The normal portal-peripheral insulin gradient is absent in patients with insulin-dependent diabetes mellitus (IDDM) managed on conventional insulin therapy. The effect of this on intermediary metabolism has been studied widely in man and animals. However, results have been conflicting and considerable uncertainty still exists regarding the importance of the gradient for the maintenance of overall metabolic homeostasis.In animal models the metabolic importance of the portal-systemic gradient has been examined using a variety of techniques including direct cannulation combined with exogenous insulin infusion, islet and pancreatic transplantation, and diversion of pancreatic venous drainage . In some studies control of hepatic glucose output or blood glucose concentrations was superior with the portal route of insulin delivery, [3,8,15,16,18,20] while in others no Diabetologia (1997Diabetologia ( ) 40: 1125Diabetologia ( -1134 The effect of portal and peripheral insulin delivery on carbohydrate and lipid metabolism in a miniature pig model of human IDDM Summary 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 ⋅ 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 ⋅ l − 1 ) were significantly higher (p < 0.05) than in portally infused (73.8 ± 5.4 pmol ⋅ l − 1 ) or pre-diabetic control animals (68.4 ± 3.6 pmol ⋅ l − 1 ). Basal hepatic glucose output was also higher (p < 0.05) in peripherally (4.2 ± 0.4 mg ⋅ kg − 1 ⋅ min − 1 ) than in portally infused animals (2.9 ± 0.4 mg ⋅ kg). 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 ⋅ kg), although both were significantly lower (p < 0.05) than that measured in prediabetic control animals (11.7 ± 1.0 ml ⋅ kg. 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. [Diabetologia (1997[Diabetologia ( ) 40: 1125[Diabetologia ( -1134

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.

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.

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.

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