G.S.G. Spencer and M.B. Enser

6.7 ±.8 I'g/ml, P < .005). Figure I A shows that an im als previously given urease had the same glucagon response to arginine as the saline-treated controls. In both groups, plasma glucagon concentrations rose significantly (P < .005) within 5 min after arginine administration. Plasma insulin also rose significantly (P < .005) within 5 min after arginine administration. However, the mean change in plasma insulin was significantly sm aller (P < .05) in the urease-treated rats than in the saline-treated controls (Fig. 1B).

hyde, Ba 2 and sulfonylurea was also inhibited by ammonia (Sener et al. 1978). The mechanism whereby ammonia antagonized indueed insulin secretion by arginine is unc1ear. However, Sener et aL (1978) found that ammonia ineubated with isolated islets decreased the intracellular islet cell concentration of pyridine nuc1eotides which may in turn reduce ealeium uptake by islet eells to reduce insulin seeretion.



Brown, M, J. Rivier, W. Vale: Endocrinol. 98: 336-343 (1976) Chaney, AL, E.P. Marbach: Clin. Chem. 8: 130-132 (962) Eisenstein, A.B., l. Strack: Fed. Proc. 38: 554 (1979) FalooM, G.R., R.H. Unger: In: Methods of Hormone Radilr immunoassay (eds. B.M. Jaffee and H.R. Behrman), Academic Press, New York (1974) Feldman, J.M, H.E. Lebovitz: Am. J. Physiol. 221: 10271032 (1971) Harms, P.G., S.R. Ojeda: J. Appl. Physiol. 36: 391-392 (1974) LippmIln, W., M Kobric: Horm. Metab. Res. 10: 280-282 The decreased ability of arginine to stimulate insulin secre(1978) tion in hyperammonemic rats is consistent with other studies Schlienger, /.L., M. Imler, J. Stahl: Biol. Gastroenterol. Pashowing that ammonia inhibits insulin secretion induced by ris 7: 101-110 (1974). various metabolie stimuli inc1uding g1ucose-induced insulin se- Schlienger, /.L., M. Imler, J. Stahl: Diabetologia 11: 439cretion from isolated pancreatic tissue of golden hamsters 443 (1975) (Feldman and Lebovitz 1971) and isolated rat islets (Sener Sener, A., J.c. Hutton, S. Kawazu, A.C. Boschero, G. So· et al. 1978). In vitro insulin secretion stimulated by glyeeraldemers, G. Devis. A. Herchuelz. W./. Malaisse: J. Clin. Invest. 62: 868-878 (1978)

The present results agree with earlier reports (Brown et al. 1976; LippmIln and Kobric 1978) that arginine stimulates in vivo release of insulin and glucagon in rats. Recently Eisenstein and Strack (1979) reported that ammonia prlr voked isolated rat islets to initially release aspike of glucagon but following this the arginine-induced release of glucagon was inhibited. In the present in vivo study, however, increased circulating ammonia did not change the basal concentration of plasma glucagon (not shown) nor the ability of arginine to stimulate glucagon release. We cannot explain the apparent lack of agreement in the results of these two studies with present evidence.

Requests for reprints should be addressed to:Anthony L. Mulloy, 190 Medieal Seiences Building, University of IIIinois, Urbana, 11. 61801 (U.S.A.)

Horm. Metab. Res. 11 (1979) 528-530

Plasma Somatomedin Activity in Obese-Hyperglycemic Mice G.S.G. Spencer and M.B. Enser A.R.C., Meat Research Institute, Langford. Bristol, U.K.

abnormalities in these mice (Herbai 1970). However, circulat· The obese-hyperglycemie syndrome in miee (genotype obI ing immunoreaetive growth hormone levels have been found ob) is associated with high insulin resistance and elevated levels of glucose, bioassayable and immunoreactive insulin to be normal or slightly redueed in ob/ob miee (Roos. Martin, Westmlln-Naeser and Hellerström 1974). in the blood (Stauffacher, Lambert. Vecchio and Renold 1967). So far, the eause of this condition has yet to be The absence of an increase in growth hormone levels suggest established, bu t it has been suggested that circulating horthat a factor(s) other than somatographin is responsible for mones may be of aetiologic importanee. Increased levels the morphological and metabolie changes, for example. somaof growth hormone could aecount for the marked insulin tomedin, which possesses both growth promoting and insulin· resistance, hyperostosis of the skull and the broadened tiIike activity (Van Wyk. Underwood. Lister. Marshall 1974). bial epiphyses in these animals (Hellerström. Westman. Herbai, The increased ineorporation of sulphate into the costal eartilPeterron, WestmIln, Barglund and Östersson 1970) and hyplr age of ob/ob mice in vivo (Herby. Westman and Hellerström physectomy has been shown to correet many of the metabolie 1970) supports this possibility. Received: 20 Aug. 1978 0018-5032/79


Accepted: 21 June 1979 S 03.00


1979 Georg Thieme Publishers

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I'lasma Somatomedin Activity in Obese-Hyperglycemic Mice


Table I Plasma somatomedin activity and cortisol in obese and lean mice Bled at 1100 ob/ob lean n wt (g) ± s.d.

12 67.2± 7.1

SM (V/mI) ± s.d.

1.06± 0.11 1.09± 0.09

Cortisol ("g/l) ± s.d. 237.0 ±43.0

12 27.5± 4.7 86.0±33.0

Bled at 2100 lean ob/ob 6 60.0± 1.3

6 23.7± 1.7

0.99 ± 0.09

0.99± 0.02

183.0± 12.0


Pair fed ob/ob 6 52.5± 3.4 1.00· 275.0±30.0

lean 6 21.4± 1.5 0.96± 0.22 108.0±25.0

*by definition the potency of the standard is 1.00

Materials and Methods Blood was collected from obese (ob/ob) mice and lean mice (not Iitter mates) of the same genetic background (C57BL/ 6J), bred in our own colony from stock obtained from the Jackson Laboratory, Bar Harbor, Maine. The mice were kept under controlled illumination, dark period 18.00 h to 06.00 h. All the mice were approximately 200 days 0111. Somatodin activity was measured in the plasma of three groups of mice: obese and lean mice fed ad libitum and bled during the morning (11.00 h to 12.00 h), obese and lean mice fed ad /ibitum bled at night (21.00 h to 22.00 h), and obese and lean mice which fed with the same weight of food over a 27 hour period. Food was removed at 08.00 hand 2.5 g of food was given at 17.00 h. At 09.00 h the next day 1.5 g of food was given and was consumed before bleeding at 11.00 h. Blood was collected by orbital bleeding and the plasma separated and frozen at - 20°C until alIsayed. Somatomedin activity was measured in the plasma Uit" ing a porcine costal cartilage bioassay (Spencer and Taylor 1978). Bovine plasma was used as the standard plasma for the comparison of potencies except in the controUed feeding study when the somatomedin activity in the plasma of each lean mouse was compared with the somatomedin acH· vity of its obese counterpart. Plasma cortisol levels were measured using a competitive pro tein binding assay.

Results The mean live weight, plasma somatomedin activity and plasma cortisol level in each group of mice are shown in Table 1. In none of the groups was the mean somatomedin potency (V/mI) in the obese-hyperglycemic mice significantly different (p < 0.05) from the somatomedin PQtency in the lean mice, and there were no differences between the sexes. On the other hand, plasma cortisol levels were always significantly higher (p < 0.001) in the obese animals.

Discussion The increased weight and cell numbers in the Iiver (a primary site of somatomedin production), the acromegaloid characteristics and increased in vivo sulphation activity in the absence of elevated growth hormone levels, all suggest that somatomedin levels would be elevated in ob/ob mice. The finding that the plasma somatomedin activity in obesehyperglycemic mice is the same as in lean mice is consistent with the absence of elevated levels of growth hormone in ob/ob mice (Roos, Martin, Westman·Naeser and Hellerström 1974), but does not resolve the obvious dissociation between growth hormone levels and sulphation activity in ob/ob mice

in vivo. Insulin has been shown to stimulate sulphate incorpQration into cartilage of hypophysectomized rats (Salmon, DuVall and Thompson 1968) and it is possible that the high levels of insulin in obese mice may account for some of the increased sulphation activity in vivo. Some of this effect however, might also be expected in vitro. Circadian variation in plasma somatomedin activity has been demonstrated in man (Preece, Taylor, Holder and Daggett, in press), and pig (Spencer, in preparation). The nocturnal activity of lean mice as compared with the nychthemerally active obese-hyperglycemic mice could have affected the comparison of plasma somatomedin activity measured only in the morning. The similarity between the somatomedin activity in the ob/ob and lean mice du ring both day and night suggests that diurnal variation in somatomedin is not affected by the continuous activity of the obese mIce. Nutritional status and food ingestion have both been shown to alter growth hormone levels. As obese mice eat more than lean mice, it was pertinent to study the effect of controlled food in take by obese mice on their plasma somatQmedin activity. No changes in somatomedin activity have been observed during acute calorie restriction in obese children (Chaussain, Donnadieu, Schimpft. Assan, Doyard andJob 1978), and no changes were apparent in the obese mice fed a reduced amount of food. Bioassayable levels of somatomedin are affected by inhibitors of the bioassay and the possibility of somatomedin inhibitors in the plasma of ob/ob mice is currently bein investigated. It has been suggested that cortisol may be an inhibitor of bioassayable somatomedin (Van den Brande, Van Buul, Heinrich, Van Roon. Zurcher and Van Steirtegem 1975). However, it is, as yet, uncertain whether cortisol at physiologicallevels is an effective inhibitor of bioassayable somatomedin. From the evidence available it would seem that increased circulating levels of somatomedin activi~y are not responsible for the acromegaloid characteristics of these animals and that, perhaps, the metabolic and morphological abnormalities may be a result of increased tissue sensitivity to somatomedin or other, yet unidentified, factors.

References Chaussain, J.L., M. Donnadieu, R.M. Schimpft. RAssan, P. Doyard, J.c. Job: Archs. Fr. Ped. 35 (suppI. 2): 5056 (1978) Hellerström, c., S. Westman, G. Herbai, B. Petersson, J. Westman, E. Barglund, C.G. Östersson: Diabetologia 6: 248-291 (1970) Herbai, G.: Acta endocr. (KbH.) 65: 712-722 (1970) Herbai, G., S. Westman, C. Hellerström: Acta endocr. (Kbh.) 64: 415-520 (1970) Roos, P., I.M. Martin, S. Westman-Naeser, C. Hellerstrom: Horm. Metab. Res. 6: 125-128 (1974) Salmon, W.D., M.R. DuVall, E. Y. Thompson: Endocrinology 82: 439-499 (1968) Spencer, G.S.G., A.M. Taylor: J. endocr. 78: 83-88 (1978)

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This communication examines the possibility that an over production of somatomedin may be involved in the pathQgenesis of the obese-hyperglycemic syndrome in mice.


J. Malmquist, B. Israelsson and U. Ljungqvist

Stauffacher, W., A.E. Lambert, D. Vecchio, A.E. Renold: Diabetologia 3: 230-237 (1967) Van den Brande, J.L., S. Van Buul, U. Heinrich, F. Van Roon, T. Zurcher, A.C. Van Steirtegem: Adv. Metab. Dis. 8: 171-181 (1975)

Van Wyk, J.J., L.E. Underwood, R.C. Lister, R.N. MarshalI: Amer. J. Dis. Childhd. 126: 705-711 (1973)

Requests for reprints should be addressed to: G.S.G. Spencer, A.R.C., Meat Research Institute, Langford, Bristol

Plasma somatomedin activity in obese-hyperglycemic mice.

G.S.G. Spencer and M.B. Enser 6.7 ±.8 I'g/ml, P < .005). Figure I A shows that an im als previously given urease had the same glucagon response to ar...
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