in: § Experimental design · p. 2 · plain
      “Fifteen subjects had previously participated in two 2-day randomized experiments (antecedent euglycemia and antecedent prolonged hypoglycemia [9,10]).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] 9. Davis SN, Shavers C, Costa F: Gender-related differences in counterregulatory responses to antecedent hypoglycemia in normal humans. J Clin Endocrinol Metab 85:2148-2157, 2000

      Not checked in the free run.

    • cites [10] 10. Davis SN, Shavers C, Davis B, Costa F: Prevention of an increase in plasma cortisol during hypoglycemia preserves subsequent counterregulatory responses . J Clin Invest 100:429-438, 1997

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    Study design and conductreasoning
    § Experimental design · p. 2

    Single blinding of the experiments was not possible because subjects would experience hypoglycemic symptoms and could deduce the duration of the hypoglycemia experiment.

    “(Single blinding of the experiments was not possible because all subjects would experience hypoglycemic symptoms and could therefore deduce the duration of the hypoglycemia experiment in which they were participating.)”
    • Also stated in: § Experimental design · p. 2 · plain
      “Subjects were not informed of the protocol in which they participated.”
    Quote in the paperNot a substantial claim

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    Premisereasoning
    § Effects of Differing Durations of Antecedent Hypoglycemia on Counterregulatory Responses to Subsequent Hypoglycemia in Normal Humans · p. 1

    Whether duration of prior hypoglycemia can independently regulate the magnitude of subsequent counterregulatory failure was unknown.

    “However, it is unknown whether duration of prior hypoglycemia can independently regulate the magnitude of subsequent counterregulatory failure.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    There is considerable debate whether cognitive function is also similarly affected by prior hypoglycemia.

    “there is considerable debate whether cognitive function is also similarly affected (5,6,35-37).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [5] 5. Veneman T, Mitrakou A, Mokan M, Cryer PE, Gerich J: Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia. Diabetes 42:1233-1237, 1993

      Not checked in the free run.

    • cites [6] 6. Dagago-Jack S, Craft S, Cryer PE: Hypoglycemia-associated autonomic failure in insulin dependent diabetes mellitus. J Clin Invest 91:819-828, 1993

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    • cites [35] 35. Cranston I, Lomas J, Maran A, Macdonald I, Amiel S: Restoration of hypoglycemia awareness in patients with long duration insulin dependent diabetes. Lancet 344:283-287, 1994

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    • cites [36] 36. Mitrakou A, Fanelli C, Veneman T, Perriello G, Calderone S, Platanisiotis D, Rambotti A, Raptis S, Brunetti P, Cryer P, Gerich J, Bolli G: Reversibility of unawareness of hypoglycemia in patients with insulinomas. N Engl J Med 329:834-839, 1993

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    • cites [37] 37. Hvidberg A, Fanelli C, Hershey T, Terkamp C, Craft S, Cryer P: Impact of recent antecedent hypoglycemia on hypoglycemic cognitive dysfunction in nondiabetic humans. Diabetes 45:1030-1036, 1996

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    Prior elevations of cortisol, increased cerebral blood glucose uptake, and increases in alternative cerebral metabolic fuels (lactate and ketone bodies) have been identified as potential mechanisms responsible for hypoglycemia-associated counterregulatory failure.

    “To date, prior elevations of cortisol (29) increased cerebral blood glucose uptake (31), and increases in alternative cerebral metabolic fuels (lactate and ketone bodies [30]) have been identified as potential mechanisms responsible for hypoglycemia-associated counterregulatory failure.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [29] 29. Davis SN, Shavers C, Costa C, Mosqueda-Garcia R: Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans. J Clin Invest 98:680-691, 1996

      Not checked in the free run.

    • cites [31] 31. Boyle P , Kempers S, O'Connor A, Nagy R: Brain glucose uptake and unawareness of hypoglycemia in patients with insulin-dependent diabetes mellitus. N Engl J Med 333:1720-1731, 1995

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    • cites [30] 30. Veneman, T, Mitrakou A, Mokan M, Cryer P, JE Gerich: Effects of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans. Diabetes 43:1311-1317, 1994

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    Study design and conductown data
    § DISCUSSION · p. 5

    The desired target of 5 min at 2.9 mmol/l was obtained in all day 1 morning and afternoon studies.

    “Although the desired target of 5 min at 2.9 mmol/l was obtained in all day 1 morning and afternoon studies”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    There is a consensus that neuroendocrine responses are blunted by prior hypoglycemia.

    “Although there is a consensus that neuroendocrine responses are blunted by prior hypoglycemia (1-8)”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [1] 1. Davis M, Shamoon H: Counterregulatory adaptation to recurrent hypoglycemia in normal humans. J Clin Endocrinol Metab 73:995-1001, 1991

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    • cites [2] 2. Widom B, Simonson D: Intermittent hypoglycemia impairs glucose counterregulation. Diabetes 41:1597-1602, 1992

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    • cites [3] 3. Davis M, Mellman M, Shamoon H: Further defects in counterregulatory responses induced by recurrent hypoglycemia in IDDM. Diabetes 41:13351340, 1992

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    • cites [4] 4. Heller S, Cryer PE: Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after one episode of hypoglycemia in nondiabetic humans. Diabetes 40:223-226, 1991

      Not checked in the free run.

    • cites [5] 5. Veneman T, Mitrakou A, Mokan M, Cryer PE, Gerich J: Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia. Diabetes 42:1233-1237, 1993

      Not checked in the free run.

    • cites [6] 6. Dagago-Jack S, Craft S, Cryer PE: Hypoglycemia-associated autonomic failure in insulin dependent diabetes mellitus. J Clin Invest 91:819-828, 1993

      Not checked in the free run.

    • cites [7] 7. Powell A, Sherwin R, Shulman G: Impaired hormonal responses to hypoglycemia in spontaneously diabetic and recurrently hypoglycemic rats. J Clin Invest 92:2667-2674, 1993

      Not checked in the free run.

    • cites [8] 8. Davis SN, Shavers C, Mosqueda-Garcia R, Costa F: Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans. Diabetes 46:1328-1335, 1997

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    Any mechanism responsible for hypoglycemia-associated autonomic failure must act at either multiple sites or one dominant coordinating center within the brain.

    “It would appear that any mechanism(s) responsible for the syndrome of hypoglycemia-associated autonomic failure must act at either multiple sites or one dominant coordinating center within the brain.”
    Quote in the paperNot a substantial claim

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    Premisecitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    Veneman et al. reported that one episode of prolonged nocturnal hypoglycemia can produce significant blunting of next-day counterregulatory responses.

    “On the other hand, Veneman et al. (5) reported that one episode of prolonged nocturnal hypoglycemia can produce significant blunting of next-day counterregulatory responses.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] 5. Veneman T, Mitrakou A, Mokan M, Cryer PE, Gerich J: Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia. Diabetes 42:1233-1237, 1993

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    Destruction of, or local neuroglycopenia in, the ventral medial nucleus of the hypothalamus can significantly regulate neuroendocrine responses to hypoglycemia in rats.

    “Borg et al. (42) demonstrated that destruction of, or local neuroglycopenia in, the ventral medial nucleus of the hypothalamus can significantly regulate neuroendocrine responses to hypoglycemia in rats.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] 42. Borg W, Sherwin R, During M, Borg M, Shulman G: Local ventromedial hypothalamus glucopenia triggers counterregulatory hormone release. Diabetes 44:180-185, 1995

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    Prior hypoglycemia can blunt some but not all ANS responses to subsequent hypoglycemia.

    “The finding that prior hypoglycemia can blunt some but not all ANS responses to subsequent hypoglycemia has also recently been observed by Paramore et al. (41).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] 41. Paramore D, Fanelli C, Shah S, Cryer P: Hypoglycemia per se stimulates sympathetic neural as well as adrenomedullary activity, but unlike the adrenomedullary response, the forearm sympathetic neural response is not reduced after recent hypoglycemia. Diabetes 48:1429-1436, 1999

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    Premisecitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    Data concerning the effects of prior hypoglycemia on hypoglycemic symptoms in type 1 patients are conflicting.

    “Furthermore, data concerning the effects of prior hypoglycemia on hypoglycemic symptoms in type 1 patients are also conflicting (33,38,39).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [33] 33. Cryer PE: Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM: a vicious cycle. Diabetes 41:255-260, 1992

      Not checked in the free run.

    • cites [38] 38. Widom B, Simonson D: Glycemic control and neuropsychologic function during hypoglycemia in patients with insulin dependent diabetes mellitus. Ann Intern Med 112:904-912, 1990

      Not checked in the free run.

    • cites [39] 39. Maran A, Lomas J, Macdonald I, Amiel S: Lack of protection of higher brain function during hypoglycemia in patients with intensively treated IDDM. Diabetologia 38:1412-1418, 1995

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § DISCUSSION · p. 5

    Depth of prior hypoglycemia, sex, increased plasma cortisol, lactate, ketone body levels, and elevated cerebral glucose extraction have been identified as independent factors regulating the magnitude of hypoglycemia-associated counterregulatory failure.

    “To date, depth of prior hypoglycemia (8), sex (9), increased plasma cortisol (29), lactate (30), or ketone body levels (30) and elevated cerebral glucose extraction (31) have all been identified as independent factors regulating the magnitude of hypoglycemia-associated counterregulatory failure.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8] 8. Davis SN, Shavers C, Mosqueda-Garcia R, Costa F: Effects of differing antecedent hypoglycemia on subsequent counterregulation in normal humans. Diabetes 46:1328-1335, 1997

      Not checked in the free run.

    • cites [9] 9. Davis SN, Shavers C, Costa F: Gender-related differences in counterregulatory responses to antecedent hypoglycemia in normal humans. J Clin Endocrinol Metab 85:2148-2157, 2000

      Not checked in the free run.

    • cites [29] 29. Davis SN, Shavers C, Costa C, Mosqueda-Garcia R: Role of cortisol in the pathogenesis of deficient counterregulation after antecedent hypoglycemia in normal humans. J Clin Invest 98:680-691, 1996

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    The results of this study relate to two rather than one episode of prior hypoglycemia.

    “Therefore, it should be emphasized that the results of this study relate to two rather than one episode of prior hypoglycemia.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    Dagogo-Jack et al. demonstrated that a period of scrupulous avoidance of hypoglycemia in type 1 patients results in a return of hypoglycemic symptoms but not neuroendocrine responses to subsequent hypoglycemia.

    “In addition, Dagogo-Jack et al. (40) have demonstrated that a period of scrupulous avoidance of hypoglycemia in type 1 patients results in a return of hypoglycemic symptoms but not neuroendocrine responses to subsequent hypoglycemia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] 40. Dagogo-Jack S, Rattarasarn C, Cryer PE: Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes 43: 1426-1434, 1994

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    Heller and Cryer demonstrated that one episode of prior hypoglycemia produces no blunting of counterregulatory responses to next-day hypoglycemia.

    “Heller and Cryer (4) demonstrated that one episode of prior hypoglycemia produces no blunting of counterregulatory responses to next-day hypoglycemia.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] 4. Heller S, Cryer PE: Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after one episode of hypoglycemia in nondiabetic humans. Diabetes 40:223-226, 1991

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    The present results confirm the multifactorial nature of the pathogenesis of syndromes of counterregulatory failure, of which hypoglycemic symptom unawareness is an important component.

    “Consistent with previous work (34), our present results confirm the multifactorial nature of the pathogenesis of the syndromes of counterregulatory failure of which hypoglycemic symptom unawareness is an important component.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] 34. Clarke WL, Gonder-Frederick L, Richards F, Cryer PE: Multifactorial origin of hypoglycemic symptom awareness in IDDM. Diabetes 40:680-685, 1991

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    Several studies have reported discordant effects of blunted neuroendocrine responses but preserved cognitive testing during subsequent hypoglycemia.

    “Several studies have reported discordant effects of blunted neuroendocrine responses but preserved cognitive testing during subsequent hypoglycemia (6,37).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] 6. Dagago-Jack S, Craft S, Cryer PE: Hypoglycemia-associated autonomic failure in insulin dependent diabetes mellitus. J Clin Invest 91:819-828, 1993

      Not checked in the free run.

    • cites [37] 37. Hvidberg A, Fanelli C, Hershey T, Terkamp C, Craft S, Cryer P: Impact of recent antecedent hypoglycemia on hypoglycemic cognitive dysfunction in nondiabetic humans. Diabetes 45:1030-1036, 1996

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    Studies have reported that prior hypoglycemia had either no effect on thresholds for hypoglycemic symptoms or significantly reduced the glucose level necessary to provoke symptoms.

    “Studies have reported that prior hypoglycemia had either no effect on thresholds for hypoglycemic symptoms (34,38) or significantly reduced the glucose level necessary to provoke symptoms (33,38).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [34] 34. Clarke WL, Gonder-Frederick L, Richards F, Cryer PE: Multifactorial origin of hypoglycemic symptom awareness in IDDM. Diabetes 40:680-685, 1991

      Not checked in the free run.

    • cites [38] 38. Widom B, Simonson D: Glycemic control and neuropsychologic function during hypoglycemia in patients with insulin dependent diabetes mellitus. Ann Intern Med 112:904-912, 1990

      Not checked in the free run.

    • cites [33] 33. Cryer PE: Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM: a vicious cycle. Diabetes 41:255-260, 1992

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    If there is one unifying mechanism responsible for hypoglycemia-associated autonomic failure, then the duration and perhaps levels of the putative agent are important to the qualitative and quantitative blunting of physiological defenses against subsequent hypoglycemia.

    “Thus, if there is one unifying mechanism responsible for the syndromes of hypoglycemia-associated autonomic failure (e.g., cortisol), then the present results imply that the duration of, and perhaps levels obtained, of the putative agent is important to the qualitative as well as quantitative blunting of physiological defenses against subsequent hypoglycemia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    In healthy overnight fasted humans, the duration of antecedent hypoglycemia results in a hierarchy of blunted physiological responses, with hypoglycemic symptom awareness less vulnerable than neuroendocrine responses.

    “2 ) the duration of antecedent hypoglycemia results in a hierarchy of blunted physiological responses, with hypoglycemic symptom awareness less vulnerable than neuroendocrine responses.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    Hindbrain catecholaminergic cells are important in ANS responses to stress.

    “Other studies have demonstrated the importance of hindbrain catecholaminergic cells in the ANS responses to stress (43).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] 43. Ritter S, Llewellyn-Smith I, Dinh T: Subgroups of hindbrain catecholamine neurons are selectively activated by 2-deoxy-D-glucose induced metabolic challenge. Brain Res 805:41-54, 1998

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning
    § SHORT-DURATION ANTECEDENT HYPOGLYCEMIA · p. 6

    These present findings suggest that advocating clinical paradigms limiting the duration of hypoglycemia in diabetic patients may have therapeutic usefulness and could help preserve symptomatic defenses against hypoglycemia even if neuroendocrine responses are blunted.

    “However, these present findings appear to suggest that advocating clinical paradigms limiting the duration of hypoglycemia in diabetic patients may have therapeutic usefulness and could help preserve symptomatic defenses against hypoglycemia even if neuroendocrine responses are blunted.”
    Quote in the paperNot a substantial claim
35 of 35

  • The paper relies on this without support.

    Many patients with diabetes experience early hypoglycemia cues but delay self-treatment, which prolongs the duration and possibly the depth of hypoglycemia.

    “Many patients with diabetes have early cues that they are hypoglycemic but often choose to delay immediate remedial action. This hesitancy to selftreat prolongs duration and possibly depth of hypoglycemia.”

  • The paper relies on this without support.

    The role played by duration of prior hypoglycemia in causing subsequent counterregulatory failure is unknown.

    “The role played by duration of prior hypoglycemia in causing subsequent counterregulatory failure is unknown.”

  • The paper relies on this without support.

    The number of episodes of prior hypoglycemia required to produce significant blunting of next-day counterregulatory responses is controversial.

    “The number of episodes of prior hypoglycemia required to produce significant blunting of next-day counterregulatory responses is controversial.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Another glucose clamp study reported that a mere 5 min of antecedent hypoglycaemia (at arterialised venous blood glucose 2.9 mmol/l) influenced subsequent counter-regulatory responses to hypoglycaemia, but not symptoms.

    “These results are in contrast to those from another glucose clamp study, which reported that a mere 5 min of antecedent hypoglycaemia (at an arterialised venous blood glucose level of 2.9 mmol/l) influenced subsequent counter-regulatory responses to hypoglycaemia, but not symptoms [16].”

    From Defining hypoglycaemia: what level has clinical relevance? (2009) · cites this paper as [16]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Glucose fall rate changes units by a factor of 1,000

    Minor

    The results give the glucose fall rate as 0.07 mol/min, while the study description gives 0.07 mmol/min. The two rates differ by a factor of 1,000.

  • Description of the cited one-episode study conflicts with its title

    Minor

    The discussion says Heller and Cryer found no blunting after one prior episode, but the cited paper's title says responses were reduced after one episode.

  • Cortisol values do not decrease stepwise with duration

    Minor

    The stated cortisol values rise from 580 nmol/l after short-duration hypoglycemia to 611 nmol/l after intermediate-duration hypoglycemia. They therefore do not show a stepwise reduction as antecedent hypoglycemia lengthens.

3 of 3

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Related

Authors
Davis, S. N., Mann, S., Galassetti, P., Neill, R. A., Tate, D., Ertl, A. C., & Costa, F.
Affiliations
Vanderbilt University (US)
ORCID
Davis, S N
Venue
Diabetes
Publisher
American Diabetes Association
Published
2000-11-01
Volume
49
Issue
11
Pages
1897-1903
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.49.11.1897
OpenAlex
W2148938779
Cited by
100
References
44
Citations by year
2026: 1 · 2025: 1 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 2 · 2020: 6 · 2019: 1 · 2018: 3 · 2017: 7 · 2016: 2 · 2015: 1 · 2014: 5 · 2013: 5 · 2012: 3
FWCI
2.43
Type
journal article
Language
en
Open access
Locations
  • Diabetes (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01dk045369-05, 3p60am020593-07s1)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK 45369)
  • National Center for Research Resources (M01RR000095, MO1-RR-00095)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
hypoglycemia, hypoglycemia duration, epinephrine, glucagon, growth hormone, cortisol, pancreatic polypeptide, muscle sympathetic nerve activity, endogenous glucose production, hypoglycemic symptoms, hyperinsulinemic hypoglycemic clamp, euglycemic clamp, overnight fasting
MeSH terms
Adult, Blood Glucose, Blood Pressure, Epinephrine, Female, Glucagon, Heart Rate, Homeostasis, Humans, Hydrocortisone, Hypoglycemia, Insulin, Kinetics, Male, Muscles, Pancreatic Polypeptide, Sympathetic Nervous System, Time Factors, Glucose Clamp Technique, Human Growth Hormone

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

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