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High serum ACE is associated with high rate of severe hypoglycaemia in type 1 diabetic patients
s310
Poster Session 2
icant counter-regulation, was shown by the Dias prediction. Only one nocturnal hypoglycaemic episode supported by the MiniMed sensor was not suspected at all using Dias. In conclusion, these data suggest that the Dias model may have a role in identifying patients with potential unrecognised hypoglycaemia, which may be verified by, for example, the MiniMed subcutaneous glucose sensor. The data furthermore support the existence of long-term hypoglycaemic counter-regulation as a common occurrence in patients with Type 1 diabetes.
P1250 The D Allele of the ACE Genotype Confers Susceptibility to Severe Hypoglycaemia in Type 1 Diabetes ULRIK PEDERSEN-BJERGAARD ‘, Birgit Agerholm-Larsen*, Stig Pramming3, Birger Thorsteinsson’. ‘Dept.Med. R Hiller@d Hospital, Hiller@d, Denmark; 2 Dept. Clin. Biochem.. Herb Universiry Hospital, Herlev, Denmark; 3 Nova Nordisk, Bagsvaerd, Denmark
Background and Aim: The angiotensin-converting enzyme (ACE) genotype has recently been demonstrated as a significant determinant of endurance performance in non-diabetics with a superior capacity of subjects with the II genotype compared to the DD genotype. As substrate deficiency is a feature in common of endurance activities and hypoglycaemia in diabetes, we tested if patients with DD genotype are more susceptible to severe hypoglycaemia (SH). Materials and Methods: 207 unselected type 1 diabetics (mean age 43f13 years, diabetes duration 18kll years, HbAlc 8.5fl.3%, untreated with ACE inhibitors) completed a questionnaire about hypoglycaemia and awareness of hypoglycaemia and were characterised by C-peptide and HbAlc determinations and clinical data. ACE genotype was determined by PCR. Primary endpoint was the rate of SH (defined as episodes needing help from other persons) during the preceding two years. Results: The genotype distribution (II 24%. ID 52%, DD 24%) was similar to that of the normal population. The rates of SH among II, ID and DD subjects were 0.7, 0.9 and 2.1 episodes/patient-year, thus showing a markedly increased rate of SH in the DD group compared to the other genotypes (p
P1251 HighSerum ACE Is Associated with High Rate of Severe Hypoglycaemia in Type 1 Diabetic Patients ULRIK PEDERSEN-BJERGAARD’, Birgit Agerholm-Larsen’, Stig Pramming 3, Birger Thorsteinsson ‘. ’ Dept. Med. E Hiller@d Hospital, Hiller@d, Denmark; 2 Dept. Clin. Biochem., Herlev University Hospital, Herlev, Denmark; ’ NovaNordisk, Bagsvaerd, Denmark
Background and Aim: The activity of angiotensin-converting enzyme (ACE) in blood and tissues is determined by a polymorphism in the ACE gene. We have demonstrated that the D-allele which confers high ACE activity is linked to an increased rate of severe hypoglycaemia (SH). Consequently, we studied whether this could as well be demonstrated for the phenotype as evaluated by serum ACE. Material and Methods: 207 non-selected type 1 diabetic patients (age 43+13 years, diabetes duration 18fll years, HbAlc 8.6%+1.3% (meat&SD), untreated with ACE inhibitors) completed a questionnaire about hypoglycaemia supervised by a trained diabetes nurse. Primary endpoints were the rate of SH (defined as episodes requiring assistance from others) during the preceding two years and the rate of mild hypoglycaemia
during the last week. Blood was drawn for serum ACE, ACE genotype and determination of C-peptide. Results: The overall rate of SH was 1.2 episodes/patient-year. In the 3 quartiles with lowest serum ACE the rates of SH were 0.7, 0.6 and 0.7 episodes/patient-year, respectively, compared to a significantly increased rate of 2.8 episodes/patient-yeain the upper quartile (P
P1252 The Effect of Oral Glucose on Responses to Hypoglycaemia: A Possible Role for the Portal Glucose Sensor? D. SMITH, A. Pemet, H. Reid, E. Bingham, M. Rosenthal, M. Umpleby, S.A. Amiel. Guy’s, King’s and St Thomas’ School of Medicine, King’s College, London, United Kingdom Awareness of the symptoms of early hypoglycaemia is the diabetic patient’s best defence against severe hypoglycaemia with cognitive dysfunction Both the brain and the hepatic portal vein can sense changes in blood glucose concentration but the role of each in initiating the symptom responses to acute hypoglycaemia in man is not known. To test the hypothesis that the portal glucose sensor’s role is to modulate centrally mediated symptomatic responses to early acute hypoglycaemia, 6 healthy men received, twice, in random order, after an overnight fast, an intravenous infusion of insulin (3 mU/kg.min). Plasma glucose was controlled by adjustment of a simultaneous glucose infusion at 5 mmohl for 60 min, then reduced to 3.2 mmol/l for 60 min. Either 20 gm oral glucose (G), labelled with di-deuterated glucose to measure glucose absorption, or an equivalent drink Aavoured with saccharine (S) was consumed IOmin prior to the hypoglycaemia. Oral glucose was absorbed as hypoglycaemia began. G significantly reduced the change in total hypoglycaemia symptom scores (visual analogue scale) from +20.75+12.06 to +1.06f1.36 (mea&&D), p=O.O39. Change in neuroglycopenic symptom scores fell from +1.83f0.77 to +0.52f0.62, p = 0.012 and in autonomic symptoms from +1.59f1.25 to +0.54+1.25, p = 0.13). We conclude that the hepatic portal vein glucose sensors, stimulated by oral glucose absorption, act to reduce a centrally mediated symptomatic response to acute hypoglycaemia. This will encourage early resolution of symptoms when hypoglycaemia is treated by eating.
P1253 Systemic, but Not Local, Propranolol Infusion Blocks Hypoglycemic Muscular Insulin Resistance ROBERT P HOFFMAN ‘, Christine A. Sinkey ‘, Bradley G. Phillips*.
’ Dept of Pediatrics, University of Iowa, Iowa City, IA. United States of America; ‘College of Pharmacy, University of Iowa, Iowa City, IA, United States of America During hypoglycemia increased epinephrine secretion causes peripheral insulin resistance. The mechanism by which this happens is not well understood. To determine whether decreased muscle glucose uptake during hypoglycemia is due to the peripheral or systemic effects of epinephrine, we studied forearm blood flow (FBF, plethysmography, mercury in silastic strain gauge, dominant arm), arterial-venous glucose difference (AV diff), and forearm glucose uptake (FGU) during 40 mU mm2 min.’ insulin infusion with 60 mm of euglycemia followed by 60 min of hypoglycemia. Propranolol was infused either systemically through an intravenous catheter in the contralateral arm (IV PROP, 80 &min,
Poster Session 2
icant counter-regulation, was shown by the Dias prediction. Only one nocturnal hypoglycaemic episode supported by the MiniMed sensor was not suspected at all using Dias. In conclusion, these data suggest that the Dias model may have a role in identifying patients with potential unrecognised hypoglycaemia, which may be verified by, for example, the MiniMed subcutaneous glucose sensor. The data furthermore support the existence of long-term hypoglycaemic counter-regulation as a common occurrence in patients with Type 1 diabetes.
P1250 The D Allele of the ACE Genotype Confers Susceptibility to Severe Hypoglycaemia in Type 1 Diabetes ULRIK PEDERSEN-BJERGAARD ‘, Birgit Agerholm-Larsen*, Stig Pramming3, Birger Thorsteinsson’. ‘Dept.Med. R Hiller@d Hospital, Hiller@d, Denmark; 2 Dept. Clin. Biochem.. Herb Universiry Hospital, Herlev, Denmark; 3 Nova Nordisk, Bagsvaerd, Denmark
Background and Aim: The angiotensin-converting enzyme (ACE) genotype has recently been demonstrated as a significant determinant of endurance performance in non-diabetics with a superior capacity of subjects with the II genotype compared to the DD genotype. As substrate deficiency is a feature in common of endurance activities and hypoglycaemia in diabetes, we tested if patients with DD genotype are more susceptible to severe hypoglycaemia (SH). Materials and Methods: 207 unselected type 1 diabetics (mean age 43f13 years, diabetes duration 18kll years, HbAlc 8.5fl.3%, untreated with ACE inhibitors) completed a questionnaire about hypoglycaemia and awareness of hypoglycaemia and were characterised by C-peptide and HbAlc determinations and clinical data. ACE genotype was determined by PCR. Primary endpoint was the rate of SH (defined as episodes needing help from other persons) during the preceding two years. Results: The genotype distribution (II 24%. ID 52%, DD 24%) was similar to that of the normal population. The rates of SH among II, ID and DD subjects were 0.7, 0.9 and 2.1 episodes/patient-year, thus showing a markedly increased rate of SH in the DD group compared to the other genotypes (p
P1251 HighSerum ACE Is Associated with High Rate of Severe Hypoglycaemia in Type 1 Diabetic Patients ULRIK PEDERSEN-BJERGAARD’, Birgit Agerholm-Larsen’, Stig Pramming 3, Birger Thorsteinsson ‘. ’ Dept. Med. E Hiller@d Hospital, Hiller@d, Denmark; 2 Dept. Clin. Biochem., Herlev University Hospital, Herlev, Denmark; ’ NovaNordisk, Bagsvaerd, Denmark
Background and Aim: The activity of angiotensin-converting enzyme (ACE) in blood and tissues is determined by a polymorphism in the ACE gene. We have demonstrated that the D-allele which confers high ACE activity is linked to an increased rate of severe hypoglycaemia (SH). Consequently, we studied whether this could as well be demonstrated for the phenotype as evaluated by serum ACE. Material and Methods: 207 non-selected type 1 diabetic patients (age 43+13 years, diabetes duration 18fll years, HbAlc 8.6%+1.3% (meat&SD), untreated with ACE inhibitors) completed a questionnaire about hypoglycaemia supervised by a trained diabetes nurse. Primary endpoints were the rate of SH (defined as episodes requiring assistance from others) during the preceding two years and the rate of mild hypoglycaemia
during the last week. Blood was drawn for serum ACE, ACE genotype and determination of C-peptide. Results: The overall rate of SH was 1.2 episodes/patient-year. In the 3 quartiles with lowest serum ACE the rates of SH were 0.7, 0.6 and 0.7 episodes/patient-year, respectively, compared to a significantly increased rate of 2.8 episodes/patient-yeain the upper quartile (P
P1252 The Effect of Oral Glucose on Responses to Hypoglycaemia: A Possible Role for the Portal Glucose Sensor? D. SMITH, A. Pemet, H. Reid, E. Bingham, M. Rosenthal, M. Umpleby, S.A. Amiel. Guy’s, King’s and St Thomas’ School of Medicine, King’s College, London, United Kingdom Awareness of the symptoms of early hypoglycaemia is the diabetic patient’s best defence against severe hypoglycaemia with cognitive dysfunction Both the brain and the hepatic portal vein can sense changes in blood glucose concentration but the role of each in initiating the symptom responses to acute hypoglycaemia in man is not known. To test the hypothesis that the portal glucose sensor’s role is to modulate centrally mediated symptomatic responses to early acute hypoglycaemia, 6 healthy men received, twice, in random order, after an overnight fast, an intravenous infusion of insulin (3 mU/kg.min). Plasma glucose was controlled by adjustment of a simultaneous glucose infusion at 5 mmohl for 60 min, then reduced to 3.2 mmol/l for 60 min. Either 20 gm oral glucose (G), labelled with di-deuterated glucose to measure glucose absorption, or an equivalent drink Aavoured with saccharine (S) was consumed IOmin prior to the hypoglycaemia. Oral glucose was absorbed as hypoglycaemia began. G significantly reduced the change in total hypoglycaemia symptom scores (visual analogue scale) from +20.75+12.06 to +1.06f1.36 (mea&&D), p=O.O39. Change in neuroglycopenic symptom scores fell from +1.83f0.77 to +0.52f0.62, p = 0.012 and in autonomic symptoms from +1.59f1.25 to +0.54+1.25, p = 0.13). We conclude that the hepatic portal vein glucose sensors, stimulated by oral glucose absorption, act to reduce a centrally mediated symptomatic response to acute hypoglycaemia. This will encourage early resolution of symptoms when hypoglycaemia is treated by eating.
P1253 Systemic, but Not Local, Propranolol Infusion Blocks Hypoglycemic Muscular Insulin Resistance ROBERT P HOFFMAN ‘, Christine A. Sinkey ‘, Bradley G. Phillips*.
’ Dept of Pediatrics, University of Iowa, Iowa City, IA. United States of America; ‘College of Pharmacy, University of Iowa, Iowa City, IA, United States of America During hypoglycemia increased epinephrine secretion causes peripheral insulin resistance. The mechanism by which this happens is not well understood. To determine whether decreased muscle glucose uptake during hypoglycemia is due to the peripheral or systemic effects of epinephrine, we studied forearm blood flow (FBF, plethysmography, mercury in silastic strain gauge, dominant arm), arterial-venous glucose difference (AV diff), and forearm glucose uptake (FGU) during 40 mU mm2 min.’ insulin infusion with 60 mm of euglycemia followed by 60 min of hypoglycemia. Propranolol was infused either systemically through an intravenous catheter in the contralateral arm (IV PROP, 80 &min,