Clinical Arginine Vasopressin Response to Insulin-Induced Hypoglycemia in Insulin-Dependent Diabetics with Asymptomatic Hypoglycemia J. P. Wolf1, J. Massol2, N. U. Nguyen1 and S. Berthelay1 1Laboratoire d'Explorations Fonctionnelles Renales, Metaboliques et Endocriniennes 2 Service de Diabetologie-Endocrinologie, Centre Hospitalier Universitaire Jean Minjoz, Besancon, France
Summary Insulin-induced hypoglycemia causes an increase in plasma vasopressin (AVP) in healthy subjects but the response in diabetics is not established. We investigated the effect of insulin-induced hypoglycemia on ten insulindependent diabetics with asymptomatic hypoglycemia, and compared the results with those for seven healthy subjects. The lack of adrenergic symptoms of hypoglycemia in insulin dependent diabetics being attributed to a diminished B-adrenergic sensitivity, the effect of isoprenaline infusion was investigated as control. Insulin-induced hypoglycemia resulted in both populations in significant increase (P < 0.01) in AVP in addition to significant increases in heart rate, plasma epinephrine (E), norepenephrine (NE) and Cortisol (COR). Effective osmolality and mean arterial blood pressure did not vary. Diabetics showed smaller increase in AVP (P < 0.01) and heart rate (P < 0.05) than controls. Maximal E, NE and COR values did not differ between the two populations. Isoprenaline infusion resulted in increase in heart rate and plasma renin activity, but AVP and COR did not vary in the two populations. In conclusion, insulin-induced hypoglycemia released AVP in diabetics with asymptomatic hypoglycemia, but the response was weaker than in healthy subjects. A causal hypothalamic alteration of P-adrenergic or glycopenia sensitivity is discussed. Key words Arginine Vasopressin - Insulin Dependent Diabetics - Insulin-Induced Hypoglycemia
Horm. meta. Res. 22 (1990) 232-236 © Georg Thieme Verlag Stuttgart -New York
It is well established that insulin-induced hypoglycemia stimulates the release of arginine vasopressin (AVP) in normal man (Baylis and Heath 1977; Baylis, Zerbe and Robertson 1981; Watanabe, Tanaka, Kumagae, Itoh, Takeda, Mono, Hasegawa, Horiuchi, Miyabe and Shimizu 1987). In other respects, 2-deoxy-D-glucose (2DG), a competitive inhibitor of glucose transport and of phosphoexoisomerase activity, stimulates AVP release, suggesting glycopenia in hypothalamic neurons as a cause (Thompson, Campbell, Lilavivat, Welle and Robertson 1981). Although it has been established that the AVP response to osmotic and volumic stimuli did not differ in diabetics when compared to healthy subjects (Zerbe, Vinicor and Robertson 1985) insofar there is no data on AVP response to insulin-induced hypoglycemia in diabetics. So, the present study was undertaken to investigate the efficiency of insulin-induced hypoglycemia on AVP release in insulin-dependent diabetics presenting asymptomatic hypoglycemia. In such a population of diabetics, the lack of adrenergic symptoms of hypoglycemia has been attributed to a diminished B-adrenergic sensitivity (Berlin, Grimaldi, Landault, Zoghbi, Thervet, Puech and Legrand 1988) which might influence AVP response directly (Brooks, Share and Crofton 1986), and indirectly by angiotensin II mediation (Bonjour and Malvin 1970). So we investigated simultaneously plasma epinephrine (E) and norepinephrine (NE) and cardiac response, in order to evaluate adrenergic response and adrenergic sensitivity to insulin-induced hypoglycemia. As control experiment, cardiac and arterial blood pressure responses, plasma renin activity (PRA) and plasma AVP have been evaluated after B-adrenergic stimulation by isoprenaline infusion, at a dose required to increase PRA (Tuck, Sambhi, and Levin 1979). In the two tests, plasma Cortisol (COR) was also measured, in order to appreciate emotional or physical stress.
Received: 24 Jan. 1989
Accepted: 11 Sept. 1989 after revision
Downloaded by: NYU. Copyrighted material.
Introduction
Horm. meta. Res. 22 (1990)
Hypoglycemia and AVP in Diabetics
233
Table 1 Insulin-induced hypoglycemia in diabetics with asymptomatic hypoglycemia. -30 min (n = 10)
Omin (n=10) 000
Hypoglycemia (n = 10)
Glucose (mmol/L)
6.99±0.84
Heart rate (beats/min)
72.0+8.1
MAP (mmHg)
88.1+7.8
87.8±9.8
89.7±8.3
Osmolality (mosmol/kg)
288.1+4.2
289.4+4.6
284.4±4.0
Eff. osm. (mosmol/kg)
277.5+3.9
7.28+0.86
°°°
81.8±9.0
3.40 ±1.09
3.18±0.98
2.30+0.70
*** 71.U7.2
+ 60 min (n=6)
+30 min (n=6)
O
** 76.8 ±10.5
73.8 ±7.4
86.5+11.6
84.6 ±13.0
**
284.5±4.0
287.0±3.7
277.4 + 3.5
279.3 ±3.9
***
0.94+0.33
E (pg/ml)
46.0 + 16.4
NE (pg/ml)
303.5 ±137.2
COR (pmol/ml)
355.5± 117.4
1.04+0.42
277.8 ±3.5
2.62 + 1.54
QO
44.9±21.1
364.4 ±253.1
* **
483.8 ±148.9
405.3 + 153.3
474.6+196.6
534.3±281.1
*** 371.1 ±123.9
176.0 + 107.8
333.2+308.9
** 297.3+160.4
1.18+0.83
2.58 ±1.43
**
O O 0
*
**
* 659.5 ±244.0
652.0+200.8
**
*
Mean(±SD) basal values and values obtained at the onset of hypoglycemia (10 subjects), at 30 and 60 min thereafter (6 subjects, see text for explanation). An iv bolus dose of insulin was given at time 0. Comparisons between basal and post insulin values are reported when significative. ***P < 0.001; **P < 0.01; *P < 0.05. Comparisons at each time between diabetics and healthy subjects (see values in Table 2) are reported when significative. °°°P < 0.001; oo P < 0 . 0 1 ; °P 5 years). Selection criteria for these 10 subjects was presence of severe hypoglycemic accidents, absence of hypoglycemic symptoms during hypoglycemia, and evidence of impaired (B-adrenergic sensitivity, established by a standardized isoprenaline sensitivity test (Arnold and Devitt 1983). The dose of isoprenaline required to increase the resting heart rate by 25 beats/min (125 test) was 3.44±0.88 |i,g in these diabetic patients compared to 1.48 + 0.38 ug in 10 healthy subjects (P
Summary Insulin-induced hypoglycemia causes an increase in plasma vasopressin (AVP) in healthy subjects but the response in diabetics is not established. We investigated the effect of insulin-induced hypoglycemia on ten insulindependent diabetics with asymptomatic hypoglycemia, and compared the results with those for seven healthy subjects. The lack of adrenergic symptoms of hypoglycemia in insulin dependent diabetics being attributed to a diminished B-adrenergic sensitivity, the effect of isoprenaline infusion was investigated as control. Insulin-induced hypoglycemia resulted in both populations in significant increase (P < 0.01) in AVP in addition to significant increases in heart rate, plasma epinephrine (E), norepenephrine (NE) and Cortisol (COR). Effective osmolality and mean arterial blood pressure did not vary. Diabetics showed smaller increase in AVP (P < 0.01) and heart rate (P < 0.05) than controls. Maximal E, NE and COR values did not differ between the two populations. Isoprenaline infusion resulted in increase in heart rate and plasma renin activity, but AVP and COR did not vary in the two populations. In conclusion, insulin-induced hypoglycemia released AVP in diabetics with asymptomatic hypoglycemia, but the response was weaker than in healthy subjects. A causal hypothalamic alteration of P-adrenergic or glycopenia sensitivity is discussed. Key words Arginine Vasopressin - Insulin Dependent Diabetics - Insulin-Induced Hypoglycemia
Horm. meta. Res. 22 (1990) 232-236 © Georg Thieme Verlag Stuttgart -New York
It is well established that insulin-induced hypoglycemia stimulates the release of arginine vasopressin (AVP) in normal man (Baylis and Heath 1977; Baylis, Zerbe and Robertson 1981; Watanabe, Tanaka, Kumagae, Itoh, Takeda, Mono, Hasegawa, Horiuchi, Miyabe and Shimizu 1987). In other respects, 2-deoxy-D-glucose (2DG), a competitive inhibitor of glucose transport and of phosphoexoisomerase activity, stimulates AVP release, suggesting glycopenia in hypothalamic neurons as a cause (Thompson, Campbell, Lilavivat, Welle and Robertson 1981). Although it has been established that the AVP response to osmotic and volumic stimuli did not differ in diabetics when compared to healthy subjects (Zerbe, Vinicor and Robertson 1985) insofar there is no data on AVP response to insulin-induced hypoglycemia in diabetics. So, the present study was undertaken to investigate the efficiency of insulin-induced hypoglycemia on AVP release in insulin-dependent diabetics presenting asymptomatic hypoglycemia. In such a population of diabetics, the lack of adrenergic symptoms of hypoglycemia has been attributed to a diminished B-adrenergic sensitivity (Berlin, Grimaldi, Landault, Zoghbi, Thervet, Puech and Legrand 1988) which might influence AVP response directly (Brooks, Share and Crofton 1986), and indirectly by angiotensin II mediation (Bonjour and Malvin 1970). So we investigated simultaneously plasma epinephrine (E) and norepinephrine (NE) and cardiac response, in order to evaluate adrenergic response and adrenergic sensitivity to insulin-induced hypoglycemia. As control experiment, cardiac and arterial blood pressure responses, plasma renin activity (PRA) and plasma AVP have been evaluated after B-adrenergic stimulation by isoprenaline infusion, at a dose required to increase PRA (Tuck, Sambhi, and Levin 1979). In the two tests, plasma Cortisol (COR) was also measured, in order to appreciate emotional or physical stress.
Received: 24 Jan. 1989
Accepted: 11 Sept. 1989 after revision
Downloaded by: NYU. Copyrighted material.
Introduction
Horm. meta. Res. 22 (1990)
Hypoglycemia and AVP in Diabetics
233
Table 1 Insulin-induced hypoglycemia in diabetics with asymptomatic hypoglycemia. -30 min (n = 10)
Omin (n=10) 000
Hypoglycemia (n = 10)
Glucose (mmol/L)
6.99±0.84
Heart rate (beats/min)
72.0+8.1
MAP (mmHg)
88.1+7.8
87.8±9.8
89.7±8.3
Osmolality (mosmol/kg)
288.1+4.2
289.4+4.6
284.4±4.0
Eff. osm. (mosmol/kg)
277.5+3.9
7.28+0.86
°°°
81.8±9.0
3.40 ±1.09
3.18±0.98
2.30+0.70
*** 71.U7.2
+ 60 min (n=6)
+30 min (n=6)
O
** 76.8 ±10.5
73.8 ±7.4
86.5+11.6
84.6 ±13.0
**
284.5±4.0
287.0±3.7
277.4 + 3.5
279.3 ±3.9
***
0.94+0.33
E (pg/ml)
46.0 + 16.4
NE (pg/ml)
303.5 ±137.2
COR (pmol/ml)
355.5± 117.4
1.04+0.42
277.8 ±3.5
2.62 + 1.54
QO
44.9±21.1
364.4 ±253.1
* **
483.8 ±148.9
405.3 + 153.3
474.6+196.6
534.3±281.1
*** 371.1 ±123.9
176.0 + 107.8
333.2+308.9
** 297.3+160.4
1.18+0.83
2.58 ±1.43
**
O O 0
*
**
* 659.5 ±244.0
652.0+200.8
**
*
Mean(±SD) basal values and values obtained at the onset of hypoglycemia (10 subjects), at 30 and 60 min thereafter (6 subjects, see text for explanation). An iv bolus dose of insulin was given at time 0. Comparisons between basal and post insulin values are reported when significative. ***P < 0.001; **P < 0.01; *P < 0.05. Comparisons at each time between diabetics and healthy subjects (see values in Table 2) are reported when significative. °°°P < 0.001; oo P < 0 . 0 1 ; °P 5 years). Selection criteria for these 10 subjects was presence of severe hypoglycemic accidents, absence of hypoglycemic symptoms during hypoglycemia, and evidence of impaired (B-adrenergic sensitivity, established by a standardized isoprenaline sensitivity test (Arnold and Devitt 1983). The dose of isoprenaline required to increase the resting heart rate by 25 beats/min (125 test) was 3.44±0.88 |i,g in these diabetic patients compared to 1.48 + 0.38 ug in 10 healthy subjects (P
