0021-972X/79/4906-0830$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1979 by The Endocrine Society
Vol. 49, No. 6 Printed in U.S.A.
Normalization of Insulin and Glucagon Secretion in Ketosis-Resistant Diabetes Mellitus with Prolonged Diet Therapy* PETER J. SAVAGE, LYNN J. BENNION, AND PETER H. BENNETT Southwestern Field Studies and Phoenix Clinical Research Sections, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Phoenix, Arizona 85016
ABSTRACT. Glucose tolerance and insulin and glucagon secretion were examined sequentially during 6 months of calorie and carbohydrate restriction in an obese, recent-onset, ketosisresistant diabetic adult. The subject was then followed for 9 additional months, during which some weight was regained. Fasting plasma glucose levels returned to normal after 1 week of calorie restriction and remained normal during periods of carbohydrate refeeding. Normalization of 2-h plasma glucose concentrations after a standard oral carbohydrate load required 5 months, and glucose disposal after an iv glucose load did not return to normal until the end of the study. Insulin secretion in response to oral gluose reached maximal levels during the first
R
ECENT studies have indicated that abnormalities of insulin and glucagon secretion found in patients with ketosis-resistant diabetes mellitus are at least partially reversible (1-5). An obese, recent-onset, ketosisresistant, diabetic adult was studied before, during, and after prolonged calorie and carbohydrate restriction to determine the maximum possible recovery of glucose tolerance, the change in resistance to glucose disposal, and the degree of reversibility of abnormalities in insulin and glucagon secretion. Complete recovery of glucose tolerance and normalization of insulin and glucagon secretion were demonstrated. In addition, dietary therapy led to reduction of resistance to the action of insulin, which also contributed to the recovery of glucose tolerance.
Case Report A 32-yr-old male (half Apache Indian and half Mexican) was admitted to the Phoenix Clinical Research Unit of the NIH, NIAMDD, with a history of nocturia for 1.5 yr and several months of polyuria and increased thirst. He had a history of marked obesity since childhood, attaining a maximum weight Received June 4,1979. Address requests for reprints to: Dr. Peter J. Savage, National Institute of Arthritis, Metabolism, and Digestive Diseases, Room 541, Phoenix Indian Medical Center, 4212 North 16th Street, Phoenix, Arizona 85016. * This work was supported in part by NIH Contract N01-AM-62219.
months of weight reduction and then decreased as glucose tolerance continued to improve. Acute phase insulin release in response to iv glucose gradually increased throughout the study. Glucagon stimulation by iv arginine and suppression by iv glucose also returned to normal levels slowly over several months. Abnormalities in glucose tolerance and glucoregulatory hormone secretion of ketosis-resistant diabetes are totally reversible with prolonged dietary therapy. Reduction in tissue resistance to the action of insulin also appeared to be of major importance in the recovery of normal glucose tolerance in this subject. (J Clin Endocrinol Metab 49: 830, 1979)
of 159 kg 1 year before admission. Since the onset of symptoms, he had lost 23 kg. He had no other illnesses and had never received medication for diabetes. On physical examination, he was afebrile, his blood pressure was 150/80 mm/Hg, his pulse was 85/min, and his respiration was 18/min. Height was 179 cm and weight was 137.5 kg. Examination was unremarkable, except for marked obesity and slight hyperpigmentation in skin fold areas. Complete blood count, serum creatinine, T4, 0800 h plasma cortisol concentrations, and electrocardiogram were within normal limits. Urinalysis was negative, except for +4 glycosuria. Alkaline phosphatase was 66, serum glutamic oxaloacetic transaminase was 75 IU, and serum bilirubin was 0.5 mg/dl. A 24-h urine collection contained 109 g glucose. Fasting plasma glucose was 220 mg/dl. Initially, he was placed on a weight-maintaining, 300-g carbohydrate diet (3300 calories/day). On the fourth day, he had a 100-g oral glucose tolerance test (Koladex, Custom Laboratories, Baltimore, MD), and on subsequent days he was given an iv glucose tolerance test (25 g glucose administered iv over 3 min) and an iv infusion of 10% L-arginine monohydrochloride (5 mg/kg-min for 40 min; R-gene, Cutter Laboratories, Berkeley, CA). He was then placed on a 500-calorie, 50-g carbohydrate diet which was continued over the next 6.5 months with four 1-week interruptions during which his diet was changed to 1500 calories with 300 g carbohydrate. After 3 days of the increased carbohydrate intake, the initial series of studies was repeated.1 [The 1
In all subsequent studies, doses were identical to those used during the initial series.
830
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DIET-INDUCED RECOVERY OF DIABETES 1500-calorie diet was selected because ealier studies on other subjects indicated that this diet would eliminate any effect of starvation diabetes and would be weight maintaining (5).] Total weight loss over the period was 54.5 kg. After completion of the weight loss period, the subject was placed on a 200-g carbohydrate, weight-maintaining diet for 5 additional weeks, and the initial series of tests was repeated once again. Weight was maintained at the end of this period with 1980 calories/day. He was then discharged with instructions for a 2000-calorie, 40% carbohydrate diet. Seven months after discharge, he was readmitted to the clinical research unit for follow-up evaluation. He had gained 13 kg and weight was maintained on a 2800-calorie, 300-g carbohydrate diet. After 3 days on this diet, the initial series of tests was repeated. Blood samples for glucose determination were collected in sodium fluoride, and plasma was separated, frozen, and subsequently analyzed by the ferricyanide method (6). Samples for measurement of insulin and glucagon concentrations were collected in tubes containing sodium EDTA and 5000 U Aprotinin (Trasylol, FBA Pharmaceuticals, New York, NY), placed immediately in ice, and centrifuged, and plasma was stored at —20 C until assay. Insulin concentrations were measured by the Herbert modification of the Yalow and Berson RIA (7), and glucagon concentrations were measured using antiserum 30K (8). Glucose disappearance rates (k; percent per min) were calculated using plasma glucose values between 10-60 min as long as they remained above 100 mg/dl (9). Urine glucose was measured by the glucose oxidase method (10).
remained above 140 mg/dl during the first 4 months of hospitalization but finally reached a level of 99 mg/dl at the time of discharge. Seven months later, after a 13-kg weight gain, fasting glucose levels remained unchanged but the 2-h level had again increased to 142 mg/dl. Fasting insulin levels also showed a progressive decline during hospitalization but were increased during the final 20 -i 10
Fasting
0 300 200 -
Increment (OGTT)
100
-
0 300 Increment (A.I.)
200 100 0
CO — —
Increment (IVGTT)
100 " 0 40
Results The changes observed in weight and glucose and glucagon concentrations during the seven series of studies conducted over the 15-month period are shown in Table 1, and changes in insulin concentrations are shown in Fig. 1. Weight declined during the period of dietary restriction, was stable during the period of weight maintenance, and increased during the 7 months after discharge. Fasting glucose levels declined rapidly after initiation of the 500-calorie diet, reaching normal levels in 1 week and remaining normal thereafter. Although the major part of the improvement in oral glucose tolerance occurred during the first month, progressive improvement continued until the end of the period of hospitalization. Two-hour plasma glucose levels
831
Acute Increment (IVGTT)
20 H
STUDY
PERIOD
FIG. 1. Insulin concentrations (microunits per ml) measured during each series of tests. A, Fasting plasma insulin concentration. B, Oral glucose tolerance test; sum of increments in insulin concentration above fasting (30, 60, 120, and 180 min). C, Arginine infusion; sum of increments in insulin concentration above fasting (5,10, 20, 30, and 40 min). D, Intravenous glucose tolerance test; sum of increments in insulin concentration above fasting (10, 20, 30, 45, and 60 min). E, Intravenous glucose tolerance test; mean acute phase (3, 4, 5, 6, and 10 min) increment in insulin concentration.
TABLE 1.
0 Days, 138 kg
Pime: rVt:
27 Days, 128 kg
70 Days, H2kg
113 Days, 94 kg
204 Days, 83 kg
245 Days, 83 kg
77 131
78 99
463 Days, 96 kg
glucose
Fasting (mg/dl) 2-h OGTT (mg/dl) K (%/min; IVGTT) jlucagon % Change from fasting (IVGTT) Sum of increment (AI; pg/ml)°
220 369
0.23 -12
1290
112 222
0.49 -20 703
84 189
0.59 -21 875
85 133
0.82 -26
858
1.02 -21 707
0.85 -32 573
OGTT, Oral glucose tolerance test; IVGTT, iv glucose tolerance test; AI, Arginine infusion. " Measured at 5, 10, 20, 30, and 40 min past the start of the infusion.
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80 143 1.28 -22 861
SAVAGE, BENNION, AND BENNETT
832
series of tests, presumably secondary to the antecedent increase in weight and caloric intake. Before diet therapy, insulin secretion in response to oral glucose was markedly impaired. Maximum insulin responses were attained during the second series of studies after the first month of diet therapy and then progressively declined as weight reduction was continued. After discharge and a period of weight gain, insulin concentrations, both fasting and in response to stimuli, were again increased but remained below the levels observed during the first months of treatment. The glucose disappearance rate after iv glucose showed a slow but progressive increase throughout the entire period of observation. In contrast to insulin response to oral glucose, the acute phase (3-10 min) insulin release after iv glucose rose progressively throughout the study. The change in the glucose disappearance rate was correlated with the change in the acute insulin response (r = 0.86; P < 0.01). The suppression of glucagon secretion by iv glucose was initially abnormal and gradually returned to the normal range by the end of hospitalization (11). Insulin responses to infusion of arginine differed considerably from responses to either oral or iv glucose. Despite initial gross impairment of glucose-stimulated insulin responses, initial insulin secretion in response to arginine was relatively normal. Arginine-induced responses, like those after oral glucose, increased during the early months of treatment but then decreased to levels as much as 25% below initial values as weight loss continued and glucose tolerance improved. Glucagon stimulation by iv arginine was abnormally elevated initially and gradually returned to normal after prolonged therapy (12). Discussion Prolonged dietary therapy was necessary in this case to attain complete recovery of normal glucose tolerance and reversal of abnormalities in the secretion of insulin and glucagon which are associated with severe, ketosisresistant diabetes. This study also suggests that reduction in resistance to the action of insulin plays a major role in the normalization of glucose tolerance. Normal fasting glucose levels were attained much more readily than normal glucose levels after an oral or iv glucose challenge. Fasting glucose levels were normal after the first week on the 500-calorie diet and remained normal thereafter despite refeeding with large amounts of carbohydrates. In contrast, glucose levels 2 h after a standard oral carbohydrate load did not reach conventionally accepted normal levels (13) until the fifth month of diet therapy, and normal disposal of an iv glucose load (9) was not observed until the end of the study. Major
JCE&M • 1979 Vol49 • No 6
improvement in oral glucose tolerance during the first few weeks of diet therapy with only small improvement thereafter has been noted previously (2). This report extends those observations and indicates that with persistent therapy all abnormalities in glucose tolerance and glucoregulatory hormone secretion can be reversed in at least some ketosis-resistant diabetics. This study also indicates that changes in sensitivity to the action of insulin are of major importance in the recovery of normal glucose tolerance. This was most clearly demonstrated by the almost 70% decline in fasting insulin levels during the period when fasting glucose levels were reduced by approximately 150 mg/dl. In addition, in response to both oral and iv glucose and to iv arginine, the total increment of insulin secretion above fasting concentrations increased during the first part of the study and then decreased from peak values while glucose tolerance was continuing to improve. These observations support the original hypothesis of Reaven (14) and more recent data (15, 16) suggesting that subjects with impaired glucose tolerance have excessive insulin secretion but, because of insulin resistance, are still unable to dispose of a glucose challenge normally. Earlier studies have indicated that a period of mild hyperglycemia accompanied by hyperinsulinemia precedes the development of overt ketosis-resistant diabetes (14, 17-19). This period has been associated with increased tissue resistance to the effects of insulin on glucose disposal (14, 15). Our patient passed through such a period of abnormal glucose tolerance, despite hypersecretion of insulin, with apparently increased insulin resistance as his overt diabetes gradually remitted toward normal, suggesting that he may have retraced the stages through which overt, ketosis-resistant diabetes ordinarily develops. The disassociation observed between the insulin responses to stimulation with glucose and arginine upon admission suggests that a major cause of symptomatic hyperglycemia in ketosis-resistant diabetes mellitus is the loss of the ability of pancreatic /?-cells to respond to changes in glucose concentration although the ability to synthesize and secrete insulin still exists (5,20). Although fasting insulin concentrations were highest at the time the patient was overtly diabetic, insulin increments in response to glucose at this time were lower than at any subsequent time during the study. We have previously reported that insulin secretion during the first 10 min of an iv glucose tolerance test remained impaired in a group of recent onset diabetics even after major improvement in glucose tolerance produced by the same dietary regimen used in this patient (5). In this case, however, a much longer period of caloric restriction and a greater loss of weight were associated
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DIET-INDUCED RECOVERY OF DIABETES with progressive improvement in acute phase insulin release, indicating that with prolonged therapy even this abnormality is potentially reversible. It was notable also that during the study the pattern of insulin response to iv glucose changed; increasing amounts of insulin were secreted during the early portion of the test, while secretion during the later portion was decreasing. This study indicates that changes in total insulin secretion, in timing of insulin secretion, in tissue resistance to the action of insulin, and in glucagon secretion accompany the complete normalization of glucose disposal in ketosis-resistant diabetes. These observations emphasize again the value of dietary therapy in the treatment of this form of diabetes and suggest that prolonged normalization of fasting glucose levels may be necessary for normalization of glucose disposal and glucoregulatory hormone secretion. References 1. Rudnick, P. A., and K. W. Taylor, Effect of prolonged carbohydrate restriction on serum insulin levels in mild diabetics, Br Med J 1: 1125, 1965. 2. Doar, J. W. H., M. E. Thompson, C. E. Wilde, and C. E. Sewell, Influence of treatment with diet alone on oral glucose tolerance test and plasma sugar and insulin levels in patients with maturity onset diabetes mellitus, Lancet 1: 1263,1975. 3. Perkins, J. R., T. E. T. West, P. H. Sonksen, C. Lawy, and C. Ices, The effects of energy and carbohydrate restriction in patients with chronic diabetes mellitus, Diabetologia 13: 607,1977. 4. Larkins, R. G., F. I. R. Martin, F. P. Alford, and D. J. Chisholm, Relationship between alpha and beta cell function before and after metabolic control in ketotic diabetic subjects, J Clin Endocrinol Metab 46: 131, 1978. 5. Savage, P. J., L. J. Bennion, E. V. Flock, M. Nagulesparan, D. Mott, J. Roth, R. H. Unger, and P. H. Bennett, Diet-induced improvement of abnormalities in insulin and glucagon secretion and in insulin receptor binding in diabetes mellitus, J Clin Endocrinol Metab 48: 999, 1979.
833
6. Hoffman, U. S., A rapid photoelectric method for the determination of glucose in blood and urine, J Biol Chem 120: 51, 1937. 7. Herbert, V., K. Lau, C. W. Gottlieb, and S. J. Bleicher, Coated charcoal immunoassay of insulin, J Clin Endocrinol Metab 25: 1375, 1965. 8. Faloona, G. R., and R. H. Unger, Glucagon, In Jaffe, B. M., and H. R. Behrman (eds.), Methods of Hormone Radioimmunoassay, Academic Press, New York, 1974, p. 317. 9. Soeldner, J. S., The intravenous glucose tolerance test, In Fajans, S. S., and K. E. Sussman (eds.), Diabetes Mellitus: Diagnosis and Treatment, American Diabetes Association, New York, 1971, pp. 107-114. 10. Alpert, N. L., Instrument series: report no. 14, glucose analyzer and BUN analyzer, Lab World 24: 40, 1973. 11. Aronoff, S. L., P. H. Bennett, and R. H. Unger, Immunoreactive glucagon (IRG) responses to intravenous glucose in prediabetes and diabetes among Pima Indians and normal Caucasians, J Clin Endocrinol Metab 44: 968, 1977. 12. Aronoff, S. L., P. H. Bennett, N. B. Rushforth, M. Miller, and R. H. Unger, Arginine stimulated hyperglucagonemia in diabetic Pima Indians, Diabetes 25: 404, 1976. 13. Fajans, S. S., and J. W. Conn, The early recognition of diabetes mellitus, Ann NY Acad Sci 82: 208, 1959. 14. Shen, S. W., G. M. Reaven, and J. W. Farquhar, Comparison of impedance to insulin-mediated glucose uptake in normal subjects and in subjects with latent diabetes, J Clin Invest 49: 2151, 1970. 15. DeFronzo, R., D. Diebert, R. Hendler, P. Felig, and V. Soman, Direct evidence of insulin resistance in maturity onset diabetes, Diabetes [Suppl 2] 27: 431,1978. 16. Olefsky, J. M., and G. M. Reaven, Insulin binding in diabetes: relationships with plasma insulin levels and insulin sensitivity, Diabetes 26: 680, 1977. 17. Yalow, R. S., and S. A. Berson, Plasma insulin concentrations in nondiabetic and early diabetic subjects. Determinations by a new sensitive immunoassay technique, Diabetes 9: 254, 1960. 18. Savage, P. J., S. E. Dippe, P. H. Bennett, P. Gorden, J. Roth, N. B. Rushforth, and M. Miller, Hyperinsulinemia and hypoinsulinemia: insulin responses to oral carbohydrate over a wide spectrum of glucose tolerance, Diabetes 24: 362,1975. 19. Genuth, S. M., Insulin secretion in obesity and diabetes: an illustrative case, Ann Intern Med 87: 714, 1977. 20. Robertson, R. P., and D. Porte, Jr., The glucose receptor: a defective mechanism in diabetes mellitus distinct from the beta adrenergic receptor, J Clin Invest 52: 870, 1973.
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Vol. 49, No. 6 Printed in U.S.A.
Normalization of Insulin and Glucagon Secretion in Ketosis-Resistant Diabetes Mellitus with Prolonged Diet Therapy* PETER J. SAVAGE, LYNN J. BENNION, AND PETER H. BENNETT Southwestern Field Studies and Phoenix Clinical Research Sections, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Phoenix, Arizona 85016
ABSTRACT. Glucose tolerance and insulin and glucagon secretion were examined sequentially during 6 months of calorie and carbohydrate restriction in an obese, recent-onset, ketosisresistant diabetic adult. The subject was then followed for 9 additional months, during which some weight was regained. Fasting plasma glucose levels returned to normal after 1 week of calorie restriction and remained normal during periods of carbohydrate refeeding. Normalization of 2-h plasma glucose concentrations after a standard oral carbohydrate load required 5 months, and glucose disposal after an iv glucose load did not return to normal until the end of the study. Insulin secretion in response to oral gluose reached maximal levels during the first
R
ECENT studies have indicated that abnormalities of insulin and glucagon secretion found in patients with ketosis-resistant diabetes mellitus are at least partially reversible (1-5). An obese, recent-onset, ketosisresistant, diabetic adult was studied before, during, and after prolonged calorie and carbohydrate restriction to determine the maximum possible recovery of glucose tolerance, the change in resistance to glucose disposal, and the degree of reversibility of abnormalities in insulin and glucagon secretion. Complete recovery of glucose tolerance and normalization of insulin and glucagon secretion were demonstrated. In addition, dietary therapy led to reduction of resistance to the action of insulin, which also contributed to the recovery of glucose tolerance.
Case Report A 32-yr-old male (half Apache Indian and half Mexican) was admitted to the Phoenix Clinical Research Unit of the NIH, NIAMDD, with a history of nocturia for 1.5 yr and several months of polyuria and increased thirst. He had a history of marked obesity since childhood, attaining a maximum weight Received June 4,1979. Address requests for reprints to: Dr. Peter J. Savage, National Institute of Arthritis, Metabolism, and Digestive Diseases, Room 541, Phoenix Indian Medical Center, 4212 North 16th Street, Phoenix, Arizona 85016. * This work was supported in part by NIH Contract N01-AM-62219.
months of weight reduction and then decreased as glucose tolerance continued to improve. Acute phase insulin release in response to iv glucose gradually increased throughout the study. Glucagon stimulation by iv arginine and suppression by iv glucose also returned to normal levels slowly over several months. Abnormalities in glucose tolerance and glucoregulatory hormone secretion of ketosis-resistant diabetes are totally reversible with prolonged dietary therapy. Reduction in tissue resistance to the action of insulin also appeared to be of major importance in the recovery of normal glucose tolerance in this subject. (J Clin Endocrinol Metab 49: 830, 1979)
of 159 kg 1 year before admission. Since the onset of symptoms, he had lost 23 kg. He had no other illnesses and had never received medication for diabetes. On physical examination, he was afebrile, his blood pressure was 150/80 mm/Hg, his pulse was 85/min, and his respiration was 18/min. Height was 179 cm and weight was 137.5 kg. Examination was unremarkable, except for marked obesity and slight hyperpigmentation in skin fold areas. Complete blood count, serum creatinine, T4, 0800 h plasma cortisol concentrations, and electrocardiogram were within normal limits. Urinalysis was negative, except for +4 glycosuria. Alkaline phosphatase was 66, serum glutamic oxaloacetic transaminase was 75 IU, and serum bilirubin was 0.5 mg/dl. A 24-h urine collection contained 109 g glucose. Fasting plasma glucose was 220 mg/dl. Initially, he was placed on a weight-maintaining, 300-g carbohydrate diet (3300 calories/day). On the fourth day, he had a 100-g oral glucose tolerance test (Koladex, Custom Laboratories, Baltimore, MD), and on subsequent days he was given an iv glucose tolerance test (25 g glucose administered iv over 3 min) and an iv infusion of 10% L-arginine monohydrochloride (5 mg/kg-min for 40 min; R-gene, Cutter Laboratories, Berkeley, CA). He was then placed on a 500-calorie, 50-g carbohydrate diet which was continued over the next 6.5 months with four 1-week interruptions during which his diet was changed to 1500 calories with 300 g carbohydrate. After 3 days of the increased carbohydrate intake, the initial series of studies was repeated.1 [The 1
In all subsequent studies, doses were identical to those used during the initial series.
830
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DIET-INDUCED RECOVERY OF DIABETES 1500-calorie diet was selected because ealier studies on other subjects indicated that this diet would eliminate any effect of starvation diabetes and would be weight maintaining (5).] Total weight loss over the period was 54.5 kg. After completion of the weight loss period, the subject was placed on a 200-g carbohydrate, weight-maintaining diet for 5 additional weeks, and the initial series of tests was repeated once again. Weight was maintained at the end of this period with 1980 calories/day. He was then discharged with instructions for a 2000-calorie, 40% carbohydrate diet. Seven months after discharge, he was readmitted to the clinical research unit for follow-up evaluation. He had gained 13 kg and weight was maintained on a 2800-calorie, 300-g carbohydrate diet. After 3 days on this diet, the initial series of tests was repeated. Blood samples for glucose determination were collected in sodium fluoride, and plasma was separated, frozen, and subsequently analyzed by the ferricyanide method (6). Samples for measurement of insulin and glucagon concentrations were collected in tubes containing sodium EDTA and 5000 U Aprotinin (Trasylol, FBA Pharmaceuticals, New York, NY), placed immediately in ice, and centrifuged, and plasma was stored at —20 C until assay. Insulin concentrations were measured by the Herbert modification of the Yalow and Berson RIA (7), and glucagon concentrations were measured using antiserum 30K (8). Glucose disappearance rates (k; percent per min) were calculated using plasma glucose values between 10-60 min as long as they remained above 100 mg/dl (9). Urine glucose was measured by the glucose oxidase method (10).
remained above 140 mg/dl during the first 4 months of hospitalization but finally reached a level of 99 mg/dl at the time of discharge. Seven months later, after a 13-kg weight gain, fasting glucose levels remained unchanged but the 2-h level had again increased to 142 mg/dl. Fasting insulin levels also showed a progressive decline during hospitalization but were increased during the final 20 -i 10
Fasting
0 300 200 -
Increment (OGTT)
100
-
0 300 Increment (A.I.)
200 100 0
CO — —
Increment (IVGTT)
100 " 0 40
Results The changes observed in weight and glucose and glucagon concentrations during the seven series of studies conducted over the 15-month period are shown in Table 1, and changes in insulin concentrations are shown in Fig. 1. Weight declined during the period of dietary restriction, was stable during the period of weight maintenance, and increased during the 7 months after discharge. Fasting glucose levels declined rapidly after initiation of the 500-calorie diet, reaching normal levels in 1 week and remaining normal thereafter. Although the major part of the improvement in oral glucose tolerance occurred during the first month, progressive improvement continued until the end of the period of hospitalization. Two-hour plasma glucose levels
831
Acute Increment (IVGTT)
20 H
STUDY
PERIOD
FIG. 1. Insulin concentrations (microunits per ml) measured during each series of tests. A, Fasting plasma insulin concentration. B, Oral glucose tolerance test; sum of increments in insulin concentration above fasting (30, 60, 120, and 180 min). C, Arginine infusion; sum of increments in insulin concentration above fasting (5,10, 20, 30, and 40 min). D, Intravenous glucose tolerance test; sum of increments in insulin concentration above fasting (10, 20, 30, 45, and 60 min). E, Intravenous glucose tolerance test; mean acute phase (3, 4, 5, 6, and 10 min) increment in insulin concentration.
TABLE 1.
0 Days, 138 kg
Pime: rVt:
27 Days, 128 kg
70 Days, H2kg
113 Days, 94 kg
204 Days, 83 kg
245 Days, 83 kg
77 131
78 99
463 Days, 96 kg
glucose
Fasting (mg/dl) 2-h OGTT (mg/dl) K (%/min; IVGTT) jlucagon % Change from fasting (IVGTT) Sum of increment (AI; pg/ml)°
220 369
0.23 -12
1290
112 222
0.49 -20 703
84 189
0.59 -21 875
85 133
0.82 -26
858
1.02 -21 707
0.85 -32 573
OGTT, Oral glucose tolerance test; IVGTT, iv glucose tolerance test; AI, Arginine infusion. " Measured at 5, 10, 20, 30, and 40 min past the start of the infusion.
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80 143 1.28 -22 861
SAVAGE, BENNION, AND BENNETT
832
series of tests, presumably secondary to the antecedent increase in weight and caloric intake. Before diet therapy, insulin secretion in response to oral glucose was markedly impaired. Maximum insulin responses were attained during the second series of studies after the first month of diet therapy and then progressively declined as weight reduction was continued. After discharge and a period of weight gain, insulin concentrations, both fasting and in response to stimuli, were again increased but remained below the levels observed during the first months of treatment. The glucose disappearance rate after iv glucose showed a slow but progressive increase throughout the entire period of observation. In contrast to insulin response to oral glucose, the acute phase (3-10 min) insulin release after iv glucose rose progressively throughout the study. The change in the glucose disappearance rate was correlated with the change in the acute insulin response (r = 0.86; P < 0.01). The suppression of glucagon secretion by iv glucose was initially abnormal and gradually returned to the normal range by the end of hospitalization (11). Insulin responses to infusion of arginine differed considerably from responses to either oral or iv glucose. Despite initial gross impairment of glucose-stimulated insulin responses, initial insulin secretion in response to arginine was relatively normal. Arginine-induced responses, like those after oral glucose, increased during the early months of treatment but then decreased to levels as much as 25% below initial values as weight loss continued and glucose tolerance improved. Glucagon stimulation by iv arginine was abnormally elevated initially and gradually returned to normal after prolonged therapy (12). Discussion Prolonged dietary therapy was necessary in this case to attain complete recovery of normal glucose tolerance and reversal of abnormalities in the secretion of insulin and glucagon which are associated with severe, ketosisresistant diabetes. This study also suggests that reduction in resistance to the action of insulin plays a major role in the normalization of glucose tolerance. Normal fasting glucose levels were attained much more readily than normal glucose levels after an oral or iv glucose challenge. Fasting glucose levels were normal after the first week on the 500-calorie diet and remained normal thereafter despite refeeding with large amounts of carbohydrates. In contrast, glucose levels 2 h after a standard oral carbohydrate load did not reach conventionally accepted normal levels (13) until the fifth month of diet therapy, and normal disposal of an iv glucose load (9) was not observed until the end of the study. Major
JCE&M • 1979 Vol49 • No 6
improvement in oral glucose tolerance during the first few weeks of diet therapy with only small improvement thereafter has been noted previously (2). This report extends those observations and indicates that with persistent therapy all abnormalities in glucose tolerance and glucoregulatory hormone secretion can be reversed in at least some ketosis-resistant diabetics. This study also indicates that changes in sensitivity to the action of insulin are of major importance in the recovery of normal glucose tolerance. This was most clearly demonstrated by the almost 70% decline in fasting insulin levels during the period when fasting glucose levels were reduced by approximately 150 mg/dl. In addition, in response to both oral and iv glucose and to iv arginine, the total increment of insulin secretion above fasting concentrations increased during the first part of the study and then decreased from peak values while glucose tolerance was continuing to improve. These observations support the original hypothesis of Reaven (14) and more recent data (15, 16) suggesting that subjects with impaired glucose tolerance have excessive insulin secretion but, because of insulin resistance, are still unable to dispose of a glucose challenge normally. Earlier studies have indicated that a period of mild hyperglycemia accompanied by hyperinsulinemia precedes the development of overt ketosis-resistant diabetes (14, 17-19). This period has been associated with increased tissue resistance to the effects of insulin on glucose disposal (14, 15). Our patient passed through such a period of abnormal glucose tolerance, despite hypersecretion of insulin, with apparently increased insulin resistance as his overt diabetes gradually remitted toward normal, suggesting that he may have retraced the stages through which overt, ketosis-resistant diabetes ordinarily develops. The disassociation observed between the insulin responses to stimulation with glucose and arginine upon admission suggests that a major cause of symptomatic hyperglycemia in ketosis-resistant diabetes mellitus is the loss of the ability of pancreatic /?-cells to respond to changes in glucose concentration although the ability to synthesize and secrete insulin still exists (5,20). Although fasting insulin concentrations were highest at the time the patient was overtly diabetic, insulin increments in response to glucose at this time were lower than at any subsequent time during the study. We have previously reported that insulin secretion during the first 10 min of an iv glucose tolerance test remained impaired in a group of recent onset diabetics even after major improvement in glucose tolerance produced by the same dietary regimen used in this patient (5). In this case, however, a much longer period of caloric restriction and a greater loss of weight were associated
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DIET-INDUCED RECOVERY OF DIABETES with progressive improvement in acute phase insulin release, indicating that with prolonged therapy even this abnormality is potentially reversible. It was notable also that during the study the pattern of insulin response to iv glucose changed; increasing amounts of insulin were secreted during the early portion of the test, while secretion during the later portion was decreasing. This study indicates that changes in total insulin secretion, in timing of insulin secretion, in tissue resistance to the action of insulin, and in glucagon secretion accompany the complete normalization of glucose disposal in ketosis-resistant diabetes. These observations emphasize again the value of dietary therapy in the treatment of this form of diabetes and suggest that prolonged normalization of fasting glucose levels may be necessary for normalization of glucose disposal and glucoregulatory hormone secretion. References 1. Rudnick, P. A., and K. W. Taylor, Effect of prolonged carbohydrate restriction on serum insulin levels in mild diabetics, Br Med J 1: 1125, 1965. 2. Doar, J. W. H., M. E. Thompson, C. E. Wilde, and C. E. Sewell, Influence of treatment with diet alone on oral glucose tolerance test and plasma sugar and insulin levels in patients with maturity onset diabetes mellitus, Lancet 1: 1263,1975. 3. Perkins, J. R., T. E. T. West, P. H. Sonksen, C. Lawy, and C. Ices, The effects of energy and carbohydrate restriction in patients with chronic diabetes mellitus, Diabetologia 13: 607,1977. 4. Larkins, R. G., F. I. R. Martin, F. P. Alford, and D. J. Chisholm, Relationship between alpha and beta cell function before and after metabolic control in ketotic diabetic subjects, J Clin Endocrinol Metab 46: 131, 1978. 5. Savage, P. J., L. J. Bennion, E. V. Flock, M. Nagulesparan, D. Mott, J. Roth, R. H. Unger, and P. H. Bennett, Diet-induced improvement of abnormalities in insulin and glucagon secretion and in insulin receptor binding in diabetes mellitus, J Clin Endocrinol Metab 48: 999, 1979.
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6. Hoffman, U. S., A rapid photoelectric method for the determination of glucose in blood and urine, J Biol Chem 120: 51, 1937. 7. Herbert, V., K. Lau, C. W. Gottlieb, and S. J. Bleicher, Coated charcoal immunoassay of insulin, J Clin Endocrinol Metab 25: 1375, 1965. 8. Faloona, G. R., and R. H. Unger, Glucagon, In Jaffe, B. M., and H. R. Behrman (eds.), Methods of Hormone Radioimmunoassay, Academic Press, New York, 1974, p. 317. 9. Soeldner, J. S., The intravenous glucose tolerance test, In Fajans, S. S., and K. E. Sussman (eds.), Diabetes Mellitus: Diagnosis and Treatment, American Diabetes Association, New York, 1971, pp. 107-114. 10. Alpert, N. L., Instrument series: report no. 14, glucose analyzer and BUN analyzer, Lab World 24: 40, 1973. 11. Aronoff, S. L., P. H. Bennett, and R. H. Unger, Immunoreactive glucagon (IRG) responses to intravenous glucose in prediabetes and diabetes among Pima Indians and normal Caucasians, J Clin Endocrinol Metab 44: 968, 1977. 12. Aronoff, S. L., P. H. Bennett, N. B. Rushforth, M. Miller, and R. H. Unger, Arginine stimulated hyperglucagonemia in diabetic Pima Indians, Diabetes 25: 404, 1976. 13. Fajans, S. S., and J. W. Conn, The early recognition of diabetes mellitus, Ann NY Acad Sci 82: 208, 1959. 14. Shen, S. W., G. M. Reaven, and J. W. Farquhar, Comparison of impedance to insulin-mediated glucose uptake in normal subjects and in subjects with latent diabetes, J Clin Invest 49: 2151, 1970. 15. DeFronzo, R., D. Diebert, R. Hendler, P. Felig, and V. Soman, Direct evidence of insulin resistance in maturity onset diabetes, Diabetes [Suppl 2] 27: 431,1978. 16. Olefsky, J. M., and G. M. Reaven, Insulin binding in diabetes: relationships with plasma insulin levels and insulin sensitivity, Diabetes 26: 680, 1977. 17. Yalow, R. S., and S. A. Berson, Plasma insulin concentrations in nondiabetic and early diabetic subjects. Determinations by a new sensitive immunoassay technique, Diabetes 9: 254, 1960. 18. Savage, P. J., S. E. Dippe, P. H. Bennett, P. Gorden, J. Roth, N. B. Rushforth, and M. Miller, Hyperinsulinemia and hypoinsulinemia: insulin responses to oral carbohydrate over a wide spectrum of glucose tolerance, Diabetes 24: 362,1975. 19. Genuth, S. M., Insulin secretion in obesity and diabetes: an illustrative case, Ann Intern Med 87: 714, 1977. 20. Robertson, R. P., and D. Porte, Jr., The glucose receptor: a defective mechanism in diabetes mellitus distinct from the beta adrenergic receptor, J Clin Invest 52: 870, 1973.
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