Neurosurgery restores late GH rise after glucose-induced suppression in cured acromegalics. (1/4435)

OBJECTIVE AND DESIGN: A decrease of GH levels below 2 microg/l after an oral glucose tolerance test (OGTT) is still currently accepted as the gold standard for assessing cure in surgically treated acromegaly. Whether glucose-induced suppression of GH is accompanied by a restoration of normal GH late rebound has not yet been evaluated in this disease. In order to assess the restoration of normal GH regulation after removal of a pituitary adenoma, we have evaluated GH changes after an OGTT in a series of selected acromegalic patients (transsphenoidal surgery and lack of pituitary failure). METHODS: Twenty-nine patients (13 male, 16 female, age range 27-70 years) entered the study. Their neuroradiological imaging before neurosurgery showed microadenoma in 7, intrasellar macroadenoma in 8 and macroadenoma with extrasellar extension in 14. Plasma GH levels were assayed up to 300 min after glucose administration (75 g p.o.) and IGF-I on basal samples. RESULTS: Basal GH levels were below 5 microg/l in 20 patients and below 2 microg/l in 5 of these. Normal age-adjusted IGF-I levels were observed in 12 patients. GH values were suppressed below 2 microg/l during an OGTT in 13 patients, and below 1 microg/l in 7 of these. In 9 patients out of these 13, a marked rise in GH levels occurred after nadir. Baseline and nadir GH values of these 9 patients were not different from the corresponding values of the other 4 patients without OGTT-induced late GH peaks. CONCLUSIONS: GH rebound after GH nadir occurs in acromegalic patients considered as cured on the basis of OGTT-induced GH suppression and/or IGF-I normalization. The restoration of this physiological response could be regarded as a marker of recovered/preserved integrity of the hypothalamic-pituitary axis. Even though the reason for this GH rebound has not yet been elucidated (GHRH discharge?/end of somatostatin inhibition?), the lack of late GH peak in the patients regarded as cured by the usual criteria could be due to injury to the pituitary stalk caused by the adenoma or by surgical manipulation.  (+info)

No association between the -308 polymorphism in the tumour necrosis factor alpha (TNFalpha) promoter region and polycystic ovaries. (2/4435)

The tumour necrosis factor (TNF)2 allele appears to be linked with increased insulin resistance and obesity, conditions often found in overweight patients with polycystic ovary syndrome (PCOS). The significance of TNFalpha polymorphism in relation to the clinical and biochemical parameters associated with PCOS was investigated in 122 well-characterized patients with polycystic ovaries (PCO). Of these, 84 had an abnormal menstrual cycle and were classified as having PCOS, while the remaining 38 had a normal menstrual cycle and were classified as having PCO. There were a further 28 individuals without PCO (non-PCO) and 108 individuals whose PCO status was undetermined (reference population). The promoter region of the TNFalpha gene was amplified by polymerase chain reaction (PCR), and the presence or absence of the polymorphism at -308 was determined by single-strand conformational polymorphism (SSCP) analysis. The less common TNF allele (TNF2) was found as TNF1/2 or TNF2/2 in 11/38 (29%) of PCO subjects, 25/84 (30%) of PCOS subjects, 7/28 (25%) of non-PCO subjects, and 45/108 (42%) of the reference population. There was no significant difference in the incidence of the TNF2 allele between the groups. The relationship of TNF genotype to clinical and biochemical parameters was examined. In both the PCO group and the PCOS group, the presence of the TNF2 allele was significantly associated with lower glucose values obtained from the glucose tolerance testing (P<0.05). The TNF genotype was not significantly associated with any clinical or biochemical parameter measured in the PCO, PCOS or non-PCOS groups. Thus, the TNFalpha -308 polymorphism does not appear to strongly influence genetic susceptibility to polycystic ovaries.  (+info)

Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs. (3/4435)

We are conducting a genome scan at an average resolution of 10 centimorgans (cM) for type 2 diabetes susceptibility genes in 716 affected sib pairs from 477 Finnish families. To date, our best evidence for linkage is on chromosome 20 with potentially separable peaks located on both the long and short arms. The unweighted multipoint maximum logarithm of odds score (MLS) was 3.08 on 20p (location, chi = 19.5 cM) under an additive model, whereas the weighted MLS was 2.06 on 20q (chi = 57 cM, recurrence risk,lambda(s) = 1. 25, P = 0.009). Weighted logarithm of odds scores of 2.00 (chi = 69.5 cM, P = 0.010) and 1.92 (chi = 18.5 cM, P = 0.013) were also observed. Ordered subset analyses based on sibships with extreme mean values of diabetes-related quantitative traits yielded sets of families who contributed disproportionately to the peaks. Two-hour glucose levels in offspring of diabetic individuals gave a MLS of 2. 12 (P = 0.0018) at 9.5 cM. Evidence from this and other studies suggests at least two diabetes-susceptibility genes on chromosome 20. We have also screened the gene for maturity-onset diabetes of the young 1, hepatic nuclear factor 4-a (HNF-4alpha) in 64 affected sibships with evidence for high chromosomal sharing at its location on chromosome 20q. We found no evidence that sequence changes in this gene accounted for the linkage results we observed.  (+info)

Training in swimming reduces blood pressure and increases muscle glucose transport activity as well as GLUT4 contents in stroke-prone spontaneously hypertensive rats. (4/4435)

Exercise improves muscle insulin sensitivity and GLUT4 contents. We investigated the beneficial effects of swimming training on insulin sensitivity and genetic hypertension using stroke-prone hypertensive rats (SHRSP). We studied the relationship between genetic hypertension and insulin resistance in SHRSP and Wistar Kyoto rats (WKY) as a control. The systolic blood pressure of SHRSP was significantly reduced by 4-week swimming training (208.4 +/- 6.8 mmHg vs. 187.2 +/- 4.1 mmHg, p < 0.05). The swimming training also resulted in an approximately 20% increase in the insulin-stimulated glucose transport activity (p < 0.05) of soleus muscle strips and an approximately 3-fold increase in the plasma membrane GLUT4 protein expression (p < 0.01) in SHRSP. However, basal and insulin-stimulated glucose transport activity and GLUT4 contents were not significantly different between WKY and SHRSP. There was no difference in insulin resistance in skeletal muscle of SHRSP as compared with WKY. Our results indicated swimming training exercise improved not only hypertension but also muscle insulin sensitivity and GLUT4 protein expression in SHRSP.  (+info)

Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. (5/4435)

Protein tyrosine phosphatase-1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B-/- mice was also evident in glucose and insulin tolerance tests. The PTP-1B-/- mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B-/- and PTP-1B+/- mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity.  (+info)

Resistance training affects GLUT-4 content in skeletal muscle of humans after 19 days of head-down bed rest. (6/4435)

This study assessed the effects of inactivity on GLUT-4 content of human skeletal muscle and evaluated resistance training as a countermeasure to inactivity-related changes in GLUT-4 content in skeletal muscle. Nine young men participated in the study. For 19 days, four control subjects remained in a -6 degrees head-down tilt at all times throughout bed rest, except for showering every other day. Five training group subjects also remained at bed rest, except during resistance training once in the morning. The resistance training consisted of 30 isometric maximal voluntary contractions for 3 s each; leg-press exercise was used to recruit the extensor muscles of the ankle, knee, and hip. Pauses (3 s) were allowed between bouts of maximal contraction. Muscle biopsy samples were obtained from the lateral aspect of vastus lateralis (VL) muscle before and after the bed rest. GLUT-4 content in VL muscle of the control group was significantly decreased after bed rest (473 +/- 48 vs. 398 +/- 66 counts. min-1. microgram membrane protein-1, before and after bed rest, respectively), whereas GLUT-4 significantly increased in the training group with bed rest (510 +/- 158 vs. 663 +/- 189 counts. min-1. microgram membrane protein-1, before and after bed rest, respectively). The present study demonstrated that GLUT-4 in VL muscle decreased by approximately 16% after 19 days of bed rest, and isometric resistance training during bed rest induced a 30% increase above the value of GLUT-4 before bed rest.  (+info)

Analysis of the relationship between fasting serum leptin levels and estimates of beta-cell function and insulin sensitivity in a population sample of 380 healthy young Caucasians. (7/4435)

OBJECTIVE: Circulating leptin levels correlate positively with the degree of obesity and prolonged hyperinsulinaemia increases serum leptin levels. Moreover, insulin secreting beta-cells express functional leptin receptors indicating a functional relationship between leptin and insulin. The aim of this study was to examine the relationship between fasting serum leptin levels and measures of insulin sensitivity and beta-cell function in a population-based sample of 380 young healthy Caucasians. DESIGN AND METHODS: Multiple regression analysis was employed to analyse the relationship between fasting serum leptin levels and levels of fasting serum insulin, insulin sensitivity index and acute insulin response (AIR) in a population-based study of 380 young healthy Caucasians who underwent a combined intravenous glucose and tolbutamide tolerance test. RESULTS AND CONCLUSION: Serum leptin levels were positively correlated to measures of adiposity and were 3.2 times higher in women than in men (P<0.00001). In multiple regression analyses adjusting for age, percentage body fat, waist circumference and maximal aerobic capacity, a significant positive correlation was observed between the fasting serum leptin concentrations and both fasting serum insulin levels (P<0.0001) and AIR (P = 0.014) for women. No significant interrelation of these variables was found in men. However, for both genders a significant negative correlation was observed between fasting serum leptin levels and measures of insulin sensitivity index (P = 0.007).  (+info)

Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerance. The Insulin Resistance Atherosclerosis Study (IRAS). (8/4435)

Hyperinsulinemia is associated with the development of coronary heart disease. However, the underlying mechanisms are still poorly understood. Hypercoagulability and impaired fibrinolysis are possible candidates linking hyperinsulinism with atherosclerotic disease, and it has been suggested that proinsulin rather than insulin is the crucial pathophysiological agent. The aim of this study was to investigate the relationship of insulin and its precursors to markers of coagulation and fibrinolysis in a large triethnic population. A strong and independent relationship between plasminogen activator inhibitor-1 (PAI-1) antigen and insulin and its precursors (proinsulin, 32-33 split proinsulin) was found consistently across varying states of glucose tolerance (PAI-1 versus fasting insulin [proinsulin], r=0.38 [r=0.34] in normal glucose tolerance; r=0.42 [r=0.43] in impaired glucose tolerance; and r=0.38 [r=0.26] in type 2 diabetes; all P<0.001). The relationship remained highly significant even after accounting for insulin sensitivity as measured by a frequently sampled intravenous glucose tolerance test. In a stepwise multiple regression model after adjusting for age, sex, ethnicity, and clinic, both insulin and its precursors were significantly associated with PAI-1 levels. The relationship between fibrinogen and insulin and its precursors was significant in the overall population (r=0.20 for insulin and proinsulin; each P<0.001) but showed a more inconsistent pattern in subgroup analysis and after adjustments for demographic and metabolic variables. Stepwise multiple regression analysis showed that proinsulin (split products) but not fasting insulin significantly contributed to fibrinogen levels after adjustment for age, sex, clinic, and ethnicity. Decreased insulin sensitivity was independently associated with higher PAI-1 and fibrinogen levels. In summary, we were able to demonstrate an independent relationship of 2 crucial factors of hemostasis, fibrinogen and PAI-1, to insulin and its precursors. These findings may have important clinical implications in the risk assessment and prevention of macrovascular disease, not only in patients with overt diabetes but also in nondiabetic subjects who are hyperinsulinemic.  (+info)