[A case of hyperthyroidism due to functioning metastasis of differentiated thyroid carcinoma. Discussion and literature review]. / Un cas d'hyperthyroïdie par métastases sécrétantes de cancer thyroïdien différencié. Revue de la littérature.

We report on a very rare case of hyperthyroidism due to multiple autonomously functioning bone metastasis of papillary thyroid cancer in a 79-year-old woman. This situation remains extremely uncommon, as shown by our review of the literature; only 47 similar cases have been published from 1946 to 2005. The pathogenic mechanism remains largely unknown in spite of several hypotheses (conjunction in volume and differentiation, auto-antibodies). Hyperthyroidism can be severe, and often T3 levels are markedly more elevated than T4 levels. Apart from hyperthyroidism caused by the hormone-production, clinical features are similar to that of usual metastatic thyroid cancer, occurring in elderly women in most cases, and of follicular type on pathology. Metastases mostly occur in bones and lungs. Treatment relies mainly on radio-iodine ((131)I), which is efficient on hormonal disorders, and prognosis appears to be correlated with the ability of the metastatic sites to concentrate radio-iodine.

Metabolic studies in lipoatrophic diabetes: mechanism of hyperglycemia and evidence of resistance to insulin of lipid metabolism.

We determined in 5 control subjects and in one patient with total congenital lipoatrophy (LA) the effect of insulin infusion on glucose flux and some aspects of lipid metabolism. In the post-absorptive state LA had moderate hyperglycemia (9.2 versus 3.80 +/- 0.07 mmol.l-1) and hyperinsulinemia (19 vs 12 +/- 3 mU.l-1) and a massive increase in glucose production (7.51 mg.kg.-1.min-1) and disappearance (7.40 mg.kg-1.min-1) rates (control subjects: 2.29 +/- 0.14 mg.kg-1 min-1). Raising peripheral insulin levels to 28 +/- 3 mU.l-1 suppressed endogenous glucose production in the control subjects whereas in LA significant (2.01 mg.kg-1.min-1) production persisted even when peripheral insulinemia was raised to 58 mU.l-1. Insulin infusion in control subjects increased progressively glucose utilization to a final value of 15.7 +/- 0.7 mg.kg-1.min-1 (corresponding plasma insulin: 482 +/- 44 mU.l-1). Insulin infusion in LA initially lowered glucose level near to normal values and exogenous glucose was infused for an insulin infusion rate of 10 mU.kg-1.min-1; at this insulin infusion rate glucose utilization rate (6.52 mg.kg-1.min-1) was decreased relative to control subjects in spite of higher insulin levels (750 mU.l-1). NEFA, glycerol and ketone bodies (KB) levels were decreased to undetectable levels by insulin infusion in the normal subjects whereas NEFA and glycerol were decreased only in part and KB were not modified in LA. In addition glycerol and KB appearance rates determined in LA were not suppressed by insulin infusion as expected.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-mediated glucose disposal in type 1 (insulin-dependent) diabetic subjects treated by continuous subcutaneous or intraperitoneal insulin fusion.

In order to determine if intraperitoneal insulin infusion could improve the insulin resistance of type 1 diabetic patients we have used the englycaemic insulin clamp technique in order to study the effects of insulin on glucose disposal in four C peptide negative type 1 diabetic patients treated by continuous subcutaneous or intraperitoneal insulin infusion and in five control subjects. Compared to control subjects, the diabetic patients treated by subcutaneous insulin infusion had a decreased maximal capacity of glucose utilization (diabetics: 12.6 +/- 0.3 mg.kg-1.min-1; controls: 15.7 +/- 0.7 mg/kg-1.min-1, p less than 0.01) and a trend towards higher half-maximally effective insulin concentrations (diabetics: 70 +/- 11 mU/l-1, controls: 48 +/- 4 mU/l-1). Treatment of the diabetic patients by intraperitoneal insulin infusion for 2 months decreased their mean peripheral free insulin levels (during subcutaneous infusion: 23.5 +/- 2.2 mU/l-1; during intraperitoneal infusion: 18.4 +/- 1.4 mU/l-1, p less than 0.05). However, mean daily insulin requirements were not decreased (during subcutaneous infusion: 0.59 +/- 0.05 U/kg-1.day-1; during intraperitoneal infusion: 0.57 +/- 0.03 U/kg-1.min-1). Moreover, the diabetic patients had a consistently lower maximal capacity of glucose utilization (12.6 +/- 0.7 mg kg-1.min-1) than control subjects (p less than 0.01) without modification of the half-maximally effective insulin concentration (62 +/- 10 mU.l-1). In conclusion, the only benefit of intraperitoneal insulin infusion was a reduction of peripheral free insulin levels; this decrease of peripheral insulinaemia was not associated with an improvement in the insulin resistance of diabetic patients.

Antiketogenic effect of glucose per se in vivo in man and in vitro in isolated rat liver cells.

The in vivo effect of glucose per se on blood ketone bodies, glycerol, and nonesterified fatty acids (NEFA) has been investigated in five normal (60 hours fasted) men receiving a somatostatin (SRIF) infusion (500 micrograms/h-1). When glycemia was raised over 10 mmol/L for 180 minutes by exogenous IV glucose infusion, neither insulin nor C peptide increase. NEFA and glycerol returned to fasting value in 40 minutes and remained stable. Ketone bodies decreased continuously and were significantly below the fasting values at the end of the study (1.3 +/- 0.3 mmol/L v 2.2 +/- 0.4 mmol/L, P less than 0.05). In order to ascertain whether glucose has been acting only on lipolysis or also on the liver ketogenic capacity, its effect was studied in vitro on isolated liver cells from 24-hour starved rats incubated with various amounts of palmitate. Glucose (30 mmol/L) did not affect the maximal ketogenic capacity (80 mumol/g (w/w)/h) measured with 1.6 mmol/L palmitate but increased the apparent palmitate K 0.5 for ketogenesis from 0.16 to 0.3 mmol/L. At physiologic free fatty acids concentration (0.22 mmol/L), glucose decreased ketogenesis by 90%. The effect was time-dependent, maximum after 30 minutes of incubation. Half-maximum inhibition by glucose was obtained at 6 mmol/L, a concentration at which lactate production was unaffected. These results suggest that glucose per se inhibits ketogenesis in vivo by acting probably both on lipolysis and on liver ketogenic capacity.

Regulation of peripheral plasma somatostatin like immunoreactivity in type I diabetes: role of the degree of metabolic control.

We have determined peripheral venous somatostatin like immunoreactivity (SLI) levels in 11 normal subjects (blood glucose--BG--: 4.4 +/- 0.1 mM; ketone bodies--KB--: 90 +/- 12 microM; plasma free fatty acids--FFA --: 340 +/- 42 microM), 4 Biostator controlled insulin dependent diabetics (BG: 5.4 +/- 0.2 mM; FFA: 418 +/- 38 microM; KB: 226 +/- 41 microM) and 7 poorly controlled ketotic diabetics (BG: 10.8 +/- 1.3 mM; FFA: 915 +/- 19 microM; KB: 2490 +/- 576 microM). SLI was determined again after 48 to 96 hours of intravenous insulin infusion for the 7 ketotic diabetics and after transient interruption of insulin infusion for the Biostator controlled diabetics. Relative to normal subjects ketotic diabetics had elevated SLI levels (29.7 +/- 5.9 vs 13.5 +/- 1.8 ng/L, p less than 0.01) whereas biostator-controlled patient had near to normal values (20.4 +/- 6.4 ng/L, p greater than 0.30). Transient arrest of insulin infusion in the Biostator controlled diabetics resulted only in a mild metabolic deterioration (BG: 12.8 +/- 2.1 mM; FFA: 640 +/- 146 microM; KB: 950 +/- 163 microM) without a significant rise of SLI. Intravenous insulin infusion in the initially ketotic patients decreased BG and KB in each subject (p less than 0.01) but decreased FFA (1097 +/- 170 to 453 +/- 74 microM, p less than 0.05) and SLI (34.0 +/- 12.0 to 9.8 +/- 2.4 ng/L, p less than 0.05) only in 4 patients whereas both FFA (737 +/- 107 to 725 +/- 25 microM) and SLI (27.6 +/- 4.7 to 20.3 +/- 4.7 ng/L) levels remained stable in the other 3. These results suggest that SLI levels in type I diabetics are dependent the degree of metabolic control and could be related to the variations of FFA concentrations.

Lack of beta-adrenergic role for catecholamines in the development of hyperglycemia and ketonaemia following acute insulin withdrawal in type I diabetic patients.

In order to evaluate the role of beta-receptor mediated effects of catecholamines in the metabolic deterioration following insulin withdrawal in insulin-dependent diabetic patients we have measured in 5 patients metabolic substrate and hormone concentrations during a 6 hours arrest of insulin infusion, without or with a simultaneous infusion of propranolol. During insulin deprivation plasma epinephrine and norepinephrine increased slightly (from 107 +/- 10 ng/L to 173 +/- 6 ng/L and from 307 +/- 37 ng/L to 518 +/- 77/ng/L respectively (p less than 0.05), cortisol decreased physiologically, but growth hormone and glucagon were not significantly modified. Free insulin decreased progressively from 12.2 +/- 2.5 mU/L to 5.4 +/- 1.1 mU/L (p less than 0.01). Blood glucose and ketone bodies rose sharply before any significant change in catecholamine levels. Plasma free fatty acids and blood glycerol increased progressively and their rise appeared somewhat temporally related to the variations of catecholamine levels. The addition of propranolol to insulin deprivation did not modify the changes in hormone concentrations in spite of a slightly greater rise of epinephrine (from 78 +/- 4 ng/L to 179 +/- 7 ng/L, p less than 0.05) and norepinephrine (from 395 +/- 80 ng/L to 679 +/- 153 ng/L, p less than 0.05). The rises of glucose and ketone bodies were unaffected whereas the increases of free fatty acids and glycerol were slightly blunted. In conclusion, we have no evidence for a beta-adrenergic mediated role for catecholamines in the development of hyperglycaemia and ketonaemia in non-stressed insulin deprived diabetic patients, and only small evidence for a permissive effect on lipolysis.

Reduction of increased levels of blood glycerol and ketone bodies by propranolol in human hyperthyroidism: role of the fall of the triiodothyronine level.

Hyperthyroid patients in the postabsorptive state have elevated levels of blood glycerol and ketone bodies (KB): this is believed to be due to increased lipolysis and ketogenesis. These increased glycerol and KB levels return toward normal after oral propranolol administration. In order to investigate the mechanism of action of propranolol in hyperthyroid patients, we compared the effects of the oral administration of propranolol with those of timolol, propylthiouracil (PTU), and a placebo. The placebo had no effect. The free thyroxine index, immunoreactive insulin level and glucagon level were not modified by propranolol, timolol, or PTU. Propranolol decreased the pulse rate (P less than 0.01) and the levels of serum triiodothyronine (T3; P less than 0.05), blood glycerol (P less than 0.01), and KB (P less than 0.01). Like propranolol, timolol decreased the pulse rate (P less than 0.01) but had no effect on the T3, glycerol, or KB levels. Propylthiouracil did not modify the pulse rate, but like propranolol, it decreased the T3 (P less than 0.05), glycerol (P less than 0.01) and KB (P less than 0.01) levels. These results suggest that the metabolic actions of propranolol are not caused by its hemodynamic effects nor its beta-blocking properties but are mediated by the decrease of the T3 level.

Regulation of somatostatin secretion in man: study of the role of free fatty acids and ketone bodies.

We have investigated in normal subjects the possible role of plasma free fatty acids (FFA) and blood ketone bodies (KB) in the regulation of human somatostatin secretion. Heparin injected during the intravenous infusion of a fat emulsion raised FFA levels acutely from 0.4 +/- 0.1 to near 3 mmol/L. Plasma somatostatin-like immunoreactivity (SLI) rose from a mean (+/- SEM) basal value of 9.2 +/- 1.0 ng Eq S14/L to 20.0 +/- 6.0 ng Eq S14/L (P less than 0.05). Plasma immunoreactive insulin (IRI) level was unchanged and glucagon (IRG) concentration decreased from 156 +/- 20 to 107 +/- 2 ng/L (P less than 0.05). During this test, there was a rise not only in FFA but also in plasma triglycerides (TG) and in blood glycerol and KB levels. The infusion of a fat emulsion alone increased triglyceride and glycerol levels to a similar extent but induced also a mild rise of FFA (0.37 +/- 0.05 to 1.13 +/- 0.5 mmol/L, P less than 0.01), KB (78 +/- 12 to 360 +/- 45 mumol/L, P less than 0.01), and SLI (14.8 +/- 4.6 to 23.8 +/- 7.1 ng Eq S14/L, P less than 0.05). The induction by DL-Na-3-hydroxybutyrate infusion of a rise of KB was associated with a decrease of FFA (P less than 0.05) and SLI (P less than 0.05) without modification of IRI or IRG levels. Phentolamine infusion did not modify the SLI or glucagon response to acute elevations of FFA, whereas propranolol suppressed the increase of SLI without preventing the concomitant decrease of IRG.(ABSTRACT TRUNCATED AT 250 WORDS)

[Absence of effect of propranolol on urinary excretion of 3-methylhistidine in hyperthyroidism]. / Absence d'effet du propranolol sur l'élimination urinaire de la 3-méthylhistidine dans l'hyperthyroïdie.

Lean body mass and muscle protein breakdown were evaluated in euthyroid and hyperthyroid subjects by measuring the urinary excretion of creatinine and 3-methylhistidine. Since catecholamines probably have an inhibitory effect on muscle protein catabolism through a beta-receptor mechanism, the effects of propranolol on 3-methylhistidine excretion were also evaluated in hyperthyroid subjects. Hyperthyroid subjects had a lower lean body mass (34.9 +/- 6.3 kg versus 47.7 +/- 8.9 kg, p less than 0.001) and a greater 3-methylhistidine excretion (25.1 +/- 7.4 versus 19.0 +/- 4.8 mumol/mmol creatinine, p less than 0.05) than euthyroid subjects. Propranolol administered orally to hyperthyroid subjects decreased pulse rate (p less than 0.01) and plasma triiodothyronine concentrations (from 5.40 +/- 2.28 to 3.61 +/- 1.61 nmol/l, p less than 0.01), but did not modify urinary 3-methylhistidine excretion (24.8 +/- 8.7 versus 25.1 +/- 7.4 mumol/mmol creatinine). These results suggest that muscle wasting in hyperthyroidism is related to increased protein catabolism. This increased protein breakdown is not modified by short term administration of propranolol, a beta-blocking agent widely used in the management of hyperthyroidism.

Reduction by propranolol of urinary hydroxyproline excretion in human hyperthyroidism: a beta-receptor blockade effect or a membrane stabilizing mechanism?

In order to investigate the mechanism whereby oral propranolol administration reduces the increased rate of urinary hydroxyproline excretion (UHxE) of patients with hyperthyroidism, a comparison was made of the effects of the oral administration of propranolol-timolol, propylthiouracil (PTU), and a placebo to patients with hyperthyroidism and to normal controls. Propranolol decreased the pulse rate (P less than 0.01), serum triiodothyronine (T3) level (P less than 0.05), and UHxE (P less than 0.01) without modifying the serum free thyroxine index (FT4I) or parathormone (PTH) level. Timolol decreased the pulse rate (P less than 0.01) to the same extent as propranolol, had no effect on T3, FT4I, or PTH, and failed to decrease UHxE. Administration of PTU decreased the T3 level (P less than 0.05) to a similar extent as propranolol without modifying the FT4I or PTH level and had no effect on UHxE. Placebo administration had no effect. These results suggest that the reduction of UHxE by propranolol is not due to the beta-receptor-blocking properties of propranolol nor mediated by the propranolol-induced decrease in the level of T3 but is probably due to the membrane-stabilizing properties of propranolol.

[Measurement of insulin sensitivity using the somatostatin-insulin-glucose test. Importance of the determination of plasma free fatty acids and insulin clearance]. / Measure de la sensibilité à l'insuline par le test somatostatine-insuline-glucose. Intérêt de la mesure des acides gras libres plasmatiques et de la clairance de l'insuline.

Insulin sensitivity was determined in normal subjects and in subjects with possible insulin-resistance by simultaneous infusion of somatostatin, insulin and glucose. C peptide, growth hormone and glucagon were decreased by somatostatin in all subjects. Steady-state blood glucose was 2.84 mM (mean) in normal subjects and between 11 and 15 mM in the other subjects (p less than 0.01), indicating severe insulin resistance. Steady state plasma insulin was 50 mU/l (mean) in control subjects, but was markedly lower in one of the subjects with insulin-resistance and higher in the other two subjects, suggesting abnormalities in insulin clearance in these subjects. An index of insulin sensitivity taking into account these variable insulin levels was decreased in the insulin-resistant subjects (21 to 61, vs 117 to 251; p less than 0.01). Insulin-resistant subjects had increased basal levels of plasma free fatty acids (p less than 0.01) which failed to decrease during the test as in control subjects, suggesting abnormal metabolic regulation. In contrast, blood ketone bodies were normal in the basal state and decreased similarly in all subjects during the test, suggesting that hepatic ketogenesis does not resist to insulin.

Regulation of ketonaemia in hyperthyroidism: study of the role of free fatty acids.

We have indirectly assessed the role of free fatty acids (FFA) and of hepatic ketogenesis in the regulation of ketone body levels in euthyroid and hyperthyroid subjects. All studies were performed under controlled dietary conditions (35 and 45 kcal/kg body weight/day respectively for euthyroid and hyperthyroid subjects). In the post-absorptive state hyperthyroid patients had normal, glucagon levels and, in spite of increased insulinemia (p less than 0.02), elevated concentrations of blood glucose (p less than 0.01), glycerol (p less than 0.001) and ketone bodies (p less than 0.05). In the face of this hyperketonaemia, there was no significant increase of plasma FFA, suggesting possible increased hepatic conversion of FFA to ketone bodies. However, when FFA were acutely raised to high levels, the induced rise of ketone bodies was similar in hyperthyroid and euthyroid subjects. Oral propranolol administration to hyperthyroid patients in the post-absorptive state decreased the concentrations of glycerol (p less than 0.05) and ketone bodies (p less than 0.05) without altering insulin concentrations. Ketone bodies fell without any significant decrease of FFA suggesting a possible direct effect of propranolol administration on hepatic ketogenesis. However, the ketone body response to raised FFA levels was unaffected by propranolol. We have evidence in hyperthyroid patients of increased lipolysis and ketogenesis in spite of increased daily caloric intake. These results suggest that these metabolic abnormalities are not merely due to relative starvation. We have tentative evidence for modification of the intra-hepatic conversion of FFA to ketone bodies in the post-absorptive state but no supporting evidence when FFA levels were experimentally raised.

Effects of somatostatin on intestinal calcium absorption in man with primary hyperparathyroidism.

Eight patients suffering from primary hyperparathyroidism were studied in basal conditions, i.e. during a saline infusion and under somatostatin administration (a 250 micrograms bolus injection followed by continuous infusion of 500 micrograms per hour over 240 min). The calcium metabolism was estimated from (i) concentrations of plasma calcium, phosphorus, 25-hydroxyvitamin D (25-OH-D), iPTH and (ii) intestinal calcium absorption determined by a double radiotracer technique using oral 47Ca and IV 45Ca. The results show that somatostatin produced no significant change in calcium, phosphorus, 25-OH-D or iPTH levels. On the contrary, the fractional absorption of calcium (FA Ca), expressed as a percentage of the total oral dose and measured at 30 minute intervals over 240 min, was significantly depressed with somatostatin during the first 2 hours. Beyond the second hour FA Ca remained slightly depressed with somatostatin, but was not significantly different from the basal conditions. From the present results, we conclude that somatostatin slows down calcium absorption, while the total amount of calcium absorbed at the completion of the absorption process is not significantly diminished. Furthermore, as 25-OH-D and iPTH remained unchanged, somatostatin seems to have no effect on the hormonal control of calcium absorption. Therefore, we suggest that somatostatin has only a mechanical effect on calcium absorption, slowing down the intestinal transit.