Insulin sensitivity of splanchnic and peripheral adipose tissue in vivo in morbidly obese man.

Epidemiologic studies demonstrate an association between increased waist to hip ratio ([WHR] android obesity, central obesity) and diabetes mellitus in man. To study the relative insulin sensitivity of splanchnic versus peripheral adipose tissue, portal vein catheterization via the collapsed umbilical vein was performed in 14 morbidly obese subjects at the time of surgery. Catheters were also placed in a peripheral artery and antecubital vein such that simultaneous arterio-venous (A-V) differences (glycerol, free fatty acids [FFA], and lactate) could be determined. After two baseline samples obtained 3 minutes apart, 25 g intravenous (i.v.) glucose (14 subjects) was administered over a 2-minute period, with samples being obtained every 5 minutes for 30 additional minutes. Arterial plasma glycerol levels decreased from 173.9 +/- 17.4 mumol/L at baseline to 89.1 +/- 7.6 mumol/L at 30 minutes (P < .01). Peripheral and splanchnic A-V glycerol differences were similar at baseline, but within 10 minutes after glucose administration the difference across the splanchnic area decreased by 52% and remained significantly less than that across the periphery (P < .01). Despite a 49% decrease in arterial plasma glycerol level, plasma FFA level decreased only 18.3% over the 30-minute period (942 +/- 74.8 to 770.0 +/- 76 mumol/L, NS). These studies in morbidly obese man (glycerol data) indicate a greater insulin sensitivity of splanchnic adipose tissue than of peripheral adipose tissue. Thus hypertrophy of fat in the splanchnic area might be an expected consequence of the hyperinsulinemia associated with insulin-resistant states.

In vivo evidence for hepatic autoregulation during FFA-stimulated gluconeogenesis in normal humans.

To examine the effect of increased gluconeogenesis [by increasing free fatty acids (FFA)] on hepatic glucose output (HGO) and on the first substrate (glucose) cycle, a primed continuous infusion of [2-3H]- and [6-14C]glucose was infused to isotopic steady state in 12 normal male volunteers after an overnight fast. Blood samples for the determination of glucose specific activity were obtained before and after an infusion of saline (n = 6) or 10% Intralipid and heparin (90 mU.kg-1.min-1, n = 6). Plasma FFA (593.3 +/- 74.5 to 971.1 +/- 127.1 mumol/l, P = 0.007) and glycerol (68.0 +/- 5.9 vs. 222.4 +/- 32.0 mumol/l, P = 0.002) increased during the lipid infusion, and beta-hydroxybutyrate levels rose from 0.24 +/- 0.12 to 0.50 +/- 0.17 mmol/l (P = 0.01). No change in plasma glucose, insulin, or glucagon levels was observed during the study, and levels of the gluconeogenic substrates alanine and lactate were also unchanged. Baseline rates of glucose cycling (rate of appearance of [2-3H]glucose minus rate of appearance of [6-14C]glucose) were similar in the two groups [1.44 +/- 0.33 vs. 1.33 +/- 0.44 mumol.kg-1.min-1, not significant (NS)] and did not change during either saline or lipid infusion, respectively. However, Cori cycle activity (the conversion of [6-14C]- to [1-14C]glucose) increased significantly from 0.59 +/- 0.19 to 1.28 +/- 0.19 mumol.kg-1.min-1 (P = 0.002) after FFA and glycerol levels had been increased, in marked contrast to the saline control (0.51 +/- 0.18 to 0.39 +/- 0.18 mumol.kg-1.min-1, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for dual control mechanism regulating hepatic glucose output in nondiabetic men.

We previously reported a fall in hepatic glucose output (HGO) during sleep accompanied by reductions in glucose utilization (Rd) and free fatty acids (FFAs). This study was undertaken to determine the potential role of changes in Rd and FFA on HGO in nondiabetic men. To determine if the fall in HGO during sleep could be reversed by FFA elevation, seven nondiabetic men underwent [3-3H]glucose infusions from 2200 to 0800, with heparin (90 mU.kg-1.min-1) added at 0200. Glucose appearance (Ra) fell from 11.7 +/- 1.1 at 2430 to 8.9 +/- 0.8 mumol.kg-1.min-1 (P less than 0.05) at 0200. The fall in Ra was associated with decreases in FFA (0.57 +/- 0.10 to 0.48 +/- 0.07 mM) and glycerol (0.08 +/- 0.01 to 0.06 +/- 0.01 mM). Infusion of heparin significantly increased FFA and glycerol (1.09 +/- 0.21 and 0.11 +/- 0.01 mM, respectively, P less than 0.01) and resulted in a significant fall in plasma alanine, suggesting that gluconeogenesis had been increased. However, rates of glucose turnover were indistinguishable from overnight studies without heparin. In additional studies (n = 6), intralipid and heparin-induced FFA elevation (from 0.61 +/- 0.07 to 0.95 +/- 0.05 mM, P less than 0.01) stimulated gluconeogenesis ([U-14C]alanine to glucose) twofold (188 +/- 22% increase compared to 114 +/- 6% in saline control studies, P less than 0.01). However, despite increasing gluconeogenesis, overall HGO did not change (10.6 +/- 0.5 vs. 10.7 +/- 0.6 mumol.kg-1.min-1) during lipid infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated plasma levels of hyaluronate in patients with osteoarthritis and rheumatoid arthritis.

Plasma levels of hyaluronate (HA) in patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA), measured by enzyme-linked immunosorbent assay, were compared with levels in a healthy, age-matched non-arthritic control group, in a retrospective study. Compared with the controls, the mean level of plasma HA was sevenfold higher in the RA group and twofold higher in the OA group. There was no statistically significant correlation between HA levels and 7 other clinical and biochemical parameters in patients with RA. In the OA group, however, plasma HA levels were found to correlate with an objective functional capacity score and with an articular index based on the total amount of cartilage in involved joints. In a retrospective longitudinal study of 6 patients with RA, plasma levels of HA did not show a significant correlation with plasma levels of elastase or with the erythrocyte sedimentation rate. These data support in part the contention that plasma HA may be unique as a marker, in that it may be a reflection of synovial involvement and inflammation, rather than only of inflammation, in arthritis.

Effects of media conditions, insulin, and dexamethasone on insulin-receptor mRNA and promoter activity in HepG2 cells.

Numerous physiological agents and conditions modulate cellular insulin sensitivity by downregulating or upregulating total cellular insulin receptors. In this study, we examined the effects of replacing complete medium in the absence or presence of insulin on the regulation of insulin-receptor gene expression in cultured human hepatoma cells (HepG2). Failure to replace complete medium resulted in growth arrest of HepG2 cells and a six- to sevenfold increase in insulin-receptor mRNA due to the prolongation of insulin-receptor mRNA half-life. Northern analysis revealed multiple insulin-receptor mRNA species; the largest species (11 kilobases) was disproportionately increased in growth-arrested cells. High concentrations of insulin (500 ng/ml) induced a 33.8% decrease in the abundance of insulin-receptor mRNA (n = 14). At lower concentrations, a trend of inhibition was observed but was not statistically significant. Insulin (500 ng/ml) did not affect insulin-receptor mRNA stability. The effect of conditioned media, insulin, and dexamethasone on insulin-receptor promoter activity was also examined. Various constructs of the 5'-flanking region of the insulin-receptor gene were attached immediately upstream to a chloramphenicol acetyltransferase (CAT) reporter gene and transiently transfected into HepG2 cells via a pBR322-derived plasmid (pCAT). In cells replaced with complete medium, 12 and 118% of the promoter activity was contained within 578 and 877 base pairs, respectively, from the major translational initiation site. Conditioned media from growth-arrested cells in culture for 7 days increased promoter activity approximately twofold in 48 h. However, this increase failed to localize to any specific region on the insulin-receptor promoter.(ABSTRACT TRUNCATED AT 250 WORDS)

Accelerated decline in hepatic glucose production during fasting in normal women compared with men.

Plasma glucose values have been reported to be lower in women than in men after a 72-hour fast. However, a comparison of glucose kinetics in fasting men and women has not been described. Therefore, five normal men and five normal women underwent sequential 3-3H-glucose infusions after both a 14- and a 64-hour fast. Plasma glucose levels fell similarly during the fast in men (5.23 +/- 0.03 v 3.96 +/- 0.14 mmol/L, P less than .01) and women (4.84 +/- 0.14 v 3.65 +/- 0.25 mmol/L, P less than .01). The fall in plasma glucose was associated with a significantly greater fall in glucose appearance (Ra) in women compared with men (P less than .05). Ra fell 15.8% +/- 3.0% in men (2.11 +/- 0.24 to 1.79 +/- 0.24 mg.kg-1.min-1, P less than .01) and 24.6% +/- 1.4% in women (2.22 +/- 0.17 to 1.67 +/- 0.12 mg.kg-1.min-1, P less than .001). During the fast, plasma glycerol, free fatty acids (FFA), and beta-hydroxybutyrate levels rose significantly and plasma alanine fell significantly in both sexes. Plasma glycerol levels were significantly higher in women compared with men after fasting (0.16 +/- 0.01 v 0.11 +/- 0.02 mmol/L, P less than .05). In addition, the transition from ambulation to bed rest demonstrated unexpected sex-related differences in glucose homeostasis after the 64-hour fast. During the two-hour equilibration period required for glucose kinetic studies (subjects reclining), significant decrements in glucose, FFA, and lactate were observed in the 64-hour fasted women but not in the men.(ABSTRACT TRUNCATED AT 250 WORDS)

Protein-bound homocyst(e)ine in patients with rheumatoid arthritis undergoing D-penicillamine treatment.

Protein-bound homocyst(e)ine was measured in the plasma of 38 nonhomocystinuric patients with rheumatoid arthritis. Nineteen of them were treated orally with D-penicillamine 100-1,500 mg/d for a period of one month to 15 years. For these patients, the mean +/- standard deviation level of plasma protein-bound homocyst(e)ine was 1.95 +/- 1.07 nmol/mL. In contrast, the mean plasma level of protein-bound homocyst(e)ine was 4.72 +/- 1.11 nmol/mL in the 19 patients who had not been treated with oral D-penicillamine. There was a statistically significant difference (P less than .0001) in the plasma protein-bound homocyst(e)ine concentrations between patients with and without oral D-penicillamine therapy. Thus, it may be speculated that oral D-penicillamine may be beneficial in protecting patients from the development of thromboembolism and arteriosclerosis.

Comparison of pain properties in fibromyalgia patients and rheumatoid arthritis patients.

Pain properties of 50 fibromyalgia patients were examined and compared with pain properties of 50 rheumatoid arthritis patients. In both fibromyalgia and rheumatoid arthritis, pain was bilateral, involved multiple sites, and was of equal intensity (60.8 versus 58.7, respectively, on a scale of 100). Fibromyalgia pain, however, was less localized to the joints and suggested greater spatial diffusion. It involved more kinds of pain experiences (radiating, steady, spreading, spasms, gnawing, unlocalized, pricking, crushing, shooting, pressing, splitting, cramping, nagging, and pins and needles), and was dispersed over larger areas of the body. The anatomic sites best for discrimination between patients with fibromyalgia and patients with rheumatoid arthritis were the lower back, thigh, abdomen, head, and hips for fibromyalgia, and wrist, foot, and fingers for rheumatoid arthritis. The traditional clinical description of aching and stiffness does not appear to accurately describe the complexity of the fibromyalgia pain syndrome.

Quantification of keratan sulfate in blood as a marker of cartilage catabolism.

We have developed an enzyme-linked immunosorbent-inhibition assay which makes use of a monoclonal antibody specific for keratan sulfate to quantify keratan sulfate present as single chains in adult human serum. In adults hospitalized with conditions not thought to affect the turnover of keratan sulfate-containing tissues, the serum levels varied from individual to individual (53-1,009 ng/ml) but did not show significant differences with respect to age, sex, or disease category. There were no significant differences between the serum levels of adult hospitalized patients and those of nonhospitalized normal adults. In contrast, the concentration of keratan sulfate in the sera of children aged 5-12 was significantly higher. No keratan sulfate was detected in the sera of 3 adult patients with macular corneal dystrophy, an inherited disorder of the cornea. This may indicate that individuals with macular corneal dystrophy have no keratan sulfate-containing proteoglycans in their cartilage. Adult patients with osteoarthritis have significantly higher concentrations of circulating keratan sulfate. This suggests that the assay could prove valuable in monitoring increased cartilage catabolism in joint diseases.

Fibrositis and psychologic disturbance.

Thirty patients with fibrositis and 2 control groups, one of rheumatoid arthritis patients and the other of arthritis patients with other than rheumatoid arthritis, were compared on the basis of the Minnesota Multiphasic Personality Inventory (MMPI) to assess the role of psychologic factors in fibrositis. Patients with fibrositis differed in both elevation and variability in their MMPI profiles, indicating that they were more psychologically disturbed than patients with rheumatoid or other types of arthritis. The fact that almost all of the fibrositis patients' MMPI scales were higher suggests that we might be dealing with a number of different psychologic disturbances that have stiffness and musculoskeletal pain as principal and common symptoms.

Diabetic vacuolation of the iris pigment epithelium.

In a postmortem study of 57 diabetic patients, 19 of 23 patients with blood glucose levels greater than 200 mg/100 ml in the 72-hour period before death showed the characteristic histologic findings of "lacy" vacuolation of the iris pigment epithelium as well as vacuolation of the renal tubules (Armanni-Ebstein nephropathy). Conversely, 33 of the remaining 34 patients with blood glucose levels below 200 mg/100 ml in the 72-hour period prior to death showed no vacuolation in the iris or kidney.