Clinical Insulin Clearance During Hypoglycemia in Patients with Insulin-Dependent Diabetes Mellitus M. Kollind1, E. Moberg1, D. Liu2, P.-E. Lins1 and U. Adamson1 Department of Internal Medicine, Danderyd Hospital, Stockholm, Sweden Department of Endocrinology, Peking Union Medical College Hospital, Peking, China
Eight male patients with insulin-dependent diabetes mellitus (IDDM) without residual beta-cell function were studied on two occasions in random order. In one experiment hypoglycemia was induced by a constant rate iv infusion of insulin (0.034 U/kg/h) during 150 minutes. At the other occasion an identical infusion of insulin was given, but this time euglycemia was maintained by a variable iv infusion of glucose. Plasma levels of free insulin were almost identical during the two experiments indicating that insulin clearance is not influenced by hypoglycemia in patients with IDDM. Key words Diabetes Mellitus — Hypoglycemia — Insulin Clearance
Introduction The elimination of exogenous insulin from the circulation is of importance for the counterregulation of hypoglycemia in patients with insulin-dependent diabetes mellitus (IDDM). This has been demonstrated in diabetics with circulating insulin binding antibodies (Bolli, DeFeo, Compagnucci, Cartechini, Angeletti, Santeusanio, Brunetti and Gerich 1983) and in diabetics with kidney failure (Berglund, Lins and Lins 1985) where the plasma clearance of insulin may be delayed. Studies in pancreatectomized dogs have indicated that hypoglycemia as well as adrenaline infusion decreases the hepatic extraction of insulin and that these effects can be inhibited by propranolol (Doi, Morita, Nakata and Baba 1987). If this also is the case in patients with IDDM, and if such an effect of hypoglycemia on hepatic extraction influences the total clearance of insulin, this could be of clinical importance in affecting the recovery from hypoglycemia in these patients. To study this issue we examined eight male patients without residual beta-cell function on two occasions.
Horm.metab.Res. 23(1991)333-335 © Georg Thieme Verlag Stuttgart -New York
In both experiments an identical constant rate of insulin infusion was given. Hypoglycemia was induced in one of the experiments, while in the other experiment euglycemia was maintained by a variable infusion of glucose. Material and Methods Eight male patients with IDDM, aged 25 — 37 years, without residual beta-cell function (C-peptide < 0.15 nmol/1 after a mixed meal) were studied. Their diabetes duration was 12.3 + 1.7 years, the body mass index 23.1 ±0.52 and HbAlc 7.5 + 0.4% (normal < 5.6%). Their regular daily insulin dose was 0.59 + 0.55 U/kg divided into four or five injections. Their plasma levels of antibodybound insulin were < 6% in all but one patient who had 26%. None had hypertension, albuminuria or signs of peripheral neuropathy and their autonomic nervous function as assessed by the Valsalva ratio and respiratory sinus arrhythmia was normal. None was taking other medication than insulin. Informed consent was obtained from all subjects and the Ethics Committee of the Karolinska Hospital had approved the study. In order to deplete the sc insulin depot, the patients had their last sc injections of intermediate acting insulin 34 h prior to the study and their last injections of regular insulin 24 h prior to the study. Thereafter they were admitted to the metabolic ward and given insulin (Actrapid Human, Novo Industri A/S, Denmark) as a variable iv infusion, adjusted every 1—3 h according to the capillary blood glucose concentration, aiming at a level between 8-10 mmol/1 over the day and between 5—6 mmol/1 at the start of the experiment the following morning. The patients had their regular meals and snacks during the day, but no food was ingested after 22.00 h. The insulin infusion allowed the patients to walk inside the hospital. On the following morning at 8.00 h the experiments were started. The patients were placed in a comfortable semirecumbent position and a short teflon catheter was inserted into a forearm vein on each side, one being used for blood sampling and the other for insulin and glucose infusions. Each patient participated in two experiments, at least one week elapsing between the two tests. In one experiment hypoglycemia was induced by a constant rate iv infusion of insulin (0.034 U/kg/h) during 150 minutes. In the other experiment an identical infusion of insulin was given, but euglycemia was maintained by a variable infusion of iv glucose (20 %). Venous blood samples were obtained every 15—30 min for measurements of blood glucose (Glucose analyzer 23 AM, Yellow Springs Instruments Inc., USA), plasma free insulin (Nakagawa, Nakayama, Sasaki, Yoshino, Yu, Shinozaki, Aoki and Mashimo 1973) and plasma adrenaline. For the analysis of free insulin extraction with polyethyleneglycol was performed immediately after blood sampling. The inter- and intraassay coefficient of variation for plasma free insulin determination was 6.5 and 5.8%, respectively and the detection
Received: 11 July 1990
Accepted: 12 Dec. 1990
Downloaded by: Universite Laval. Copyrighted material.
Summary
Horm. metab. Res. 23 (1991)
M. Kollind, E. Moberg, D. Liu, P.-E. Lins and U. Adamson
Fig. 1 Blood glucose levels during the hypoglycemic and the euglycemic experiment (upper panel) and the glucose infusion rate during the euglycemic experiment (lower panel). For details see text.
Fig. 2 Plasma adrenaline and plasma free insulin levels during the hypoglycemic ( • ) and euglycemic ( • ) experiment. For details see text.
limit was 2.5 mU/1. Adrenaline was analysed by liquid chromatography with electrochemical detection (Hallman, Farnebo, Hamberger and Jonsson 1978).
Hypoglycemia induces several haemodynamic and hormonal changes which could be of importance for the absorption, distribution and clearance of insulin. Decreased insulin absorption during hypoglycemia has recently been shown in healthy subjects (Fernqvist-Forbes, Linde and Gunnarsson 1988) but not in diabetics {Fernqvist-Forbes, Gunnarsson and Linde 1989). During hypoglycemia the heart rate, systolic blood pressure, cardiac output and the blood flow in the brain and skeletal muscles is increased whereas the diastolic blood pressure and the total peripheral resistance is decreased (Hilsted, Bonde-Petersen, Ncergaard, Greniman, Christensen, Parving and Suzuki 1984; Gale, Bennet, MacDonald, Hoist and Matthews 1983; Neil, Gale, Hamilton, Lopez-Espinosa, Kaura and McCarthy 1987). The hepatosplanchnic vascular resistance however seems to be unaffected during hypoglycemia (Hilsted et al. 1984).
The mean plasma free insulin concentration between 60 and 150 min was calculated for each patient and used as a measure of the steady state level of insulin. Unless otherwise stated data are expressed as means + SEM. Results During the insulin induced hypoglycemia a blood glucose nadir of 2.6 + 0.2 mmol/1 was reached compared to 5.8 + 0.2 mmol/1 in the experiment without hypoglycemia (Fig. 1). During the latter experiment a total of 172 ± 13 ml of the 20% glucose solution was infused. The steady state plasma free insulin level was almost identical in the hypo- and euglycemic experiments, 28.5+1.8 mU/1 vs 28.8 ± 2 . 2 mU/1 respectively (Fig. 2), whereas a rise in the plasma adrenaline levels was only seen during the hypoglycemic experiment (Fig. 2). Discussion In normal man the liver is responsible for more than half of the total metabolism of insulin and the kidneys for approximately one-third {Duckworth and Kitabchi 1981). To a minor part insulin is also metabolized in muscle and adipose tissue (Duckworth and Kitabchi 1981). In patients with I D D M insulin is administrated peripherally rather than into the portal circulation and thus the kidneys probably play a greater role in the total insulin clearance (Rabkin, Ryan and Duckworth 1984), but the relative contribution of different tissues in the total insulin metabolism is unclear (Tiran, Avruch and Albisser 1979; Ferrannini, Wahren, Faber, Felig, Binder and DeFronzo 1983).
Not much is known about insulin clearance during hypoglycemia in patients with IDDM. Doi et al. (1987) reported that in diabetic dogs both hypoglycemia and adrenaline infusion reduced the hepatic extraction of insulin and that this effect was blocked by propranolol. Somewhat in contrast, in patients with IDDM it was reported on a reduced clearance rate of insulin during hypoglycemia when metoprolol was concomitantly infused (Clausen-Sjobom, Lins, Adamson, Curstedt and Hamberger 1987). In this study plasma levels of adrenaline were higher in the experiment with metoprolol and it was speculated upon whether the reduced insulin clearance was due to an exaggerated alpha-adrenergic effect on the splanchnic vascular bed. In the present study the plasma adrenaline levels increased during hypoglycemia, but in spite of this the plasma levels of free insulin were close to identical in the experiments with and without hypoglycemia. As only patients without residual beta-cell function were studied the plasma
Downloaded by: Universite Laval. Copyrighted material.
334
Insulin Clearance During Hypoglycemia in Patients with IDDM
Horm. metab. Res. 23 (1991)
335
Doi, K., S. Morita, K, Nakata, S. Baba: Influence of insulin-counterregulatory hormone on hepatic extraction of exogenous insulin. Diabetes 36: 2 Suppl. 95 (1987) Duckworth, W. C, A. E. Kitabchi: Insulin metabolism and degradaThe divergent findings in the study of Doi et al. tion. Endocrine Reviews 2:210-233 (1981) and our study could possibly be explained by the different exFemqvist-Forbes, E., R. Gunnarsson, B. Linde: Insulin-induced hyperimental protocols used. Thus, Doi et al. used the portal vein poglycemia and absorption of injected insulin in diabetic patients. Diabetic Medicine 6:621 -626 (1989) for insulin infusion whereas we used a peripheral vein. This Femqvist-Forbes, E., B. Linde, R. Gunnarsson: Insulin absorption and probably alters the relation between hepatic and kidney resubcutaneous blood flow in normal subjects during insulin-inmoval of insulin, in our study making the kidney part more imduced hypoglycemia. J. Clin. Endocrinol. Metab. 67: 619—623 portant. Furthermore, we only analyzed plasma levels of free (1988) insulin during steady state as a measure of the total plasma Ferrannini, E., J. Wahren, O. K. Faber, P. Felig, C. Binder, R. A. Declearance of insulin, but the relative contribution of hepatic Fronzo: Splanchnic and renal metabolism of insulin in human suband kidney insulin removal is not known. In view of the findjects: a dose response study. Am. J. Physiol. 244 (Endocrinol. Metab. 7):E517-527(1983) ings in the previous mentioned animal study it may be specuGale, E. A. M., T. Bennet, I. A. MacDonald, J. J. Hoist, J. A. Matthews: lated upon whether hypoglycemia affects hepatic and kidney The physiological effects of insulin-induced hypoglycemia in removal of insulin in different directions. man: responses at different levels of blood glucose. Clin. Sci. 65: 263-271(1983) It is well known that insulin clearance may be Hallman, H, L. O. Farnebo, B. Hamberger, G. Jonsson: A sensitive delayed by insulin-binding antibodies. However, if insulin-anmethod for the determination of plasma catecholamines using liquid chromatography with electrochemical detection. Life Sci. 23: tibody-binding is below 10%, insulin metabolism is not 1049-1052(1978) believed to be affected (Van Hceften, Bolli, Dimitriadis, GottesHilsted, J., F. Bonde-Petersen, M. B. Nasrgaard, M. Greniman, N. J. man, Horwitz and Gerich 1986). All but one patient in our Christensen, H. H. Parving, M. Suzuki: Haemodynamic changes in study had unmeasurable levels of insulin binding antibodies. insulin-induced hypoglycemia in normal man. Diabetologia 26: This one patient did not differ from the others concerning 328-332(1984) blood glucose values or plasma levels of free insulin. Nakagawa, S., H. Nakayama, T. Sasaki, K. Yoshino, Y. Y. Yu, K. Shinozaki, S. Aoki, K. Mashimo: A simple method for the determination of serum free insulin levels in insulin-treated patients. DiaIn conclusion, in the present study on patients betes 22:590-600 (1973) with IDDM, insulin induced hypoglycemia did not affect the Neil, H. A. W., E. A. M. Gale, S. J. C. Hamilton, I. Lopez-Espinosa, R. plasma clearance of insulin. Kaura, S. T. McCarthy: Cerebral blood flow increases during insulin-induced hypoglycemia in Type 1 (insulin-dependent) diaAcknowledgements betic patients and control subjects. Diabetologia 30: 305-309 (1987) We wish to thank Miss Anne Ekelund, Mrs Renee Rabkin, R., M. P. Ryan, W. C. Duckworth: The renal metabolism of inLidbom-Hedin for their excellent help in the studies, which were supsulin. Diabetologia 27:351-357 (1984) ported by grants from the Swedish Medical Council (19x-6589 and Tiran, J., L. I. Avruch, A. M. Albisser: A circulation and organ model 19x-2330) and the Karolinska Institute. for insulin dynamics. Am. J. Physiol. 6: E331-339 (1979) Van Hceften, T. W., G. B. Bolli, G. D. Dimitriadis, I. S. Gottesman, D. L. Horwitz, J. E. Gerich: Effect of insulin antibodies and their References kinetic characteristics on plasma free insulin dynamics in patients with diabetes mellitus. Metabolism 35:649-656 (1986) Berglund, J., L. E. Lins, P. E. litis: Metabolic and blood pressure monitoring in diabetic renal failure. Acta Med. Scand. 218: 401-408 (1985) Bolli, G., P. DeFeo, P. Compagnucci, M. G. Cartechini, G. Angeletti, F. Requests for reprints should be addressed to: Santeusanio, P. Brunetti J. E. Gerich: Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of Dr. Magnus Kollind anti-insulin antibodies and impaired glucagon and epinephrine Department of Internal Medicine secretion. Diabetes 32:134-141 (1983) Clausen-Sjobom, N, P. E. Lins, U. Adamson, T. Curstedt, B. Ham- Danderyd Hospital berger: Effects of metoprolol on the counter-regulation and recog- S-182 88 Danderyd, Stockholm (Sweden) nition of prolonged hypoglycemia in insulin-dependent diabetics. ActaMed. Scand. 222:57-63 (1987)
Downloaded by: Universite Laval. Copyrighted material.
levels of free insulin during the steady state insulin infusion reflected the total plasma clearance of insulin.
Eight male patients with insulin-dependent diabetes mellitus (IDDM) without residual beta-cell function were studied on two occasions in random order. In one experiment hypoglycemia was induced by a constant rate iv infusion of insulin (0.034 U/kg/h) during 150 minutes. At the other occasion an identical infusion of insulin was given, but this time euglycemia was maintained by a variable iv infusion of glucose. Plasma levels of free insulin were almost identical during the two experiments indicating that insulin clearance is not influenced by hypoglycemia in patients with IDDM. Key words Diabetes Mellitus — Hypoglycemia — Insulin Clearance
Introduction The elimination of exogenous insulin from the circulation is of importance for the counterregulation of hypoglycemia in patients with insulin-dependent diabetes mellitus (IDDM). This has been demonstrated in diabetics with circulating insulin binding antibodies (Bolli, DeFeo, Compagnucci, Cartechini, Angeletti, Santeusanio, Brunetti and Gerich 1983) and in diabetics with kidney failure (Berglund, Lins and Lins 1985) where the plasma clearance of insulin may be delayed. Studies in pancreatectomized dogs have indicated that hypoglycemia as well as adrenaline infusion decreases the hepatic extraction of insulin and that these effects can be inhibited by propranolol (Doi, Morita, Nakata and Baba 1987). If this also is the case in patients with IDDM, and if such an effect of hypoglycemia on hepatic extraction influences the total clearance of insulin, this could be of clinical importance in affecting the recovery from hypoglycemia in these patients. To study this issue we examined eight male patients without residual beta-cell function on two occasions.
Horm.metab.Res. 23(1991)333-335 © Georg Thieme Verlag Stuttgart -New York
In both experiments an identical constant rate of insulin infusion was given. Hypoglycemia was induced in one of the experiments, while in the other experiment euglycemia was maintained by a variable infusion of glucose. Material and Methods Eight male patients with IDDM, aged 25 — 37 years, without residual beta-cell function (C-peptide < 0.15 nmol/1 after a mixed meal) were studied. Their diabetes duration was 12.3 + 1.7 years, the body mass index 23.1 ±0.52 and HbAlc 7.5 + 0.4% (normal < 5.6%). Their regular daily insulin dose was 0.59 + 0.55 U/kg divided into four or five injections. Their plasma levels of antibodybound insulin were < 6% in all but one patient who had 26%. None had hypertension, albuminuria or signs of peripheral neuropathy and their autonomic nervous function as assessed by the Valsalva ratio and respiratory sinus arrhythmia was normal. None was taking other medication than insulin. Informed consent was obtained from all subjects and the Ethics Committee of the Karolinska Hospital had approved the study. In order to deplete the sc insulin depot, the patients had their last sc injections of intermediate acting insulin 34 h prior to the study and their last injections of regular insulin 24 h prior to the study. Thereafter they were admitted to the metabolic ward and given insulin (Actrapid Human, Novo Industri A/S, Denmark) as a variable iv infusion, adjusted every 1—3 h according to the capillary blood glucose concentration, aiming at a level between 8-10 mmol/1 over the day and between 5—6 mmol/1 at the start of the experiment the following morning. The patients had their regular meals and snacks during the day, but no food was ingested after 22.00 h. The insulin infusion allowed the patients to walk inside the hospital. On the following morning at 8.00 h the experiments were started. The patients were placed in a comfortable semirecumbent position and a short teflon catheter was inserted into a forearm vein on each side, one being used for blood sampling and the other for insulin and glucose infusions. Each patient participated in two experiments, at least one week elapsing between the two tests. In one experiment hypoglycemia was induced by a constant rate iv infusion of insulin (0.034 U/kg/h) during 150 minutes. In the other experiment an identical infusion of insulin was given, but euglycemia was maintained by a variable infusion of iv glucose (20 %). Venous blood samples were obtained every 15—30 min for measurements of blood glucose (Glucose analyzer 23 AM, Yellow Springs Instruments Inc., USA), plasma free insulin (Nakagawa, Nakayama, Sasaki, Yoshino, Yu, Shinozaki, Aoki and Mashimo 1973) and plasma adrenaline. For the analysis of free insulin extraction with polyethyleneglycol was performed immediately after blood sampling. The inter- and intraassay coefficient of variation for plasma free insulin determination was 6.5 and 5.8%, respectively and the detection
Received: 11 July 1990
Accepted: 12 Dec. 1990
Downloaded by: Universite Laval. Copyrighted material.
Summary
Horm. metab. Res. 23 (1991)
M. Kollind, E. Moberg, D. Liu, P.-E. Lins and U. Adamson
Fig. 1 Blood glucose levels during the hypoglycemic and the euglycemic experiment (upper panel) and the glucose infusion rate during the euglycemic experiment (lower panel). For details see text.
Fig. 2 Plasma adrenaline and plasma free insulin levels during the hypoglycemic ( • ) and euglycemic ( • ) experiment. For details see text.
limit was 2.5 mU/1. Adrenaline was analysed by liquid chromatography with electrochemical detection (Hallman, Farnebo, Hamberger and Jonsson 1978).
Hypoglycemia induces several haemodynamic and hormonal changes which could be of importance for the absorption, distribution and clearance of insulin. Decreased insulin absorption during hypoglycemia has recently been shown in healthy subjects (Fernqvist-Forbes, Linde and Gunnarsson 1988) but not in diabetics {Fernqvist-Forbes, Gunnarsson and Linde 1989). During hypoglycemia the heart rate, systolic blood pressure, cardiac output and the blood flow in the brain and skeletal muscles is increased whereas the diastolic blood pressure and the total peripheral resistance is decreased (Hilsted, Bonde-Petersen, Ncergaard, Greniman, Christensen, Parving and Suzuki 1984; Gale, Bennet, MacDonald, Hoist and Matthews 1983; Neil, Gale, Hamilton, Lopez-Espinosa, Kaura and McCarthy 1987). The hepatosplanchnic vascular resistance however seems to be unaffected during hypoglycemia (Hilsted et al. 1984).
The mean plasma free insulin concentration between 60 and 150 min was calculated for each patient and used as a measure of the steady state level of insulin. Unless otherwise stated data are expressed as means + SEM. Results During the insulin induced hypoglycemia a blood glucose nadir of 2.6 + 0.2 mmol/1 was reached compared to 5.8 + 0.2 mmol/1 in the experiment without hypoglycemia (Fig. 1). During the latter experiment a total of 172 ± 13 ml of the 20% glucose solution was infused. The steady state plasma free insulin level was almost identical in the hypo- and euglycemic experiments, 28.5+1.8 mU/1 vs 28.8 ± 2 . 2 mU/1 respectively (Fig. 2), whereas a rise in the plasma adrenaline levels was only seen during the hypoglycemic experiment (Fig. 2). Discussion In normal man the liver is responsible for more than half of the total metabolism of insulin and the kidneys for approximately one-third {Duckworth and Kitabchi 1981). To a minor part insulin is also metabolized in muscle and adipose tissue (Duckworth and Kitabchi 1981). In patients with I D D M insulin is administrated peripherally rather than into the portal circulation and thus the kidneys probably play a greater role in the total insulin clearance (Rabkin, Ryan and Duckworth 1984), but the relative contribution of different tissues in the total insulin metabolism is unclear (Tiran, Avruch and Albisser 1979; Ferrannini, Wahren, Faber, Felig, Binder and DeFronzo 1983).
Not much is known about insulin clearance during hypoglycemia in patients with IDDM. Doi et al. (1987) reported that in diabetic dogs both hypoglycemia and adrenaline infusion reduced the hepatic extraction of insulin and that this effect was blocked by propranolol. Somewhat in contrast, in patients with IDDM it was reported on a reduced clearance rate of insulin during hypoglycemia when metoprolol was concomitantly infused (Clausen-Sjobom, Lins, Adamson, Curstedt and Hamberger 1987). In this study plasma levels of adrenaline were higher in the experiment with metoprolol and it was speculated upon whether the reduced insulin clearance was due to an exaggerated alpha-adrenergic effect on the splanchnic vascular bed. In the present study the plasma adrenaline levels increased during hypoglycemia, but in spite of this the plasma levels of free insulin were close to identical in the experiments with and without hypoglycemia. As only patients without residual beta-cell function were studied the plasma
Downloaded by: Universite Laval. Copyrighted material.
334
Insulin Clearance During Hypoglycemia in Patients with IDDM
Horm. metab. Res. 23 (1991)
335
Doi, K., S. Morita, K, Nakata, S. Baba: Influence of insulin-counterregulatory hormone on hepatic extraction of exogenous insulin. Diabetes 36: 2 Suppl. 95 (1987) Duckworth, W. C, A. E. Kitabchi: Insulin metabolism and degradaThe divergent findings in the study of Doi et al. tion. Endocrine Reviews 2:210-233 (1981) and our study could possibly be explained by the different exFemqvist-Forbes, E., R. Gunnarsson, B. Linde: Insulin-induced hyperimental protocols used. Thus, Doi et al. used the portal vein poglycemia and absorption of injected insulin in diabetic patients. Diabetic Medicine 6:621 -626 (1989) for insulin infusion whereas we used a peripheral vein. This Femqvist-Forbes, E., B. Linde, R. Gunnarsson: Insulin absorption and probably alters the relation between hepatic and kidney resubcutaneous blood flow in normal subjects during insulin-inmoval of insulin, in our study making the kidney part more imduced hypoglycemia. J. Clin. Endocrinol. Metab. 67: 619—623 portant. Furthermore, we only analyzed plasma levels of free (1988) insulin during steady state as a measure of the total plasma Ferrannini, E., J. Wahren, O. K. Faber, P. Felig, C. Binder, R. A. Declearance of insulin, but the relative contribution of hepatic Fronzo: Splanchnic and renal metabolism of insulin in human suband kidney insulin removal is not known. In view of the findjects: a dose response study. Am. J. Physiol. 244 (Endocrinol. Metab. 7):E517-527(1983) ings in the previous mentioned animal study it may be specuGale, E. A. M., T. Bennet, I. A. MacDonald, J. J. Hoist, J. A. Matthews: lated upon whether hypoglycemia affects hepatic and kidney The physiological effects of insulin-induced hypoglycemia in removal of insulin in different directions. man: responses at different levels of blood glucose. Clin. Sci. 65: 263-271(1983) It is well known that insulin clearance may be Hallman, H, L. O. Farnebo, B. Hamberger, G. Jonsson: A sensitive delayed by insulin-binding antibodies. However, if insulin-anmethod for the determination of plasma catecholamines using liquid chromatography with electrochemical detection. Life Sci. 23: tibody-binding is below 10%, insulin metabolism is not 1049-1052(1978) believed to be affected (Van Hceften, Bolli, Dimitriadis, GottesHilsted, J., F. Bonde-Petersen, M. B. Nasrgaard, M. Greniman, N. J. man, Horwitz and Gerich 1986). All but one patient in our Christensen, H. H. Parving, M. Suzuki: Haemodynamic changes in study had unmeasurable levels of insulin binding antibodies. insulin-induced hypoglycemia in normal man. Diabetologia 26: This one patient did not differ from the others concerning 328-332(1984) blood glucose values or plasma levels of free insulin. Nakagawa, S., H. Nakayama, T. Sasaki, K. Yoshino, Y. Y. Yu, K. Shinozaki, S. Aoki, K. Mashimo: A simple method for the determination of serum free insulin levels in insulin-treated patients. DiaIn conclusion, in the present study on patients betes 22:590-600 (1973) with IDDM, insulin induced hypoglycemia did not affect the Neil, H. A. W., E. A. M. Gale, S. J. C. Hamilton, I. Lopez-Espinosa, R. plasma clearance of insulin. Kaura, S. T. McCarthy: Cerebral blood flow increases during insulin-induced hypoglycemia in Type 1 (insulin-dependent) diaAcknowledgements betic patients and control subjects. Diabetologia 30: 305-309 (1987) We wish to thank Miss Anne Ekelund, Mrs Renee Rabkin, R., M. P. Ryan, W. C. Duckworth: The renal metabolism of inLidbom-Hedin for their excellent help in the studies, which were supsulin. Diabetologia 27:351-357 (1984) ported by grants from the Swedish Medical Council (19x-6589 and Tiran, J., L. I. Avruch, A. M. Albisser: A circulation and organ model 19x-2330) and the Karolinska Institute. for insulin dynamics. Am. J. Physiol. 6: E331-339 (1979) Van Hceften, T. W., G. B. Bolli, G. D. Dimitriadis, I. S. Gottesman, D. L. Horwitz, J. E. Gerich: Effect of insulin antibodies and their References kinetic characteristics on plasma free insulin dynamics in patients with diabetes mellitus. Metabolism 35:649-656 (1986) Berglund, J., L. E. Lins, P. E. litis: Metabolic and blood pressure monitoring in diabetic renal failure. Acta Med. Scand. 218: 401-408 (1985) Bolli, G., P. DeFeo, P. Compagnucci, M. G. Cartechini, G. Angeletti, F. Requests for reprints should be addressed to: Santeusanio, P. Brunetti J. E. Gerich: Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of Dr. Magnus Kollind anti-insulin antibodies and impaired glucagon and epinephrine Department of Internal Medicine secretion. Diabetes 32:134-141 (1983) Clausen-Sjobom, N, P. E. Lins, U. Adamson, T. Curstedt, B. Ham- Danderyd Hospital berger: Effects of metoprolol on the counter-regulation and recog- S-182 88 Danderyd, Stockholm (Sweden) nition of prolonged hypoglycemia in insulin-dependent diabetics. ActaMed. Scand. 222:57-63 (1987)
Downloaded by: Universite Laval. Copyrighted material.
levels of free insulin during the steady state insulin infusion reflected the total plasma clearance of insulin.
