Relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses to, symptoms of, and deterioration of cognitive function in hypoglycaemia in male and female humans
Open accessAbstract
To assess the relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses, symptoms and deterioration of cognitive function (12 cognitive tests) during progressive decreases in plasma glucose, and to quantitate glycaemic thresholds, 22 normal, non-diabetic subjects (11 males, 11 females) were studied on four occasions: prolonged fast (n = 8, saline euglycaemia study, SA-EU), stepped hypoglycaemia (plasma glucose plateaus of 4.3, 3.7, 3 and 2.3 mmol/l) or euglycaemia during insulin infusion at 1 and 2 mU.kg-1.min-1 (n = 22, high-insulin hypoglycaemia and euglycaemia studies, HI-INS-HYPO and HI-INS-EU, respectively), and stepped hypoglycaemia during infusion of insulin at 0.35 mU.kg-1.min-1 (n = 9, low-insulin hypoglycaemia study, LO-INS-HYPO). Insulin per se (SA-EU vs HI-INS-EU), suppressed plasma glucagon (approximately 20%) and pancreatic polypeptide (approximately 30%), whereas it increased plasma noradrenaline (approximately 10%, p < 0.05). Hypoglycaemia per se (HI-INS-HYPO vs HI-INS-EU) induced responses of counterregulatory hormones (CR-HORM), symptoms and deteriorated cognitive function. With the exception of suppression of endogenous insulin secretion, which had the lowest glycaemic threshold of 4.44 +/- 0.06 mmol/l, pancreatic polypeptide, glucagon, growth hormone, adrenaline and cortisol had similar glycaemic thresholds (approximately 3.8-3.6 mmol/l); noradrenaline (3.1 +/- 0.0 mmol/l), autonomic (3.05 +/- 0.06 mmol/l) and neuroglycopenic (3.05 +/- 0.05 mmol/l) symptoms had higher thresholds. All 12 tests of cognitive function deteriorated at a glycaemic threshold of 2.45 +/- 0.06 mmol/l, but 7 out of 12 tests were already abnormal at a glycaemic threshold of 2.89 +/- 0.06 mmol/l. Although all CR-HORM had a similar glycaemic threshold, the lag time of response (the time required for a given parameter to increase) of glucagon (15 +/- 1 min) and growth hormone (14 +/- 3 min) was shorter than adrenaline (19 +/- 3 min) and cortisol (39 +/- 4 min) (p < 0.05). With the exception of glucagon (which was suppressed) and noradrenaline (which was stimulated), insulin per se (HI-INS-HYPO vs LO-INS-HYPO) did not affect the responses of CR-HORM, and did not influence the symptoms or the cognitive function during hypoglycaemia. Despite lower responses of glucagon, adrenaline and growth hormone (but not thresholds) in females than males, females were less insulin sensitive than males during stepped hypoglycaemia.
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- Findingown data
Hypoglycaemia itself, independent of high insulin, produced counterregulatory hormone responses, symptoms, and cognitive decline.
“Hypoglycaemia per se (HI-INS-HYPO vs HI-INS-EU) induced responses of counterregulatory hormones (CR-HORM), symptoms and deteriorated cognitive function.”
Quote in the paperSubstantial claim - Findingown data
There were no differences in symptom responses or cognitive deterioration between high- and low-insulin hypoglycaemia.
“There were no differences in the responses of autonomic, neuroglycopenic and total symptoms, either in the deterioration of cognitive function or during decreases in plasma glucose concentrations induced by high-and low-insulin, respectively (p = NS).”
Quote in the paperSubstantial claim - Findingown data
Pancreatic polypeptide, glucagon, growth hormone, adrenaline, and cortisol had similar glycaemic thresholds, about 3.8 to 3.6 mmol/l.
“With the exception of suppression of endogenous insulin secretion, which had the lowest glycaemic threshold of 4.44 + 0.06 mmol/1, pancreatic polypeptide, glucagon, growth hormone, adrenaline and cortisol had similar glycaemic thresholds (-3.8-3.6 mmol/1);”
Quote in the paperSubstantial claim - Findingown data
Noradrenaline, autonomic symptoms, and neuroglycopenic symptoms had higher glycaemic thresholds, about 3.1, 3.05, and 3.05 mmol/l.
“noradrenaline (3.1 + 0.0 mmol/1), autonomic (3.05 + 0.06 retool/l) and neuroglycopenic (3.05 + 0.05 mmol/1) symptoms had higher thresholds.”
Quote in the paperSubstantial claim - Findingown data
Except for glucagon suppression and noradrenaline stimulation, insulin per se did not affect counterregulatory hormone responses, symptoms, or cognitive function during hypoglycaemia.
“With the exception of glucagon (which was suppressed) and noradrenaline (which was stimulated), insulin per se (HI-INS-HYPO vs LO-INS-HYPO) did not affect the responses of CR-HORM, and did not influence the symptoms or the cognitve function during hypoglycaemia.”
Quote in the paperSubstantial claim
- Findingown data
In the present studies, glucagon, adrenaline, cortisol and growth hormone all had the same glycaemic threshold of response, around 3.7-3.6 mmol/l.
“Regarding the classic counterregulatory hormones glucagon, adrenaline, cortisol and growth hormone [24], in the present studies all exhibited the same glycaemic threshold of response (-3.7-3.6 mmol/1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Bolli GB (1990) From physiology of glucose counterregulation to prevention of hypoglycaemia in type 1 diabetes mellitus. Diab Nutr Metab 3: 333?349
Not checked in the free run.
- Findingown data
Glucagon and growth hormone had shorter lag times than adrenaline and cortisol.
“Although all CR-HORM had a similar glycaemic threshold, the lag time of response (the time required for a given parameter to increase) of glucagon (15+1min) and growth hormone (14 + 3 min) was shorter than adrenaline (19 + 3 min) and cortisol (39 + 4 min) (p < 0.05).”
Quote in the paperNot a substantial claim - Findingown data
In high-insulin hypoglycaemia, cognitive test performance deteriorated.
“All 12 psychomotor tests deteriorated between 330 and 360 min, as indicated by the increase in the percentage of the sum of the z scores of 20.6 + 5.0 % (p < 0.05).”
Quote in the paperSubstantial claim - Findingown data
The parasympathetic and sympathoadrenal systems are activated at the same time during decrements in plasma glucose.
“The present studies indicate that the parasympathetic and sympathoadrenal systems are activated at the same time during decrements in plasma glucose concentrations.”
Quote in the paperSubstantial claim - Findingown data
The glycaemic thresholds of neuroglycopenic symptoms (3.16±0.06 mmol/l) and autonomic symptoms (3.05±0.06 mmol/l) were similar (p=NS).
“In the present studies, the glycaemic thresholds of neuroglycopenic (3.16 + 0.06 mmol/1) and autonomic symptoms (3.05 + 0.06 mmol/1) were similar (p = NS).”
Quote in the paperSubstantial claim - Findingown data
The glycaemic threshold for suppression of plasma C-peptide reported by Cryer (4.6±0.2 mmol/l) is very similar to that found in the present studies.
“Interestingly, the glycaemic threshold of suppression of plasma C-peptide reported by Cryer (4.6 _+ 0.2 mmol/1) [23] is very similar to that found in the present studies.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Cryer [23] Cryer PE (1993) Glucose counterregulation: prevention and correction of hypoglycemia in humans. Am J Physiol 264:E149-E155
Not checked in the free run.
- Findingown data
Seven of 12 cognitive tests were already abnormal at a glycaemic threshold of 2.89 ± 0.06 mmol/l.
“All 12 tests of cognitive function deteriorated at a glycaemic threshold of 2.45 + 0.06 mmol/1, but 7 out of 12 tests were already abnormal at a glycaemic threshold of 2.89 + 0.06 mmol/1.”
Quote in the paperSubstantial claim - Findingown data
The glycaemic threshold of cortisol in the present study (3.61±0.06 mmol/l) is lower than in previous studies using a similar methodological approach.
“On the other hand, the glycaemic thresholds of cortisol found in the present study (3.61 _+ 0.06 mmol/1) are lower, i.e. a smaller decrease in plasma glucose is sufficient to elicit a response, as compared to previous studies [1,3] using a similar methodological approach.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [1] Schwartz N, Clutter W, Shah S, Cryer P (1987) Glycemic thresholds for activation of glucose counterregulatory systems are higher than the thresholds for symptoms. J Clin Invest 79: 777?781 source
Not checked in the free run.
- cites [3] Mitrakou A, Ryan C, Veneman T et al. (1991) Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 260:E67-E74 source
Not checked in the free run.
- Findingown data
All 12 cognitive tests deteriorated at a glycaemic threshold of 2.45 ± 0.06 mmol/l.
“All 12 tests of cognitive function deteriorated at a glycaemic threshold of 2.45 + 0.06 mmol/1, but 7 out of 12 tests were already abnormal at a glycaemic threshold of 2.89 + 0.06 mmol/1.”
Quote in the paperSubstantial claim - Findingcitation
The glycaemic thresholds for increases in pancreatic polypeptide (3.83±0.06 mmol/l) and adrenaline (3.66±0.06 mmol/l) were similar.
“This is indicated by the similar glycaemic thresholds of increase in pancreatic polypeptide (3.83 • 0.06 mmol/1) -a hormone which is not autonomic itself, but largely under vagal control during hypoglycaemia [25] -and adrenaline (3.66 + 0.06 mmol/1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Schwartz TW (1983) Pancreatic polypetide: a hormone under vagal control. Gastroenterology 85: 1411?1425 source
Not checked in the free run.
- Findingnone given
Females were less insulin sensitive than males during stepped hypoglycaemia.
“Despite lower responses of glucagon, adrenaline and growth hormone (but not thresholds) in females than males, females were less insulin sensitive than males during stepped hypoglycaemia.”
Quote in the paperSubstantial claim - Findingown data
During a 360-min saline fast, plasma glucose, insulin, and C-peptide decreased progressively.
“When subjects were monitored during a 360-min fast (saline euglycaemia), plasma glucose, insulin and Cpeptide concentrations decreased progressively.”
Quote in the paperNot a substantial claim - Findingown data
Suppression of endogenous insulin secretion had the lowest glycaemic threshold, 4.44 ± 0.06 mmol/l.
“With the exception of suppression of endogenous insulin secretion, which had the lowest glycaemic threshold of 4.44 + 0.06 mmol/1, pancreatic polypeptide, glucagon, growth hormone, adrenaline and cortisol had similar glycaemic thresholds (-3.8-3.6 mmol/1);”
Quote in the paperSubstantial claim - Findingown data
The present studies indicate that plasma glucose, not insulin concentration, regulates the responses of adrenaline and growth hormone.
“In contrast, the present studies indicate that plasma glucose, not insulin concentration regulates the responses of adrenaline and growth hormone.”
Quote in the paperSubstantial claim - Findingown data
The present studies show that physiological hyperinsulinaemia suppresses glucagon in euglycaemic and hypoglycaemic conditions.
“On the other hand, the present studies point out that physiological hyperinsulinaemia suppresses glucagon in euglycaemic and hypoglycaemic conditions.”
Quote in the paperSubstantial claim - Findingcitation
These data are partly at variance with Amiel et al., who found lower adrenaline but not glucagon responses in females than males.
“These data are partly at variance with those of Widom et al. [13] who found higher thresholds for all counterregulatory hormones and symptoms in female as compared to male subjects, and those of Amiel et al. [12] who found lower adrenaline, but not glucagon responses in females as compared to males, but are largely in agreement with those of Davis et al. [15].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Amiel S, Maran A, Powrie JK, Umpleby AM, Macdonald IA (1993) Gender differences in counterregulation to hypoglycaemia. Diabetologia 36: 460?464 source
Not checked in the free run.
- Findingown data
Physiological hyperinsulinaemia suppressed plasma pancreatic polypeptide concentration proportionally to the degree of hyperinsulinaemia.
“In the present studies, physiological hyperinsulinaemia suppressed plasma pancreatic polypeptide concentration proportionally to hyperinsulinaemia.”
Quote in the paperSubstantial claim - Findingreasoning
The lag time of response of plasma noradrenaline was greater than that of autonomic symptoms (40±3 vs 12±1 min, p<0.05).
“However, the lag time of response of plasma noradrenaline is greater than the autonomic symptoms (40 + 3 vs 12 + 1 min, p < 0.05), a finding which may be explained by the fact that plasma noradrenaline is only a remote indicator of the sympathetic activity [33].”
Quote in the paperNot a substantial claim - Findingown data
Physiological hyperinsulinaemia suppressed the plasma glucagon response to hypoglycaemia.
“However, physiological hyperinsulinaemia suppressed plasma glucagon response to hypoglycaemia.”
Quote in the paperSubstantial claim - Findingown data
The present studies confirm that physiological hyperinsulinaemia activates the sympathetic nervous system, as indicated by increased plasma noradrenaline in hyperinsulinaemic-euglycaemic clamp studies.
“The present studies confirm that physiological hyperinsulinaemia activates the sympathetic nervous system, as indicated by the increase in plasma noradrenaline in the hyperinsulinaemic-euglycaemic clamp studies.”
Quote in the paperSubstantial claim - Findingown data
Plasma noradrenaline concentration increased directly in response to hyperinsulinaemia under euglycaemic conditions.
“The fact that plasma noradrenaline concentration increased directly in response to hyperinsulinaemia under euglycaemic conditions, is relevant to the calculation of the glycaemic threshold of plasma noradrenaline in hypoglycaemia.”
Quote in the paperSubstantial claim - Findingown data
These data are partly at variance with Widom et al., who found higher thresholds for all counterregulatory hormones and symptoms in females than males.
“These data are partly at variance with those of Widom et al. [13] who found higher thresholds for all counterregulatory hormones and symptoms in female as compared to male subjects, and those of Amiel et al. [12] who found lower adrenaline, but not glucagon responses in females as compared to males, but are largely in agreement with those of Davis et al. [15].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Widom B, Kinsley BT, Simonson DC (1991) Women and men differ in counterregulatory hormone responses to hypoglycemia. Diabetes 40 [Suppl 1]: 543 A (Abstract)
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- Findingown data
The present studies point out differences in counterregulatory responses to insulin-induced hypoglycaemia between male and female subjects.
“Finally, the present studies point out the differences in counterregulatory responses to insulin-induced hypoglycaemia in male as compared to female subjects [12][13][14][15].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12][13][14][15]
Not checked in the free run.
- Premisecitation
Different studies have reported different glycaemic thresholds for plasma noradrenaline and cortisol responses.
“For example, different glycaemic thresholds for responses of plasma noradrenaline and cortisol have been reported in different studies [1][2][3]6].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1][2][3]6]
Not checked in the free run.
- Premisecitation
Studies agree well on glycaemic thresholds for glucagon, adrenaline, and growth hormone release.
“There is quite a good agreement among studies, regarding glycaemic thresholds for release of the counterregulatory hormones glucagon, adrenaline and growth hormone [1][2][3][4][5][6].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1][2][3][4][5][6]
Not checked in the free run.
- Interpretationcitation
The discrepancy in cortisol threshold may be more apparent than real because cortisol response is delayed by ACTH activation of the adrenal cortex, which can overestimate the threshold if the glycaemic plateau is not long enough.
“However, such a discrepancy may be more apparent than real, because the response of cortisol is delayed due to the activation of the adrenal cortex by ACTH, a fact which may lead to an overestimation of the threshold if the glycaemic plateau is not sufficiently prolonged [2,26].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [2] De Feo P, Gallai V, Mazzotta G et al. (1988) Modest decrements in plasma glucose concentration cause early impairment in cognitive function and later activation of glucose counterregulation in the absence of hypoglycemic symptoms in normal man. J Clin Invest 82: 436?444 source
Not checked in the free run.
- cites [26] Mitrakou A, Mokan M, Ryan C, Veneman T, Cryer P, Gerich J (1993) Influence of plasma glucose rate of decrease on hierarchy of responses to hypoglycemia. J Clin Endocrinol Metab 76: 462?465
Not checked in the free run.
- Interpretationcitation
The low glycaemic threshold for suppression of pancreatic insulin secretion in response to a plasma glucose decrement is important for limiting portal hyperinsulinaemia and favouring the rebound increase in hepatic glucose production after counterregulatory hormone secretion.
“Teleologically, the low glycaemic threshold of suppression of pancreatic insulin secretion in response to a decrement in plasma glucose, is important in limiting portal hyperinsulinaemia and favouring the rebound increase in hepatic glucose production in response to the subsequent secretion of counterregulatory hormones [24].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Bolli GB (1990) From physiology of glucose counterregulation to prevention of hypoglycaemia in type 1 diabetes mellitus. Diab Nutr Metab 3: 333?349
Not checked in the free run.
- Premisecitation
In the study that found suppressive effects of insulin on adrenaline and growth hormone, plasma insulin was increased to supraphysiological levels (about 2600 pmol/l).
“It should be noted that in the study [10] in which suppressive effects of insulin on adrenaline and growth hormone was found, plasma insulin concentration was increased to supraphysiological levels (-2600 pmol/1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Davis SN, Goldstein RE, Jacobs J et al. (1993) The effects of differing insulin levels on the hormonal and metabolic response to equivalent hypoglycemia in normal humans. Diabetes 42: 263?272 source
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- Premisecitation
Glucagon and adrenaline play a similar key role in the very early phase of counterregulation.
“Thus, although both glucagon and adrenaline play a similar key role in a very early phase of counterregulation [27,28], the fact that glucagon increases slightly earlier than adrenaline in response to hypoglycaemia, suggests that glucagon may be a more important counterregnlatory hormone than adrenaline.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27] De Feo P, Perriello G, Torlone E et al. (1991) Evidence against important catecholamine compensation for absent glucagon counterregulation. Am J Physiol 260:E203-E212
Not checked in the free run.
- cites [28] De Feo P, Perriello G, Torlone E et al. (1991) The contribution of adrenergic mechanisms to glucose counterregulation in humans. Am J Physiol 261:E725-E736
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- Premisecitation
Autonomic symptoms are induced by sympathetic activation.
“The glycaemic threshold of plasma noradrenaline was greater than that of the counterregulatory hormones (3.05 + 0.06 vs 3.65 + 0.06 mmol/1, p < 0.05), but interestingly identical to the glycaemic threshold of the autonomic symptoms, which are induced by sym-pathetic activation [31].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Gerich J, Mokan M, Veneman T et al. (1991) Hypoglycemia unawareness. Endo Rev 12: 356?371 source
Not checked in the free run.
- Premisecitation
Pancreatic polypeptide is largely under vagal control during hypoglycaemia.
“This is indicated by the similar glycaemic thresholds of increase in pancreatic polypeptide (3.83 • 0.06 mmol/1) -a hormone which is not autonomic itself, but largely under vagal control during hypoglycaemia [25] -and adrenaline (3.66 + 0.06 mmol/1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Schwartz TW (1983) Pancreatic polypetide: a hormone under vagal control. Gastroenterology 85: 1411?1425 source
Not checked in the free run.
- Interpretationreasoning
The glycaemic threshold of plasma noradrenaline could be underestimated if the hyperinsulinaemic-euglycaemic experiments were not taken into account.
“In fact, the threshold could be underestimated if the hyperinsulinaemic-euglycaemic experiments were not taken into account.”
Quote in the paperSubstantial claim - Interpretationown data
This suggests that females are less insulin sensitive than males, at least under hypoglycaemic conditions, as previously reported by Amiel et al.
“This suggests that females are less insulin sensitive as compared to males, at least under hypoglycaemic conditions, as previously reported by Amiel et al. [12].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Amiel S, Maran A, Powrie JK, Umpleby AM, Macdonald IA (1993) Gender differences in counterregulation to hypoglycaemia. Diabetologia 36: 460?464 source
Not checked in the free run.
- Rests on an assumption: The rate of glucose infusion required to maintain a given hypoglycaemic plateau is a valid measure of insulin sensitivity under hypoglycaemic conditions.
- Premisecitation
Growth hormone and cortisol play an important role in defense against prolonged hypoglycaemia.
“Similarly, although both growth hormone [29] and cortisol [30] play an important role in defense against prolonged hypoglycaemia, growth hormone is probably more important than cortisol because it increases eartier.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [29] De Feo P, Perriello G, Torlone E et al. (1989) Demonstration of a role for growth hormone in glucose counterregulation. Am J Physiol 256:E835-E843
Not checked in the free run.
- cites [30] De Feo P, Perriello G, Torlone E et al. (1989) Contribution of cortisol to glucose counterregulation in man. Am J Physiol 257:E35-E42
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- Interpretationown data
This is the first report clearly describing in vivo suppression of pancreatic polypeptide by physiological hyperinsulinaemia.
“Although previous studies have suggested the possibility that pancreatic polypeptide is suppressed by endogenous insulin secretion in vivo [36], or modulated by hyperinsulinaemia in vitro [37], to the best of our knowledge, this is the first report clearly describing such an effect in vivo.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [36] Zandomegneghi R, Luciani A, Massari M et al. (1990) Interactions between endogenous and exogenous insulin and human pancreatic polypeptide secretion. Diab Metab 16: 21?25
Not checked in the free run.
- cites [37] Brunicardi FC, Druck P, Sun YS, Elahi D (1988) Regulation of pancreatic polypeptide secretion in the isolated perfused human pancreas. Am J Surg 155: 63?69 source
Not checked in the free run.
- Interpretationreasoning
A similar correction may apply to calculations of thresholds of plasma glucagon and pancreatic polypeptide.
“A qualitatively similar comment can be extended to calculations of thresholds of plasma glucagon and pancreatic polypeptide.”
Quote in the paperNot a substantial claim - Study design and conductown data
In the present studies, it was not possible to examine the magnitude of responses because with an insulin infusion rate of 0.35 mU/kg/min, plasma glucose did not fall below 3 mmol/l.
“It was not possible in the present studies to examine the magnitude of responses because with the insulin infusion rate of 0.35 mU.kg -1.min -t, plasma glucose did not decrease below 3 mmol/1.”
Quote in the paperSubstantial claim - Interpretationcitation
The greater lag time of plasma noradrenaline compared with autonomic symptoms may be explained by plasma noradrenaline being only a remote indicator of sympathetic activity.
“However, the lag time of response of plasma noradrenaline is greater than the autonomic symptoms (40 + 3 vs 12 + 1 min, p < 0.05), a finding which may be explained by the fact that plasma noradrenaline is only a remote indicator of the sympathetic activity [33].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Shah SD, Tse TF, Clutter WE, Cryer PE (1984) The human sympathochromoaffin system. Am J Physiol 247:E380-E384
Not checked in the free run.
- The quote only partly states this claim. 4
- May combine two claims. 29
- Classified as probably not a substantial claim. 20
The quote only partly states this claim.
Findingown dataA plasma glucose decrease of only 0.28±0.02 mmol/l below post-absorptive values was sufficient to initiate suppression of endogenous insulin secretion.
“Thus, a plasma glucose decrement of only -0.28 mmol/1 below the values of the post-absorptive state was sufficient to initiate suppression of endogenous insulin secretion.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFemales had lower glucagon, adrenaline, and growth hormone responses than males, but similar thresholds.
“Despite lower responses of glucagon, adrenaline and growth hormone (but not thresholds) in females than males, females were less insulin sensitive than males during stepped hypoglycaemia.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Findingown dataThe present results agree with the majority of previous studies, including those of Vea et al.
“However, our results are in agreement with the majority of previous studies [1,2], including those of Vea et al. [6].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Schwartz N, Clutter W, Shah S, Cryer P (1987) Glycemic thresholds for activation of glucose counterregulatory systems are higher than the thresholds for symptoms. J Clin Invest 79: 777?781 source
Not checked in the free run.
- cites [2] De Feo P, Gallai V, Mazzotta G et al. (1988) Modest decrements in plasma glucose concentration cause early impairment in cognitive function and later activation of glucose counterregulation in the absence of hypoglycemic symptoms in normal man. J Clin Invest 82: 436?444 source
Not checked in the free run.
- cites [6] Vea H, Jorde R, Sager G, Vaaler S, Sundsfjord J (1992) Reproducibility of glycaemic thresholds for activation of counterregulatory hormones and hypoglycaemic symptoms in healthy subjects. Diabetologia 35: 958?961 source
Not checked in the free run.
May combine two claims.
Findingown dataIn the present studies, glucagon and growth hormone increased within about 15 min after reaching the glycaemic threshold, while adrenaline and cortisol increased later, about 19 and 40 min respectively, at the same plateau plasma glucose of about 3.7 mmol/l.
“In the present studies, glucagon and growth hormone increased within approximately 15 min after reaching the glycaemic threshold, whereas adrenaline, and to a larger extent cortisol, increased later, approximately 19 and 40 rain, respectively, in response to the same plateau plasma glucose of approximately 3.7 mmol/1.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Findingown dataIn high-insulin hypoglycaemia, plasma glucose was clamped at plateaus of 4.3, 3.6, 3, and 2.4 mmol/l.
“In the high-insulin hypoglycaemia studies, plasma glucose concentration was decreased to plateaus of 4.3 + 0.02, 3.6 + 0.02, 3 + 0.02, and 2.4 + 0.02 mmol/1, between 45-90, 135-180, 225-270, and 315-360 rain, respectively.”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataIn high-insulin hypoglycaemia, glucagon, adrenaline, pancreatic polypeptide, growth hormone, and cortisol increased, while noradrenaline increased only after 300 min.
“plasma glucagonincreasedprogressively after 120 min to a peak of 185 + 14 pg/ml at 360 min; plasma adrenaline concentration increased after 150 min to a peak of 5.1 + 0.3 nmol/1 at 360 min; noradrenaline increased only after 300 min.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn the present studies, the most sensitive glucoregulatory mechanism activated against falling plasma glucose was suppression of pancreatic insulin secretion, with a glycaemic threshold of 4.44±0.06 mmol/l.
“In the present studies, the most sensitive glucoregulatory mechanism activated in defense against decrements in plasma glucose concentration was suppression of pancreatic insulin secretion which yielded a glycaemic threshold of 4.44_+0.06mmol/1.”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataDuring high-insulin euglycaemia, plasma insulin rose to about 445 pmol/l and then 925 pmol/l, C-peptide was suppressed by about 25%, glucagon decreased, noradrenaline increased, and pancreatic polypeptide was suppressed.
“When subjects were infused with insulin and glucose to maintain euglycaemia (high-insulin euglycaemia studies), plasma insulin concentration increased to plateau values of -445 pmol/1 (0-270 min), and to -925 pmol/1 (300-360 min), plasma C-peptide was suppressed by -25 % and plasma glucagon concentration decreased by -13% between 30-270min, and by -23 % between 300360 min.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataGrowth hormone and glucagon increased in plasma about 5 min earlier than adrenaline and about 25 min earlier than cortisol.
“However, growth hormone and glucagon increased in plasma about 5 rain earlier than adrenaline, and about 25 min earlier than cortisol.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn euglycaemic subjects, insulin infusion by itself lowered plasma glucagon and pancreatic polypeptide and raised noradrenaline.
“Insulin per se (SA-EU vs HI-INS-EU), suppressed plasma glucagon (-20 %) and pancreatic polypeptide (-30 %), whereas it increased plasma noradrenaline (-10 %, p < 0.05).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDuring saline euglycaemia, glucagon, adrenaline, noradrenaline, pancreatic polypeptide, and growth hormone did not change, while cortisol decreased.
“Plasma glucagon, adrenaline, noradrenaline, pancreatic polypeptide and growth hormone concentrations did not change, whereas plasma cortisol decreased (Tables 1 and 2).”
Quote in the paperNot a substantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataIn low-insulin compared with high-insulin hypoglycaemia, glucagon was less suppressed initially and then increased more, pancreatic polypeptide was initially less suppressed, and growth hormone and cortisol responses did not differ.
“Plasma glucagon concentration initially was less suppressed between 60 and 90 min (146+12 pg/ml) in the low-insulin hypoglycaemia studies than in the high-insulin hypoglycaemia studies (124 + 14 pg/ml, p < 0.05).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe glycaemic thresholds of glucagon, growth hormone and adrenaline in the present studies confirm previous reports.
“Regarding the glycaemic thresholds of glucagon, growth hormone and adrenaline, the results of the present studies confirm previous reports [1,3].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [1] Schwartz N, Clutter W, Shah S, Cryer P (1987) Glycemic thresholds for activation of glucose counterregulatory systems are higher than the thresholds for symptoms. J Clin Invest 79: 777?781 source
Not checked in the free run.
- cites [3] Mitrakou A, Ryan C, Veneman T et al. (1991) Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 260:E67-E74 source
Not checked in the free run.
May combine two claims.
Findingown dataSeven out of 12 cognitive tests deteriorated at a glycaemic threshold of 2.89±0.06 mmol/l, and all 12 tests deteriorated at a glycaemic threshold of 2.45±0.06 mmol/l.
“Seven out of the 12 cognitive tests deteriorated at a glycaemic threshold of 2.89 + 0.06 mmol/1, whereas all tests deteriorated at a glycaemic threshold of 2.45 + 0.06 mmol/1.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe responses of glucagon, adrenaline and growth hormone, but not their thresholds, were lower in females than in males.
“The responses of glucagon, adrenaline and growth hormone, but not thresholds, were lower in females than males.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDespite no difference in age and BMI between males and females, and despite lower counterregulatory hormone responses in females, less glucose was required in females than in males to clamp plasma glucose at the same insulin-induced hypoglycaemic plateaus.
“In the present studies, despite the fact that males and females did not differ regarding age and BMI, and despite lower counterregulatory hormone responses in females, less glucose was required in females than in males to clamp plasma glucose concentration at the same insulin-induced hypoglycaemic plateaus.”
Quote in the paperSubstantial claim- Rests on an assumption: The rate of glucose infusion required to maintain a given hypoglycaemic plateau is a valid measure of insulin sensitivity under hypoglycaemic conditions.
May combine two claims.
Findingown dataThe responses of noradrenaline, pancreatic polypeptide and cortisol did not differ between females and males, nor did symptom scores.
“Similarly, the responses of noradrenaline, pancreatic polypeptide and cortisol were no different, neither were the symptom scores different.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
FindingcitationAlthough this contrasts with a previous report of ours, it is in accordance with several recent reports.
“Although this contrasts with a previous report of ours [35], it is in accordance with several recent reports [7][8][9].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [35] Bolli G, De Feo P, Perriello G et al. (1984) Mechanisms of glucagon secretion during insulin-induced hypoglycemia in man: role of the beta-cell and arterial hyperinsulinemia. J Clin Invest 73: 917?922 source
Not checked in the free run.
- cites [7][8][9]
Not checked in the free run.
May combine two claims.
Findingown dataPhysiological hyperinsulinaemia in the range 150-500 pmol/l did not appreciably influence the thresholds of adrenaline, growth hormone and cortisol responses to hypoglycaemia, and did not affect symptoms or cognitive deterioration during hypoglycaemia.
“In the present studies, physiologic hyperinsulinaemia in the range of 150-500 pmol/1, did not appreciably influence thresholds of responses of adrenaline, growth hormone and cortisol to hypoglycaemia, and did not affect either symptoms or deterioration of cognitive function during hypoglycaemia.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe cognitive test results confirm previous findings by Mitrakou et al.
“This confirms previous findings by Mitrakou et al. [3].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Mitrakou A, Ryan C, Veneman T et al. (1991) Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 260:E67-E74 source
Not checked in the free run.
May combine two claims.
Findingown dataNeither thresholds nor maximal responses of symptoms differed between females and males.
“On the other hand, neither thresholds nor maximal responses of symptoms were different in females as compared to males.”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationThe glycaemic threshold of plasma noradrenaline was greater than that of the counterregulatory hormones (3.05±0.06 vs 3.65±0.06 mmol/l, p<0.05) but identical to the glycaemic threshold of autonomic symptoms.
“The glycaemic threshold of plasma noradrenaline was greater than that of the counterregulatory hormones (3.05 + 0.06 vs 3.65 + 0.06 mmol/1, p < 0.05), but interestingly identical to the glycaemic threshold of the autonomic symptoms, which are induced by sym-pathetic activation [31].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [31] Gerich J, Mokan M, Veneman T et al. (1991) Hypoglycemia unawareness. Endo Rev 12: 356?371 source
Not checked in the free run.
May combine two claims.
Findingnone givenFasting and insulin per se did not affect cognitive function.
“On the other hand, fasting, and insulin per se did not affect cognitive function.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationThese data are largely in agreement with Davis et al.
“These data are partly at variance with those of Widom et al. [13] who found higher thresholds for all counterregulatory hormones and symptoms in female as compared to male subjects, and those of Amiel et al. [12] who found lower adrenaline, but not glucagon responses in females as compared to males, but are largely in agreement with those of Davis et al. [15].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Davis SN, Cherrington AD, Goldstein RE, Jacobs J, Price L (1993) Effects of insulin on the counterregulatory response to equivalent hypoglycemia in normal females. Am J Physiol 265:E680-E689 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationA previous study reported that the glycaemic threshold for autonomic symptoms was lower than that for neuroglycopenic symptoms.
“This is different as compared to a previous study [3], in which the glycaemic threshold for autonomic symptoms was reported to be lower than that for neuroglycopenic symptoms.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3] Mitrakou A, Ryan C, Veneman T et al. (1991) Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 260:E67-E74 source
Not checked in the free run.
May combine two claims.
PremisecitationInsulin appears to be involved in some counterregulatory hormone responses and in symptom appearance.
“In addition, insulin appears to be involved in the responses of some counterregulatory hormones [7][8][9][10] and appearance of symptoms [11].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [7][8][9][10]
Not checked in the free run.
- cites [11] Kerr D, Reza M, Smith N, Leatherdale BA (1991) Importance of insulin in subjective, cognitive, and hormonal responses to hypoglycemia in patients with IDDM. Diabetes 40: 1057?1062 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisenone givenNormal humans respond to an acute fall in plasma glucose by suppressing endogenous insulin secretion and increasing counterregulatory hormones.
“It is well established that normal humans respond to an acute decrease in plasma glucose concentration, first, by suppressing endogenous insulin secretion, and, second, by increasing counterregulatory hormones.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataThe sequence of high-insulin euglycaemia and high-insulin hypoglycaemia studies was randomized.
“The sequence of high-insulin euglycaemia and high-insulin hypoglycaemia studies was varied at random.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataAlthough growth hormone and cortisol both play an important role in defense against prolonged hypoglycaemia, growth hormone is probably more important than cortisol because it increases earlier.
“Similarly, although both growth hormone [29] and cortisol [30] play an important role in defense against prolonged hypoglycaemia, growth hormone is probably more important than cortisol because it increases eartier.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [29] De Feo P, Perriello G, Torlone E et al. (1989) Demonstration of a role for growth hormone in glucose counterregulation. Am J Physiol 256:E835-E843
Not checked in the free run.
- cites [30] De Feo P, Perriello G, Torlone E et al. (1989) Contribution of cortisol to glucose counterregulation in man. Am J Physiol 257:E35-E42
Not checked in the free run.
May combine two claims.
InterpretationcitationThe present studies confirm and extend previous reports that progressive plasma glucose decrements first activate counterregulatory mechanisms, then produce symptoms, and then impair cognitive function.
“The present studies confirm and extend previous reports [reviewed in 23], which indicate that, in response to progressive decrements in plasma glucose concentration, the first event is activation of the counterregulatory mechanisms; that the second, should hypoglycaemia progress, is appearance of the symptoms and, if hypoglycaemia becomes more severe, third, cognitive function deteriorates.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [reviewed in 23]
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe hypoglycaemic clamp technique has been used to quantify glycaemic thresholds for counterregulatory hormone release, symptoms, and cognitive dysfunction.
“The hypoglycaemic clamp technique has been used to quantitate the glycaemic thresholds for release of counterregulatory hormones, appearance of symptoms and onset of cognitive dysfunction [1--6].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1--6]
Not checked in the free run.
May combine two claims.
Interpretationown dataAlthough glucagon and adrenaline both play a key role in the very early phase of counterregulation, the fact that glucagon increases slightly earlier than adrenaline suggests glucagon may be a more important counterregulatory hormone than adrenaline.
“Thus, although both glucagon and adrenaline play a similar key role in a very early phase of counterregulation [27,28], the fact that glucagon increases slightly earlier than adrenaline in response to hypoglycaemia, suggests that glucagon may be a more important counterregnlatory hormone than adrenaline.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [27] De Feo P, Perriello G, Torlone E et al. (1991) Evidence against important catecholamine compensation for absent glucagon counterregulation. Am J Physiol 260:E203-E212
Not checked in the free run.
- cites [28] De Feo P, Perriello G, Torlone E et al. (1991) The contribution of adrenergic mechanisms to glucose counterregulation in humans. Am J Physiol 261:E725-E736
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIt is controversial whether autonomic symptoms have a lower glycaemic threshold than neuroglycopenic symptoms.
“In addition, it is controversial as to whether the glycaemic threshold for appearance of autonomic symptoms is lower than that of neuroglycopenic symptoms (i.e. a smaller decrease in plasma glucose concentration is sufficient to elicit the autonomic as compared to neuroglycopenic symptoms) [2,3,6].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [2] De Feo P, Gallai V, Mazzotta G et al. (1988) Modest decrements in plasma glucose concentration cause early impairment in cognitive function and later activation of glucose counterregulation in the absence of hypoglycemic symptoms in normal man. J Clin Invest 82: 436?444 source
Not checked in the free run.
- cites [3] Mitrakou A, Ryan C, Veneman T et al. (1991) Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 260:E67-E74 source
Not checked in the free run.
- cites [6] Vea H, Jorde R, Sager G, Vaaler S, Sundsfjord J (1992) Reproducibility of glycaemic thresholds for activation of counterregulatory hormones and hypoglycaemic symptoms in healthy subjects. Diabetologia 35: 958?961 source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataSubjects were blinded to their plasma glucose and insulin levels during experiments.
“Subjects were not informed of their plasma glucose and insulin level during experiments.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataMale and female subject groups did not differ in age and BMI.
“Male and female subject groups did not differ regarding age and BMI.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMore recently, similar findings have been reported when plasma insulin was increased at physiological levels.
“More recently, similar findings have been reported also when plasma insulin was increased at physiological levels [34].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] Davis SN, Collins L, Price L, Hedstrom C, Shawers C (1993) The effects of physiological insulinemia on the counterregulatory response to prolonged hypoglycemia in normal man. Diabetes 42 [Suppl 1]: 44 A (Abstract)
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe fact that insulin does not affect adrenaline and growth hormone responses but suppresses glucagon suggests that insulin is unlikely to impair central recognition of hypoglycaemia and indicates that insulin directly suppresses glucagon secretion by pancreatic alpha cells.
“The fact that insulin does not affect responses of adrenaline and growth hormone, but suppresses those of glucagon, suggests that it is unlikely that insulin impairs central recognition of hypoglycaemia [7], and indicates that insulin directly suppresses the secretion of glucagon by the pancreatic alpha cells.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Diamond MP, Hallarman L, Starick-Zych K et al. (1991) Suppression of counterregulatory hormone response to hypoglycemia by insulin per se. J Clin Endocrinol Metab 72: 1388?1390 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationNoradrenaline is a neurotransmitter, not a hormone.
“This should not be surprising, because noradrenaline is a neurotransmitter, not a hormone [32].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Silverberg AB, Shah SD, Haymond MW, Cryer PE (1980) Norepinephrine: hormone and neurotransmitter in man. Am J Physiol 234:E252-E256
Not checked in the free run.
May combine two claims.
PremisecitationKerr et al. found in nine patients with long-duration IDDM but apparently no hypoglycaemia unawareness that supraphysiological hyperinsulinaemia (about 300 pmol/l) blunts autonomic symptoms and cortisol and growth hormone counterregulatory responses, while adrenaline and cognitive function were not impaired.
“Kerr et al. [11] found in nine patients with IDDM of long duration, but apparently no hypoglycaemia unawareness, that supraphysiological hyperinsulinaemia (M300pmol/1) blunts the autonomic symptoms, and the counterregulatory responses of cortisol and growth hormone, whereas those of adrenaline and cognitive function were not impaired at all.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Kerr D, Reza M, Smith N, Leatherdale BA (1991) Importance of insulin in subjective, cognitive, and hormonal responses to hypoglycemia in patients with IDDM. Diabetes 40: 1057?1062 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHypoglycaemia unawareness is a condition in which subjects with IDDM have lost autonomic symptoms.
“Thus, although less specific than the autonomic, the neuroglycopenic symptoms might be used by subjects with IDDM who have lost the autonomic symptoms, a condition referred to as hypoglycaemia unawareness [28], to alert them to impending hypoglycaemia.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [28] De Feo P, Perriello G, Torlone E et al. (1991) The contribution of adrenergic mechanisms to glucose counterregulation in humans. Am J Physiol 261:E725-E736
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrevious reports have described either suppression or enhancement of adrenaline and growth hormone responses to hypoglycaemia by insulin.
“Previous reports have described either a suppression [7], or an enhancement [10,34] of adrenaline and growth hormone responses to hypoglycaemia by insulin.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [7] Diamond MP, Hallarman L, Starick-Zych K et al. (1991) Suppression of counterregulatory hormone response to hypoglycemia by insulin per se. J Clin Endocrinol Metab 72: 1388?1390 source
Not checked in the free run.
- cites [10] Davis SN, Goldstein RE, Jacobs J et al. (1993) The effects of differing insulin levels on the hormonal and metabolic response to equivalent hypoglycemia in normal humans. Diabetes 42: 263?272 source
Not checked in the free run.
- cites [34] Davis SN, Collins L, Price L, Hedstrom C, Shawers C (1993) The effects of physiological insulinemia on the counterregulatory response to prolonged hypoglycemia in normal man. Diabetes 42 [Suppl 1]: 44 A (Abstract)
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe classic counterregulatory hormones are glucagon, adrenaline, cortisol and growth hormone.
“Regarding the classic counterregulatory hormones glucagon, adrenaline, cortisol and growth hormone [24], in the present studies all exhibited the same glycaemic threshold of response (-3.7-3.6 mmol/1).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24] Bolli GB (1990) From physiology of glucose counterregulation to prevention of hypoglycaemia in type 1 diabetes mellitus. Diab Nutr Metab 3: 333?349
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenPrevious studies have ignored the glycaemic threshold for suppression of insulin secretion in response to insulin-induced hypoglycaemia.
“Although the concept of suppression of endogenous insulin secretion during hypoglycaemia is not new at all, it is surprising that previous studies [1][2][3][4][5][6] have ignored the glycaemic threshold for suppression of insulin secretion in response to insulin-induced hypoglycaemia.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1][2][3][4][5][6]
Not checked in the free run.
May combine two claims.
InterpretationreasoningIf the glycaemic thresholds of neuroglycopenic and autonomic symptoms are identical, as indicated by Vea et al. and the present studies, then neuroglycopenic symptoms do not indicate more severe hypoglycaemia than autonomic symptoms.
“If the glycaemic thresholds of neuroglycopenic and autonomic symptoms are identical, as the studies of Vea et al. [6] and the present studies indicate, it can be concluded that the appearance of neuroglycopenic symptoms does not indicate a more severe hypoglycaemia, as compared to that inducing autonomic symptoms, as previously suggested [3].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [6] Vea H, Jorde R, Sager G, Vaaler S, Sundsfjord J (1992) Reproducibility of glycaemic thresholds for activation of counterregulatory hormones and hypoglycaemic symptoms in healthy subjects. Diabetologia 35: 958?961 source
Not checked in the free run.
- cites [3] Mitrakou A, Ryan C, Veneman T et al. (1991) Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 260:E67-E74 source
Not checked in the free run.
May combine two claims.
PremisecitationVea et al. demonstrated that the glycaemic thresholds of autonomic and neuroglycopenic symptoms are identical (about 3.5 mmol/l) and reproducible on different days.
“These authors demonstrated that the glycaemic thresholds of autonomic and neuroglycopenic symptoms are identical (-3.5 mmol/1) and reproducible on different days.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Vea H, Jorde R, Sager G, Vaaler S, Sundsfjord J (1992) Reproducibility of glycaemic thresholds for activation of counterregulatory hormones and hypoglycaemic symptoms in healthy subjects. Diabetologia 35: 958?961 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe only available data on the glycaemic threshold for suppression of insulin secretion are those of Cryer based on the studies of Schwartz et al.
“The only available data are those of Cryer [23] based on the studies of Schwartz et al. [1].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [23] Cryer PE (1993) Glucose counterregulation: prevention and correction of hypoglycemia in humans. Am J Physiol 264:E149-E155
Not checked in the free run.
- cites [1] Schwartz N, Clutter W, Shah S, Cryer P (1987) Glycemic thresholds for activation of glucose counterregulatory systems are higher than the thresholds for symptoms. J Clin Invest 79: 777?781 source
Not checked in the free run.
The authors state this as an assumption.
The glycaemic thresholds for suppression of endogenous insulin secretion and for pancreatic polypeptide increase in response to insulin-induced hypoglycaemia had not been studied.
“Furthermore, the glycaemic thresholds of suppression of endogenous insulin secretion and increase in pancreatic polypeptide in response to insulin-induced hypoglycaemia have not been studied.”
The authors state this as an assumption.
The contribution of insulin, independent of hypoglycaemia, to glycaemic thresholds and magnitude of counterregulatory hormone responses, symptoms, and cognitive deterioration is unclear.
“However, the contribution of insulin, independent of hypoglycaemia, on glycaemic thresholds and magnitude of responses of counterregulatory hormones, symptoms and deterioration of cognitive function, is unclear.”
The paper relies on this without support.
The rate of glucose infusion required to maintain a given hypoglycaemic plateau is a valid measure of insulin sensitivity under hypoglycaemic conditions.
“In the present studies, despite the fact that males and females did not differ regarding age and BMI, and despite lower counterregulatory hormone responses in females, less glucose was required in females than in males to clamp plasma glucose concentration at the same insulin-induced hypoglycaemic plateaus.”
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?
The recommended alert threshold of 3.9 mmol/l (70 mg/dl) is above the glucose levels that cause symptoms in non-diabetic people (about 2.8-3.1 mmol/l [50-55 mg/dl]).
“It is higher than the glucose levels required to produce symptoms in non-diabetic individuals (approximately 2.8-3.1 mmol/l [50-55 mg/dl] [6-9])”
From Preventing hypoglycaemia: what is the appropriate glucose alert value? (2009) · cites this paper as [9]
Consuming sucrose-electrolyte beverages before and throughout simulated soccer match-play caused transient reductions in blood glucose concentrations in the initial stages of the second half.
“we have consistently reported that consuming sucrose-electrolyte beverages before, and throughout, simulated soccer match-play caused transient reductions in blood glucose concentrations in the initial stages of the second half of soccer-specific exercise 5, 6, 58 .”
From Half-time strategies to enhance second-half performance in team-sports players: A review and recommendations (2015) · cites this paper as [58]
Evidence exists in nondiabetic and type 1 diabetic subjects to implicate hyperinsulinemia per se in suppressing the release of glucagon in response to hypoglycemia while increasing catecholamine and cortisol release, although this has been disputed.
“Evidence exists in nondiabetic and type 1 diabetic subjects to implicate hyperinsulinemia per se in suppressing the release of glucagon in response to hypoglycemia (43-46) while increasing catecholamine and cortisol release (47), although this has been disputed (48).”
From Hypoglycemia in Type 2 Diabetes (2005) · cites this paper as [43]
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.
Neuroglycopenic symptom threshold differs between abstract and results
MajorThe abstract gives a threshold of 3.05 mmol/l, whereas Table 3 gives 3.16 mmol/l for the same symptom category.
“neuroglycopenic (3.05 + 0.05 mmol/1) symptoms had higher thresholds.”
“| Neuroglycopenic symptoms | 3.16 + 0.06 c | 1.56 + 0.03 c | 11 + 1 |”
Cognitive deterioration is described with opposite score directions
MinorThe results describe deterioration as an increase in the percentage of summed z scores, but the figure caption defines deterioration as a decrease in that percentage.
“All 12 psychomotor tests deteriorated between 330 and 360 min, as indicated by the increase in the percentage of the sum of the z scores of 20.6 + 5.0 % (p < 0.05).”
“Deterioration in cognitive function is represented as decrease in the percentage of sum of z scores of psychomotor tests (see "method" section) from baseline”
High-insulin total symptom score does not equal its components at 180 minutes
MinorTable 5 gives autonomic and neuroglycopenic scores of 0.9 and 2.9 at 180 minutes. Their sum is 3.8, not the reported total of 4.7.
Reported 4.7 · recomputed 3.8
“| Total | HI-INS | 0.5 + 0.08 | 1.6 + 0.1 | 4.7 + 0.2 | 9.2 _+ 0.7" |”
High-insulin total symptom score does not equal its components at 270 minutes
MinorThe component scores at 270 minutes are 3.5 and 5.5, summing to 9.0 rather than the reported 9.2. The gap exceeds rounding of the printed component scores.
Reported 9.2 · recomputed 9
“| Total | HI-INS | 0.5 + 0.08 | 1.6 + 0.1 | 4.7 + 0.2 | 9.2 _+ 0.7" |”
Not all 22 subjects had a third study occasion
MinorThe methods say the subjects were studied on three occasions, but describe third studies for only eight plus nine of the 22 subjects. At least five therefore had only the first two occasions.
“Informed consent was given by 22 (11 males, 11 females) healthy, non-obese (body mass index, BMI, 22.3 + 0.6 kg/m 2) volunteers aged 31 + 3 years.Male and female subject groups did not differ regarding age and BMI.The subjects were studied on three different occasions, separated by at least 10-14 days.”
“Eight subjects (four male, four female) participated in a third study which consisted of a prolonged fast (saline euglycaemia).Nine subjects (five males, four females) participated in a third study in which hypoglycaemia was induced by a low dose of insulin (low-insulin hypoglycaemia).”
Low-insulin total symptom score does not equal its components at 270 minutes
MinorThe autonomic and neuroglycopenic scores at 270 minutes are 3.3 and 5.9, summing to 9.2 rather than the reported 9.4. Rounding to one decimal place cannot explain the gap.
Reported 9.4 · recomputed 9.2
“| symptom score | LO-INS | 0.4 + 0.07 | 1.5 + 0.3 | 3.8 + 0.3 | 9.4 + 0.8 a |”
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“In accordance with previous classifications [1-3, 19], the first five symptoms were considered neuroglycopenic and the last six, autonomic.”
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Self-citationContribution of cortisol to glucose counterregulation in humans
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Self-citationDemonstration of a role for growth hormone in glucose counterregulation
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Self-citationGender differences in counterregulation to hypoglycaemia
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Self-citationSUPPRESSION OF COUNTERREGULATORY HORMONE RESPONSE TO HYPOGLYCEMIA BY INSULIN PER SE
DIAMOND, M. P., HALLARMAN, L., STARICK-ZYCH, K., JONES, T. W., CONNOLLY-HOWARD, M., TAMBORLANE, W. V., & SHERWIN, R. S. (1991) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-72-6-1388 · Cited by 107 · see citing works
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Hypoglycmic Thresholds for Cognitive Dysfunction in Humans
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Feo, P. D., Perriello, G., Cosmo, S. D., et al. (1986) · Diabetes · doi:10.2337/diabetes.35.5.563 · Cited by 82 · see citing works
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Self-citationDavis, S. N., Goldstein, R. E., Jacobs, J., Price, L., Wolfe, R., & Cherrington, A. D. (1993) · Diabetes · doi:10.2337/diab.42.2.263 · Cited by 73 · see citing works
Effects of insulin on the counterregulatory response to equivalent hypoglycemia in normal females
Davis, S. N., Cherrington, A. D., Goldstein, R. E., Jacobs, J. K., & Price, L. (1993) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1993.265.5.e680 · Cited by 69 · see citing works
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Self-citationThe human sympathochromaffin system
Shah, S. D., Tse, T. F., Clutter, W. E., & Cryer, P. E. (1984) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1984.247.3.e380 · Cited by 64 · see citing works
Kerr, D., Reza, M., Smith, N., & Leatherdale, B. A. (1991) · Diabetes · doi:10.2337/diab.40.8.1057 · Cited by 55 · see citing works
Porcellati, F., Fanelli, C. G., Bottini, P., et al. (1993) · Diabetes · doi:10.2337/diab.42.7.1055 · Cited by 39 · see citing works
Self-citationLiu, D., Adamson, U., LINS, P.-E. S., Kollind, M., Moberg, E. A. R., & Andréasson, K. (1992) · Diabetes Care · doi:10.2337/diacare.15.1.59 · Cited by 38 · see citing works
Contribution of adrenergic mechanisms to glucose counterregulation in humans
Feo, P. D., Perriello, G., Torlone, E., Fanelli, C. G., Ventura, M. M., Santeusanio, F., Brunetti, P., Gerich, J. E., & Bolli, G. B. (1991) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1991.261.6.e725 · Cited by 38 · see citing works
Self-citationRegulation of pancreatic polypeptide secretion in the isolated perfused human pancreas
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Evidence against important catecholamine compensation for absent glucagon counterregulation
Feo, P. D., Perriello, G., Torlone, E., Fanelli, C. G., Ventura, M. M., Santeusanio, F., Brunetti, P., Gerich, J. E., & Bolli, G. B. (1991) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1991.260.2.e203 · Cited by 27 · see citing works
Self-citationInfluence of plasma glucose rate of decrease on hierarchy of responses to hypoglycemia
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Interactions between endogenous and exogenous insulin and human pancreatic polypeptide secretion.
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Flagged first, then by citations
Research works printed but not linked: 5
- Widom B, Kinsley BT, Simonson DC (1991) Women and men differ in counterregulatory hormone responses to hypoglycemia. Diabetes 40 [Suppl 1]: 543 A (Abstract)
- Diamond MP, Jones TW, Caprio S et al. (1991) Gender: a determinant of the adrenergic response to hypoglycemia. Diabetes 40 [Suppl 1]: 27 A (Abstract)
- Bolli GB (1990) From physiology of glucose counterregulation to prevention of hypoglycaemia in type 1 diabetes mellitus. Diab Nutr Metab 3: 333?349
- Shah SD, Tse TF, Clutter WE, Cryer PE (1984) The human sympathochromoaffin system. Am J Physiol 247:E380-E384
- Davis SN, Collins L, Price L, Hedstrom C, Shawers C (1993) The effects of physiological insulinemia on the counterregulatory response to prolonged hypoglycemia in normal man. Diabetes 42 [Suppl 1]: 44 A (Abstract)
Cited by
Sorted by citations
Defining and Reporting Hypoglycemia in Diabetes
American Diabetes Association Workgroup on Hypoglycemia (2005) · Diabetes Care · doi:10.2337/diacare.28.5.1245 · Cited by 1,146 · see citing works
Cryer, P. E., Davis, S. N., & Shamoon, H. (2003) · Diabetes Care · doi:10.2337/diacare.26.6.1902 · Cited by 1,160 · see citing works
Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes.
Cryer, P. (2002) · Diabetologia · doi:10.1007/s00125-002-0822-9 · Cited by 794 · see citing works
Hypoglycemia in Type 2 Diabetes
Zammitt, N. N., & Frier, B. M. (2005) · Diabetes Care · doi:10.2337/diacare.28.12.2948 · Cited by 435 · see citing works
Hypoglycemia in patients with type 2 diabetes mellitus
Miller, C. D., Phillips, L. S., Ziemer, D. C., Gallina, D. L., Cook, C. B., & El-Kebbi, I. M. (2001) · Archives of Internal Medicine · doi:10.1001/archinte.161.13.1653 · Cited by 341 · see citing works
Assessment and monitoring of glycemic control in children and adolescents with diabetes
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Self-citationNeuroendocrine responses to hypoglycemia
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Hypoglycemia-associated autonomic failure in diabetes
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Central mechanisms of glucose sensing and counterregulation in defense of hypoglycemia
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PHYSIOLOGY OF GLUCOSE COUNTERREGULATION TO HYPOGLYCEMIA
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Influence of Exercise on Skill Proficiency in Soccer
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Preventing hypoglycaemia: what is the appropriate glucose alert value?
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Effects of Glycemic Control on Protective Responses Against Hypoglycemia in Type 2 Diabetes
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The physiology and pathophysiology of the neural control of the counterregulatory response
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Impaired hypoglycaemia awareness in type 1 diabetes: Lessons from the lab
McNeilly, A. D., & McCrimmon, R. J. (2018) · Diabetologia · doi:10.1007/s00125-018-4548-8 · Cited by 55 · see citing works
Verhulst, C. E. M., Fabricius, T. W., Teerenstra, S., Kristensen, P. L., Tack, C. J., McCrimmon, R. J., Heller, S., Evans, M. L., Amiel, S. A., Pedersen-Bjergaard, U., et al. (2022) · Diabetologia · doi:10.1007/s00125-022-05749-8 · Cited by 34 · see citing works
Hypoglycaemia and gastric emptying
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The Prevention and Correction of Hypoglycemia
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- Authors
- Fanelli, C., Pampanelli, S., Epifano, L., Rambotti, A. M., Ciofetta, M., Modarelli, F., Di Vincenzo, A., Annibale, B., Lepore, M., Lalli, C., Del Sindaco, P., Brunetti, P., & Bolli, G. B.
- Affiliations
- University of Perugia (IT)
- Sapienza University of Rome (IT)
- Venue
- Diabetologia
- Published
- 1994-08
- Volume
- 37
- Issue
- 8
- Pages
- 797-807
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2092876947
- Semantic Scholar
- 34cc65c74894afbbc95e080a082ed279ccae5ac2
- Cited by
- 193
- References
- 37
- Citations by year
- 2026: 7 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 8 · 2018: 8 · 2017: 6 · 2016: 7 · 2015: 9 · 2014: 13 · 2013: 5 · 2012: 6
- FWCI
- 1.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- 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 › Neurological and metabolic disorders
- Keywords
- hypoglycemia, insulin, neuroendocrine response, counterregulatory hormones, cognitive function, hypoglycaemic symptoms, norepinephrine, glucagon, pancreatic polypeptide, growth hormone, epinephrine, cortisol, autonomic symptoms, neuroglycopenic symptoms, sex differences, insulin infusion, prolonged fasting, normoglycemia
- MeSH terms
- Insulin Secretion, Adult, Autonomic Nervous System, Blood Glucose, C-Peptide, Cognition, Cognition Disorders, Epinephrine, Female, Glucagon, Hormones, Humans, Hydrocortisone, Hypoglycemia, Insulin, Male, Norepinephrine, Pancreatic Polypeptide, Reference Values, Sex Factors, Growth Hormone, Time Factors, Glucose Clamp Technique
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.
Statistics and arithmetic are recomputed, not judged.
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