Thiazolidinediones are a new class of antidiabetic agent that improve insulin sensitivity and reduce plasma glucose and blood pressure in subjects with type 2 diabetes. Although these agents can bind and activate an orphan nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARgamma), there is no direct evidence to conclusively implicate this receptor in the regulation of mammalian glucose homeostasis. Here we report two different heterozygous mutations in the ligand-binding domain of PPARgamma in three subjects with severe insulin resistance. In the PPARgamma crystal structure, the mutations destabilize helix 12 which mediates transactivation. Consistent with this, both receptor mutants are markedly transcriptionally impaired and, moreover, are able to inhibit the action of coexpressed wild-type PPARgamma in a dominant negative manner. In addition to insulin resistance, all three subjects developed type 2 diabetes mellitus and hypertension at an unusually early age. Our findings represent the first germline loss-of-function mutations in PPARgamma and provide compelling genetic evidence that this receptor is important in the control of insulin sensitivity, glucose homeostasis and blood pressure in man.

The posterior pituitary response to immobilization was studied in male and female rats. Plasma levels of arginine vasopressin (AVP) and oxytocin (OT) were measured both in control rats and in rats immobilized in an acrylic restrainer for 1 min. In male rats immobilization did not result in any change in AVP (control: 1.3 +/- 0.2 pmol/liter, mean +/- SEM; immobilized: 2.3 +/- 0.6 pmol/liter), although there was a small but significant increase in OT (control; 4.1 +/- 0.5 pmol/liter; immobilized: 10.2 +/- 2.2 pmol/liter; P less than 0.005). In female rats a marked rise was observed in AVP (control: 1.4 +/- 0.3 pmol/liter; immobilized: 5.5 +/- 1.3 pmol/liter; P less than 0.005), and the rise in OT was considerably greater (P less than 0.01) than that found in males (control: 4.7 +/- 0.8 pmol/liter; immobilized: 26.0 +/- 5.6 pmol/liter; P less than 0.001). Further groups of male and female rats were gonadectomized 2 weeks before immobilization. Basal levels of AVP and OT were unchanged. Orchidectomized males had an increased OT response to immobilization compared with sham-operated males (P less than 0.05) whereas the AVP response was not significantly changed. Ovariectomy did not significantly affect either the AVP or OT responses. Although the neural pathways responsible for the neurohypophyseal response to immobilization are not known, this data demonstrate that the response is dependent on the sex of the rat.

After dehydration, oral rehydration causes a fall in plasma arginine vasopressin (AVP) that precedes changes in plasma osmolality. To investigate further the stimulus for this effect, its specificity, and association with thirst, six volunteers were deprived of water for 24 h and given a salt load on two separate occasions. On each study day they then drank rapidly 10 ml/kg of either tap water or hypertonic saline (360 mosmol/kg). There was a significant fall in plasma AVP from 2.0 +/- 0.3 to 1.2 +/- 0.4 pmol/l (P less than 0.05) 5 min after drinking water and from 1.8 +/- 0.3 to 0.9 +/- 0.2 pmol/l (P less than 0.05) after hypertonic saline. Plasma osmolality fell 30-60 min after water and was unchanged after saline. Plasma renin activity, oxytocin, and total protein all remained unchanged. All subjects reported diminished thirst after hypertonic saline. Gargling with water reduced thirst but did not affect plasma AVP. There appears to be a drinking-mediated neuroendocrine reflex that decreases plasma AVP irrespective of the osmolality of the liquid consumed. The sensation of thirst did not correlate with plasma osmolality and was not always related to plasma AVP concentration.

Heart-lung transplantation results in afferent and efferent denervation of the transplanted organs including interruption of the central connections from the low-pressure receptors in the atria and pulmonary veins. We investigated whether the cardiovascular and neurohumoral responses to the postural stimulus of head-up tilt were affected after transplantation. Responses in eight heart-lung transplant recipients were studied and compared with those in eight normal subjects matched for age and sex during passive head-up tilt at 450 for 1 hour. The transplant group had a higher initial heart rate (99±2 versus 68+2 beats/min, p<0.001) and diastolic blood pressure (88± 5 versus 76±2 mm Hg, p<0.05) than did the control group. The increases in heart rate and diastolic blood pressure during head-up tilt were similar in the two groups. Systolic blood pressure remained unchanged. The decrease in cardiac output (30% versus 18%,p <0.05) and the increase in systemic vascular resistance (52% versus 28%,p<0.05) were greater in the transplant group. Baseline levels of norepinephrine, epinephrine, vasopressin, and plasma renin activity were similar in the two groups. Atrial natriuretic peptide concentrations were higher in the transplant group (26+3.8 versus 9.7±1.6 pmol/l, p <0.001). During head-up tilt, plasma norepinephrine levels increased to a greater extent in the transplant group than in the control group (83% versus 53%, p<0.01), indicating an increased sympathetic response. In contrast, plasma renin activity increased significantly in the control group but not in the transplant group. Plasma vasopressin concentrations remained unchanged, whereas atrial natriuretic peptide concentrations decreased significantly in both groups. The pattern of cardiovascular and neuroendocrine responses to head-up tilt was altered in heart-lung transplant recipients, who had a greater dependence on sympathetic-mediated vasoconstriction, although their ability to maintain systemic blood pressure during this postural stress was unaffected. (Circulation 1990;82:863-871) T he nervous system plays a central role in the regulation of the cardiovascular system.' Lung and heart transplantations are now established forms of therapy for a variety of endstage pulmonary and cardiac diseases. These procedures result in surgical denervation of the transplanted organs. Heart transplantation produces efferent denervation of the heart2 and ventricular deafferentation,3 and it results in altered cardiovascular control and performance.24 The most extensive denervation occurs in combined heart-lung transFrom the Cardiothoracic Unit (N.R

The regulation of both arginine vasopressin (AVP) and oxytocin secretion was studied during rapid and prolonged osmotic stimuli in normal adult volunteers. In five subjects given an intravenous infusion of 0.85 mol NaCl at 0.05 ml/kg per min over 2 h there was a significant (P less than 0.05) rise only in plasma AVP, with no significant change in plasma levels of oxytocin. In six further subjects 5 days of restriction to 500 ml fluid daily resulted in significant increases of both plasma and 24-h urinary AVP, whereas there was no change in corresponding oxytocin levels. During another 5-day period in which the same subjects were given an additional 200 mmol sodium as well as having their fluid intake restricted to 1000 ml daily, there were again significant rises in plasma and 24 h urinary AVP with no change in corresponding oxytocin levels. We conclude that, in man, AVP is selectively secreted in response to both dehydration and high sodium intake, whilst even after the stimulus of rapidly increasing plasma osmolality during intravenous infusion of hypertonic saline the rise in oxytocin is not statistically significant. It therefore appears unlikely that oxytocin has a significant role in the physiological control of fluid balance in man.