Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms.

Schwartz, Natalie; Clutter, William E.; Shah, Suresh D.; Cryer, Philip E.

doi:10.1172/jci112884

Cited by 386 publications

(259 citation statements)

References 36 publications

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“…Overall, 13% of studies had FPG !60 mg/dl (3.9 mmol/l), considered the lower threshold for normoglycemia by most laboratories, including ours, because in healthy individuals counter-regulatory responses take place between 70 and 60 mg/dl (3.3-3.9 mmol/l) (35,36). Nobody reported symptoms or had signs of hypoglycemia at the time of blood drawing, despite glucose concentrations as low as 35-55 mg/dl (1.9-3.1 mmol/l; usually symptomatic in healthy subjects), nor had previously reported hypoglycemic coma or severe hypoglycemia requiring outside help to treat the occurrence (37).…”

Section: Discussionmentioning

confidence: 81%

Spontaneous hypoglycemia in patients with cystic fibrosis

Battezzati¹,

Battezzati²,

Costantini³

et al. 2007

eur j endocrinol

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Objective: Diabetes frequently complicates cystic fibrosis (CF) without fasting hyperglycemia or despite spontaneous hypoglycemia (anecdotally ascribed to malnutrition), whose prevalence, clinical meaning, and relationship with glucose tolerance and clinical/nutritional status were not previously investigated. The relationship of CF genotype with insulin secretion control is also unclear. Design and methods: A total of 129 CF patients without stable diabetes received 188 oral glucose tolerance tests. Distribution of fasting plasma glucose (FPG), glucose, insulin and C-peptide responses, clinical/nutritional variables, and their relationships were analyzed. Results: FPG!60 mg/dl (3.3 mmo/l) was detected in 14% of studies and reactive hypoglycemia (PG!50 mg/dl (2.8 mmo/l)) in 15%. OGTT-based diabetes frequency was similar in the lowest quartile (Q1) and Q2-3 for FPG (10 and 8%), with higher glucose increment and area under the curve in Q1. Insulin and C-peptide levels were similar among FPG quartiles. Class I cystic fibrosis transmembrane conductance regulator mutation carriers had higher insulin concentrations than class II, especially in Q1 for FPG. Age, sex, nutritional, and anthropometric parameters including fat and lean body mass were unrelated to FPG. Lower FPG was associated with more frequent hospitalization rates (PZ0.002) and lower Shwachman scores (PZ0.041). Steroids weaning was accurately evaluated but then excluded as a possible cause of hypoglycemia. Conclusions/interpretation: Fasting asymptomatic hypoglycemia is frequent and possibly related to inappropriate insulin secretion control in class I mutation carriers. Low FPG does not exclude impaired glucose tolerance (IGT) and diabetes in CF and reflects worse clinical status.

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Section: Discussionmentioning

confidence: 81%

Spontaneous hypoglycemia in patients with cystic fibrosis

Battezzati¹,

Battezzati²,

Costantini³

et al. 2007

eur j endocrinol

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“…Elevation of plasma insulin to a mean steadystate level of 46 mU/1 [22] or 100-200 mU/1 failed to elevate plasma catecholamines [23,24], whereas other investigations have found minor but significant elevations of plasma noradrenaline at plasma insulin concentrations ranging from a level corresponding to postprandial hyperinsulinaemia in normal and insulin-resistant subjects, i. e. less than 100 mU/1 [25] to supraphysiological levels [6,7,26]. The occasional failure to observe increases in plasma noradrenaline may be methodological, as moderate hyperinsulinaemia is apparently a weak sympathetic stimulus.…”

Section: Discussionmentioning

confidence: 92%

The sympathetic response to euglycaemic hyperinsulinaemia

Fagius²,

et al. 1992

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Summary. Sympathetic nervous system activation by insulin has been suggested as a mechanism explaining the association between insulin resistance and hypertension. We further examined the effect of insulin by direct microneurographic muscle and skin nerve sympathetic activity recordings during euglycaemic insulin clamps in healthy subjects. The mean plasma insulin level was elevated from 5.3 + 0.7 to 92.2 + 2.2 mU/1 in seven subjects during a 90-min one-step clamp. In six other subjects plasma insulin was further raised from 85.7 _+ 4.0 mU/1 to 747 + 53 mU/1 between 45-90 min (two-step clamp). Four of the latter subjects received a sham clamp with NaC1 infusions only on a second recording session. At the low dose of insulin muscle nerve sympathetic activity increased from a resting level of 22.7 + 5.0 bursts per min to 27.7 + 5.0 bursts per rain at 15 min (p < 0.05). The increases in muscle nerve sympathetic activity were significant (p < 0.001; ANOVA) throughout insulin infusion, with a slight further increase (from 29.2 + 1.6 to 32.3 + 1.9 bursts per min) at the supraphysiological insulin concentration. During sham clamps muscle nerve sympathetic activity did not increase. Both insulin clamps induced minor, but significant, increases in forearm venous plasma noradrenaline concentrations. Skin nerve sympathetic activity (n = 3) did not change during insulin infusions. Heart rate increased slightly but significantly (p < 0.005), during the insulin damps. Blood pressure was not notably affected. In conclusion, hyperinsulinaemia was associated with increased vasoconstrictor nerve activity to skeletal muscle and with no change of sympathetic outflow to skin.

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“…Because the arterial plasma glucagon level and glucagon secretion decreased so little (if at all) in response to hyperglycemia, it is evident that hyperglycemia per se, even in the presence of modestly increased plasma insulin, had little effect on basal glucagon secretion. On the other hand, a decrease in plasma glucose from 5.8 to 5.2 mmol/l triggered a significant increase in arterial glucagon and glucagon secretion (>200% of basal) at a plasma glucose value well above the well-recognized threshold of 3.8 mmol/l observed in the presence of insulin-induced hypoglycemia in humans (1,12,25,32,33) and dogs (2)(3)(4)15). However, because basal plasma glucose levels in overnight-fasted humans (~4.7 mmol/l) (1-6) are usually lower than those in overnightfasted dogs (~5.8 mmol/l), the extent of the decrease in plasma glucose required to initiate an increase in glucagon secretion in the present study (0.6 mmol/l) was only about half (~1.2 mmol/l) of that reported to initiate glucagon release in response to insulin-induced hypoglycemia in humans (1,25).…”

Section: Discussionmentioning

confidence: 96%

α- and β-Cell Responses to Small Changes in Plasma Glucose in the Conscious Dog

et al. 2001

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The responses of the pancreatic ␣-and ␤-cells to small changes in glucose were examined in overnight-fasted conscious dogs. Each study consisted of an equilibration (-140 to -40 min), a control (-40 to 0 min), and a test period (0 to 180 min), during which BAY R3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally, either alone to create mild hypoglycemia or with peripheral glucose infusion to maintain euglycemia or create mild hyperglycemia. Drug administration in the hypoglycemic group decreased net hepatic glucose output (NHGO) from 8.9 ± 1.7 (basal) to 6.0 ± 1.7 and 5.8 ± 1.0 µmol · kg -1 · min -1 by 30 and 90 min. As a result, the arterial plasma glucose level decreased from 5.8 ± 0.2 (basal) to 5.2 ± 0.3 and 4.4 ± 0.3 mmol/l by 30 and 90 min, respectively (P < 0.01). Arterial plasma insulin levels and the hepatic portalarterial difference in plasma insulin decreased (P < 0.01) from 78 ± 18 and 90 ± 24 to 24 ± 6 and 12 ± 12 pmol/l over the first 30 min of the test period and decreased to 18 ± 6 and 0 pmol/l by 90 min, respectively. The arterial glucagon levels and the hepatic portal-arterial difference in plasma glucagon increased from 43 ± 5 and 4 ± 2 to 51 ± 5 and 10 ± 5 ng/l by 30 min (P < 0.05) and to 79 ± 16 and 31 ± 15 ng/l by 90 min (P < 0.05), respectively. In euglycemic dogs, the arterial plasma glucose level remained at 5.9 ± 0.1 mmol/l, and the NHGO decreased from 10 ± 0.6 to -3.3 ± 0.6 µmol · kg -1 · min -1 (180 min). The insulin and glucagon levels and the hepatic portal-arterial differences remained constant. In hyperglycemic dogs, the arterial plasma glucose level increased from 5.9 ± 0.2 to 6.2 ± 0.2 mmol/l by 30 min, and the NHGO decreased from 10 ± 1.7 to 0 µmol · kg -1 · min -1 by 30 min. The arterial plasma insulin levels and the hepatic portal-arterial difference in plasma insulin increased from 60 ± 18 and 78 ± 24 to 126 ± 30 and 192 ± 42 pmol/l by 30 min, after which they averaged 138 ± 24 and 282 ± 30 pmol/l, respectively. The arterial plasma glucagon levels and the hepatic portal-arterial difference in plasma glucagon decreased slightly from 41 ± 7 and 4 ± 3 to 34 ± 7 and 3 ± 2 ng/l during the test period. These data show that the ␣-and ␤-cells of the pancreas respond as a coupled unit to very small decreases in the plasma glucose level. Diabetes 50:367-375, 2001 G lucagon secretion increases in response to a decrease in the plasma glucose concentration and decreases in response to a rise in the plasma glucose level. Furthermore, insulin has been postulated to exert a paracrine influence on glucagon secretion when its release is modified in response to changes in the plasma glucose concentration. To date, studies have not provided a complete understanding of the relationship between a decrement in the plasma glucose level and glucagon or insulin secretion, because the insulin level itself has been elevated to decrease the glucose level, and insulin per se can affect not only its own secretion (1), but also the release of other counterregulatory hormones, inclu...

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Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms.

Cited by 386 publications

References 36 publications

Spontaneous hypoglycemia in patients with cystic fibrosis

Spontaneous hypoglycemia in patients with cystic fibrosis

The sympathetic response to euglycaemic hyperinsulinaemia

α- and β-Cell Responses to Small Changes in Plasma Glucose in the Conscious Dog

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