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Insulin-induced hyperphagia in alloxan-diabetic rats fed a high-fat diet
Physiology & Behavior, Voi. 19, pp. 597-599. Pergamon Press and Brain Research Publ., 1977. Printed in the U.S.A.
Insulin-Induced Hyperphagia in Alloxan-Diabetic Rats Fed a High-Fat Diet I MARK I. FRIEDMAN 2
University o f Massachusetts (Received 7 February 1977) FRIEDMAN, M. I. Insulin-induced hyperphagia in alloxan-diabetic rats fed a high-fat diet. PHYSIOL. BEHAV. 19(5) 597-599, 1977. - Alloxan-diabetic rats fed a standard, low-fat diet lost body weight and were hyperphagic; those fed a high-fat diet lost comparable amounts of weight, but did not overeat compared to normal animals. When given injections of protamine-zinc insulin, all diabetic rats gained weight; however, while those fed the low-fat food reduced food intake from elevated levels, diabetics fed the high-fat diet became hyperphagic. Diabetic rats maintained on a high-fat diet increased food intake during long-term insulin treatment sooner and to a greater extent than normal controls. These findings are interpreted in light of the effects of insulin on storage and supply of metabolic fuels. Feeding
Hunger
Hyperphagia
Alloxan-diabetes
RATS WITH experimental diabetes mellitus are hyperphagic when maintained on a standard, low-fat diet [1, 8, 9], but do not eat more than normal when they are fed a diet rich in fats [2,3]. It has been shown that insulin replacement treatment reduces food consumption of hyperphagic diabetic rats [9]. In the experiments presented here, I examined the effects of insulin treatment on food intake of alloxan-diabetic rats that were eating normal amounts of a high-fat diet.
Insulin
High-fat diet
Procedures Ten days after alloxan injection, 13 diabetic and 10 controls were divided into two groups, each matched for body weight. Seven diabetic and five control rats were given a high-fat diet comprised of two-thirds powdered Purina chow and one-third Crisco shortening (by weight; [5] ) i n place of Purina chow. The other rats were given daily a freshly made wet-mash diet containing, by weight, 50% powdered Purina chow and 50% water. Three weeks after introduction of the new diets, diabetic rats began receiving subcutaneous injections of long-acting, protamine-zinc insulin (Lilly) twice daily at noon and midnight. Every three days, the dose of insulin was increased starting from 0.5 U/day to 1.0, 2.0 and, finally, 3.0 U/day where it remained for a week. The daily dose was divided evenly between the two daily injections, except that when 3 U/day was administered rats were injected with 2 U at noon and 1 U at midnight. Food intake (to the nearest 0.1 g) and body weights (to the nearest g) were measured daily. Food spillage was negligible in this and the next experiment, and when it occurred, crumbs were collected and added to the remaining food before weighing. Two days after insulin treatment was terminated, the diets were switched and rats that had been eating the high-fat diet were given the wet mash food and vice versa. Three weeks later, food intakes and body weights were measured daily for three consecutive days. In another experiment, six diabetic and seven normal
METH OD
Animals The animals were female Sprague-Dawley rats (ZivicMiller, Pittsburgh) weighing between 2 2 5 - 2 6 0 g at the start of the experiment. Rats were housed in wire mesh cages and maintained on Purina Laboratory Chow and tap water except as noted. Lights in the colony room were on between 7 a.m. and 8 p.m.
Experimental Diabetes Rats were made diabetic with a subcutaneous injection of alloxan monohydrate (Sigma; 200 mg/kg, dissolved in 0.15 M NaC1) given under light ether anesthesia. Approximately 70% of the rats injected with alloxan survived and of these all were severely diabetic showing glycosuria, polydipsia and weight loss. Control, nondiabetic rats were either injected as above with 0.15 M NaC1 or left untreated.
1Portions of this work were completed at the University of Pittsburgh, and were supported by USPHS Postdoctoral Fellowship MH-54187 (to the author) and NIMH Grant MH-25140 to E. M. Stricker. The author is grateful to Edward Stricker for his support. Preliminary reports of this work were presented in 1975 at the meetings of the Eastern Psychological Association and the Federation of American Societies for Experimental Biology. Reprint requests should be addressed to Mark Friedman, Department of Psychology, University of Massachusetts, Amherst, MA 01003. 597
598
FRIEDMAN
rats were given the high-fat diet described above starting 2 - 3 weeks after alloxan injection. Daily determinations of food intake and body weights began ten days later and continued until the end of the experiment. After three days of baseline measures, all rats began to receive two daily subcutaneous injections of protamine-zinc insulin. Beginning at 1 U/day, the dose was increased every two days to 1.5, 2.0 and, finally, 3.0 U/day. As above, injections were given at noon and midnight, and the daily dose was divided evenly except at the highest dose. Urinary glucose and ketones were determined qualitatively with Ames Keto-Diastix on the day before and for two days after the start of insulin treatment. RESULTS
The results displayed in Fig. 1 show daily food intakes and body weights of rats for the week before and 16 days during insulin treatment. Before insulin treatment (A), both groups of diabetic rats weighed approximately 40 g less than normal controls; however, while diabetics eating the wet mash diet were hyperphagic, those fed the high-fat food ate the same amount as controls. During insulin treatment (B), all diabetic rats gained weight; however, while diabetics eating the wet mash diet reduced food intake toward normal levels, those fed the fat diet became hyperphagic. After the diets were switched, the same pattern of results was obtained in untreated diabetic rats: all diabetics lost weight but only those eating the wet mash diet became hyperphagic. Thus differences in the severity of diabetes apparently do not account for the effects of the fat diet observed earlier in the experiment. The results of the second experiment are summarized in Fig. 2. Before insulin treatment, caloric intakes of normal and diabetic rats did not differ significantly and diabetic rats weighed significantly less than normal controls (253 +23 g vs. 326 +- 12 g, respectively p<0.02, two-tailed t-test). During insulin treatment, both groups of rats increased food consumption; however, compared to normals, diabetic rats increased intakes more (F(1,11 ) = 6.83 ; p<0.025) and at a lower dose of insulin (F (8,86) = 2.91; p<0.01). Because rats were not given insulin on a body weight basis, it is possible that diabetics were responding to an effectively higher dose of the hormone. However, since diabetics gained more weight than controls (46 -+ 10 g vs. 18 +- 2 g, p<0.02, two-tailed t-test) during the course of treatment, one would expect the difference in caloric intake between the two groups to diminish rather than increase as it did. The day before insulin treatment began all diabetic rats showed severe glycosuria (>2%); no trace of urinary ketones were found in one diabetic and ketosuria was moderate to severe in the rest. On the first day of insulin, ketosuria was abolished in all diabetics except two which showed some trace of urinary ketones. Severe glycosuria persisted in all diabetics for at least the first two days of insulin treatment. Normal rats showed no glycosuria or ketosuria at any time during the experiment. DISCUSSION
Considering only those diabetic rats fed the low-fat, wet mash, the results described above are consistent with traditional theories of hunger which emphasize glucostasis and maintenance of fat stores [7,10]. Thus, hyperphagia was associated with body weight loss and impaired glucose
A
WET MASH DIET
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FIG. 1. Effects of feeding low-fat, wet mash or high-fat diets on food intake and body weight of normal and diabetic rats. A, no insulin treatment; B, administration of increasing doses of protamine-zinc insulin to diabetic rats starting at 0.5 U/day and maintained at 3.0 U/day beginning on Day 10. I
l
I
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150 -
: 140
--
Normal
•
Diabetic
/
/
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W Y n
120 Z U -.I U I00
80 DAY
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I N S U L I N (U) 0
t
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I 6
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I 8
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1.5
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3.0
FIG. 2. Effects of protamine-zinc insulin on food intake of normal and diabetic rats fed a high-fat diet. Asterisks denote intakes significantly (p<0.05) greater than baseline.
utilization when diabetics were not receiving insulin, while the reduction of food intake during insulin treatment was accompanied by weight gain and presumably increased glucose utilization. However, traditional theories offer little help in understanding the changes in food intake of diabetic rats fed the high-fat diet. Left untreated, these rats did not
INSULIN-INDUCED FEEDING IN DIABETIC RATS become hyperphagic despite considerable weight loss and an impairment in glucose utilization (as evidenced by glycosuria), and when given insulin, they increased food intake although body weights were restored and apparently glucose utilization improved. Presumably, an increased availability of circulating, oxidizable fuels in the form of lipid metabolites reduced the need to eat in fat-fed diabetic rats [3,4]. Because fat-fed diabetics were ketotic (as evidenced by ketonuria), severe ketoacidosis may have debilitated these rats and prevented them from becoming hyperphagic. However, not all diabetics that ate normal amounts of the high-fat diet were ketonuric. In addition, abolition of urinary ketones, and presumably ketosis, early during insulin treatment did not lead to an immediate change in food intake. Furthermore, diabetic rats prefer fat [ 12], rather than avoid it as one might expect if it made them sick [13]. And finally, diabetics fed the high-fat diet appeared generally healthier than those that were hyperphagic eating the low-fat diet. These considerations indicate that diabetics eating the high-fat food did not reduce feeding to normal levels because of general malaise. It has been suggested that lipogenesis may affect feeding indirectly by removing utilizable fuels from the circulation [4]. Insulin promotes the storage of metabolic fuels and this action of the hormone may explain the effects of
599 insulin treatment observed in this experiment. Presumably, diabetic rats eating the low-fat, high-carbohydrate diet gained weight and reduced food intake when given insulin because the hormone increased both the capacity to store as well as oxidize carbohydrates, their major source of dietary fuels. On the other hand, while insulin promotes the clearance and storage of circulating fats [15], it also thereby decreases their oxidation. Thus, during insulin treatment, diabetic rats fed the high-fat diet may have increased food intake because fats, their major source energy from the diet, were removed from the circulation and sequestered in storage. It is not clear why diabetic rats increased feeding during insulin treatment more readily than normal rats (Fig. 2). It is tempting to speculate that because insulin lowers plasma free fatty acid levels at doses which are without effect on blood glucose [6, 11, 16], diabetic rats may have been deprived of their most readily oxidizable fuel before glucose utilization was appreciably restored. To the extent that insulin-induced feeding is asociated with a reduction of circulating lipids in fat-fed diabetics, the present results may indicate that insulin treatment produces hunger by decreasing the availability of all metabolic fuels, not just glucose [ 14]. Presumably, normal rats must be given enough insulin to reduce the availability of both glucose and fats in order to stimulate feeding.
REFERENCES 1. Booth, D. A. Some characteristics of feeding during streptozotocin-induced diabetes in the rat. J. comp. physiol. Psychol. 80: 238-249, 1972. 2, Friedman, M. I. Effects of alloxan diabetes on hypothalamic hyperphagia and obesity. Am. J. Physiol. 222: 174-178, 1972. 3. Friedman, M. I. Hyperphagia in rats with experimental diabetes mellitus: A response to a decreased supply of utilizable fuels. J. comp. physiol. Psychol., in press. 4. Friedman, M. I. and E. M. Stricker. The physiological psychology of hunger: A physiological perspective. Psychol. Rev. 83: 409-431, 1976. 5. Gold, R. M. Hypothalamic hyperphagia: Males get just as fat as females. J. comp. physioL Psychol. 71: 347-356, 1970. 6. Goodner, C. J., M. J. Conway and P. Chi Chu. Regulation of lipolysis in the presence of hyperglycemia; and explanation for ketosis resistant diabetes. J. clin. Invest. 46: 1061, 1967, (Abstract). 7. Kennedy, G. C. The role of depot fat in the hypotlialamic control of food intake in the rat. Proc. R. Soc. 140: 578-592, 1953. 8. Kumaresan, P. and C. W. Turner. Effect of alloxan on feed consumption in rats. Proc. Soc. exp. Biol. Med. 119: 400-402, 1965. 9. Kumaresan, P. and C. W. Turner. Effect of alloxan on feed consumption and replacement therapy with graded levels of insulin in rats. Proc. Soc. exp. Biol. Med. 122: 526-527, 1966.
10. Mayer, J. Regu.ation of energy intake and the body weight: The glucostatic theory and the lipostatic hypothesis. Ann. N. Y. Acad. Sci. 63: 15-41, 1955. 11. Mirsky, I. A. Relative effects of insulin, oxytocin and vasopressin on the free fatty acid concentration of the plasma of nondiabetic and diabetic dogs. Endocrinology 73:613-618, 1963. 12. Richter, C. P. and E. C. H. Schmidt. Increased fat and decreased carbohydrate appetite of pancreatectomized rats. Endocrinology 28:179-192, 1941. 13. Rozin, P. and J. W. Kalat. Specific hungers and poison avoidance as adaptive specializations of learning. Psychol. Rev. 78: 459-486, 1971. 14. Stricker, E. M., N. Rowland, C. F. Sailer and M. I. Friedman. Homeostasis during hypoglycemia: Central control of adrenal secretion and peripheral control of feeding. Science, 196: 79-81, 1977. 15. Winegrad, A. I. Adipose tissue in diabetes. In: Handbook o f Physiology, Vol. 5, edited by A. E. Renold and G. F. Cahill. Baltimore: Williamsand Wilkins, 1965. 16. Zieder, K. L. and D. Robinowitz. Effect of very small concentrations of insulin on forearm metabolism. Persistance of its effect on potassium and fatty acids without its effect on glucose. J. clin. Invest. 43: 950-962, 1964.
Insulin-Induced Hyperphagia in Alloxan-Diabetic Rats Fed a High-Fat Diet I MARK I. FRIEDMAN 2
University o f Massachusetts (Received 7 February 1977) FRIEDMAN, M. I. Insulin-induced hyperphagia in alloxan-diabetic rats fed a high-fat diet. PHYSIOL. BEHAV. 19(5) 597-599, 1977. - Alloxan-diabetic rats fed a standard, low-fat diet lost body weight and were hyperphagic; those fed a high-fat diet lost comparable amounts of weight, but did not overeat compared to normal animals. When given injections of protamine-zinc insulin, all diabetic rats gained weight; however, while those fed the low-fat food reduced food intake from elevated levels, diabetics fed the high-fat diet became hyperphagic. Diabetic rats maintained on a high-fat diet increased food intake during long-term insulin treatment sooner and to a greater extent than normal controls. These findings are interpreted in light of the effects of insulin on storage and supply of metabolic fuels. Feeding
Hunger
Hyperphagia
Alloxan-diabetes
RATS WITH experimental diabetes mellitus are hyperphagic when maintained on a standard, low-fat diet [1, 8, 9], but do not eat more than normal when they are fed a diet rich in fats [2,3]. It has been shown that insulin replacement treatment reduces food consumption of hyperphagic diabetic rats [9]. In the experiments presented here, I examined the effects of insulin treatment on food intake of alloxan-diabetic rats that were eating normal amounts of a high-fat diet.
Insulin
High-fat diet
Procedures Ten days after alloxan injection, 13 diabetic and 10 controls were divided into two groups, each matched for body weight. Seven diabetic and five control rats were given a high-fat diet comprised of two-thirds powdered Purina chow and one-third Crisco shortening (by weight; [5] ) i n place of Purina chow. The other rats were given daily a freshly made wet-mash diet containing, by weight, 50% powdered Purina chow and 50% water. Three weeks after introduction of the new diets, diabetic rats began receiving subcutaneous injections of long-acting, protamine-zinc insulin (Lilly) twice daily at noon and midnight. Every three days, the dose of insulin was increased starting from 0.5 U/day to 1.0, 2.0 and, finally, 3.0 U/day where it remained for a week. The daily dose was divided evenly between the two daily injections, except that when 3 U/day was administered rats were injected with 2 U at noon and 1 U at midnight. Food intake (to the nearest 0.1 g) and body weights (to the nearest g) were measured daily. Food spillage was negligible in this and the next experiment, and when it occurred, crumbs were collected and added to the remaining food before weighing. Two days after insulin treatment was terminated, the diets were switched and rats that had been eating the high-fat diet were given the wet mash food and vice versa. Three weeks later, food intakes and body weights were measured daily for three consecutive days. In another experiment, six diabetic and seven normal
METH OD
Animals The animals were female Sprague-Dawley rats (ZivicMiller, Pittsburgh) weighing between 2 2 5 - 2 6 0 g at the start of the experiment. Rats were housed in wire mesh cages and maintained on Purina Laboratory Chow and tap water except as noted. Lights in the colony room were on between 7 a.m. and 8 p.m.
Experimental Diabetes Rats were made diabetic with a subcutaneous injection of alloxan monohydrate (Sigma; 200 mg/kg, dissolved in 0.15 M NaC1) given under light ether anesthesia. Approximately 70% of the rats injected with alloxan survived and of these all were severely diabetic showing glycosuria, polydipsia and weight loss. Control, nondiabetic rats were either injected as above with 0.15 M NaC1 or left untreated.
1Portions of this work were completed at the University of Pittsburgh, and were supported by USPHS Postdoctoral Fellowship MH-54187 (to the author) and NIMH Grant MH-25140 to E. M. Stricker. The author is grateful to Edward Stricker for his support. Preliminary reports of this work were presented in 1975 at the meetings of the Eastern Psychological Association and the Federation of American Societies for Experimental Biology. Reprint requests should be addressed to Mark Friedman, Department of Psychology, University of Massachusetts, Amherst, MA 01003. 597
598
FRIEDMAN
rats were given the high-fat diet described above starting 2 - 3 weeks after alloxan injection. Daily determinations of food intake and body weights began ten days later and continued until the end of the experiment. After three days of baseline measures, all rats began to receive two daily subcutaneous injections of protamine-zinc insulin. Beginning at 1 U/day, the dose was increased every two days to 1.5, 2.0 and, finally, 3.0 U/day. As above, injections were given at noon and midnight, and the daily dose was divided evenly except at the highest dose. Urinary glucose and ketones were determined qualitatively with Ames Keto-Diastix on the day before and for two days after the start of insulin treatment. RESULTS
The results displayed in Fig. 1 show daily food intakes and body weights of rats for the week before and 16 days during insulin treatment. Before insulin treatment (A), both groups of diabetic rats weighed approximately 40 g less than normal controls; however, while diabetics eating the wet mash diet were hyperphagic, those fed the high-fat food ate the same amount as controls. During insulin treatment (B), all diabetic rats gained weight; however, while diabetics eating the wet mash diet reduced food intake toward normal levels, those fed the fat diet became hyperphagic. After the diets were switched, the same pattern of results was obtained in untreated diabetic rats: all diabetics lost weight but only those eating the wet mash diet became hyperphagic. Thus differences in the severity of diabetes apparently do not account for the effects of the fat diet observed earlier in the experiment. The results of the second experiment are summarized in Fig. 2. Before insulin treatment, caloric intakes of normal and diabetic rats did not differ significantly and diabetic rats weighed significantly less than normal controls (253 +23 g vs. 326 +- 12 g, respectively p<0.02, two-tailed t-test). During insulin treatment, both groups of rats increased food consumption; however, compared to normals, diabetic rats increased intakes more (F(1,11 ) = 6.83 ; p<0.025) and at a lower dose of insulin (F (8,86) = 2.91; p<0.01). Because rats were not given insulin on a body weight basis, it is possible that diabetics were responding to an effectively higher dose of the hormone. However, since diabetics gained more weight than controls (46 -+ 10 g vs. 18 +- 2 g, p<0.02, two-tailed t-test) during the course of treatment, one would expect the difference in caloric intake between the two groups to diminish rather than increase as it did. The day before insulin treatment began all diabetic rats showed severe glycosuria (>2%); no trace of urinary ketones were found in one diabetic and ketosuria was moderate to severe in the rest. On the first day of insulin, ketosuria was abolished in all diabetics except two which showed some trace of urinary ketones. Severe glycosuria persisted in all diabetics for at least the first two days of insulin treatment. Normal rats showed no glycosuria or ketosuria at any time during the experiment. DISCUSSION
Considering only those diabetic rats fed the low-fat, wet mash, the results described above are consistent with traditional theories of hunger which emphasize glucostasis and maintenance of fat stores [7,10]. Thus, hyperphagia was associated with body weight loss and impaired glucose
A
WET MASH DIET
18c A
HIGH-FAT DiET
13
=~o---,o Normal
]
140 1
120
-- I 0 0 Q:
q 8o .
Iii
iI.
I I 1 1 . 1
, l , l t
I i i 1 1
* I .
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,
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~240 220 200
-
? * l l l , l J
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.
10 12 14 16
2 4
6
2
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i
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4 6
I I I i I ,
I i
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8 10 12 14 16
DAYS
FIG. 1. Effects of feeding low-fat, wet mash or high-fat diets on food intake and body weight of normal and diabetic rats. A, no insulin treatment; B, administration of increasing doses of protamine-zinc insulin to diabetic rats starting at 0.5 U/day and maintained at 3.0 U/day beginning on Day 10. I
l
I
'
I
'
I
r
150 -
: 140
--
Normal
•
Diabetic
/
/
/
o (.~ 130
W Y n
120 Z U -.I U I00
80 DAY
I 0
I N S U L I N (U) 0
t
I 2
I
I 4
I
I 6
I
I 8
I.O
i.O
1.5
1.5
2.0
2.0
5.0
3.0
FIG. 2. Effects of protamine-zinc insulin on food intake of normal and diabetic rats fed a high-fat diet. Asterisks denote intakes significantly (p<0.05) greater than baseline.
utilization when diabetics were not receiving insulin, while the reduction of food intake during insulin treatment was accompanied by weight gain and presumably increased glucose utilization. However, traditional theories offer little help in understanding the changes in food intake of diabetic rats fed the high-fat diet. Left untreated, these rats did not
INSULIN-INDUCED FEEDING IN DIABETIC RATS become hyperphagic despite considerable weight loss and an impairment in glucose utilization (as evidenced by glycosuria), and when given insulin, they increased food intake although body weights were restored and apparently glucose utilization improved. Presumably, an increased availability of circulating, oxidizable fuels in the form of lipid metabolites reduced the need to eat in fat-fed diabetic rats [3,4]. Because fat-fed diabetics were ketotic (as evidenced by ketonuria), severe ketoacidosis may have debilitated these rats and prevented them from becoming hyperphagic. However, not all diabetics that ate normal amounts of the high-fat diet were ketonuric. In addition, abolition of urinary ketones, and presumably ketosis, early during insulin treatment did not lead to an immediate change in food intake. Furthermore, diabetic rats prefer fat [ 12], rather than avoid it as one might expect if it made them sick [13]. And finally, diabetics fed the high-fat diet appeared generally healthier than those that were hyperphagic eating the low-fat diet. These considerations indicate that diabetics eating the high-fat food did not reduce feeding to normal levels because of general malaise. It has been suggested that lipogenesis may affect feeding indirectly by removing utilizable fuels from the circulation [4]. Insulin promotes the storage of metabolic fuels and this action of the hormone may explain the effects of
599 insulin treatment observed in this experiment. Presumably, diabetic rats eating the low-fat, high-carbohydrate diet gained weight and reduced food intake when given insulin because the hormone increased both the capacity to store as well as oxidize carbohydrates, their major source of dietary fuels. On the other hand, while insulin promotes the clearance and storage of circulating fats [15], it also thereby decreases their oxidation. Thus, during insulin treatment, diabetic rats fed the high-fat diet may have increased food intake because fats, their major source energy from the diet, were removed from the circulation and sequestered in storage. It is not clear why diabetic rats increased feeding during insulin treatment more readily than normal rats (Fig. 2). It is tempting to speculate that because insulin lowers plasma free fatty acid levels at doses which are without effect on blood glucose [6, 11, 16], diabetic rats may have been deprived of their most readily oxidizable fuel before glucose utilization was appreciably restored. To the extent that insulin-induced feeding is asociated with a reduction of circulating lipids in fat-fed diabetics, the present results may indicate that insulin treatment produces hunger by decreasing the availability of all metabolic fuels, not just glucose [ 14]. Presumably, normal rats must be given enough insulin to reduce the availability of both glucose and fats in order to stimulate feeding.
REFERENCES 1. Booth, D. A. Some characteristics of feeding during streptozotocin-induced diabetes in the rat. J. comp. physiol. Psychol. 80: 238-249, 1972. 2, Friedman, M. I. Effects of alloxan diabetes on hypothalamic hyperphagia and obesity. Am. J. Physiol. 222: 174-178, 1972. 3. Friedman, M. I. Hyperphagia in rats with experimental diabetes mellitus: A response to a decreased supply of utilizable fuels. J. comp. physiol. Psychol., in press. 4. Friedman, M. I. and E. M. Stricker. The physiological psychology of hunger: A physiological perspective. Psychol. Rev. 83: 409-431, 1976. 5. Gold, R. M. Hypothalamic hyperphagia: Males get just as fat as females. J. comp. physioL Psychol. 71: 347-356, 1970. 6. Goodner, C. J., M. J. Conway and P. Chi Chu. Regulation of lipolysis in the presence of hyperglycemia; and explanation for ketosis resistant diabetes. J. clin. Invest. 46: 1061, 1967, (Abstract). 7. Kennedy, G. C. The role of depot fat in the hypotlialamic control of food intake in the rat. Proc. R. Soc. 140: 578-592, 1953. 8. Kumaresan, P. and C. W. Turner. Effect of alloxan on feed consumption in rats. Proc. Soc. exp. Biol. Med. 119: 400-402, 1965. 9. Kumaresan, P. and C. W. Turner. Effect of alloxan on feed consumption and replacement therapy with graded levels of insulin in rats. Proc. Soc. exp. Biol. Med. 122: 526-527, 1966.
10. Mayer, J. Regu.ation of energy intake and the body weight: The glucostatic theory and the lipostatic hypothesis. Ann. N. Y. Acad. Sci. 63: 15-41, 1955. 11. Mirsky, I. A. Relative effects of insulin, oxytocin and vasopressin on the free fatty acid concentration of the plasma of nondiabetic and diabetic dogs. Endocrinology 73:613-618, 1963. 12. Richter, C. P. and E. C. H. Schmidt. Increased fat and decreased carbohydrate appetite of pancreatectomized rats. Endocrinology 28:179-192, 1941. 13. Rozin, P. and J. W. Kalat. Specific hungers and poison avoidance as adaptive specializations of learning. Psychol. Rev. 78: 459-486, 1971. 14. Stricker, E. M., N. Rowland, C. F. Sailer and M. I. Friedman. Homeostasis during hypoglycemia: Central control of adrenal secretion and peripheral control of feeding. Science, 196: 79-81, 1977. 15. Winegrad, A. I. Adipose tissue in diabetes. In: Handbook o f Physiology, Vol. 5, edited by A. E. Renold and G. F. Cahill. Baltimore: Williamsand Wilkins, 1965. 16. Zieder, K. L. and D. Robinowitz. Effect of very small concentrations of insulin on forearm metabolism. Persistance of its effect on potassium and fatty acids without its effect on glucose. J. clin. Invest. 43: 950-962, 1964.