- Email: [email protected]
DIURNAL VARIATION IN INSULIN SENSITIVITY
947
although the
results for each subject conformed to the mean behaviour of blood-sugar, not every subject had a lower insulin response in the afternoon. To explain these results it is necessary to postulate that changes in insulin sensitivity are partly responsible for the diurnal difference in the effect of tolbutamide upon the blood-sugar, as we earlier suggested for the The role of differences in oral-glucose tolerance. diurnal changes in insulin sensitivity is considered elsewhere.4 We thank our volunteers; Dr. R. V. Boyd and Dr. C. N. Mallinson for permission to approach their patients; the nursing staff of New Cross and Greenwich District Hospital for help with the tests; and Mr. T. Adrian, Mr. K. Kilborn, and Mr.
TABLE I-DETAILS OF THE PARTICIPANTS
M. Wood for their expert technical assistance. Requests for reprints should be addressed to R. J. J. REFERENCES
2.
R. J., Baker, I. A., Keen, H., Oakley, N. W. Br. med. J. 1972, i, 199. Keane, P. M., Pearson, J., Walker, W. H. C. Diabetologia, 1968, 4,
3. 4.
Jarrett, R. J., Keen, H. Br. med. J. 1970, iv, 334. Gibson, T., Jarrett, R. J. Lancet, 1972, ii, 947.
1.
Jarrett, 339.
DIURNAL VARIATION IN INSULIN SENSITIVITY T. GIBSON
R.
J. JARRETT
Guy’s Hospital, London SE1
9RT
Intravenous insulin-tolerance tests were performed on the same subjects on two occasions, once in the morning and once in the afternoon. The fall in blood-sugar was consistently and significantly greater in the morning. If there is a similar diurnal variation in the sensitivity to endogenous insulin, it would partly explain the phenomenon of diurnal variation in oral-glucose tolerance.
Summary
fasting blood-samples obtained. Further samples were taken 5, 10, 15, 20, 30, and 40 minutes after the rapid intravenous injection of insulin. Duplicate estimates of the blood-sugar were made by the ferricyanide-reduction micro-method (Technicon method N-9a). ’ Actrapid B a porcine insulin with a very low glucagon content, was used. The insulin, supplied as 40 I.U. per ml., was diluted with sterile neutral isotonic saline solution to 1 I.U. per ml. before use. Twenty subjects were given the " standard " dose of 0-1 I.U. per kg., six 0-05 I.U. per kg., and six 0-025 I.U. per kg. body-weight. two
Results Introduction
IN other reports on the diurnal variation of oralglucose tolerance1 and of the blood-sugar and plasmainsulin response to tolbutamide2 the results suggested that part of the diurnal difference might be attributable to a diurnal variation in sensitivity to endogenous insulin. The hypothesis has been tested by performing insulin-sensitivity tests in the same subjects on two occasions, once in the morning and once in the afternoon. Materials and Methods
Subjects for this study were male volunteers selected patients at New Cross Hospital in the Guy’s Hospital Group. They were included only if they had conditions or were taking drugs which were judged unlikely to affect glucose tolerance. Details of the participants are presented in table I. They were either undergoing complete bed rest or were ambulant for short periods during the day. Before the tests, subjects had a normal diet containing adequate amounts of carbohydrate. The period of fasting
from
before each test was 9 hours and the last meal before the fast was standardised to contain approximately 50 g. of carbohydrate as a glucose drink (235 ml.’Lucozade’). The morning test was begun at 8 A.M. and the afternoon test at 5 P.M. An indwelling venous catheter was inserted and
The first twenty subjects received the standard insulin dose of 0-1 I.U. per kg. In this group the lowest blood-sugar level was recorded at 30 minutes. Several subjects experienced mild hypoglycxmic symptoms and in many the blood-sugar fell below 40 mg. per 100 ml. We therefore decided to perform tests in two smaller groups using one half and one quarter of the standard dose. With 0-05 i.u. per kg., the bloodsugar level in each of six subjects was again lowest 30 minutes after the injection. With 0-025 I.U. per kg., the time of the lowest blood-sugar level varied. The results have therefore been expressed as perTABLE II-MEAN FALL IN BLOOD-SUGAR AFTER INTRAVENOUS INSULIN
*
Expressed as percentage fall t Expressed as percentage fall
at
30 minutes.
per
minute.
948
together with diurnal variation in insulin-secretory response to explain the previously reported effects of oral-glucose loads 1,4 and of tolbutamide.2 Relative obesity is associated with less diurnal variation of oral-glucose toleranceand in the present study it also seems to be associated with less diurnal variation in insulin sensitivity. We thank the volunteers for their willing cooperation; Dr. H. Burry and Dr. R. Grahame for allowing us access to their patients at New Cross Hospital; and Mr. K. Kilborn and Mr. M. Wood for expert technical assistance. Actrapid was supplied by Dr. G. Carnachan, Novo Industri. Requests for reprints should be addressed to R. J. J. REFERENCES
Jarrett, R. J., Baker, I. A., Keen, H., Oakley, N. W. Br. med. J. 1972, i, 199. 2. Baker, I. A., Jarrett, R. J. Lancet, 1972, ii, 945. 3. Rabinowitz, D., Zierler, K. L. J. clin. Invest. 1962, 41, 2173. 4. Jarrett, R. J., Keen, H. Br. med. J. 1970, iv, 334. 1.
Ponderalindex Relation between the difference in insulin sensitivity morning and afternoon) and obesity expressed as the
(between ponderal
index.
centage fall from fasting at 30 minutes for the two larger doses of insulin and as percentage fall per minute for the smaller dose (see table 11). At each dose level, the fall in blood-sugar in the afternoon was less than that in the morning, the differences being significant (P<0.05) for the two larger doses and almost for the smallest dose. significant (0-1>P>0’05) As insulin sensitivity is less in obese individuals,3 we examined our results in relation to obesity, using the ponderal index (height divided by the cubed root of the weight) as a measure of adiposity. There was a below, negative correlation (r=-0°291; P>0.05) tween the ponderal index and the percentage fall in blood-sugar in the morning test-i.e., the fatter people tended to have a smaller fall in blood-sugar. There were, in fact, no grossly obese subjects in the series, the lowest ponderal index being 11-6. The interaction between obesity and diurnal variation in insulin sensitivity was assessed by correlating the ponderal index with the difference between the percentage fall in the morning and that in the afternoon (see accompanying figure). For this assessment, the two groups having the larger doses of insulin were comThe correlation coefficient was -0389, bined. which was just significant at the 5% level, suggesting that the fatter people tended to have the least difference between morning and afternoon response to insulin. Discussion
There are many factors known to influence the effects of insulin upon the blood-sugar-i.e., insulin sensitivity. These include several hormones-e.g., growth hormone, glucagon, cortisol, and adrenaline-obesity and exercise. To these can now be added the time of administration, though it is possible that an explanation of this may be found in terms of the hormones previously listed. Whether the diurnal change in insulin sensitivity is primarily a peripheral or a hepatic phenomenon cannot be determined from our results. Assuming that the results with exogenous insulin can be extended to endogenous insulin, then diurnal variation in insulin sensitivity must be postulated
Addendum
We have become aware of the paper by J. Mirouze, F. Collard, and J.-P. Teisseire (Cah. Nutr. Diet. 1972, 7, 2). These workers present evidence from studies in diabetic patients that insulin administered before the midday meal is more effective than the same quantity of insulin administered before an evening meal containing an equal amount of carbohydrate.
ADIPOSE-CELL SIZE AND IMMUNOREACTIVE INSULIN LEVELS IN OBESE AND NORMAL-WEIGHT ADULTS
JUDITH S. STERN NINA HOLLANDER
BRUCE R. BATCHELOR CAL K. COHN HIRSCH
JULES Rockefeller University, New York, N.Y. 10021,
U.S.A.
The relationship between adipose-cell size and plasma levels of immunoreactive insulin (I.R.I.) was studied in 73 normal and obese individuals and in 12 obese patients before and after weight reduction. A strong positive correlation was found between adipose-cell size and fasting I.R.I. in both groups. This relation exists despite the widely differing degrees of obesity (and, therefore, their probable different total carbohydrate intakes). It is suggested that the increased adipose-cell size seen in obesity could sensitise the pancreas to produce more insulin.
Sum ary
Introduction
CARBOHYDRATE tolerance is often impaired in obesity.1 Even when glucose tolerance is normal, levels of immunoreactive insulin (I.R.I.) in the plasma are raised, and there is an outpouring of LR.I. in response to a glucose load .2 Sims et al., studying experimental obesity in man, found that the raised plasma-I.R.I. levels result from the obesity and not from a defect in the pancreas.3 The mechanism of production of this hyperinsulinaemia is not known.
although the
results for each subject conformed to the mean behaviour of blood-sugar, not every subject had a lower insulin response in the afternoon. To explain these results it is necessary to postulate that changes in insulin sensitivity are partly responsible for the diurnal difference in the effect of tolbutamide upon the blood-sugar, as we earlier suggested for the The role of differences in oral-glucose tolerance. diurnal changes in insulin sensitivity is considered elsewhere.4 We thank our volunteers; Dr. R. V. Boyd and Dr. C. N. Mallinson for permission to approach their patients; the nursing staff of New Cross and Greenwich District Hospital for help with the tests; and Mr. T. Adrian, Mr. K. Kilborn, and Mr.
TABLE I-DETAILS OF THE PARTICIPANTS
M. Wood for their expert technical assistance. Requests for reprints should be addressed to R. J. J. REFERENCES
2.
R. J., Baker, I. A., Keen, H., Oakley, N. W. Br. med. J. 1972, i, 199. Keane, P. M., Pearson, J., Walker, W. H. C. Diabetologia, 1968, 4,
3. 4.
Jarrett, R. J., Keen, H. Br. med. J. 1970, iv, 334. Gibson, T., Jarrett, R. J. Lancet, 1972, ii, 947.
1.
Jarrett, 339.
DIURNAL VARIATION IN INSULIN SENSITIVITY T. GIBSON
R.
J. JARRETT
Guy’s Hospital, London SE1
9RT
Intravenous insulin-tolerance tests were performed on the same subjects on two occasions, once in the morning and once in the afternoon. The fall in blood-sugar was consistently and significantly greater in the morning. If there is a similar diurnal variation in the sensitivity to endogenous insulin, it would partly explain the phenomenon of diurnal variation in oral-glucose tolerance.
Summary
fasting blood-samples obtained. Further samples were taken 5, 10, 15, 20, 30, and 40 minutes after the rapid intravenous injection of insulin. Duplicate estimates of the blood-sugar were made by the ferricyanide-reduction micro-method (Technicon method N-9a). ’ Actrapid B a porcine insulin with a very low glucagon content, was used. The insulin, supplied as 40 I.U. per ml., was diluted with sterile neutral isotonic saline solution to 1 I.U. per ml. before use. Twenty subjects were given the " standard " dose of 0-1 I.U. per kg., six 0-05 I.U. per kg., and six 0-025 I.U. per kg. body-weight. two
Results Introduction
IN other reports on the diurnal variation of oralglucose tolerance1 and of the blood-sugar and plasmainsulin response to tolbutamide2 the results suggested that part of the diurnal difference might be attributable to a diurnal variation in sensitivity to endogenous insulin. The hypothesis has been tested by performing insulin-sensitivity tests in the same subjects on two occasions, once in the morning and once in the afternoon. Materials and Methods
Subjects for this study were male volunteers selected patients at New Cross Hospital in the Guy’s Hospital Group. They were included only if they had conditions or were taking drugs which were judged unlikely to affect glucose tolerance. Details of the participants are presented in table I. They were either undergoing complete bed rest or were ambulant for short periods during the day. Before the tests, subjects had a normal diet containing adequate amounts of carbohydrate. The period of fasting
from
before each test was 9 hours and the last meal before the fast was standardised to contain approximately 50 g. of carbohydrate as a glucose drink (235 ml.’Lucozade’). The morning test was begun at 8 A.M. and the afternoon test at 5 P.M. An indwelling venous catheter was inserted and
The first twenty subjects received the standard insulin dose of 0-1 I.U. per kg. In this group the lowest blood-sugar level was recorded at 30 minutes. Several subjects experienced mild hypoglycxmic symptoms and in many the blood-sugar fell below 40 mg. per 100 ml. We therefore decided to perform tests in two smaller groups using one half and one quarter of the standard dose. With 0-05 i.u. per kg., the bloodsugar level in each of six subjects was again lowest 30 minutes after the injection. With 0-025 I.U. per kg., the time of the lowest blood-sugar level varied. The results have therefore been expressed as perTABLE II-MEAN FALL IN BLOOD-SUGAR AFTER INTRAVENOUS INSULIN
*
Expressed as percentage fall t Expressed as percentage fall
at
30 minutes.
per
minute.
948
together with diurnal variation in insulin-secretory response to explain the previously reported effects of oral-glucose loads 1,4 and of tolbutamide.2 Relative obesity is associated with less diurnal variation of oral-glucose toleranceand in the present study it also seems to be associated with less diurnal variation in insulin sensitivity. We thank the volunteers for their willing cooperation; Dr. H. Burry and Dr. R. Grahame for allowing us access to their patients at New Cross Hospital; and Mr. K. Kilborn and Mr. M. Wood for expert technical assistance. Actrapid was supplied by Dr. G. Carnachan, Novo Industri. Requests for reprints should be addressed to R. J. J. REFERENCES
Jarrett, R. J., Baker, I. A., Keen, H., Oakley, N. W. Br. med. J. 1972, i, 199. 2. Baker, I. A., Jarrett, R. J. Lancet, 1972, ii, 945. 3. Rabinowitz, D., Zierler, K. L. J. clin. Invest. 1962, 41, 2173. 4. Jarrett, R. J., Keen, H. Br. med. J. 1970, iv, 334. 1.
Ponderalindex Relation between the difference in insulin sensitivity morning and afternoon) and obesity expressed as the
(between ponderal
index.
centage fall from fasting at 30 minutes for the two larger doses of insulin and as percentage fall per minute for the smaller dose (see table 11). At each dose level, the fall in blood-sugar in the afternoon was less than that in the morning, the differences being significant (P<0.05) for the two larger doses and almost for the smallest dose. significant (0-1>P>0’05) As insulin sensitivity is less in obese individuals,3 we examined our results in relation to obesity, using the ponderal index (height divided by the cubed root of the weight) as a measure of adiposity. There was a below, negative correlation (r=-0°291; P>0.05) tween the ponderal index and the percentage fall in blood-sugar in the morning test-i.e., the fatter people tended to have a smaller fall in blood-sugar. There were, in fact, no grossly obese subjects in the series, the lowest ponderal index being 11-6. The interaction between obesity and diurnal variation in insulin sensitivity was assessed by correlating the ponderal index with the difference between the percentage fall in the morning and that in the afternoon (see accompanying figure). For this assessment, the two groups having the larger doses of insulin were comThe correlation coefficient was -0389, bined. which was just significant at the 5% level, suggesting that the fatter people tended to have the least difference between morning and afternoon response to insulin. Discussion
There are many factors known to influence the effects of insulin upon the blood-sugar-i.e., insulin sensitivity. These include several hormones-e.g., growth hormone, glucagon, cortisol, and adrenaline-obesity and exercise. To these can now be added the time of administration, though it is possible that an explanation of this may be found in terms of the hormones previously listed. Whether the diurnal change in insulin sensitivity is primarily a peripheral or a hepatic phenomenon cannot be determined from our results. Assuming that the results with exogenous insulin can be extended to endogenous insulin, then diurnal variation in insulin sensitivity must be postulated
Addendum
We have become aware of the paper by J. Mirouze, F. Collard, and J.-P. Teisseire (Cah. Nutr. Diet. 1972, 7, 2). These workers present evidence from studies in diabetic patients that insulin administered before the midday meal is more effective than the same quantity of insulin administered before an evening meal containing an equal amount of carbohydrate.
ADIPOSE-CELL SIZE AND IMMUNOREACTIVE INSULIN LEVELS IN OBESE AND NORMAL-WEIGHT ADULTS
JUDITH S. STERN NINA HOLLANDER
BRUCE R. BATCHELOR CAL K. COHN HIRSCH
JULES Rockefeller University, New York, N.Y. 10021,
U.S.A.
The relationship between adipose-cell size and plasma levels of immunoreactive insulin (I.R.I.) was studied in 73 normal and obese individuals and in 12 obese patients before and after weight reduction. A strong positive correlation was found between adipose-cell size and fasting I.R.I. in both groups. This relation exists despite the widely differing degrees of obesity (and, therefore, their probable different total carbohydrate intakes). It is suggested that the increased adipose-cell size seen in obesity could sensitise the pancreas to produce more insulin.
Sum ary
Introduction
CARBOHYDRATE tolerance is often impaired in obesity.1 Even when glucose tolerance is normal, levels of immunoreactive insulin (I.R.I.) in the plasma are raised, and there is an outpouring of LR.I. in response to a glucose load .2 Sims et al., studying experimental obesity in man, found that the raised plasma-I.R.I. levels result from the obesity and not from a defect in the pancreas.3 The mechanism of production of this hyperinsulinaemia is not known.