The effect of portal and peripheral insulin delivery on carbohydrate and lipid metabolism in a miniature pig model of human IDDM.

A pig model of insulin-dependent diabetes was used to examine the importance of the portal-systemic insulin gradient for whole-body metabolic control. Six pigs had jugular vein, portal vein, and carotid artery cannulae implanted before being made diabetic (150 mg kg[-1] streptozotocin). Each animal received 4 weeks of portal and 4 weeks of peripheral insulin delivery in random order. The blood glucose target range was 5-10 mmol x l(-1), and serum fructosamine and fasting and postprandial blood glucose concentrations were not different between peripheral and portal insulin infusion. Insulin requirement was not different between the 4 week infusion periods, but fasting peripheral insulin levels after peripheral delivery (124 +/- 16 (mean +/- SEM) pmol x l[-1]) were significantly higher (p < 0.05) than in portally infused (73.8 +/- 5.4 pmol x l[-1]) or pre-diabetic control animals (68.4 +/- 3.6 pmol x l[-1]). Basal hepatic glucose output was also higher (p < 0.05) in peripherally (4.2 +/- 0.4 mg x kg[-1] x min[-1]) than in portally infused animals (2.9 +/- 0.4 mg x kg[-1] x min[-1]) or controls (3.0 +/- 0.3 mg x kg[-1] x min[-1]). Clamp glucose metabolic clearance rate was, however, not different between the peripheral and portal insulin delivery routes (8.1 +/- 1.0 vs 9.0 +/- 0.7 ml x kg[-1] x min[-1]), although both were significantly lower (p < 0.05) than that measured in prediabetic control animals (11.7 +/- 1.0 ml x kg[-1] x min[-1]). Lipid profiles and subfractions were similar in all three groups. It is concluded that the portal route of delivery is superior to the peripheral in maintaining more appropriate insulin concentrations and control of hepatic glucose output, although in the absence of euglycaemia it is still associated with significant metabolic abnormalities.

Renal enlargement and insulin-like growth factor-1 accumulation in the Wistar rat model of experimental diabetes is not prevented by angiotensin converting enzyme inhibition.

Experimental diabetes is associated with renal enlargement and glomerular hyperfiltration. Possible mechanisms for these changes could be the direct effects of growth factors such as insulin-like growth factor-1 and angiotensin II. We investigated whether treatment with trandolapril, an angiotensin converting enzyme inhibitor, prevented renal enlargement in streptozotocin-diabetic rats. Seven groups of male Wistar rats were studied: C (control + placebo); CL (control + low-dose trandolapril, 0.01 mg.kg-1.day-1); CH (control + high-dose trandolapril, 0.5 mg.kg-1.day-1; DP (diabetic + placebo); DI (diabetic, insulin-treated); DL (diabetic + low-dose trandolapril); DH (diabetic + high-dose trandolapril) and DI (diabetic + insulin). From day 2 glucose concentrations and body weight were similar in the non-diabetic and diabetic animals treated with insulin. Diabetic animals treated with placebo and low-dose trandolapril weighed significantly less compared to the control group. The diabetic groups, not treated with insulin, showed marked hyperglycaemia throughout the study. Kidney weight was greater in the diabetic, non insulin-treated groups compared with the control and insulin-treated groups. After 24 h of diabetes, kidney insulin-like growth factor-1 content was significantly increased from baseline levels in groups DP, DL and DH but by 48 h these levels had returned to normal. Renal tissue angiotensin converting enzyme activity was similar in groups C and DI but significantly reduced in all trandolapril-treated animals. Despite inhibiting renal angiotensin converting enzyme activity renal enlargement with increased tissue insulin-like growth factor-1 still occurred. This suggests that neither angiotensin II nor glomerular hyperfiltration, with raised intraglomerular pressure, play a role in the initial renal enlargement seen in experimental diabetes. Renal accumulation of insulin-like growth factor-1 appears to be an important factor in early renal hypertrophy and its effects are not modulated by angiotensin converting enzyme or angiotensin II.

Thyroid-induced changes in the growth of the liver, kidney, and diaphragm of neonatal rats.

Eu-, hypo- and hyper-thyroid rats were studied 12 days postpartum. Hypothyroidism was induced by administering propylthiouracil (PTU) via the mother's drinking water between late gestation and throughout lactation. This procedure effectively blocked the normal early postnatal surge of T3 and T4. In contrast, hyperthyroidism was induced in the young pups by daily injections of T4 from day 3 postpartum. The effects of these experimental manipulations of thyroid status on the rates of protein turnover and growth of the liver, kidney, and diaphragm were studied and compared with measurements made on appropriate euthyroid control tissues. Tissue rates of protein synthesis were decreased in response to hypothyroidism with consequent growth retardation of all three tissues and the whole animal. In contrast, the three body tissues responded very differently to the induction of hyperthyroidism. Hepatic rates of protein synthesis and growth were completely unaffected by thyroid excess. The response of the diaphragm was essentially the reverse of that seen with hypothyroidism, i.e., the enhanced rates of protein synthesis and protein degradation leading to muscle hypertrophy. The rates of protein turnover in the kidney were also increased, but unlike the diaphragm the net result was renal atrophy. Clearly, thyroid hormones influence the normal rapid growth of the neonate and its individual tissues. However, beyond a certain concentration the threshold of responsiveness to these hormones seems to vary between individual tissues.

The influence of thyroid hormones on the growth of the atria and ventricles of the heart in immature rats.

The normal plasma concentrations of tri-iodothyronine (T3) and thyroxine (T4) increase approximately six- and fourfold respectively between the end of gestation and weaning in the rat. This early postnatal surge of thyroid hormones was experimentally modified to produce either a state of hypo- or hyperthyroidism. The growth and rates of protein turnover in the atria and ventricles of the heart were studied, 12 and 20 days postpartum, both as a function of age and of changing thyroid status. Neonatal hypothyroidism was induced by adding propylthiouracil to the mothers' drinking water late in gestation and throughout lactation. Hyperthyroidism was achieved by giving the suckling pups daily injections of T4 from day 3 postpartum onwards. Between 12 and 20 days the weight and protein mass of the combined ventricles of the euthyroid animals approximately doubled, along with substantial increases (50%) in the RNA and DNA contents. Over this same 8 days, growth in the combined atria was much slower. During the same period, hypothyroidism significantly retarded the growth of these immature rats and their atria and ventricles. Both the rates of protein synthesis and protein degradation were decreased in the atria and ventricles. In contrast, hyperthyroidism significantly increased growth in both types of cardiac tissue, this being more pronounced in the atria than in the ventricles between 12 and 20 days. The rates of protein synthesis were increased accordingly, principally by increases in the ribosomal activities. In conclusion, thyroid hormones clearly influence the early postnatal growth of the atria and ventricles of the heart in the rat.

The influence of thyroid hormones on the growth of the lungs in perinatal rats.

The growth and rates of protein turnover in the perinatal lung have been studied in the rat during normal development between late gestation and weaning, and after altering their thyroid status. The aim was to establish what influence thyroid hormones have on the early stages of growth in the lungs. Perinatal hypothyroidism was induced by administering propylthiouracil (PTU) via the mothers' drinking water from late gestation and throughout lactation. A precocious and elevated surge of thyroid hormones was induced by daily injections of T4 from day 3 postpartum onwards. Hypothyroidism in the neonate, but not the fetus, significantly retarded the growth of the animal and its lungs. This was attributable to a decrease in both the pulmonary rates of protein synthesis and protein degradation; the effect on the former rate exceeding that on the latter. Neonatal hyperthyroidism did not significantly alter protein turnover or the growth of the lungs, compared with euthyroid control tissues. This contrasts with the accelerated growth of some other body tissues in the presence of excess thyroid hormones.

The effects of established diabetes on the growth of the fetal liver and skin in the rat.

1. The effects of uncontrolled maternal diabetes on the growth of the whole rat fetus and its liver and skin were studied over the last 4 days of gestation. 2. Smaller fetuses, with growth-retarded livers and skins, were consistently found between 18 and 21 days in the diabetic pregnancies. 3. The smaller diabetic livers and skins (i.e. combined epidermis and dermis) possessed lower protein, RNA and DNA contents, compared with the same fetal tissues from normal pregnancies. 4. The growth retardation of the livers in diabetic fetuses was attributed to fewer normally sized hepatic cells. 5. Whilst hepatic rates of protein synthesis (measured in vivo) remained largely unchanged, these were actually increased in the skin, compared with normal control tissues. 6. These findings point to an elevated rate of protein degradation in both diabetic tissues as the most likely cause of their retarded growth.

Growth of the rat foetal liver in gestational diabetes.

1. Through a combination of streptozotocin and insulin injections an animal model of gestational diabetes has been established, whereby blood glucose concentrations are elevated over the second-half of pregnancy. 2. Between 18 and 21 days of gestation the diabetic mothers carried smaller foetuses, which in turn possessed growth retarded livers. 3. This suppression of hepatic growth in diabetic foetuses was evident in terms of consistently decreased (7-27%) liver weights and protein and nucleic acid contents. 4. No differences were found between the rates of hepatic protein synthesis (measured in vivo) in control and diabetic foetuses. 5. Hence, the growth retardation of the foetal liver, arising from maternal hyperglycaemia, must necessarily involve an increase in protein degradation.

Beta-adrenergic stimulation of cyclic AMP is defective in cultured dermal fibroblasts of psoriatic subjects.

Epidermal cells from psoriatic lesions demonstrate a very low cAMP response to beta-adrenergic stimuli. We have shown that a similar abnormality occurs in dermal fibroblasts from affected areas of skin. The cells, after 5-12 passages in tissue culture, had a much reduced response to 10(-8) M and 10(-6) M isoproterenol when compared with fibroblasts from control subjects. The abnormality was not abolished by the addition of the phosphodiesterase inhibitor, 3-isobutyl-I-methylxanthine. Other putative agonists tested were vasoactive intestinal peptide and peptide histidine methionine. Neither of these had an effect on dermal fibroblasts from either normal controls or from lesions of psoriasis.

Maternal diabetes in rats. I. Effects on placental growth and protein turnover.

The developmental growth of the rat placenta was investigated between days 14 and 21 of gestation in normal control, gestational-diabetic, established-diabetic, and insulin-maintained-diabetic mothers. While established-diabetic mothers were hyperglycemic for 2 wk before and throughout the pregnancy, gestational-diabetic mothers were only hyperglycemic for the second half of pregnancy. Daily insulin replacements successfully restored normoglycemia. The wet weight and protein content of control placentas increased linearly between days 14 and 21. Although placentas from diabetic animals were initially smaller, placentomegaly was found at full term. Placental glycogen concentrations were also markedly increased in all diabetic animals. These changes were largely prevented by insulin replacement. The changes in placental size during normal development and in association with the diabetic state were explained by measuring placental rates of protein turnover (in vivo). In normal placentas, protein synthetic and degradative rates progressively declined over the last week of gestation. Because synthesis rates were unchanged in placentas of diabetic mothers, it appears that the differences in placental size primarily arise from alterations in protein degradation.

Maternal diabetes in rats. II. Effects on fetal growth and protein turnover.

The developmental growth of the rat fetus was studied between days 14 and 21 of pregnancy in normal control, established-diabetic, gestational-diabetic, and insulin-maintained-diabetic mothers. Measurements of fetal body weights and protein mass revealed a suppression of growth in the diabetic pregnancies, probably arising from reduced hyperplasia. Growth of the liver and skin appeared to be suppressed in proportion to the whole fetus, whereas the lung, brain, and particularly the heart were relatively well protected from growth retardation. Fetal growth during development, and its retardation in association with the hyperglycemic state, was explained by measuring the rates of fetal protein turnover in vivo. Both the protein synthetic and degradative rates gradually declined during normal development. However, in the diabetic pregnancies, fetal protein synthesis was consistently lower than control rates, whereas protein degradation increased sharply toward the end of gestation. These changes in protein synthesis and breakdown probably combine to yield a smaller fetus in the absence of normoglycemia.