Nitrogen Metabolism and Insulin Requirements in Obese Diabetic Adults on a Protein-Sparing Modified Fast Bruce R. Bistrian, M.D., Ph.D., George L. Blackburn, M.D., Ph.D., Jean-Pierre Flatt, Ph.D., Jack Sizer, M.D., Nevin S. Scrimshaw, Ph.D., M.D., and Mindy Sherman, B.A., Boston and Cambridge, Massachusetts SUMMARY
A protein-sparing modified fast (PSMF), which is a total fast modified by the intake of 1.2-1.4 gm. protein per kilogram ideal body weight (IBW), fluids ad libitum, and vitamin and mineral supplementation, allows effective control of carbohydrate metabolism and hunger. It reduces serum glucose and insulin concentrations in obese diabetic patients and increases free fatty acid and ketone body concentrations; ketonuria appears within 24-72 hours. When this fast was applied to seven obese adult-onset diabetics who were receiving 30-100 units of insulin per day, insulin could be discontinued after 0-19 days (mean, 6.5). In the three patients who had extensive nitrogen-balance studies, balance could
be maintained chronically by 1.3 gm. protein per kilogram IBW, despite the gross caloric inadequacy of the diet. The PSMF was tolerated well in an outpatient setting after the initial insulinwithdrawal phase had occurred in the hospital. Significant improvements in blood pressure, lipid abnormalities, parameters of carbohydrate metabolism, and cardiorespiratory symptoms were associated with weight loss and/or the PSMF. For diabetics with some endogenous insulin reserve, the PSMF offers significant advantages for weight reduction, including preservation of lean body mass (as reflected in nitrogen balance) and withdrawal of exogenous insulin. DIABETES 25:494-504, June, 1976.
Adult-onset diabetes mellitus is frequently associated with obesity,1 and weight loss has repeatedly been shown to have a beneficial effect on pancreatic endocrine function.2"5 Unfortunately, the obese seldom achieve weight reduction by diet therapy, irrespective of their state of carbohydrate tolerance:6 a comprehensive review of conventional, outpatient treatment of obesity revealed that less than 5 per cent of the patients studied lost 40 pounds or more.7 In the obese diabetic receiving insulin, the problems of insulin regulation further complicate dieting unless the dietary composition remains relatively stable from day to day.
Total fasting reduces or eliminates hunger8 and has proved an effective method of inducing rapid weight loss.9 Its widespread application has been limited, however, by significant protein catabolism (representing nearly half the weight loss in the first month10) coupled with undesirable physiologic effects (i.e., fasting lowers renal creatinine clearance,11 increases retention of sodium sulfobromophthalein by the liver,12 raises levels of serum bilirubin,13 reduces concentrations of both triiodothyronine14 and urinary 17-hydroxy- and ketosteroids, 15 and induces neutropenia16). When a fasting patient is fed small amounts of protein as egg albumin, 17 casein,18 casein with glucose,19 or amino acids with glucose,20 the fastassociated nitrogen loss declines but does not completely disappear, if one includes estimated integumental nitrogen losses, which was not done in the previous studies.17"20 When fecal and cutaneous losses are not measured or estimated, the meaning of the term "positive nitrogen balance" is open to question.
From the Cancer Research Institute, New England Deaconess Hospital, Harvard Medical School, Boston, Massachusetts 02215, and the Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142. Address reprint requests to Dr. Bruce R. Bistrian, Cancer Research Institute, 194 Pilgrim Road, Boston, Massachusetts 02215. Accepted for publication February 18, 1976.
494
DIABETES, VOL. 2 5 , NO. 6
BRUCE R. BISTRIAN, M . D . , PH.D., A N D ASSOCIATES
In extensive studies we have found that 1.2-1.4 gm. protein, in the form of egg albumin or lean beef,21 per kilogram ideal body weight (IBW) as an estimate of lean body mass is sufficient to maintain nitrogen balance and to preserve normal liver, endocrine, and hematopoietic functions in the fasting obese patient. The beneficial effects of total fasting on carbohydrate metabolism in diabetic patients were known even before the discovery of insulin. 22 This modified fast produces a similar fall in serum insulin and glucose concentrations, a rise in free fatty acids and ketone bodies, and the appearance of ketonuria. 21 With the expected fall in insulin requirements combined with preservation of nitrogen balance and weight loss, the protein-sparing modified fast (PSMF) was considered appropriate for treatment of obese diabetics. Six such patients were monitored carefully as inpatients while their insulin dosages were gradually eliminated, and in a seventh, an outpatient, insulin was eliminated. This report details the experience of these patients and emphasizes the first three cases because of the extensive nitrogen-balance studies conducted.
TABLE l Anthropometric characteristics of study patients and results of weight loss in the first year of a protein-sparing modified fast Patient 1 2 3 4 5 6 7
Height cm. 177.8 152.4 160 180.3 165.1 154.9 172.7
1 2 3 4 5 6 7
Weight loss on PSMF kg74 28 38 19 18 9 21
Initial weight kg152 97.5 103 125 93.6 71 114
Ideal body weight kg65.1 48.4 52.6 71.4 54.0 49.9 65.8
Time required (months)
Weight loss at 1 year kg74
12 12 10 1 1/2 4
2 4
28 28.5 8.5*
18t 6t o§
*20 months. f 10 months. |Seven months. §17 months.
EXPERIMENTAL PROCEDURE analyzed for the following: fasting glucose, urea niSubjects and diets. Six diabetics requiring insulin to trogen, electrolytes, magnesium, calcium, phoscontrol hyperglycemia, who were obese according to phorus, uric acid, creatinine, total bilirubin, transthe Metropolitan Life Insurance Company aminase, alkaline phosphatase, creatine phosphokiweight/height/sex standards 23 (table 1), were am- nase, lactic dehydrogenase, total protein, albumin, bulatory inpatients, and the seventh was an outpa- cholesterol, triglyceride, A.M. and P.M. cortisol, and tient. Patients 1-3 were maintained on a PSMF sup- total thyroxine. A chest x-ray and electrocardiogram plying 0.8-1.0 gm. protein (as lean beef or equivalent (ECG) were also obtained. animal protein) per kilogram body weight (BW) per Body weights, urinary ketones (by Acetest), and day, at least 1,500 cc. of water, 1 K-Lyte tablet vital signs were recorded daily. Urinalysis, CBC, and (potassium bicarbonate) (25 mEq.), a One-a-Day Vi- the above assays in blood serum were repeated weekly, tamin with Iron, two Turns (calcium carbonate, 197 except for the endocrine studies. A substrate mg. calcium/tablet) twice daily for calcium, and salt profile—which included levels of insulin, free fatty ad libitum. This regimen supplied 300-750 calories acids, B-hydroxybutyrate, and acetoacetate (measured per day. Four less severely obese patients (4-7; table 1) by previously described methods 24 )—was obtained were also fed the PSMF. We had recognized by this approximately every week while the subjects were time that protein requirements needed to be based on CRC inpatients (table 2). While they were inpatients, some stable measure of lean body mass, such as IBW, dietary nitrogen content was determined by Kjeldahl if nitrogen balance was to be achieved; these three analysis of samples of meat bought in large lots in patients therefore consumed 1.3-1.5 gm. protein per patients 1-3 and estimated from values found in stankilogram IBW, in addition to the vitamin, mineral, dard tables 25 in patients 4-6 during hospitalization and fluid supplements listed above. and in all patients after discharge. Twenty-four-hour Protocol. Patients 1-3 were admitted to the Mas- urine samples were collected either continuously or sachusetts Institute of Technology Clinical Research during three consecutive days each week and were used to measure total nitrogen by the Kjeldahl proceCenter (CRC) and underwent a full clinical evaluation, including history, physical exam, complete dure. Fecal nitrogen (N) was estimated as the mean blood count (CBC), and urinalysis. Blood serum was excretion, 0.4 gm. N , calculated from pooled weekly JUNE, 1976
495
NITROGEN METABOLISM AND INSULIN REQUIREMENTS
TABLE 2 Free fatty acid and ketone body levels in patients 1-3
Patient 1:
2:
3:
Prefast Week 1 Week 2 Week 3 Prefast* Week 1 Week 2 Week 3 Prefast Week 1 Week 2 Week 3
/3-Hydroxybutyrate /imoles/ml. 0.37 0.75 0.93 0.53 — 0.65 1.24 1.23 0.11 1.45 2.06 1.34
Acetoacetate ^moles/ml. 0.01 0.00 0.00 0.04 — 0.14 0.22 0.31 0.10 0.01 0.00 0.18
Free fatty acids fiEq./ml. 0.65 0.81 1.09 1.45 — 0.66 0.70 0.40 0.28 1.29 1.04 0.95
*Patient 2 was on a PSMF on admission.
collections from eight healthy, obese control patients undergoing a similar modified fast. Integumental and miscellaneous N losses were assumed to be 5 mg. N per kilogram BW. 2 6 Nitrogen balance was calculated according to this formula: N balance = N intake — (urine N + fecal N 4estimated integumental and miscellaneous N losses) After discharge, each patient was instructed to follow the PSMF with weekly or biweekly monitoring until hospital readmission. During the outpatient visits, weight, urinary ketones, blood pressure, CBC, and standard serum analysis were measured. The case reports outline the management of insulin dosage. Patients 4-6 were admitted to the New England Deaconess Hospital (NEDH) for a similar full clinical study, except that substrate profiles and N balance measurements were not obtained. The outpatient phase included one or two weekly visits for weight, urinary ketones, blood pressure, and blood glucose check, with CBC and standard serum chemistries determined at six-to-eight-week intervals. Patient 7, with easily regulated diabetes, received the same clinical evaluation but remained an outpatient throughout the study. In these four patients technics of behavior modification27 and instruction in nutrition education were included in the treatment program.
mained relatively stable, although insulin requirements to regulate hyperglycemia and glycosuria increased to 52 units per day. At the beginning of this study, her weight was 152 kg., height 178 cm., blood pressure 225/130 mm. Hg (despite antihypertensive medications), glucose 288 mg./lOO ml., triglyceride 268 mg./lOO ml., and uric acid 6.9 mg./lOO ml. (figures 1-3). The patient began the PSMF with 150 gm. protein per day; she was given 10 units of regular insulin for 3 ~ 4 + glycosuria in urine samples examined four times daily. She received 40 units for each of the first three days, then 20 units for four days, and 10 units for 11 days; after this period (18 days), no further glycosuria appeared and insulin was suspended. As shown in figures 1-3, weight, blood pressure, glucose, insulin, uric acid, and triglyceride levels fell rapidly with little change in N balance or serum cholesterol. Free fatty acids and ketone bodies increased in serum (table 2), and ketonuria appeared within 24 hours. Uric acid levels increased initially (an effect related to high serum Patient # I 6 I 7 47y.o. $ hgt. 178cm _
3
300 rr
0 -(152) 10
' ^
RESULTS Patient 1
Patient 1, E.S., was a 47-year-old woman with morbid obesity beginning in her early teens and a family history of diabetes. Diabetes was discovered 11 years earlier, when she weighed 141 kg. and required 25-30 units of insulin per day. Her condition re496
20
(13 2)
I
150
C)
3
1
16
24
no
1 55 i
32
gm Protein/Day
1
40
Days
40ucl eor +I2u h PH FIG. 1. Acute effects on selected biochemical and clinical parameters of a PSMF in patient 1 . DIABETES, VOL. 25, NO. 6
BRUCE R. BISTRIAN, M.D., PH.D., AND ASSOCIATES
Patient
#
1617 47y.o. J hgt. 178 cm
Patient #1617 47y.o. J hgt. 178 cm 250 r
o
14
Q
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3
10
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O o o
270-^
-
230
S£ 190 o
'
150
A
230
190
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-6* gm Protein/Doy [
\
£.2
.
no
f
12 Months
+I2UNPH
i
FIG..3. Long-term effects on selected biochemical and clinical parameters of a PSMF in patient 1. Mean N balance ± standard deviation for three-to-seven-day periods.
70 16
I
24 Days
32
40
40u clear •H2u NPH FIG. 2. Acute effects on selected biochemical and clinical parameters of a PSMF in patient 1.
ketones 28 ), but fell after three months despite maintenance of the PSMF. N balance remained positive when the patient consumed 150, 110, and 100 gm. protein per day but became negative when consumption fell to 55 gm. protein per day. Patient 1 was discharged after 10 weeks on 1 gm. protein per kilogram BW (550-600 calories) and was followed at 1- or 2-week intervals as an outpatient. One month later, she was readmitted for two months to confirm N balance, which remained positive on JUNE, 1976
I
0 2 t 40u Clear
100 gm. protein per day (figure 3). A 30-day admission after one year revealed a mildly negative N balance at intakes of 45 and 60 gm. protein per day (figure 3). She lost 74 kg. during the 12 months the PSMF was consumed. Serum glucose, monitored weekly for the first six months and biweekly thereafter, remained less than 100 mg./lOO ml. despite only fair adherence to the diet as an outpatient. Patient 2
Patient 2, F.F., was a 63-year-old woman with obesity beginning after age 20; her diabetes, initially requiring oral agents, had been diagnosed six years earlier. After four years of clinical diabetes, she suffered a cardiac arrest during an acute asthmatic attack, after which 50 units of NPH insulin daily was prescribed. On admission to the NEDH because of poor diabetic control, the dosage had increased to 100 units of NPH insulin per day. Additional medical problems 497
NITROGEN METABOLISM AND INSULIN REQUIREMENTS
included atherosclerotic heart disease, chronic obstructive pulmonary disease, and asthma. Clinical data on admission were weight 97.5 kg.; height 152.5 cm.; blood pressure 140/80 mm. Hg; wheezes in both lung fields; and serum glucose 173 mg./lOO ml. A chest x-ray showed left ventricular predominance, ECG revealed possible pulmonary disease, and pulmonary function tests substantiated the presence of severe, obstructive pulmonary disease. The PSMF began at 75 gm. of protein per day, with 25 gm. of carbohydrate added for five days; NPH insulin was initially reduced to 60 units in the morning and 20 units in the evening, further lowered to 40 units after nine days, and discontinued after 10 more days, with serum glucose remaining in the high 100s range. The patient lost 7 kg. in the three weeks of admission. Her serum glucose following discharge was noted to be in poor control because of deviations from the PSMF, so she was started on oral agents (tolbutamide, 1.5 gm. daily).
Patient # I 8 6 5 63y.o. J hgt. 152.5cm 200
140 -
s8'6o o E
100 ~
120 60
?i o
80
20
+2 0 -4 (83)
0 2 4
(78)
6 65gm Protein/Oay
Three months later she was readmitted to the CRC weighing 83 kg., with serum glucose 207 mg./lOO ml., uric acid 9.6 mg./lOO ml., cholesterol 293 mg./lOO ml., and triglyceride 174 mg./lOO ml. The PSMF continued at 65 gm. protein per day; serum glucose dropped to 140 mg./lOO ml. after 24 hours and to below 120 mg./lOO ml. three days later (figure 4). Tolbutamide was discontinued after six days, and subsequent glucose levels were 80-110 mg./lOO ml. during this 18-day admission. N balance was positive on the eighth day (figure 4). As expected, glucose, insulin, and triglyceride levels fell while uric acid concentrations increased (uric acid subsequently returned to normal levels despite continued fasting (figure 5)). Ketonemia (table 2) and ketonuria were persistent. Although patient 2 did not adhere closely to the diet in the next four months as an outpatient, her serum glucose remained less than 140 mg./lOO ml. off medications. On readmission at one year, her weight was 68 kg., serum glucose 109 mg./lOO ml., uric acid 6.2 mg./lOO ml., cholesterol 222 mg./lOO ml., and triglyceride 134 mg./lOO ml. N balance was minimally negative on 55 gm. protein per day (0.8 gm. per kilogram BW). Glucose levels were subsequently less than 100 mg./lOO ml. during the twoweek admission (figure 5). Patient 3 Patient 3, S.G., was a 60-year-old woman, obese since age 26, with a family history of diabetes. Diabetes had been diagnosed 11 years earlier and was managed initially with oral agents, then with insulin after she had suffered a transient, drug-induced renal 498
16 Days 1.5 gm Orinose
FIG. 4.
Acute and long-term effects on selected biochemical and clinical parameters of a PSMF in patient 2. Mean N balance ± standard deviation for three-to-seven-day periods.
failure. The patient received 55 units of lente insulin daily to regulate hyperglycemia, although diabetic control was poor even with this dose. Additional medical problems were atherosclerotic heart disease (with a previous myocardial infarction and angina), a previous parathyroidectomy accompanied by mild hypothyroidism, gout, and a previous hysterectomy and cholecystectomy. Her clinical data upon admission to the Thorndike Clinical Research Center (Boston City Hospital) were weight 103 kg.; height 160 cm.; blood pressure 120/60 mm. Hg; mild peripheral neuropathy; serum glucose 178 mg./lOO ml.; triglyceride 363 mg./lOO ml.; uric acid 4.7 mg./lOO ml.; and thyroxine 4.5 /ug/100 ml.; ECG normal. A chest x-ray revealed left ventricular hypertrophy. She initially began the PSMF at 99 gm. protein per day (1 gm. per kilogram BW), and insulin was discontinued simultaneously. Blood sugar levels remained normal and N balance was positive (figure 6). She was discharged after 15 days (and a 3-kg. weight loss) and then readmitted to the CRC for brief periods every month to monitor the PSMF and to confirm N balance (figure 7), which remained essentially positive at 80, 75, 70, and 65 gm. of protein. Glucose, insulin, and DIABETES, VOL. 25, NO. 6
BRUCE R. BISTRIAN, M.D., PH.D., AND ASSOCIATES
Patient #1865
Patient # I676 6Oy.o. J hgt. 160 cm
63y.o. J hgt. 152.5cm
200 =
T= 160
7 0
140
50 S
: 8 120
in O
lioo
S o - "X 120
~ E
30 J
80
o ~~ — — —
A protein-sparing modified fast (PSMF), which is a total fast modified by the intake of 1.2-1.4 gm. protein per kilogram ideal body weight (IBW), fluids ad libitum, and vitamin and mineral supplementation, allows effective control of carbohydrate metabolism and hunger. It reduces serum glucose and insulin concentrations in obese diabetic patients and increases free fatty acid and ketone body concentrations; ketonuria appears within 24-72 hours. When this fast was applied to seven obese adult-onset diabetics who were receiving 30-100 units of insulin per day, insulin could be discontinued after 0-19 days (mean, 6.5). In the three patients who had extensive nitrogen-balance studies, balance could
be maintained chronically by 1.3 gm. protein per kilogram IBW, despite the gross caloric inadequacy of the diet. The PSMF was tolerated well in an outpatient setting after the initial insulinwithdrawal phase had occurred in the hospital. Significant improvements in blood pressure, lipid abnormalities, parameters of carbohydrate metabolism, and cardiorespiratory symptoms were associated with weight loss and/or the PSMF. For diabetics with some endogenous insulin reserve, the PSMF offers significant advantages for weight reduction, including preservation of lean body mass (as reflected in nitrogen balance) and withdrawal of exogenous insulin. DIABETES 25:494-504, June, 1976.
Adult-onset diabetes mellitus is frequently associated with obesity,1 and weight loss has repeatedly been shown to have a beneficial effect on pancreatic endocrine function.2"5 Unfortunately, the obese seldom achieve weight reduction by diet therapy, irrespective of their state of carbohydrate tolerance:6 a comprehensive review of conventional, outpatient treatment of obesity revealed that less than 5 per cent of the patients studied lost 40 pounds or more.7 In the obese diabetic receiving insulin, the problems of insulin regulation further complicate dieting unless the dietary composition remains relatively stable from day to day.
Total fasting reduces or eliminates hunger8 and has proved an effective method of inducing rapid weight loss.9 Its widespread application has been limited, however, by significant protein catabolism (representing nearly half the weight loss in the first month10) coupled with undesirable physiologic effects (i.e., fasting lowers renal creatinine clearance,11 increases retention of sodium sulfobromophthalein by the liver,12 raises levels of serum bilirubin,13 reduces concentrations of both triiodothyronine14 and urinary 17-hydroxy- and ketosteroids, 15 and induces neutropenia16). When a fasting patient is fed small amounts of protein as egg albumin, 17 casein,18 casein with glucose,19 or amino acids with glucose,20 the fastassociated nitrogen loss declines but does not completely disappear, if one includes estimated integumental nitrogen losses, which was not done in the previous studies.17"20 When fecal and cutaneous losses are not measured or estimated, the meaning of the term "positive nitrogen balance" is open to question.
From the Cancer Research Institute, New England Deaconess Hospital, Harvard Medical School, Boston, Massachusetts 02215, and the Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142. Address reprint requests to Dr. Bruce R. Bistrian, Cancer Research Institute, 194 Pilgrim Road, Boston, Massachusetts 02215. Accepted for publication February 18, 1976.
494
DIABETES, VOL. 2 5 , NO. 6
BRUCE R. BISTRIAN, M . D . , PH.D., A N D ASSOCIATES
In extensive studies we have found that 1.2-1.4 gm. protein, in the form of egg albumin or lean beef,21 per kilogram ideal body weight (IBW) as an estimate of lean body mass is sufficient to maintain nitrogen balance and to preserve normal liver, endocrine, and hematopoietic functions in the fasting obese patient. The beneficial effects of total fasting on carbohydrate metabolism in diabetic patients were known even before the discovery of insulin. 22 This modified fast produces a similar fall in serum insulin and glucose concentrations, a rise in free fatty acids and ketone bodies, and the appearance of ketonuria. 21 With the expected fall in insulin requirements combined with preservation of nitrogen balance and weight loss, the protein-sparing modified fast (PSMF) was considered appropriate for treatment of obese diabetics. Six such patients were monitored carefully as inpatients while their insulin dosages were gradually eliminated, and in a seventh, an outpatient, insulin was eliminated. This report details the experience of these patients and emphasizes the first three cases because of the extensive nitrogen-balance studies conducted.
TABLE l Anthropometric characteristics of study patients and results of weight loss in the first year of a protein-sparing modified fast Patient 1 2 3 4 5 6 7
Height cm. 177.8 152.4 160 180.3 165.1 154.9 172.7
1 2 3 4 5 6 7
Weight loss on PSMF kg74 28 38 19 18 9 21
Initial weight kg152 97.5 103 125 93.6 71 114
Ideal body weight kg65.1 48.4 52.6 71.4 54.0 49.9 65.8
Time required (months)
Weight loss at 1 year kg74
12 12 10 1 1/2 4
2 4
28 28.5 8.5*
18t 6t o§
*20 months. f 10 months. |Seven months. §17 months.
EXPERIMENTAL PROCEDURE analyzed for the following: fasting glucose, urea niSubjects and diets. Six diabetics requiring insulin to trogen, electrolytes, magnesium, calcium, phoscontrol hyperglycemia, who were obese according to phorus, uric acid, creatinine, total bilirubin, transthe Metropolitan Life Insurance Company aminase, alkaline phosphatase, creatine phosphokiweight/height/sex standards 23 (table 1), were am- nase, lactic dehydrogenase, total protein, albumin, bulatory inpatients, and the seventh was an outpa- cholesterol, triglyceride, A.M. and P.M. cortisol, and tient. Patients 1-3 were maintained on a PSMF sup- total thyroxine. A chest x-ray and electrocardiogram plying 0.8-1.0 gm. protein (as lean beef or equivalent (ECG) were also obtained. animal protein) per kilogram body weight (BW) per Body weights, urinary ketones (by Acetest), and day, at least 1,500 cc. of water, 1 K-Lyte tablet vital signs were recorded daily. Urinalysis, CBC, and (potassium bicarbonate) (25 mEq.), a One-a-Day Vi- the above assays in blood serum were repeated weekly, tamin with Iron, two Turns (calcium carbonate, 197 except for the endocrine studies. A substrate mg. calcium/tablet) twice daily for calcium, and salt profile—which included levels of insulin, free fatty ad libitum. This regimen supplied 300-750 calories acids, B-hydroxybutyrate, and acetoacetate (measured per day. Four less severely obese patients (4-7; table 1) by previously described methods 24 )—was obtained were also fed the PSMF. We had recognized by this approximately every week while the subjects were time that protein requirements needed to be based on CRC inpatients (table 2). While they were inpatients, some stable measure of lean body mass, such as IBW, dietary nitrogen content was determined by Kjeldahl if nitrogen balance was to be achieved; these three analysis of samples of meat bought in large lots in patients therefore consumed 1.3-1.5 gm. protein per patients 1-3 and estimated from values found in stankilogram IBW, in addition to the vitamin, mineral, dard tables 25 in patients 4-6 during hospitalization and fluid supplements listed above. and in all patients after discharge. Twenty-four-hour Protocol. Patients 1-3 were admitted to the Mas- urine samples were collected either continuously or sachusetts Institute of Technology Clinical Research during three consecutive days each week and were used to measure total nitrogen by the Kjeldahl proceCenter (CRC) and underwent a full clinical evaluation, including history, physical exam, complete dure. Fecal nitrogen (N) was estimated as the mean blood count (CBC), and urinalysis. Blood serum was excretion, 0.4 gm. N , calculated from pooled weekly JUNE, 1976
495
NITROGEN METABOLISM AND INSULIN REQUIREMENTS
TABLE 2 Free fatty acid and ketone body levels in patients 1-3
Patient 1:
2:
3:
Prefast Week 1 Week 2 Week 3 Prefast* Week 1 Week 2 Week 3 Prefast Week 1 Week 2 Week 3
/3-Hydroxybutyrate /imoles/ml. 0.37 0.75 0.93 0.53 — 0.65 1.24 1.23 0.11 1.45 2.06 1.34
Acetoacetate ^moles/ml. 0.01 0.00 0.00 0.04 — 0.14 0.22 0.31 0.10 0.01 0.00 0.18
Free fatty acids fiEq./ml. 0.65 0.81 1.09 1.45 — 0.66 0.70 0.40 0.28 1.29 1.04 0.95
*Patient 2 was on a PSMF on admission.
collections from eight healthy, obese control patients undergoing a similar modified fast. Integumental and miscellaneous N losses were assumed to be 5 mg. N per kilogram BW. 2 6 Nitrogen balance was calculated according to this formula: N balance = N intake — (urine N + fecal N 4estimated integumental and miscellaneous N losses) After discharge, each patient was instructed to follow the PSMF with weekly or biweekly monitoring until hospital readmission. During the outpatient visits, weight, urinary ketones, blood pressure, CBC, and standard serum analysis were measured. The case reports outline the management of insulin dosage. Patients 4-6 were admitted to the New England Deaconess Hospital (NEDH) for a similar full clinical study, except that substrate profiles and N balance measurements were not obtained. The outpatient phase included one or two weekly visits for weight, urinary ketones, blood pressure, and blood glucose check, with CBC and standard serum chemistries determined at six-to-eight-week intervals. Patient 7, with easily regulated diabetes, received the same clinical evaluation but remained an outpatient throughout the study. In these four patients technics of behavior modification27 and instruction in nutrition education were included in the treatment program.
mained relatively stable, although insulin requirements to regulate hyperglycemia and glycosuria increased to 52 units per day. At the beginning of this study, her weight was 152 kg., height 178 cm., blood pressure 225/130 mm. Hg (despite antihypertensive medications), glucose 288 mg./lOO ml., triglyceride 268 mg./lOO ml., and uric acid 6.9 mg./lOO ml. (figures 1-3). The patient began the PSMF with 150 gm. protein per day; she was given 10 units of regular insulin for 3 ~ 4 + glycosuria in urine samples examined four times daily. She received 40 units for each of the first three days, then 20 units for four days, and 10 units for 11 days; after this period (18 days), no further glycosuria appeared and insulin was suspended. As shown in figures 1-3, weight, blood pressure, glucose, insulin, uric acid, and triglyceride levels fell rapidly with little change in N balance or serum cholesterol. Free fatty acids and ketone bodies increased in serum (table 2), and ketonuria appeared within 24 hours. Uric acid levels increased initially (an effect related to high serum Patient # I 6 I 7 47y.o. $ hgt. 178cm _
3
300 rr
0 -(152) 10
' ^
RESULTS Patient 1
Patient 1, E.S., was a 47-year-old woman with morbid obesity beginning in her early teens and a family history of diabetes. Diabetes was discovered 11 years earlier, when she weighed 141 kg. and required 25-30 units of insulin per day. Her condition re496
20
(13 2)
I
150
C)
3
1
16
24
no
1 55 i
32
gm Protein/Day
1
40
Days
40ucl eor +I2u h PH FIG. 1. Acute effects on selected biochemical and clinical parameters of a PSMF in patient 1 . DIABETES, VOL. 25, NO. 6
BRUCE R. BISTRIAN, M.D., PH.D., AND ASSOCIATES
Patient
#
1617 47y.o. J hgt. 178 cm
Patient #1617 47y.o. J hgt. 178 cm 250 r
o
14
Q
12
•»«.
3
10
E
O o o
270-^
-
230
S£ 190 o
'
150
A
230
190
I 1 '50
-6* gm Protein/Doy [
\
£.2
.
no
f
12 Months
+I2UNPH
i
FIG..3. Long-term effects on selected biochemical and clinical parameters of a PSMF in patient 1. Mean N balance ± standard deviation for three-to-seven-day periods.
70 16
I
24 Days
32
40
40u clear •H2u NPH FIG. 2. Acute effects on selected biochemical and clinical parameters of a PSMF in patient 1.
ketones 28 ), but fell after three months despite maintenance of the PSMF. N balance remained positive when the patient consumed 150, 110, and 100 gm. protein per day but became negative when consumption fell to 55 gm. protein per day. Patient 1 was discharged after 10 weeks on 1 gm. protein per kilogram BW (550-600 calories) and was followed at 1- or 2-week intervals as an outpatient. One month later, she was readmitted for two months to confirm N balance, which remained positive on JUNE, 1976
I
0 2 t 40u Clear
100 gm. protein per day (figure 3). A 30-day admission after one year revealed a mildly negative N balance at intakes of 45 and 60 gm. protein per day (figure 3). She lost 74 kg. during the 12 months the PSMF was consumed. Serum glucose, monitored weekly for the first six months and biweekly thereafter, remained less than 100 mg./lOO ml. despite only fair adherence to the diet as an outpatient. Patient 2
Patient 2, F.F., was a 63-year-old woman with obesity beginning after age 20; her diabetes, initially requiring oral agents, had been diagnosed six years earlier. After four years of clinical diabetes, she suffered a cardiac arrest during an acute asthmatic attack, after which 50 units of NPH insulin daily was prescribed. On admission to the NEDH because of poor diabetic control, the dosage had increased to 100 units of NPH insulin per day. Additional medical problems 497
NITROGEN METABOLISM AND INSULIN REQUIREMENTS
included atherosclerotic heart disease, chronic obstructive pulmonary disease, and asthma. Clinical data on admission were weight 97.5 kg.; height 152.5 cm.; blood pressure 140/80 mm. Hg; wheezes in both lung fields; and serum glucose 173 mg./lOO ml. A chest x-ray showed left ventricular predominance, ECG revealed possible pulmonary disease, and pulmonary function tests substantiated the presence of severe, obstructive pulmonary disease. The PSMF began at 75 gm. of protein per day, with 25 gm. of carbohydrate added for five days; NPH insulin was initially reduced to 60 units in the morning and 20 units in the evening, further lowered to 40 units after nine days, and discontinued after 10 more days, with serum glucose remaining in the high 100s range. The patient lost 7 kg. in the three weeks of admission. Her serum glucose following discharge was noted to be in poor control because of deviations from the PSMF, so she was started on oral agents (tolbutamide, 1.5 gm. daily).
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Three months later she was readmitted to the CRC weighing 83 kg., with serum glucose 207 mg./lOO ml., uric acid 9.6 mg./lOO ml., cholesterol 293 mg./lOO ml., and triglyceride 174 mg./lOO ml. The PSMF continued at 65 gm. protein per day; serum glucose dropped to 140 mg./lOO ml. after 24 hours and to below 120 mg./lOO ml. three days later (figure 4). Tolbutamide was discontinued after six days, and subsequent glucose levels were 80-110 mg./lOO ml. during this 18-day admission. N balance was positive on the eighth day (figure 4). As expected, glucose, insulin, and triglyceride levels fell while uric acid concentrations increased (uric acid subsequently returned to normal levels despite continued fasting (figure 5)). Ketonemia (table 2) and ketonuria were persistent. Although patient 2 did not adhere closely to the diet in the next four months as an outpatient, her serum glucose remained less than 140 mg./lOO ml. off medications. On readmission at one year, her weight was 68 kg., serum glucose 109 mg./lOO ml., uric acid 6.2 mg./lOO ml., cholesterol 222 mg./lOO ml., and triglyceride 134 mg./lOO ml. N balance was minimally negative on 55 gm. protein per day (0.8 gm. per kilogram BW). Glucose levels were subsequently less than 100 mg./lOO ml. during the twoweek admission (figure 5). Patient 3 Patient 3, S.G., was a 60-year-old woman, obese since age 26, with a family history of diabetes. Diabetes had been diagnosed 11 years earlier and was managed initially with oral agents, then with insulin after she had suffered a transient, drug-induced renal 498
16 Days 1.5 gm Orinose
FIG. 4.
Acute and long-term effects on selected biochemical and clinical parameters of a PSMF in patient 2. Mean N balance ± standard deviation for three-to-seven-day periods.
failure. The patient received 55 units of lente insulin daily to regulate hyperglycemia, although diabetic control was poor even with this dose. Additional medical problems were atherosclerotic heart disease (with a previous myocardial infarction and angina), a previous parathyroidectomy accompanied by mild hypothyroidism, gout, and a previous hysterectomy and cholecystectomy. Her clinical data upon admission to the Thorndike Clinical Research Center (Boston City Hospital) were weight 103 kg.; height 160 cm.; blood pressure 120/60 mm. Hg; mild peripheral neuropathy; serum glucose 178 mg./lOO ml.; triglyceride 363 mg./lOO ml.; uric acid 4.7 mg./lOO ml.; and thyroxine 4.5 /ug/100 ml.; ECG normal. A chest x-ray revealed left ventricular hypertrophy. She initially began the PSMF at 99 gm. protein per day (1 gm. per kilogram BW), and insulin was discontinued simultaneously. Blood sugar levels remained normal and N balance was positive (figure 6). She was discharged after 15 days (and a 3-kg. weight loss) and then readmitted to the CRC for brief periods every month to monitor the PSMF and to confirm N balance (figure 7), which remained essentially positive at 80, 75, 70, and 65 gm. of protein. Glucose, insulin, and DIABETES, VOL. 25, NO. 6
BRUCE R. BISTRIAN, M.D., PH.D., AND ASSOCIATES
Patient #1865
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