Regulation of skeletal muscle stem cell behavior by Pax3 and Pax7.

Pax genes have important roles in the regulation of stem cell behavior, leading to tissue differentiation. In the case of skeletal muscle, Pax3 and Pax7 perform this function both during development and on regeneration in the adult. The myogenic determination gene Myf5 is directly activated by Pax3, leading to the formation of skeletal muscle. Fgfr4 is also a direct Pax3 target and Sprouty1, which encodes an intracellular inhibitor of fibroblast growth factor (FGF) signaling, is under Pax3 control. Orchestration of FGF signaling, through Fgfr4/Sprouty1, modulates the entry of cells into the myogenic program, thus controling the balance between stem cell self-renewal and tissue differentiation. This and other aspects of Pax3/7 function in regulating the behavior of skeletal muscle stem cells are discussed.

Decreased hypoglycemic effect of insulin at night in insulin-dependent diabetes mellitus and healthy subjects.

Diurnal variations in insulin-induced hypoglycemia and in plasma counterregulatory hormone concentrations were explored in eight insulin-dependent diabetic and six healthy subjects during a 100-min iv insulin infusion performed at 0300 h and 1500 h. In healthy subjects, plasma glucose concentrations (mean +/- SD) fell by 35 +/- 2% during the daytime test and by 26.5 +/- 2% during the nocturnal test (P less than 0.01). Plasma cortisol, GH, and epinephrine concentrations increased more during the daytime than during the nocturnal test. In contrast, plasma glucagon concentrations rose more during the nocturnal tests. In insulin-dependent diabetes mellitus patients, insulin infusion had to be interrupted in three subjects because plasma glucose fell below 1.9 mmol/L 80 min after the beginning of the test. In the other five patients plasma glucose fell by 34 +/- 5% during the daytime test while no significant decrease in plasma glucose was observed in any of the eight patients during the nighttime test. Counterregulatory hormone concentrations were consistent with the results of plasma glucose, with no change during the nocturnal test and significant increases in cortisol, GH, and epinephrine during the daytime test. These results show that insulin sensitivity is decreased at night in comparison to midafternoon in healthy subjects and that in insulin-dependent diabetes mellitus patients this phenomenon is exaggerated, even in patients with defective counterregulation to hypoglycemia.

Effect of sustained hyperglycemia on GHRH induced GH secretion in man.

Effect of sustained and severe hyperglycemia (greater than 200 mg/dl) on GHRH induced GH secretion was studied in 9 healthy volunteers who received GHRH (1 microgram/kg/BW, iv) during either saline or dextrose infusions which were started 2 hours before testing. During the latter, plasma glucose concentration plateaued at 303 mg/dl +/- 82 (mean +/- SD, range 200-450 mg/dl). Hyperglycemia resulted in a 57% decrease of peak plasma GH concentration: 9.3 +/- 4 vs 21.8 +/- 12 ng/ml (P less than 0.05). Two subjects had no change in GHRH induced plasma GH rise during hyperglycemia. No correlation was found between plasma glucose or insulin concentrations and percentage change in GHRH induced GH secretion. These data suggest that: 1) inhibition by hyperglycemia of GHRH induced GH secretion in non-diabetic subjects is neigter complete nor constant; 2) plasma glucose levels cannot predict the magnitude of the inhibition.

[Restoration of insulin sensitivity after correction of hypokalemia due to chronic tubulopathy in a diabetic patient]. / Normalisation de la sensibilité a l'insuline après correction d'une hypokaliémie par tubulópathie chronique chez une patiente diabétique.

In a type II diabetic patient presenting with chronic hypokaliemia secondary to a selective renal tubulopathy, insulin sensitivity was explored three times during a euglycemic hyperinsulinemic clamp procedure at two rates of insulin infusion: 1 and 10 mU/kg/min: once before treatment of hypokaliemia and once after successful correction of hypokaliemia with indomethacine or spironolactone. During insulin infusion, a 20% dextrose solution was infused by a Biostator in order to maintain the patient's glycemia at 90 mg/dl. Amounts of glucose infused during the last 20 min of each 2 hour insulin infusion were (at 1 and 10 m/kg/min respectively): before treatment (K+ = 2.7 mmol/l): 2.4 and 8.4 mg/kg/min; after spironolactone (K+ = 3.9 mmol/l): 3.3 and 15.4 mg/kg/min; after indomethacine (K+ = 3.7 mmol/l): 5 and 19 mg/kg/min after stopping drugs (K+ = 2.9 mmol/l): 2.5 and 5.3 mg/kg/min. These data suggest that potassium metabolism plays a critical role in the mechanisms of insulin sensitivity.

Acute effect of glyburide on insulin sensitivity in type I diabetic patients.

Possible extrapancreatic effects of glyburide on insulin action were studied in six patients with insulin-dependent diabetes mellitus. Each patient was studied on two separate occasions with continuous iv infusions of either glyburide (0.3 mg/h after a 1-mg iv bolus dose) or NaCl. During the studies blood glucose concentrations were controlled by a glucose-controlled infusion system (Biostator). The study included the 12-h period after the evening meal, followed by a 4-h period during which euglycemic hyperinsulinemic clamp studies were performed at two rates of insulin infusion: 1 and 10 mU/kg.min. During the glyburide infusion, the Biostator-determined insulin delivery rate was similar to that during the NaCl infusion for the first 6 h after the meal, but it decreased by 32% between the 6th and 12th hours after the meal. During the hyperinsulinemic clamp studies, glucose was delivered at a significantly higher rate when glyburide was infused; this was true for both rates of insulin infusion [5.6 +/- 1.9 (+/- SD) vs. 3.6 +/- 1.4 mg/kg.min and 12.1 +/- 2.4 vs. 9.1 +/- 2.1 mg/kg.min; P less than 0.05, glyburide vs. NaCl, respectively]. Plasma C-peptide was undetectable in all patients during both studies. These results indicate that 1) glyburide has an acute effect on insulin action in insulin-dependent diabetic patients; and 2) this effect occurs at physiological as well as pharmacological insulin concentrations.

The 24-h cortisol secretory pattern in Cushing's syndrome.

The 24-h plasma cortisol profile was obtained at 20-min intervals in 18 patients with Cushing's syndrome (10 with Cushing's disease, 5 with adrenal adenoma, 2 with ectopic ACTH secretion and 1 of questionable aetiology). The mean cortisol level was maximum in the case of ectopic ACTH secretion. The coefficient of variation of cortisol levels was subnormal in all except 2 subjects. Periodogram calculations, providing a best-fit curve (B F C) for each profile, showed that the existence of a significant baseline variation is a frequent feature. In certain cases, it is compatible with the persistence of a true circadian rhythm (2 patients with Cushing's disease; 1 patient with adrenal adenoma). The alteration of plasma cortisol pulsatility is much more pronounced in patients with adrenal adenoma than in patients with Cushing's disease. This is consistent with the hypothesis of a predominantly tonic secretion blunting the episodic hormone release. In 9 patients with Cushing's disease, the plasma cortisol pattern was suggestive of a combination of episodic cortisol release under CRF control and of continuous cortisol secretion due to constant stimulation from an autonomous ACTH source. Two cases were possibly of hypothalamic origin, as suggested by the presence of enhanced cortisol pulsatility and of a normal circadian amplitude. The analysis of the 24-h profile of plasma cortisol in Cushing's syndrome contributes to our understanding of the physiopathological mechanisms underlying this disorder and may help the diagnosis of its aetiology.

24 hour melatonin secretory pattern in Cushing's syndrome.

The concentrations of plasma melatonin and cortisol were determined every 20 min during a 24 h period in 6 women aged 24 to 45 years with Cushing's syndrome of differing aetiologies (4 adrenal adenomas, 2 adrenal hyperplasia). Melatonin was assayed after chloroform extraction according to the method of Rollag and Niswender (1976). Abnormal melatonin secretory patterns were found in all the patients; 24 h melatonin concentration means varied from 130 to 413 pg/ml and were not significantly higher than the 24 h mean in 4 controls (215 +/- 126 pg/ml). All six subjects however showed a significant increase of melatonin during the day period (302 +/- 109 as compared with controls 129 +/- 65 mg/ml, mean +/- SD; P less than 0.005). No relationship could be found between abnormal melatonin levels and the sexual status of the patients (4 with amenorrhoea, 2 normally menstruating women). An alteration of melatonin secretory pattern is present in Cushing's syndrome, whatever the aetiology. It is suggested that hypercortisolism, by itself, may modify the pattern of melatonin secretion.

Twenty-four hour melatonin secretory pattern in men with idiopathic hemochromatosis.

In idiopathic hemochromatosis, iron deposits in endocrine tissue can be associated with hormonal disorders including hypogonadism. We have studied the functional status of the pineal gland in this disease in relation to gonadotrophin levels and cortisol rhythm. Plasma melatonin, luteinizing hormone (LH) and cortisol concentrations were measured by radioimmunoassay every 20 min over a 24 hr period in nine men with idiopathic hemochromatosis aged 36 to 66 years. In six patients a circadian melatonin rhythm was present. The 24 hr means were in the normal range in three patients, and varied below the control values in two patients and above the control values in one patient. These variations seemed unrelated to gonadotrophin status. In the three other patients no plasma melatonin rhythm was observed; two patients with gonadotrophin insufficiency had low melatonin levels, and one with normal gonadotrophin function had high melatonin concentrations. In all cases, the plasma cortisol rhythm was normal. We concluded that the circadian melatonin rhythmicity can be disturbed in some cases of idiopathic hemochromatosis without relationship to the cortisol rhythm and associated endocrine disorders.