Valve diseases in the aged: when to operate?]

BACKGROUND: Patients with Raynaud's phenomenon due to systemic sclerosis exhibit a functional microangiopathy with endothelial cell damage. The aim of this study was to assess differences in the so-called nutritive and thermoregulative skin blood flow and to obtain further information by Fourier transformation and by nonlinear analysis of laser Doppler flux (LDF) time series. PATIENTS AND METHODS: A local cold stress test was performed in 10 patients and 10 age- and sex-matched healthy controls. Significant differences were detected between nutritive blood flow in the nailfold capillaries, assessed by capillary red blood cell velocity (CBV), and thermoregulatory blood flow, which was synchronously assessed by LDF. RESULTS: CBV was reduced during cooling, the drop being significantly larger in the patients than in the controls. In contrast, there was no significant difference in the decrease of LDF during cooling. The difference between the fall in CBV values and that in LDF was significantly more pronounced in patients. Further analysis of the LDF frequency spectrum by fast Fourier transformation revealed a significantly greater decrease in amplitude at the heart frequency level in healthy volunteers. A further analysis of the LDF signal revealed significant differences at rest and after cooling in fractal dimensions, suggesting an increased complexity of LDF signals in patients. SUMMARY: The patient's increased sensitivity towards local cold cn be observed best at the capillary level. But the changes of LDF in the frequency spectrum during cooling as calculated by fast Fourier transformation revealed significant differences. In addition differences in fractal dimensions of LDF time series suggest that an analysis of nonlinear dynamics may be a promising approach.     

Oral glucose ingestion increases endurance capacity in normal and diabetic (type I) humans

The effects of an oral glucose administration (1 g/kg) 30 min before exercise on endurance capacity and metabolic responses were studied in 21 type I diabetic patients [insulin-dependent diabetes mellitus (IDDM)] and 23 normal controls (Con). Cycle ergometer exercise (55-60% of maximal O2 uptake) was performed until exhaustion. Glucose administration significantly increased endurance capacity in Con (112 +/- 7 vs. 125 +/- 6 min, P < 0.05) but only in IDDM patients whose blood glucose decreased during exercise (70.8 +/- 8.2 vs. 82.8 +/- 9.4 min, P < 0.05). Hyperglycemia was normalized at 15 min of exercise in Con (7.4 +/- 0.2 vs. 4.8 +/- 0.2 mM) but not in IDDM patients (12.4 +/- 0.7 vs. 15.6 +/- 0.9 mM). In Con, insulin and C-peptide levels were normalized during exercise. Glucose administration decreased growth hormone levels in both groups. In conclusion, oral glucose ingestion 30 min before exercise increases endurance capacity in Con and in some IDDM patients. In IDDM patients, in contrast with Con, exercise to exhaustion attenuates hyperglycemia but does not bring blood glucose levels to preglucose levels.     

Muscle sympathetic nerve activity is reduced in IDDM before overt autonomic neuropathy

Studies of heart-rate variability have demonstrated that abnormal cardiac parasympathetic activity in individuals with IDDM precedes the development of other signs or symptoms of diabetic autonomic neuropathy. To determine whether IDDM patients have impaired sympathetic activity compared with normal control subjects before the onset of overt neuropathy, we directly recorded MSNA. We also examined the effects of changes in plasma glucose and insulin on sympathetic function in each group. MSNA was recorded by using microneurographic techniques in 10 IDDM patients without clinically evident diabetic complications and 10 control subjects. MSNA was compared during a 15-min fasting baseline period and during insulin infusion (120 mU.m-2.min-1) with 30 min of euglycemia. A cold pressor test was performed at the end of euglycemia. Power spectral analysis of 24-h RR variability was used to assess cardiac autonomic function. IDDM patients had lower MSNA than control subjects at baseline (8 +/- 1 vs. 18 +/- 3 burst/min, P < 0.02). MSNA increased in both groups with insulin infusion (P < 0.01) but remained lower in IDDM patients (20 +/- 3 vs. 28 +/- 3 burst/min, P < 0.01). In the IDDM group, we found no relationships between MSNA and plasma glucose, insulin, or HbA1c concentrations. BP levels did not differ at rest or during insulin. Heart-rate variability and the MSNA response to cold pressor testing in IDDM patients did not differ from those in healthy control subjects. IDDM patients had reduced MSNA at rest and in response to insulin. The lower MSNA is not attributable to differences in plasma glucose or insulin, but, rather, is most likely an early manifestation of diabetic autonomic neuropathy that precedes impaired cardiac parasympathetic control.     

Relation of factor V Leiden genotype to risk for acute deep venous thrombosis after joint replacement surgery

C-peptide, which is released from the pancreatic beta cells into the circulation in amounts equimolar with insulin, fulfills an important function in the assembly of the two-chain insulin structure, but has otherwise been considered to be biologically inactive. However, during the last few years several experimental and clinical studies have demonstrated that replacement of C-peptide in patients with insulin-dependent diabetes mellitus elicits several physiological effects. Thus, during short-term substitution of C-peptide (1-3 h) decreased glomerular hyperfiltration, augmented whole body and skeletal muscle glucose utilisation, improved autonomic nerve function and a redistribution of microvascular skin blood flow could be observed. In addition, replacement of C-peptide during a period of 1-3 months has been shown to improve renal function as well as autonomic and sensory nerve function in IDDM patients. The mechanisms behind these effects remain unclear, but recent investigations have indicated that an increase in Na+K+ATPase activity and a stimulation of the endothelial nitric oxide synthase may contribute to the observed physiological effects of C-peptide. Not only the intact C-peptide molecule, but also fragments from the C-terminal and mid-portion of the molecule have been shown to exert biological effects. Further research will be necessary to evaluate the underlying mechanism and the clinical impact of C-peptide replacement in IDDM patients.     

Prolactin and beta-endorphin responses to hypoglycemia are reduced in well-controlled insulin-dependent diabetes mellitus

Several pituitary hormones, including corticotropin (ACTH), growth hormone (GH), prolactin, and beta-endorphin (but not thyrotropin, follicle-stimulating hormone, or luteinizing hormone), are released in response to hypoglycemia in normal subjects. In patients with insulin-dependent diabetes mellitus (IDDM), the degree of glycemic control is known to alter ACTH and GH responses to hypoglycemia. The current study was performed to examine the effect of glycemic control on prolactin and beta-endorphin responses to hypoglycemia in subjects with IDDM. We performed 3-hour stopped hypoglycemic-hyperinsulinemic clamp studies (12 pmol/kg/min) during which plasma glucose was decreased from 5.0 mmol/L to 2.2 mmol/L in steps of 0.6 mmol/L every 30 minutes in 20 subjects with uncomplicated IDDM (12 males and eight females; age, 26 +/- 2 years; IDDM duration, 10 +/- 1 years; body mass index, 23.6 +/- 0.6 kg/m2) and 10 healthy subjects (five males and five females aged 30 +/- 1 years). The 10 diabetic subjects in good glycemic control (mean hemoglobin A1 [HbA1], 7.5% +/- 0.3%; normal range, 5.4% to 7.4%) were compared with the 10 poorly controlled patients (mean HbA1, 12.6% +/- 0.5%; P < .001 v well-controlled diabetic group). During hypoglycemia, prolactin levels in the well-controlled diabetic group did not change (7 +/- 1 microgram/L at plasma glucose 5.0 mmol/L to 9 +/- 2 micrograms/L at plasma glucose 2.2 mmol/L), whereas prolactin levels increased markedly in the poorly controlled diabetic group (7 +/- 2 micrograms/L to 44 +/- 17 micrograms/L) and healthy volunteers (12 +/- 2 micrograms/L to 60 +/- 19 micrograms/L, P < .05 between IDDM groups). The plasma glucose threshold required for stimulation of prolactin secretion was 2.2 +/- 0.1 mmol/L in well-controlled IDDM, 3.0 +/- 0.4 mmol/L in poorly controlled IDDM, and 2.4 +/- 0.1 mmol/L in healthy subjects (P < .05 between IDDM groups). Responses in males and females were similar. The increase in beta-endorphin levels was also attenuated in well-controlled IDDM patients (4 +/- 1 pmol/L at plasma glucose 5.0 mmol/L to 11 +/- 4 pmol/L at plasma glucose 2.2 mmol/L) versus poorly controlled IDDM patients (5 +/- 1 pmol/L to 26 +/- 7 pmol/L) and healthy subjects (8 +/- 1 pmol/L to 56 +/- 13 pmol/L). The plasma glucose threshold required for stimulation of beta-endorphin release was again lower in well-controlled IDDM versus poorly controlled IDDM patients (2.2 +/- 0.1 v 3.0 +/- 0.3 mmol/L) and healthy subjects (2.5 +/- 0.4 mmol/L, P < .05 between IDDM groups). In conclusion, prolactin and beta-endorphin responses to a standardized hypoglycemic stimulus (plasma glucose, 2.2 mmol/L) are reduced and plasma glucose levels required to stimulate release of prolactin and beta-endorphin are lower in well-controlled IDDM compared with poorly controlled IDDM and healthy subjects. Thus, stress hormones not previously considered to have a primary role in plasma glucose recovery from hypoglycemia are affected by glycemic control, suggesting a more generalized alteration of hypothalamic-pituitary responses to hypoglycemia in IDDM patients with strict glycemic control.     

Regional deposition of inhaled particles in human lungs: comparison between men and women

We measured detailed regional deposition patterns of inhaled particles in healthy adult male (n = 11; 25 +/- 4 yr of age) and female (n = 11; 25 +/- 3 yr of age) subjects by means of a serial bolus aerosol delivery technique for monodisperse fine [particle diameter (Dp) = 1 micron] and coarse aerosols (Dp = 3 and 5 micron). The bolus aerosol (40 ml half-width) was delivered to a specific volumetric depth (Vp) of the lung ranging from 100 to 500 ml with a 50-ml increment, and local deposition fraction (LDF) was assessed for each of the 10 local volumetric regions. In all subjects, the deposition distribution pattern was very uneven with respect to Vp, showing characteristic unimodal curves with respect to particle size and flow rate. However, the unevenness was more pronounced in women. LDF tended to be greater in all regions of the lung in women than in men for Dp = 1 micron. For Dp = 3 and 5 micron, LDF showed a marked enhancement in the shallow region of Vp 200 ml. Total lung deposition was comparable between men and women for fine particles but was consistently greater in women than men for coarse particles regardless of flow rates used: the difference ranged from 9 to 31% and was greater with higher flow rates (P < 0.05). The results indicate that 1) particle deposition characteristics differ between healthy men and women under controlled breathing conditions and 2) deposition in women is greater than that in men.     

Carotid atherosclerosis in adolescents and young adults with IDDM. Relation to urinary endothelin, albumin, free cortisol, and other factors

OBJECTIVE: To investigate 1) alterations of carotid intimal-plus-medial thickness (IMT) in subjects with IDDM and 2) the relation of IMT to indexes of diabetic angiopathy and to risk factors of atherosclerosis. RESEARCH DESIGN AND METHODS: IMT was assessed by ultrasound B-mode imaging in 39 subjects with IDDM (23 male, 16 female young adults aged 17.5 +/- 5.2 years, diabetes duration 8.8 +/- 5.9) and in 22 control subjects (healthy siblings of the IDDM subjects) of comparable age. Urinary endothelin (UET1) and urinary free cortisol (UFC) were determined by radioammunoassay (RIA), urinary albumin by nephelometry, HbA1c by high-performance liquid chromatography (HPLC), and plasma renin by immunoradiometric assay (IRMA). RESULTS: The IMT values were greater in IDDM subjects than in control subjects (0.49 +/- 0.1 mm, 0.44 +/- 0.09 mm, respectively; P = 0.048) and greater in IDDM male subjects than in control male subjects (0.52 +/- 0.09 and 0.44 +/- 0.06 mm, respectively; P = 0.015), with no difference between IDDM and control female subjects. The IMT values were greater in diabetic male subjects than in female subjects (0.52 +/- 0.09 and 0.45 +/- 0.1 mm, respectively; P = 0.017). In IDDM subjects, but not in control subjects, there was a positive correlation of IMT to urinary albumin (P = 0.008), systolic blood pressure (P = 0.023), UET1 (P = 0.016), UFC (P = 0.002), and BMI (P = 0.021). Multiple regression analysis demonstrated that in IDDM subjects the variable that interacts independently with IMT was the BMI (P = 0.001). CONCLUSIONS: IMT, an index of atherosclerosis (macroangiopathy), is increased in IDDM subjects quite early (already in adolescence), and it is positively related to urinary albumin, UET1, blood pressure, and UFC.     

The design and performance of an experimental external fixator with variable axial stiffness and a compressive force transducer

The present study was carried out to evaluate the effect of a low-dose intravenous supplementation of L-arginine on insulin-mediated vasodilatation and insulin sensitivity. The study was performed in healthy subjects (n = 7) and patients with obesity (n = 9) and non-insulin-dependent diabetes mellitus (NIDDM) (n = 9). Insulin-mediated vasodilatation was measured by venous occlusion plethysmography during the insulin suppression test, evaluating insulin sensitivity. Experiments were performed twice in each subject in the presence or absence of a concomitant infusion of L-arginine (0.52 mg kg-1 min-1). L-Arginine restored the imparied insulin-mediated vasodilatation observed in obesity (22.4 +/- 4.1%, P < 0.01 vs. without L-arginine) and NIDDM (20.3 +/- 3.2%, P < 0.01 vs. without L-arginine). In healthy subjects, no effect on insulin mediated-vasodilatation was observed (24.8 +/- 3.1% vs. 21.4 +/- 3.1%). Insulin sensitivity was improved significantly (P < 0.001) in all three groups by infusion of L-arginine. No effect of L-arginine was observed on insulin, insulin-like growth factor I (IGF-I), free fatty acids (FFAs) or C-peptide levels during the insulin suppression test. Our data indicate that defective insulin-mediated vasodilatation in obesity and NIDDM can be normalized by intravenous L-arginine. Furthermore, L-arginine improves insulin sensitivity in obese patients and NIDDM patients as well as in healthy subjects, indicating a possible mechanism that is different from the restoration of insulin-mediated vasodilatation.     

Urinary excretion of extracellular matrix proteins in insulin dependent diabetes mellitus

The purpose of the study was to assess urinary excretion of extracellular matrix proteins and proteolytic enzymes in 12 subjects with IDDM with albuminuria, 12 subjects with IDDM without microalbuminuria and 10 normal healthy subjects. Urinary excretion of FN was significantly higher in subjects with IDDM and albuminuria as compared to patients with IDDM without microalbuminuria and healthy subjects (223.6 +/- 143.2 vs. 103.2 +/- 59.7 vs. 58.3 +/- 12.0 ng/mg creatinine, p < 0.01). Urinary level of type IV collagen was significantly elevated in subjects with IDDM and albuminuria as compared to IDDM without microalbuminuria and healthy subjects of cathepsin B was significantly higher in diabetic patients with albuminuria as compared to patients without microalbuminuria and healthy subjects (0.82 +/- 0.53 vs. 0.25 +/- 0.17 vs. 0.22 +/- 0.05 mlU/mg creatinine, p < 0.01). Urinary activity of plasmin was significantly elevated in diabetic patients with albuminuria as compared to subjects without microalbuminuria and healthy control (0.477 +/- 0.37 vs. 0.194 +/- 0.09 vs. 0.21 +/- 0.02 mlU/mg creatinine, p < 0.01). Our data indicate that increase in the urinary excretion of extracellular matrix proteins may be the useful tool for monitoring glomerular injury.     

Sonographic patterns by transcranial Doppler in acute cerebral infarction

Microcirculatory changes occur early in insulin-dependent diabetes mellitus (IDDM) and are believed to be an early feature of late diabetic complications, leading to reduced oxygen pressure and hypoxia in the skin and other tissues. Whether muscle oxygen supply is also altered is unknown. Therefore, the authors analyzed polarographic measurements of muscle oxygen tension in 44 healthy type I diabetic patients (mean age 28 years; mean diabetes duration 7 years) and in 57 healthy controls, matched for age, sex, and body mass index, and the corresponding influencing factors. Two measurements were taken at rest 60 minutes apart in the anterior tibial muscle. Muscle oxygen tensions did not differ between IDDM patients and controls (23.0 +/- 8.6 vs 25.3 +/- 9.0 mmHg) and were reproducible on repeated measurements (25.3 +/- 9.7 vs 25.5 +/- 7.4 mmHg). Coefficients of variation were 13.5 +/- 10.8% in IDDM patients and 13.1 +/- 9.3% in controls. Compared with controls, in IDDM patients hemoglobin A1c (HbA1c) and blood glucose concentrations were elevated, and arterial oxygen pressure was significantly lower. Muscle oxygen tensions were positively correlated with blood glucose concentrations in IDDM patients (Rho=0.48, P=0.002) but not with HbA1c or with insulin concentrations. The authors conclude that the polarographic measurement of muscle oxygen tension is a reliable method with good reproducibility. Hypoxia in the anterior tibial muscle of type I diabetic patients can be excluded. In IDDM patients the level of muscle oxygen tension is correlated with the level of blood glucose concentration.     

Role of nitric oxide in the vasodilator response to mental stress in normal subjects

Vascular production of nitric oxide (NO) plays an important role in a variety of physiologic processes. This study examines the contribution of NO to the vasodilator response to mental stress. The effects of mental arithmetic testing on forearm vascular dynamics were analyzed in 15 normal subjects (9 men; age 45 +/- 12 years) during intraarterial infusion of either saline or N(G)-monomethyl-L-arginine (L-NMMA; 4 micromol/min for 15 minutes), an inhibitor of NO synthesis. The effect of L-NMMA on endothelium-independent vasodilation induced by intraarterial infusion of sodium nitroprusside was also studied in 11 of the 15 subjects. Forearm blood flow was measured by plethysmography. Mental stress increased forearm blood flow from 2.35 +/- 0.84 to 5.06 +/- 2.66 ml/min/dl (115%) during saline and from 1.72 +/- 0.59 to 2.81 +/- 0.99 ml/min/dl (63%) during L-NMMA infusion. The vasodilator effect of mental stress was significantly lower during L-NMMA infusion than during saline (1.1 +/- 0.65 vs 2.71 +/- 2.15 ml/min/dl; p = 0.01). L-NMMA administration did not significantly change mean arterial pressure and heart rate responses to mental stress. In contrast, the vasodilator effect of sodium nitroprusside (1.6 microg/min) was similar during infusion of L-NMMA and during saline (3.75 +/- 1.55 vs 2.85 +/- 1.38 ml/min/dl; p = 0.16). These findings indicate that local release of NO is involved in the forearm vasodilator response to mental stress.     

Basal and stimulated sympathetic responses after epinephrine: no evidence of augmented responses

Delayed facilitation of norepinephrine release through the action of epinephrine (NE) at presynaptic beta-adrenoceptors has been postulated to account for the delayed hemodynamic effects of epinephrine and to be a mechanism causally related to the development of hypertension. To determine whether a short-term increase in epinephrine concentrations resulted in subsequent facilitation of sympathetic responses, 9 healthy subjects (age, 21+/-0.9 years) were studied at rest and during physiological stress on 2 occasions when they received an infusion of either saline or epinephrine (20 ng/kg per minute) in random order. Heart rate, blood pressure, forearm blood flow, epinephrine concentrations, and NE spillover were measured at rest, during mental stress (Stroop test), and during a cold pressor test. Measurements were performed before, during the 1-hour infusion of epinephrine or placebo, and 1 hour after the infusion. A radioisotope dilution method was used to measure NE spillover. Hemodynamic measurements and NE spillover were increased during the infusion of epinephrine, but 1 hour after discontinuation of epinephrine there was no significant augmentation of hemodynamic or sympathetic responses. NE spillover 1 hour after saline or epinephrine infusion was similar (0.85+/-0.2 versus 0. 87+/-0.2 microg/min; P=0.92). In addition, there was no delayed facilitation of stress-induced hemodynamic or NE responses after epinephrine. These findings do not support the hypothesis that epinephrine results in delayed facilitation of NE release.     

Influence of circulating epinephrine and norepinephrine on insulin-like growth factor binding protein-1 in humans

The aim of the present study was to investigate the influence of circulating epinephrine (Epi) and norepinephrine (Norepi) on serum insulin-like growth factor binding protein-1 (IGFBP-1) concentrations. Healthy men received 0.3 nmol.kg.min Epi iv (n = 6), 0.5 nmol.kg.min Norepi iv (n = 7), or saline (n = 5) during 30 min. Arterial blood samples were obtained before, during, and 120 min after infusion. During the catecholamine infusion arterial Epi and Norepi plasma concentrations reached 6.35 +/- 0.53 and 15.65 +/- 2.71 nmol/L, respectively, which resulted in significant increases in glucose concentrations. When Epi was infused, IGFBP-1 increased from 45 +/- 6 micrograms/L to 76 +/- 10 micrograms/L (P < 0.05) 60 min after the infusion. Epi was also followed by increases in insulin, C-peptide, and glucagon. Norepi resulted in a slight increase in circulating IGFBP-1 (43 +/- 6 to 54 +/- 8 nmol/L, NS). The findings suggest that Epi, at plasma concentrations similar to those reached during physical stress, stimulates the production of IGFBP-1 in humans.     

Caring, patient autonomy and the stigma of paternalism

BACKGROUND: Epinephrine increases the metabolic rate and contributes to the hypermetabolic state in severe illness. OBJECTIVE: We sought to determine the effect of prolonged elevation of epinephrine on resting energy expenditure (REE). DESIGN: Thirteen healthy men were placed on a well-defined diet for 5 d. Beginning on the morning of the second diet day, the subjects were infused for 24 h with saline, then for 23 h with epinephrine (0.18 nmol x kg(-1) x min(-1)) to increase plasma epinephrine concentrations into the high physiologic range (4720 +/- 340 pmol/L). REE and the respiratory quotient (RQ) were measured by indirect calorimetry in the postabsorptive state at the same time every morning. RESULTS: Infusion of epinephrine significantly increased heart rate and systolic blood pressure, but the response was transient (values after 23 h of epinephrine infusion were not significantly different from those on the day saline was infused). Infusion of epinephrine significantly increased REE by 12% and increased the RQ. These changes were apparent at the end of the 23-h infusion (REE: 97.5 +/- 2.3 kJ x kg(-1) x d(-1) with saline infusion and 108.9 +/- 2.3 kJ x kg(-1) x d(-1) with epinephrine infusion; RQ: 0.832 +/- 0.012 with saline infusion and 0.879 +/- 0.013 with epinephrine infusion). REE returned to baseline by 24 h after the epinephrine infusion ended, but the postabsorptive RQ remained modestly elevated. Infusion of epinephrine also produced a transient increase in urine flow and in urinary nitrogen excretion. This diuresis was compensated for by a drop in urine volume and nitrogen excretion after the epinephrine infusion was stopped. CONCLUSIONS: Epinephrine produced a prolonged increase in REE in healthy subjects. The fuel for this increase in REE, determined by the RQ, was from increased carbohydrate oxidation, not from that of fat or protein.     

Maternal country of origin and infant birthplace: implications for birth-weight

Insulin-dependent diabetes mellitus (IDDM) is characterized by altered composition of atherogenic lipoproteins, especially a depletion in choline-containing phospholipids (PL) of apolipoprotein (apo) B lipoproteins (LpB). To determine the effects of continuous intraperitoneal (IP) insulin infusion (CIPII) on this qualitative lipoprotein abnormality, we compared lipoprotein profiles of 14 IDDM patients treated by continuous subcutaneous insulin infusion (CSII) and at 2 and 4 months after treatment with CIPII using an implantable pump. IDDM patients were in fair metabolic control and were compared with 14 healthy control subjects matched for sex, age, body mass index, and plasma lipids. The following parameters were studies: hemoglobin A1c (HbA1c), monthly blood glucose, daily insulin dose (units per kilogram per day), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, apo A-I, and apo B. Choline-containing PL were assessed in plasma and in apo B- and no-apo B-containing lipoprotein particles (LpB and Lp no B). As compared with the control group, plasma PL and LpB-PL were significantly lower in IDDM patients treated by CSII (2.95 +/- 0.26 v 3.30 +/- 0.45 mmol/L,P<.05, and 1.09 +/- 0.45 v 1.68 +/- 0.33 mmol/L,P<.01, respectively). No significant differences were observed for Lp no B lipid determinations between both groups. After initiation of CIPII, IDDM patients did not experience any significant changes in mean values for body mass index, HbA1c, and monthly blood glucose throughout the study. Daily insulin doses were identical to those observed before IP therapy. Lipid parameters remained unchanged in IDDM patients (TC, TG, HDL and LDL cholesterol, apo A-I, and apo B). A moderate but progressive elevation of plasma PL was noted, and after 4 months of CIPII, PL and LpB-PL levels were no longer significantly different between IDDM patients and controls. The increase in plasma and LpB choline-containing PL observed after 2 and 4 months of CIPII is not linked to changes in blood glucose control, body weight or daily insulin requirements. These changes may be related to the route of insulin administration, which may be accompanied by a reduction of lipoprotein lipase (LPL) activity and consequently a reduction of phospholipase activity. These results suggest that IP insulin delivery may be a more physiological route that increases the choline-containing PL content of LpB particles.     

Glucagon-like peptide 1 improves the ability of the beta-cell to sense and respond to glucose in subjects with impaired glucose tolerance

Impaired glucose tolerance (IGT) and NIDDM are both associated with an impaired ability of the beta-cell to sense and respond to small changes in plasma glucose concentrations. The aim of this study was to establish if glucagon-like peptide 1 (GLP-1), a natural enteric peptide and potent insulin secretagogue, improves this defect. Two weight-matched groups, one with eight subjects having IGT (2-h glucose, 10.1 +/- 0.3 mmol/l) and another with seven subjects with diet-treated NIDDM (2-h glucose, 14.5 +/- 0.9 mmol/l), were studied on two occasions during a 12-h oscillatory glucose infusion, a sensitive test of the ability of the beta-cell to sense and respond to glucose. Glucose was infused with a mean rate of 4 mg x kg(-1) x min(-1), amplitude 33% above and below the mean rate, and periodicity of 144 min, with infusion of saline or GLP-1 at 0.4 pmol x kg(-1) x min(-1) for 12 h. Mean glucose levels were significantly lower in both groups during the GLP-1 infusion compared with during saline infusion: 9.2 +/- 0.4 vs. 6.4 +/- 0.1 mmol/l in the IGT subjects (P < 0.0004) and 14.6 +/- 1.0 vs. 9.3 +/- 0.7 mmol/l in NIDDM subjects (P < 0.0002). Despite this significant reduction in plasma glucose concentration, insulin secretion rates (ISRs) increased significantly in IGT subjects (513.3 +/- 77.6 vs. 583.1 +/- 100.7 pmol/min; P < 0.03), with a trend toward increasing in NIDDM subjects (561.7 +/- 122.16 vs. 642.8 +/- 128 pmol/min; P = 0.1). These results were compatible with enhanced insulin secretion in the presence of GLP-1. Spectral power was used as a measure of the ability of the beta-cell to secrete insulin in response to small changes in the plasma glucose concentration during the oscillatory infusion. Spectral power for ISR increased from 2.1 +/- 0.9 during saline infusion to 7.4 +/- 1.3 during GLP-1 infusion in IGT subjects (P < 0.004), but was unchanged in NIDDM subjects (1.0 +/- 0.4 to 1.5 +/- 0.6; P = 0.3). We concluded that low dosage GLP-1 improves the ability of the beta-cell to secrete insulin in both IGT and NIDDM subjects, but that the ability to sense and respond to subtle changes in plasma glucose is improved in IGT subjects, with only a variable response in NIDDM subjects. Beta-cell dysfunction was improved by GLP-1 infusion, suggesting that early GLP-1 therapy may preserve beta-cell function in subjects with IGT or mild NIDDM.     

Physiologic hyperinsulinemia enhances counterregulatory hormone responses to hypoglycemia in IDDM

We evaluated the effect of physiologic hyperinsulinemia (plasma insulin 329 +/- 62 vs 687 +/- 62 pmol/L) on counterregulatory hormone responses in 8 IDDM subjects studied during a 2-hour hypoglycemic clamp study with an equivalent degree of hypoglycemia (plasma glucose 3.1 +/- 0.1 and 3.0 +/- 0.1 mmol/L, respectively). Plasma epinephrine levels were increased by 71% during the last 60 minutes of hypoglycemia in the high insulin study (840 +/- 180 vs 1440 +/- 310 pmol/L, respectively p = 0.006). In addition, plasma cortisol and norepinephrine were also increased in the high insulin study (by 19% and 24% respectively, p < 0.01, for both). Plasma growth hormone and glucagon concentrations were not altered by high dose insulin infusion. In spite of increased epinephrine secretion, the glucose infusion rate required to maintain glucose was 2-fold greater in the high insulin study, and there was greater suppression of lipolysis in that group. We conclude that hyperinsulinemia may enhance counterregulatory hormone secretion in IDDM.     

Glucagon-like peptide-1 reduces hepatic glucose production indirectly through insulin and glucagon in humans

The effect of glucagon-like peptide-1 (GLP-1) on hepatic glucose production and peripheral glucose utilization was investigated with or without infusion of somatostatin to inhibit insulin and glucagon secretion in 13 healthy, non-diabetic women aged 59 years. After 120 min 3-(3)H-glucose infusion, GLP-1 was added (4.5 pmol kg(-1) bolus + 1.5 pmol kg(-1) min(-1)). Without somatostatin (n = 6), GLP-1 decreased plasma glucose (from 4.8 +/- 0.2 to 4.2 +/- 0.3 mmol L(-1), P = 0.007). Insulin levels were increased (48 +/- 3 vs. 243 +/- 67 pmol L(-1), P = 0.032), as was the insulin to glucagon ratio (P = 0.044). The rate of glucose appearance (Ra) was decreased (P = 0.003) and the metabolic clearance rate of glucose (MCR) was increased during the GLP-1 infusion (P = 0.024 vs. saline). Also, the rate of glucose disappearance (Rd) was reduced during the GLP-1 infusion (P = 0.004). Since Ra was reduced more than Rd, the net glucose flow was negative, which reduced plasma glucose. Somatostatin infusion (500 microg h(-1), n = 7) abolished the effects of GLP-1 on plasma glucose, serum insulin, insulin to glucagon ratio, Ra, Rd, MCR and net glucose flow. The results suggest that GLP-1 reduces plasma glucose levels mainly by reducing hepatic glucose production and increasing the metabolic clearance rate of glucose through indirectly increasing the insulin to glucagon ratio in healthy subjects.     

Modulation of the immunologic response to acute stress in humans by beta-blockade or benzodiazepines

Autoantibodies against heat shock protein (hsp) 60 have been reported to be detected in sera of non-obese diabetic mice, in an experimental model of IDDM. However, there are only a few studies which have examined IDDM patients for antibodies against mammalian hsp60. We produced murine hsp60 derived from pancreatic beta cells which has high homology to human hsp60 and examined antibodies against the hsp60 in IDDM patients using an enzyme-linked immunosorbent assay. We extended the analysis to patients with other immune-mediated diseases and non-insulin-dependent diabetes mellitus (NIDDM). Positive sera for hsp60 antibody were more frequently detected in 13 out of 84 IDDM (15.5%) and 5 out of 25 rheumatoid arthritis patients (20%), when compared to healthy subjects (1/85; 1.2%, P < 0.001 and P < 0.01, respectively). The levels of hsp60 antibodies of IDDM (0.218 +/- 0.227) and rheumatoid arthritis patients (0.259 +/- 0.191) were significantly higher than those of healthy subjects (0.076 +/- 0.131, P < 0.001, P < 0.01, respectively). Patients with slowly progressive IDDM (n = 26), autoimmune thyroid disease (n = 42), or NIDDM (n = 40) had levels of hsp60 antibodies similar to those in healthy subjects. We found no relationship between the levels of hsp60 antibodies and islet cell antibodies (ICA) or antibodies to glutamic acid decarboxylase (GAD65) in IDDM patients. In conclusion, hsp60 antibodies were detected in Japanese IDDM as well as in rheumatoid arthritis patients. Although the positivity was low, the detection of hsp60 antibodies may be helpful for diagnosis of IDDM especially in GAD65 Ab- or JCA-negative Japanese patients.     

Immune response to glycated and oxidized LDL in IDDM patients with and without renal disease

OBJECTIVE: To study autoantibodies to oxidized and glycated LDL in IDDM patients with and without diabetic nephropathy and in nephropathy-related macroangiopathy RESEARCH DESIGN AND METHODS: The study included 101 IDDM patients with a long duration of diabetes and 54 healthy subjects. Patients were divided into two groups according to their median urinary albumin excretion rate (AER); the normoalbuminuric group had AER <20 microg/min and the albuminuric group >200 microg/min. The groups were matched for age and BMI, and the two diabetic groups were matched for duration of diabetes and glycemic control. Antibodies against oxidized LDL (using malondialdehyde-modified LDL as the antigen) and against glycated LDL were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The mean antibody levels against glycated LDL were higher in IDDM patients (0.305 +/- 0.399) than in healthy subjects (0.166 +/- 0.22 optical density [OD]; P = 0.019), but levels did not differ significantly between normoalbuminuric and albuminuric IDDM patients (0.258 +/- 0.354 vs. 0.388 +/- 0.459, respectively). Among the three groups, antibody levels to oxidized LDL did not differ. IDDM patients showed an inverse correlation between antibodies to oxidized LDL and HbA1 (r = -0.211, P = 0.04). The antibody levels to glycated and oxidized LDL did not differ among albuminuric IDDM patients with or without clinical macroangiopathy. CONCLUSIONS: Antibodies to glycated and oxidized LDL do not seem to associate with diabetic nephropathy or nephropathy-related macroangiopathy.