Osteocalcin increase after bariatric surgery predicts androgen recovery in hypogonadal obese males.

OBJECTIVE: Bone modulates testis function through osteocalcin (OCN) production. This paper assesses the association between serum OCN and androgen production recovery in morbidly obese males at 9 months after bariatric surgery. SUBJECTS: A cohort of n=103 obese males with mean±s.d. body mass index (BMI) 47.7±8.2 kg m(-2), age 42±11 years, consisting of n=76 patients undergoing gastric bypass and n=27 in the waiting list for surgery. RESULTS: At 9 months from surgery, a significant increase was observed in mean±s.d. total OCN (tOCN=10.4±10.3 ng ml(-1), P<0.001) and undercarboxylated OCN (ucOCN=5.4±3.7 ng ml(-1), P<0.001), total testosterone (TT, 5.6±6.5 nM, P<0.001) and calculated free testosterone (cFT, 0.035±0.133 nM, P<0.006), sex hormone binding globulin (SHBG, 21.2±16.7 nM, P<0.001) and decrease in estradiol (E2, -30.1±51.9 pM, P<0.001) levels only in operated patients, with a significant reduction in BMI (24%) and waist (20%). A positive correlation existed between tOCN and ucOCN (age-adjustment (age-adj.): ß=0.692, P<0.001) and their variations (age-adj.: ß=0.629, P<0.001) after surgery. Multivariate analysis in operated patients showed a significant positive association between variations in tOCN and TT (age-adj.: ß=0.289, P=0.012), SHBG (age-adj.: ß=0.326, P=0.005) but not with cFT variation. tOCN, but not luteinizing hormone (LH) variation was the only significant predictive factor of cFT recovery in the hypogonadal (TT<12 nM) operated subjects even after age- and BMI-adjustment (adj.: ß=0.582, P<0.05). cFT improvement was significantly higher when considering operated patients with tOCN increase (0.045±0.123 vs -0.02±0.118 nM, P=0.015), hypogonadism (0.059±0.111 vs -0.059±0.138 nM, P=0.002) and younger than 35 years (0.102±0.108 vs -0.019±0.123 nM, P=0.009). CONCLUSION: OCN recovery observed after bariatric surgery is significantly associated with cFT improvement independently of BMI variation and age in hypogonadal morbidly obese males.

Gender effect on the relation between diabetes and hospitalization for heart failure.

AIMS: Cardiovascular risk among diabetic patients is at least twice as much the one for non-diabetic individuals and even greater when diabetic women are considered. Heart failure (HF) is a common unfavorable outcome of cardiovascular disease in diabetes. However, since the comparison among sexes of heart failure prevalence in diabetic patients remains limited, this study is aimed at expanding the information about this point. METHODS: We have evaluated the association between diabetes and HF by reviewing the medical records of all subjects discharged from the Internal Medicine and Cardiology Units of all hospitals in the Tuscany region, Italy, during the period January 2002 through December 2008. In particular we sought concomitance of ICD-9-CM codes for diabetes and HF. RESULTS: Patients discharged by Internal Medicine were on average older, more represented by women, and had a lesser number of individuals coded as diabetic (p<0.05 for all). Relative risk for HF (95% CI) was significantly higher in patients with diabetes, irrespective of gender 1.39 (1.36-1.41) in males; 1.40 (1.37-1.42) in females. When the diabetes-HF association was analyzed according to decades of age, a "horse-shoe" pattern was apparent with an increased risk in 40-59 years old in female patients discharged by Internal Medicine. CONCLUSIONS: Although there is not a difference in the overall HF risk between hospitalized male and female diabetic patients, women have an excess risk at perimenopausal age.

Long term predictors of post-partum glucose metabolism in women with gestational diabetes mellitus.

AIMS: The question asked by this study was whether ß-cell function expressed by insulin secretion/sensitivity measured during pregnancy in women with gestational diabetes (GDM) predicts post-partum long-term derangement in glucose metabolism. METHODS: Seventy-four Caucasian women with previous GDM were retested through a 75 g-2-h-OGTT after 8 [6] years (median[interquartile range]) from index pregnancy, measuring at pregnancy and follow-up insulin sensitivity, insulin secretion (1-h-incremental-insulin-area/incremental-glucose-area: ΔAUC60 (I)/ΔAUC60 (G)) as well as the product of Stumvoll-first-phase - secretion x insulin sensitivity (insulin-secretion-sensitivity index (ISSI). RESULTS: At follow-up 47 women were normotelerant to glucose and 27 had altered glucose metabolism (AGM:10 with type 2 diabetes and 17 with IGT). Women progressed to AGM had at their index pregnancy higher mean 2-h-OGTT-glucose area (1.15±0.09 VS. 1.09±0.09 mol l 2-h (-1);p=0.014), and lower ΔAUC60 (I)/ΔAUC60 (median [interquantile range]) (54.4 [51.7] vs. 73.4 [60] pmol mmol (-1)) and ISSI (2 977 [766] vs. 3 708 [1 141]; p<0.05 for both), but similar insulin sensitivity index 2.9 [2.5] VS. 3.2 [2.2] ml min (-1) m (-2);p=NS). Two-h-OGTT-glucose area, or decrease in ΔAUC60 (I)/ΔAUC60 (G) and ISSI were significantly associated with glucose tolerance impairment and with raised adjusted risk for AGM while insulin sensitivity at pregnancy did no predict AGM development. CONCLUSIONS: In this group of women increased post-load plasma glucose and impaired ß-cell function assessed during GDM pregnancy predict long-term post-partum AGM, while insulin sensitivity measured at the same time does not.

Total plasma homocysteine correlates in women with gestational diabetes.

AIM: We aim to assess serum total homocysteine (tHcy) associations with metabolic syndrome components and B-vitamins in women with gestational diabetes mellitus (GDM). METHODS: We studied 61 consecutive pregnant women, 44 with GDM and 17 with normal glucose tolerance (CG). Serum homocysteine levels were analyzed by ELISA, using Bio-Rad reagents. Serum folates and vitamin B(12) concentrations were determined by chemiluminescent immunoassay, free fatty acids (FFA) and lipids enzymatically. RESULTS: Serum homocysteine levels were similar in both the GDM and the CG groups (8+/-2.0 vs 7.4+/-1.1 micromol/l, respectively). Women with GDM in comparison to CG women were characterized by higher values of homeostasis model of insulin resistance (HOMA-IR) (2.8+/-1.7 vs 1.6+/-0.9, P<0.01), serum triglycerides (2.7+/-0.9 vs 1.9+/-0.5 mmol/l, P<0.01) and FFA (0.6+/-0.2 vs 0.46+/-0.2 mmol/l, P<0.05). In GDM women serum tHcy correlated with vitamin B(12) (r= -0.47, P<0.01) and folates (r= -0.51, P<0.001); in CG women with HOMA-IR, a marker of insulin resistance (r= -0.49, P<0.05). In multiple regression analysis with serum tHcy as a dependent variable, folate and vitamin B(12) entered the analysis in GDM women (beta= -0.42 and -0.34, respectively, P<0.05), whereas in CG cystatin C and HOMA-IR entered the analysis (P<0.05). CONCLUSIONS: In women with GDM, serum homocysteine is significantly associated with vitamin B(12) and folate levels, while in healthy pregnant women with HOMA-IR and with kidney function. The results suggest the importance of the B-group vitamins in regulation of serum tHcy levels in women with insulin resistance/gestational diabetes, what might be relevant in protection against pregnancy complications associated with elevated tHcy in GDM women.

Influence of gestational diabetes on the long-term control of glucose tolerance.

AIMS/HYPOTHESIS: Gestational diabetes (GDM) carries a high risk of subsequent diabetes. We asked what impact prior GDM has on beta cell function and insulin action in women who maintain normal glucose tolerance (NGT) for a long time. METHODS: Ninety-one women with NGT (aged 41 +/- 8 years, mean+/-SD) were studied (by mathematical modelling of the C-peptide response to an OGTT) 7 [6] years (median [interquartile range]) after the index pregnancy, during which 52 had GDM (pGDM) and 39 had NGT (pNGT). In all women an OGTT had also been performed at 29 +/- 3 weeks of the index pregnancy. RESULTS: Women with pGDM were matched with women with pNGT for age, familial diabetes, time and weight gain since index pregnancy, parity, BMI (25.4 +/- 3.9 vs 26.8 +/- 6.4 kg/m(2)), and fasting (4.64 +/- 0.56 vs 4.97 +/- 0.46 mmol/l) and 2 h plasma glucose levels (5.91 +/- 1.14 vs 5.91 +/- 1.21 mmol/l). Nonetheless, fasting (49 [29] vs 70 [45] pmol min(-1) m(-2), p < 0.001) and total insulin secretion (32 [17] vs 48 [21] nmol m(-2), p < 0.0001) and beta cell glucose sensitivity (slope of the insulin secretion/plasma glucose concentration-response function) (95 [71] vs 115 [79] pmol min(-1) m(-2) (mmol/l)(-1), p = 0.025) were reduced in the pGDM group compared with the pNGT group, while insulin sensitivity was preserved (424 [98] vs 398 [77] ml min(-1) m(-2)). At index pregnancy, women with pGDM and those with pNGT had similar age and BMI. However, both insulin sensitivity (359 [93] vs 417 [92] ml min(-1) m(-2), p = 0.0012) and the insulin/glucose incremental area ratio (an empirical index of beta cell function; 98 [74] vs 138 [122] pmol/mmol, p = 0.028) were reduced in women with pGDM. CONCLUSIONS: Even in women who maintain normal insulin sensitivity, impaired beta cell function is carried over into the NGT status several years after a GDM pregnancy.

Sentinel lymph node biopsy in patients with thick (= 4 mm) melanoma: a single-centre experience.

BACKGROUND AND OBJECTIVE: Lymphatic mapping/sentinel lymph node biopsy (LM/SLNB) have become routine techniques for staging the regional lymph nodes in early stage melanoma, yet their role in the management of thick (= 4 mm) melanoma is debated. The aim of the present study is to review our experience with LM/SLNB in a series of patients with thick primary melanoma, to evaluate its utility in this melanoma subset. PATIENTS AND METHODS: Thirty patients (18 men and 12 women; mean age 70.6 years; median 75 years) with thick primary melanoma underwent LM/SLNB, using both radioisotope and blue dye. The statistical tests were performed by using SAS software for Windows, version 8.2. RESULTS: The primary tumour sites were head/neck (n = 5; 16.6%), trunk (n = 10; 33.3%), and extremities (n = 15; 50%). Tumour thickness ranged from 4 to 17 mm (mean 5.14 mm; median 4.5 mm). Ulceration was observed in 23 (76.6%) tumours. Eleven patients (36.6%) had at least a positive sentinel lymph node (SLN). The mean follow-up was 27.3 months (median 26 months; range 5-63 months). Patients without SLN metastases had a 5-year disease-free survival rate of 78.9%, vs. 18.2% for patients with SLN metastases (P = 0.0121 by log rank test). The 5-year overall survival rate for patients without SLN metastases was 89.5%, whereas patients with SLN metastases had a 5-year overall survival rate of 36.4% (P = 0.0272 by log rank test). CONCLUSION: Our retrospective analysis indicates that the SLN status is predictive of recurrence and survival in patients with thick melanoma, and LM/SLNB should be routinely performed in this subset of melanoma patients.

Does parity increase insulin resistance during pregnancy?

AIMS: To study the effect of parity on impairment of insulin sensitivity during pregnancy and on the risk of gestational diabetes (GDM). METHODS: We studied the relationship between parity and peripheral insulin sensitivity index (ISI(OGTT)) or GDM in 1880 caucasian women, who underwent a 100-g, 3-h oral glucose tolerance test (OGTT) between the 24th and 28th gestational week and in 75 women who underwent an OGTT in two consecutive pregnancies. A proxy for beta-cell function (basal plasma C peptide/fasting plasma glucose; CP/FPG) was also measured. RESULTS: By univariate analysis parity was related to decreased ISI(OGTT) and to increased CP/FPG in those with parity > 3 and likewise GDM, diagnosed in 124 women (6.58%), was linearly related to parity (P = 0.0034) and strongly age dependent. The relationships between parity and ISI(OGTT), CP/FPG and GDM were no longer significant after adjustment for age, pregestational body mass index (BMI), and weight gain. GDM was significantly related to age and pregestational weight, while ISI(OGTT) and CP/FPG were inversely related to prepregnancy BMI or weight gain. In comparison with the index pregnancy, the subsequent pregnancy was characterized by an increase in actual and prepregnancy BMI, in 2 h area under curve (AUC) glucose and by a decrease in ISI(OGTT) (P = 0.0001). The longer the time interval between pregnancies and the higher the increment in pregestational BMI or in weight gain during the pregnancy, the greater were the ISI(OGTT) decrease and 2-h AUC glucose increase. CONCLUSIONS: Parity is not directly linked to insulin sensitivity deterioration, to CP/FPG increase during pregnancy, or to GDM appearance, although it is linked through the mediation of progressive ageing and weight gain either before or during pregnancy, when there is a sufficiently long time interval between pregnancies.

Taurine administration during lactation modifies hippocampal CA1 neurotransmission and behavioural programming in adult male mice.

Taurine plays a role in neuronal development. In this study, we examined whether postnatal taurine administration influences the long-term consequences induced by mild neonatal stressors (10 min maternal deprivation plus sham injection, applied daily to neonatal mice up to 21 days). At 30 days of age stressed mice showed higher pain threshold both in the tail-flick--which measures mostly the spinal mechanisms of pain--and in the hot-plate test--which reflects mainly the supraspinal mechanisms of pain. The latter effect was prevented completely by neonatal taurine administration, while the tail-flick test was not affected, thus suggesting that spinal pain is not sensitive to taurine treatment. At 140 days of age, mice which were stressed during the neonatal period showed consistent decrease in immobility time in forced swimming test, and taurine did not influence this parameter. At the same age, the fear/anxiety axis, measured with elevated plus maze test, did not show any consistent changes. Electrophysiological experiments in brain slices obtained from adult mice showed that input-output curves in hippocampal CA1 were increased by taurine administration in lactation. Hence, neonatal administration of taurine might permanently modify the functioning of hippocampus, a brain area which is known to be crucial for learning and memory.

Defective regulation and action of atrial natriuretic peptide in type 2 diabetes.

Increased plasma atrial natriuretic peptide (ANP) levels and impaired ANP action have been reported in patients with diabetes or insulin resistance. The aim of this study was to assess the interaction between insulin and ANP in type 2 diabetes. In 12 normotensive, normoalbuminuric type 2 diabetics, we infused insulin at a high (6.6 pmol/min/kg) or, on a different day, at a low rate (0.6 pmol/min/kg) during 4 hours of isoglycemia under isovolumic, isoosmolar conditions. The normal response was established in 12 healthy volunteers using an identical protocol. Despite higher baseline ANP levels (17.7 +/- 2.8 vs. 10.8 +/- 1.8 pg/ml, p = 0.04), urinary sodium excretion was similar in diabetics and controls (113 +/- 8.5 vs. 102 +/- 8.8 mEq/24 hours, p = ns). In both groups, hyperinsulinemia caused a decrease in blood volume (0.33 +/- 0.10 l, p < 0.01), diastolic blood pressure (6 %, p < 0.02), and natriuresis. However, plasma ANP decreased in controls (from 12.7 +/- 1.9 to 8.6 +/- 1.4 pg/ml, p = 0.01) but not in type 2 diabetics (15.1 +/- 2.7 vs. 17.2 +/- 3.8 pg/ml, p = ns). We conclude that ANP release is resistant to volume stimulation in type 2 diabetic patients, and natriuresis is resistant to ANP action. This dual disruption of ANP control may play a role in blood pressure regulation in diabetes.

Platelet antioxidant enzymes in insulin-dependent diabetes mellitus.

BACKGROUND: The measurement of the peroxidase scavenging system represented by the activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px) in blood cells of diabetic patients has, in the past, given equivocal results. Likewise, the role of these intracellular enzymatic scavengers against the oxidative stress of diabetes-associated microangiopathic complications is unknown. METHODS: Choosing platelets as cell model (as commonly done in previous studies), the aim of this study was to relate the platelet content of SOD, catalase and GSH-Px to the presence of diabetes, as well as to the presence of nephropathy and retinopathy in 35 insulin-dependent diabetic patients, as compared to 10 age-matched control subjects. RESULTS: The enzymatic activities were not changed in diabetic patients in comparison with healthy controls. After stratifying patients according to presence of nephropathy (24-h urinary albumin excretion rate persistently > or =20 microg min(-1)) or retinopathy, the group of albuminuric patients was characterized by a significant decrease in SOD activity as compared to those in the normoalbuminuric range (4.36+/-1.06 vs. 6.81+/-2.26 mU 10(-9) platelets; p=0.01). Catalase and GSH-Px did not change. No modification in platelet enzyme activities has been found in diabetic subjects with retinopathy. CONCLUSIONS: These results suggest that diabetic nephropathy, at least in its early stage, may be related to an altered redox state of platelets, as tested by the reduction in SOD activity, thus, indicating that the renal damage in these patients may be associated to a selective increase in platelet susceptibility to variation in the redox state.

Polymorphisms in the hANP (human atrial natriuretic peptide) gene, albuminuria, and hypertension.

Atrial natriuretic peptide (ANP) jointly affects kidney function and blood pressure homeostasis and is a candidate susceptibility gene for both essential hypertension and kidney disease. We evaluated the relation between the ScaI and BstXI polymorphisms of the human ANP (hANP) gene, hypertension, and albuminuria in a clinical cohort of 1033 subjects, including type 1 and type 2 diabetic patients, nondiabetic subjects with essential hypertension, and nondiabetic normotensive control subjects. Microalbuminuria was present in 15%, 29%, and 2%, respectively, of type 1 diabetic, type 2 diabetic, and nondiabetic patients. Macroalbuminuria was present in 9% of type 1 diabetics, 21% of type 2 diabetics, and 31% of nondiabetics. Prevalence of hypertension was 31%, 58%, and 61% in normoalbuminuric, microalbuminuric, and macroalbuminuric subjects, respectively (P<0.0001). Genotype distributions were in Hardy-Weinberg equilibrium in all 4 patient subgroups. The frequency of the ScaI mutated allele (A(1)) was significantly lower in hypertensive than in control subjects (11% versus 19%, P=0.018) and in patients with macroalbuminuria (5%) as compared with normoalbuminuric subjects (16%; P<0.0001). In a nominal logistic model adjusting for gender, age, obesity, diabetes, micro/macroalbuminuria, and hypertension, the A(1) allele was independently associated with macroalbuminuria (odds ratio, 0.57; confidence interval, 1.39 to 3.59; P=0.003) but not with hypertension. In the same model, the frequency of the BstXI mutated allele (T(708)) was increased in the presence of microalbuminuria (odds ratio, 2.25; confidence interval, 1.39 to 3.59; P<0.001). We conclude that the mutated genotypes of the ScaI polymorphism are negatively associated with overt nephropathy, whereas the mutated genotypes of BstXI polymorphism are positively associated with microalbuminuria. hANP gene variants may exert a protective effect against the development and progression of kidney damage in diabetes.

Relationship between metabolic glycaemic control and platelet content of glutathione and its related enzymes, in insulin-dependent diabetes mellitus.

The relationship between glycaemic metabolic control and intracellular concentration of reduced glutathione (GSH) and related enzymes GSH-peroxidase (GSH-Px), GSH-reductase (GSH-Red), GSH-transferase (GSH-Tr), glucose-6-P-dehydrogenase (G6PDH), and thioltransferase (TT) in patients with insulin-dependent diabetes mellitus (IDDM) is controversial. Choosing platelets as cell model (as commonly done in previous studies), the aim of this study was to relate the platelet content of GSH and related enzymes to glycaemic metabolic control, expressed as glycated haemoglobin (HbA1c), as well as to presence of retinopathy and nephropathy in 114 IDDM patients. As compared to controls, both GSH and GSH-Red (geometric means (95% CI)) were significantly increased in platelets of diabetic patients: 3.3 (0.7-9.6) vs. 2.4 (0.8-7.6) mmol 10(-9) platelets; P=0.01 for GSH, and 30.6 (14.7-61.6) vs. 22.2 (8.7-52.2) mU 10(-9) platelets, P=0.0002 for GSH-Red, and TT activity was marginally decreased in the IDDM group (P=0.06). While no clear relationship was present between GSH-related enzymes and HbA1c, a trend was present toward a non-linear relation between HbA1c and GSH, being significantly related by a parabolic curve (P=0.002). As compared to patients with normoalbuminuria (n=88), diabetic patients with increased urinary albumin excretion rate (n=26) had a significant decrease in platelet TT concentration (3.2 (0.9-6.7) vs. 5.1 (1.9-18.7) mU 10(-9) platelets; P=0.0002), whereas retinopathy was not associated to modifications in GSH or in the enzymatic pattern. In summary: (a) platelet GSH and GSH-Red are increased in IDDM, while other enzymes are unmodified; (b) GSH seems to be related to metabolic control according to non-linear parabolic curve; (c) presence of increased albuminuria is associated to a selective decrease in platelet TT content.

Insulin: new roles for an ancient hormone.

Recent research has greatly expanded the domain of insulin action. The classical action of insulin is the control of glucose metabolism through the dual feedback loop linking plasma insulin with plasma glucose concentrations. This canon has been revised to incorporate the impact of insulin resistance or insulin deficiency, both of which alter glucose homeostasis through maladaptive responses (namely, chronic hyperinsulinaemia and glucose toxicity). A large body of knowledge is available on the physiology, cellular biology and molecular genetics of insulin action on glucose production and uptake. More recently, a number of newer actions of insulin have been delineated from in vitro and in vivo studies. In sensitive individuals, insulin inhibits lipolysis and platelet aggregation. In the presence of insulin resistance, dyslipidaemia, hyper-aggregation and anti-fibrinolysis may create a pro-thrombotic milieu. Preliminary evidence indicates that hyperinsulinaemia per se may be pro-oxidant both in vitro and in vivo. Insulin plays a role in mediating diet-induced thermogenesis, and insulin resistance may therefore be implicated in the defective thermogenesis of diabetes. In the kidney, insulin spares sodium and uric acid from excretion; in chronic hyperinsulinaemic states, these effects may contribute to high blood pressure and hyperuricaemia. Insulin hyperpolarises the plasma membranes of both excitable and non-excitable tissues, with consequences ranging from baroreceptor desensitisation to cardiac refractoriness (prolongation of QT interval). Under some circumstances insulin is vasodilatory-the mechanism involving both the sodium-potassium pump and intracellular calcium transients. Finally, by crossing the blood-brain barrier insulin exerts a host a central effects (sympatho-excitation, vagal withdrawal, stimulation of corticotropin releasing factor), collectively resembling a stress reaction. Description and understanding of these new roles, their interactions, the interplay between insulin resistance and hyperinsulinaemia, and their implications for cardiovascular disease have only begun.

Respiratory muscle function and hypoxic ventilatory control in patients with type I diabetes.

STUDY OBJECTIVES: The interaction among pulmonary mechanics, respiratory muscle performance, and ventilatory control in subjects with insulin-dependent diabetes mellitus has so far received little attention. We therefore decided to assess the role of central factors and peripheral factors on the ventilatory response to a hypoxic stimulus in type I diabetic patients. SUBJECTS: Eight patients in stable condition aged 19 to 48 years old, with insulin-dependent diabetes mellitus (duration of the disease, 36 to 240 months) and no history of smoking, cardiopulmonary involvement, or autonomic neuropathy; and an age- and gender-matched control group. MEASUREMENTS: In each patient, we measured the following: pulmonary volumes; diffusing capacity of the lung for carbon monoxide (D(LCO)); time and volume components of ventilation (tidal volume [V(T)] and respiratory frequency); static compliance (Clstat) and dynamic compliance (Cldyn); swings in pleural pressure (Pes) and gastric pressure (Pg); and transdiaphragmatic pressure (Pdi), obtained by subtracting Pes from Pg. Maximal inspiratory Pes and Pdi during a maximal sniff maneuver were also measured. Swings in Pes and Pdi during V(T) as a percentage of Pes and Pdi during the maximal sniff maneuver [Pessw(%Pessn) and Pdisw(%Pdisn), respectively] were both considered as a measure of central respiratory output, and the Pessw(%Pessn)/V(T) ratio was considered as an index of neuroventilatory dissociation (NVD) of the inspiratory pump. Subjects were studied at baseline and during hypoxic rebreathing. RESULTS: Pulmonary volumes and D(LCO) were normal or slightly reduced. A lower Cldyn, higher central respiratory output, and NVD were found. During hypoxic rebreathing, patients had lower V(T), similar central respiratory output, and greater NVD per unit change in arterial oxygen saturation compared with values in control subjects. An increase in dynamic elastance, computed as 1/Cldyn, during hypoxia was found in patients, but not in normal subjects, and was directly related to concurrent changes in NVD. CONCLUSIONS: We have shown that the assessment of a normal Clstat and normal routine parameters of airway obstruction does not permit the definite exclusion of the role of peripheral airway involvement in insulin-dependent diabetes mellitus. Peripheral airway involvement is likely to influence indices of hypoxic ventilator) drive by modulating a normal central motor output into a rapid and shallow pattern of ventilatory response.

Dyspnoea, peripheral airway involvement and respiratory muscle effort in patients with type I diabetes mellitus under good metabolic control.

Dyspnoea and pulmonary dysfunction have recently been associated with Type I (insulin-dependent) diabetes mellitus. The putative role of altered pulmonary mechanics and of performance of inspiratory muscles in inducing dyspnoea has not been yet assessed in Type I diabetes. To better focus on this topic we evaluated nine patients with Type I diabetes mellitus, aged 19 to 48 years with good and stable metabolic control, without a history of smoking and microvascular complications, alongside a group of 14 healthy control subjects. In each subject, pulmonary volumes, static and dynamic compliance, pleural pressure swings (Pplsw), maximal inspiratory pressures (Pplsn), Pplsw(%Pplsn), a measure of respiratory muscle effort, and tension-time index [TTI=TI/TTOTxPplsw(%Pplsn)] were measured (TI=inspiratory time;TTOT=total time of the respiratory cycle). All subjects were studied at baseline and during hypoxic rebreathing. Patients had normal pulmonary volumes. During hypoxic rebreathing, a normal change in respiratory muscle effort [DeltaPplsw(%Pplsn)/DeltaSaO2] and DeltaTTI/DeltaSaO2, and a lower change in tidal volume versus change in oxygen saturation [DeltaVT(% vital capacity)/DeltaSaO2], resulted in a higher ratio of respiratory effort to tidal volume [Pplsw(%Pplsn)/VT(% vital capacity)], a measure of neuroventilatory dissociation of the respiratory pump. Hypoxic dyspnoea, assessed by a modified Borg scale, showed a greater rate of rise (DeltaBorg/DeltaSaO2) and a greater increase for a given level of respiratory effort in patients. Moreover, neuroventilatory dissociation related to the expression of peripheral airway involvement, as assessed in terms of low dynamic compliance, and to concurrent change in dyspnoea sensation. Patients with Type I diabetes mellitus under good metabolic control and with normal lung volumes may have abnormal peripheral airway function. The latter is thought to be responsible for the association between dyspnoea sensation and neuroventilatory dissociation.

Plasma and platelet ascorbate pools and lipid peroxidation in insulin-dependent diabetes mellitus.

BACKGROUND: As diabetes mellitus represents a situation in which production of peroxides is increased, the aim of this study was to investigate the relationship between plasma and platelet levels of ascorbic acid (AA)/dehydroascorbic acid (DHA) and those of malonyldialdehyde (MDA), an indirect marker of lipoperoxides, both assayed using high-performance liquid chromatography (HPLC), in 59 patients with insulin-dependent diabetes mellitus (IDDM) compared with 51 healthy control subjects matched for sex, age, smoking habits, as well as for dietary intake of energy, alcohol and vitamin C. RESULTS: Mean plasma and platelet MDA were significantly higher in the patients affected with IDDM than in control subjects. Moreover, the diabetic group was characterized by a huge decrease in plasma AA [8.45 +/- 5.5 mumol L-1 (SD) vs. 33.4 +/- 7.6 mumol L-1, P = 0.0001], mirrored by a significant increase in plasma DHA (11.9 +/- 3.9 mumol L-1 vs. 3.9 +/- 2.5 mumol L-1, P = 0.0001). No detectable DHA was observed in the platelets from both diabetic and control subjects, whereas AA was significantly increased in platelets from diabetic patients compared with control subjects (42.6 +/- 7.4 vs. 34.8 +/- 5.1 nmol 10(-9) platelets, P = 0.0001). Platelet AA in the diabetic group was significantly inversely correlated with glycated haemoglobin (r = -0.34; P = 0.04) and directly with plasma AA (r = 0.39; P = 0.02), the sum of plasma AA + DHA (r = 0.44; P = 0.009) and with platelet MDA (r = 0.38; P = 0.02). CONCLUSION: (a) The ratio plasma AA/DHA is significantly lowered in IDDM in association with an increase in MDA levels; (b) only AA is detected in platelets, being augmented in the diabetic group; (c) plasma ascorbate depletion does not reflect platelet levels of AA; and, finally, (d) metabolic control, as well as intracellular lipoperoxides, modulates platelet AA in IDDM.

Further insights into the anti-aggregating activity of NMDA in human platelets.

1. In the present study the effect of N-methyl-D-aspartate (NMDA) on thromboxane B2 synthesis and on [Ca2+]i was studied in human platelets. 2. NMDA (10(-7) M) completely inhibited the synthesis of thromboxane B2 from exogenous arachidonic acid (AA), while it did not interfere with the aggregating effect of the thromboxane A2 receptor agonist U-46619. 3. NMDA (0.1 microM - 10 microM) dose-dependently increased intracellular calcium in washed platelets preloaded with fura 2 AM, and this effect was not additive with that of AA. 4. NMDA shifted the dose-response curve of AA to the right. At the highest AA concentrations platelet aggregation was not inhibited. 5. The antiaggregating effect of NMDA was not antagonized by N(G)-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase (NOS) inhibitor. 6. Finally, NMDA (0.01 nM - 100 nM) associated with either aspirin or indomethacin significantly potentiated the antiaggregating activity of both cyclo-oxygenase inhibitors. 7. It was concluded that NMDA is a potent inhibitor of platelet aggregation and thromboxane B2 synthesis in human platelet rich plasma (PRP).

Effects of troglitazone on insulin action and cardiovascular risk factors in patients with non-insulin-dependent diabetes.

OBJECTIVE: Insulin resistance is a potential target for pharmacologic intervention in non-insulin-dependent diabetes. Troglitazone is being evaluated as an insulin enhancer in insulin resistant states. RESEARCH DESIGN AND METHODS: We randomized 40 patients with non-insulin-dependent diabetes to diet plus placebo (n = 15) or diet plus troglitazone (n = 25; 200 mg/day) treatment for 8 weeks. Fasting endogenous glucose production (EGP, by the stable isotope technique) and whole-body insulin sensitivity (by the insulin suppression test) were measured at baseline and on days 3, 7, 14, 28, and 56 of treatment. RESULTS: By day 56, fasting plasma glucose had risen from 12.0 +/- 0.9 to 12.8 +/- 1.2 mmol/L in the placebo group and had fallen from 12.4 +/- 0.6 to 11.3 +/- 0.6 mmol/L in the troglitazone group (p = 0.03). This was the result of small improvements in whole-body insulin sensitivity (steady-state plasma glucose during the insulin suppression test: from 11.09 +/- 1.1 to 10.3 +/- 0.8 mmol/L versus 13.8 +/- 1.0 to 10.0 +/- 0.9 mmol/L, placebo versus troglitazone; p = 0.01) and EGP (from 103% +/- 3% versus 96% +/- 2% of baseline, placebo versus troglitazone; p = 0.09). The time course of insulin action showed an early (first week of treatment) decrease in EGP in the troglitazone group that was maintained throughout, whereas steady-state plasma glucose levels began to diverge toward the end of treatment. The effects of insulin on plasma free fatty acid and potassium concentrations were not different between placebo and troglitazone. The cardiovascular risk profile (heart rate; serum triglycerides; total, low-density lipoprotein, and high-density lipoprotein cholesterol; proinsulin; uric acid; plasminogen activator inhibitor-1 antigen and activity; 24-hour blood pressure monitoring and urinary albumin excretion) was unaltered by troglitazone treatment. CONCLUSIONS: Troglitazone as monotherapy for typical non-insulin-dependent diabetes had a modest anti-hyperglycemic effect and, at the dose used in this study, had no effect on cardiovascular risk factors.

Raised erythrocyte polyamine levels in non-insulin-dependent diabetes mellitus with great vessel disease and albuminuria.

Erythrocyte content of polyamines has been previously found increased in insulin-dependent diabetes mellitus with microalbuminuria. Since increased urinary albumin excretion (AER) is associated with the presence of vascular diseases in non-insulin-dependent diabetes mellitus (NIDDM) the aim of this study was to verify the hypothesis that the presence of increased urinary albumin excretion (AER), and of macroangiopathy in NIDDM would be related to a significant modification in polyamine erythrocyte levels. The erythrocyte content of spermine and spermidine was measured by a HPLC method in 39 patients affected with NIDDM and in 24 age- and sex-matched healthy control subjects, evaluating the relationship between erythrocyte polyamines of NIDDM patients with the presence of macroangiopathy as well as with retinopathy or increased AER (> or = 20 micrograms/ml). Both spermidine and spermine were not modified in the group of NIDDM patients while the presence of raised urinary AER was characterised by an increase in erythrocyte spermine (11 +/- 1.7 vs. 7.7 +/- 1.7 nmol/ml packed erythrocytes; P = 0.04) and spermidine (18.9 +/- 1.7 vs. 12.6 +/- 1.5 nmol/ml packed erythrocytes; P = 0.02), being both polyamines significantly related to AER and to metabolic control. Erythrocyte spermidine and spermine were moreover significantly higher in the group of patients with macroangiopathy (22.8 +/- 1.5 vs. 12.3 +/- 1.5 nmol/ml; P = 0.0001 and 11.5 +/- 1.7 vs. 7.8 +/- 1.7 nmol/l packed erythrocytes; P = 0.04) and being, moreover, erythrocyte spermidine augmented in patients with retinopathy (24.2 +/- 1.5 vs. 12.2 +/- 1.5 nmol/ml packed erythrocytes; P = 0.009). In conclusion the levels of erythrocyte spermine and spermidine are both associated with the presence of albuminuria and macroangiopathy in NIDDM, while spermidine is on the average increased in the group of diabetic patients with retinopathy.

Reciprocal association between insulin sensitivity and the haematocrit in man.

In epidemiological studies, a high haematocrit has been associated both with increased cardiovascular risk and with hyperinsulinaemia, a surrogate of insulin resistance. To examine directly the relationship between the haematocrit and insulin sensitivity, we studied 12 healthy volunteers and 12 patients with non-insulin-dependent diabetes mellitus (NIDDM) with the use of a 4-hour hyperinsulinaemic [1 mU min-1 kg-1] isoglycaemic clamp. In the whole group, insulin sensitivity (as the ratio of insulin-mediated glucose clearance to steady-state plasma insulin concentrations) was inversely related to the haematocrit (r = 0.50, P < 0.01). To test whether acute changes in the haematocrit affect insulin sensitivity, in two NIDDM patients and three healthy subjects the clamp study was repeated after lowering (-18%) the haematocrit by erythro-apheresis. In all five subjects, the lower haematocrit was associated with slightly reduced (-7% on average, P = NS) rather than increased insulin sensitivity. We conclude that insulin sensitivity is inversely related to the haematocrit independently of the glucose tolerance status. The association does not result from acute haemodynamic effects on insulin sensitivity, and may therefore reflect an action of insulin resistance/ hyperinsulinaemia on blood viscosity, or the presence of a common determinant.