Evidence for alteration of the vitamin D-endocrine system in blacks

As compared with values in white subjects, bone mass is known to be increased and urinary calcium to be diminished in black individuals. To evaluate the possibility that these changes are associated with alterations in the vitamin D-endocrine system, an investigation was performed in 12 black subjects, 7 men and 5 women, and 14 white subjects, 8 men and 6 women, ranging in age from 20 to 35 yr. All of them were hospitalized on a metabolic ward and were given a constant daily diet containing 400 mg of calcium, 900 mg of phosphorus, and 110 meq of sodium. Whereas mean serum calcium, ionized calcium, and phosphate were the same in the two groups, mean serum immunoreactive parathyroid hormone (350 +/- 34 vs. 225 +/- 26 pg/ml, P less than 0.01) and mean serum 1,25-dihydroxyvitamin D (1,25(OH)2D) (41 +/- 3 vs. 29 +/- 2 pg/ml, P less than 0.01) were significantly higher, and mean serum 25-hydroxy-vitamin D (25-OHD) was significantly lower in the blacks than in the whites (6 +/- 1 vs. 20 +/- 2 ng/ml, P less than 0.001). Mean urinary sodium and 24-h creatinine clearance were the same in the two groups, whereas mean urinary calcium was significantly lower (101 +/- 14 vs. 166 +/- 13 mg/d, P less than 0.01) and mean urinary cyclic AMP was significantly higher (3.11 +/- 0.47 vs. 1.84 +/- 0.25 nM/dl glomerular filtrate, P less than 0.01) in the blacks. Further, the blacks excreted an intravenous calcium load, 15 mg/kg body weight, as efficiently as the whites (49 +/- 3 vs. 53 +/- 3%, NS). Mean serum Gla protein was lower in blacks than in whites (14 +/- 2 vs. 24 +/- 3 ng/ml, P less than 0.02), and increased significantly in both groups in response to 1,25(OH)2D3, 4 micrograms/d for 4 d. There was a blunted response of urinary calcium to 1,25(OH)2D3 in the blacks, and mean serum calcium did not change. The results indicate that alteration of the vitamin D-endocrine system with enhanced renal tubular reabsorption of calcium and increased circulating 1,25(OH)2D as a result of secondary hyperparathyroidism may contribute to the increased bone mass in blacks. Their low serum 25-OHD is attributed to diminished synthesis of vitamin D in the skin because of increased pigment.     

Dietary considerations for obese diabetic subjects

Individuals with an upper-body form of obesity show greater associations with higher glucose excursions, exacerbated insulin resistance, increased abnormality of lipoprotein profile, and higher cardiovascular risk. Individuals with obesity and diabetes are at great risk for cardiovascular disease. Weight reduction and improvement in blood glucose control through dietary interventions for the obese person with non-insulin-dependent diabetes mellitus (NIDDM) hold the greatest potential for reducing morbidity and mortality. The relative merits of different weight-reduction programs are unclear, but regimens should be nutritionally complete, easy to follow, and include a program for maintaining the reduced weight level. Improvement in insulin action and the possibility of slowing development of clinical nephropathy or end-stage renal disease in NIDDM through weight loss have been found. Very low calorie diets, when used with medical supervision, may lead to significant weight loss, improved metabolic status, and even reduction or elimination of the need for oral hypoglycemic agents or insulin; however, further studies are needed to examine possible negative outcomes in people with NIDDM before very low calorie diets can be recommended. The causes of obesity and its connection with diabetes are unclear, but even modest calorie restriction may be beneficial to obese diabetic patients because of the positive effects on blood glucose levels and requirements for insulin and oral antidiabetic agents.     

Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting.

Little is known about leptin's interaction with other circulating proteins which could be important for its biological effects. Sephadex G-100 gel filtration elution profiles of 125I-leptin-serum complex demonstrated 125I-leptin eluting in significant proportion associated with macromolecules. The 125I-leptin binding to circulating macromolecules was specific, reversible, and displaceable with unlabeled leptin (ED50: 0.73 +/- 0.09 nM, mean +/- SEM, n = 3). Several putative leptin binding proteins were detected by leptin-affinity chromatography of which either 80- or 100-kD proteins could be the soluble leptin receptor as approximately 10% of the bound 125I-leptin was immunoprecipitable with leptin receptor antibodies. Significantly higher (P < 0.001) proportions of total leptin circulate in the bound form in lean (46.5 +/- 6.6%) compared with obese (21.4 +/- 3.4%) subjects. In lean subjects with 21% or less body fat, 60-98% of the total leptin was in the bound form. Short-term fasting significantly decreased basal leptin levels in three lean (P < 0.0005) and three obese (P < 0.005) subjects while refeeding restored it to basal levels. The effects of fasting on free leptin levels were more pronounced in lean subjects (basal vs. 24-h fasting: 19.6 +/- 1.9 vs. 1.3 +/- 0.4 ng/ml) compared with those in obese subjects (28.3 +/- 9.8 vs. 14.7 +/- 5.3). No significant (P > 0.05) decrease was observed in bound leptin in either group. These studies suggest that in obese individuals the majority of leptin circulates in free form, presumably bioactive protein, and thus obese subjects are resistant to free leptin. In lean subjects with relatively low adipose tissue, the majority of circulating leptin is in the bound form and thus may not be available to brain receptors for its inhibitory effects on food intake both under normal and food deprivation states.     

Vancomycin pharmacokinetics in normal and morbidly obese subjects.

In an uncontrolled study, vancomycin pharmacokinetics were determined in four normal (total body weight [TBW], 65.9 to 89.1 kg) and six morbidly obese (TBW, 111.4 to 226.4 kg) subjects. The morbidly obese subjects were investigated 3 to 4 h after gastric bypass surgery. Mean terminal half-lives, volumes of distribution, and total body clearances for the normal controls and the morbidly obese (TBW, 111.4 to 226.4 kg) subjects. The morbidly obese subjects were investigated 3 to 4 h after gastric bypass surgery. Mean terminal half-lives, volumes of distribution, and total body clearances for the normal controls and the morbidly obese subjects were 4.8 h, 0.39 liter/kg, and 1.085 ml/min per kg versus 3.2 h, 0.26 liter/kg TBW, and 1.112 ml/min per kg TBW. The mean terminal half-life and volume of distribution values were significantly different between the two groups. Strong correlations were found between TBW and both volume of distribution (correlation coefficient, 0.943) and total body clearance (correlation coefficient, 0.981). There results implied that TBW should be used to calculate vancomycin doses for morbidly obese patients. This was supported by the finding that there was no significant difference in the daily dose (in milligrams per kilogram per day) required to produce an average steady-state concentration of 15 micrograms/ml in the two groups (23.4 +/- 1.5 mg/kg per day for normal weight subjects and 24.0 +/- 3.4 mg/kg per day TBW for the postsurgery morbidly obese subjects). Therefore, the morbidly obese required higher total doses (in milligrams per day) than did normal weight subjects to achieve the same mean steady-state concentrations. In addition, normal weight and morbidly obese subjects had similar volumes of the central compartment (7.7 and 6.4 liters, respectively). To avoid high transient peak concentrations which would occur when obese patients are given larger total doses (in milligrams per day), maintenance doses may be given at more frequent intervals. The shorter mean terminal half-lives observed in morbidly obese patients allows more frequent dosing without excessive accumulation.     

Reference values for the 6-Min Walking Test in obese subjects

Purpose: The 6-Min Walking Test (6MWT) is widely used to measure the performance in various chronic conditions, such as in obese subjects. Reference equations for predicting distance walked during 6MWT specifically in adult obese subjects are not available. The aim of the paper is to establish reference values for 6MWT in an adult obese population. Methods: 323 obese patients (body mass index: BMI > 30?kg/m², age range 20–60 years) admitted to our hospital for multidisciplinary rehabilitation and weight reduction programs were evaluated using 6MWT, heart rate, blood pressure, oxygen saturation, anthropometric measurements and level of dyspnoea were considered as outcome measure. Results: Distance walked during the 6MWT was significantly correlated to age, gender and BMI. The proposed reference equation is: 6MWTm = 894.2177 ? (2.0700 × age_yrs) ? (51.4489 × gender_{males = 0; females = 1}) ? 5.1663 × BMI_Kg/m2. In the multiple linear regression analysis age, gender and BMI explained 48% of the total variance in 6MWT. The average difference between predicted and measured 6MWT values (11.33?±?52.98 m) did not reach statistical significance and the correlation was significant (r = 0.698). Conclusions: A reference equation specific for the obese population was provided; it can be used as realistic benchmark in the rehabilitation setting to assess functional capacity, plan exercise intensity and monitor changes over time.

Implications for Rehabilitation

• The 6-Min Walking Test (6MWT) is generally used to measure functional capacity in various chronic conditions.

• Obesity is associated with reduced aerobic capacity and mobility disability but no reference equations for predicting distance walked during 6MWT are present.

• This study provides reference values specific for the obese population.

     

Cardiac autonomic dysfunction in obese subjects

1. The prevalence of cardiac autonomic alterations was evaluated in 23 obese subjects with body mass index 37.2 +/- 3.03 kg/m2 (mean +/- SD), compared with 78 controls with body mass index 22.5 +/- 2.6 kg/m2 (P less than 0.001). 2. Cardiac autonomic function was assessed by four standard tests (heart rate response to deep breathing and to the Valsalva manoeuvre, systolic blood pressure fall after standing and diastolic pressure rise during handgrip) and by the cross-correlation test, a new method of computerized analysis of respiratory sinus arrhythmia based on spectral analysis of electrocardiographic and respiratory signal. 3. Considering tests indicative of parasympathetic function, only the heart rate response to the deep breathing and the cross-correlation test were significantly lower in the obese than in the control group [deep breathing = 13.95 +/- 8.65 beats/min (mean +/- SD) vs 24.5 +/- 7.65, P less than 0.001; cross-correlation 4.28 +/- 0.74 units vs 5.14 +/- 0.63, P less than 0.001]. Deep breathing and/or cross-correlation were abnormal in 10 (43.5%) obese subjects (deep breathing: seven subjects, cross-correlation: eight subjects). No significant difference between groups was found for the response to the Valsalva manoeuvre: the Valsalva ratio was 1.69 +/- 0.45 in obese subjects and 1.88 +/- 0.33 in controls (P = NS). The Valsalva ratio was abnormal in three obese subjects. 4. No significant differences were found between groups for tests indicative of sympathetic function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies of liver insulin receptors in non-obese and obese human subjects.

The insulin-binding isotherms and the structural composition of human liver insulin receptors were examined by using plasma membranes that were prepared from liver biopsies of nine non-obese and 10 obese subjects undergoing elective surgery. The insulin-binding characteristics of liver membranes from non-obese subjects were quite similar to those previously described in rat liver membranes. However, when the membranes from obese subjects were compared with the non-obese group, insulin-binding activity was reduced by 50% (P less than 0.01). The reduction in obesity resulted primarily from a decrease in total receptor number, although a small decrease in receptor affinity was also observed. Insulin binding was not correlated with sex or with the fasting plasma insulin level. The insulin-binding sites of liver membranes were affinity-labeled with 125I-insulin and the cross-linking reagent, disuccinimidyl suberate. The liver membranes from both the non-obese and the obese group had heterogenous (nonreduced) insulin-binding species of 300,000, 260,000, and 150,000 mol wt, which were again comparable to the findings reported in rat liver. Sulfhydryl reduction demonstrated a major sub-unit of 125,000 and a minor component of 40,000-45,000 in both groups. These results indicate a close similarity between the hepatic insulin receptor of man and the more intensely studied rat hepatic receptor. Obesity in human subjects is associated with a loss of hepatic insulin receptors. This alteration may contribute to the insulin resistance reported in this organ as well as to obesity-mediated glucose tolerance.     

Relationship between apolipoproteins and the alteration of HDL subclasses in hyperlipidemic subjects

BACKGROUND: To elucidate the relationship between the apolipoproteins, especially apoA-I and the alteration of HDL subclasses in hyperlipidemic, HTC and HTG subjects. METHODS: ApoA-I contents of plasma HDL subclasses were quantitated by two-dimensional gel electrophoresis coupled with immunodetection in 233 normolipidemic subjects and 312 hyperlipidemic subjects (132 HTC and 180 HTG subjects). Making use of the mean +/-1 SD of apoA-I levels, we further subdivided normolipidemic, hyperlipidemic, HTC and HTG subjects into 3 subgroups, respectively. RESULTS: Subjects in the middle and low apoA-I subgroups had decreased HDL-C and apoA-I while increased TG, apoB100, apoCII, apoCIII and apoE concentrations. With the reduction of apoA-I concentrations, the apoA-I contents of all HDL subclasses decreased successively and significantly. The relative percentage of small-sized HDL increased significantly while those of large-sized HDL(2a), HDL(2b) decreased significantly in hyperlipidemic, especially in HTG group. Multiple liner regression result revealed that apoA-I was positively and significantly correlated with all HDL subclasses and apoA-I level influenced the distribution of HDL subclasses powerfully in hyperlipidemic subjects. CONCLUSIONS: Both the rate and efficiency of RCT might be weakened more seriously in hyperlipidemic, especially in HTG subjects with low apoA-I levels. ApoA-I level might be a powerful factor correlated with the distributions of HDL subclasses.     

Quantitative study of insulin secretion and clearance in normal and obese subjects.

The secretion and hepatic extraction of insulin were compared in 14 normal volunteers and 15 obese subjects using a previously validated mathematical model of insulin secretion and rate constants for C-peptide derived from analysis of individual decay curves after intravenous bolus injections of biosynthetic human C-peptide. Insulin secretion rates were substantially higher than normal in the obese subjects after an overnight fast (86.7 +/- 7.1 vs. 50.9 +/- 4.8 pmol/m2 per min, P less than 0.001, mean +/- SEM), over a 24-h period on a mixed diet (279.6 +/- 24.2 vs. 145.8 +/- 8.8 nmol/m2 per 24 h, P less than 0.001), and during a hyperglycemic intravenous glucose infusion (102.2 +/- 10.8 vs. 57.2 +/- 2.8 nmol/m2 per 180 min, P less than 0.001). Linear regression analysis revealed a highly significant relationship between insulin secretion and body mass index. Basal hepatic insulin extraction was not significantly different in the normal and obese subjects (53.1 +/- 3.8 vs. 51.6 +/- 4.0%). In the normal subjects, fasting insulin did not correlate with basal hepatic insulin extraction, but a significant negative correlation between fasting insulin and hepatic insulin extraction was seen in obesity (r = -0.63, P less than 0.02). This finding reflected a higher extraction in the six obese subjects with fasting insulin levels within the range of the normal subjects than in the nine subjects with elevated fasting insulin concentrations (61 +/- 3 vs. 45 +/- 6%, P less than 0.05). During the hyperglycemic clamp, the insulin secretion rate increased to an average maximum of 6.2-fold over baseline in the normal subjects and 5.8-fold in the obese subjects. Over the same time, the peripheral insulin concentration increased 14.1-fold over baseline in the normals and 16.6-fold over baseline in the obese, indicating a reduction in the clearance of endogenously secreted insulin. Although the fall in insulin clearance tended to be greater in the obese subjects, the differences between the two groups were not statistically significant. Thus, under basal, fasting conditions and during ingestion of a mixed diet, the hyperinsulinemia of obesity results predominantly from increased insulin secretion. In patients with more marked basal hyperinsulinemia and during intense stimulation of insulin secretion, a reduction in insulin clearance may contribute to the greater increase in peripheral insulin concentrations that are characteristic of the obese state.+     

Dietary induced subclinical vitamin K deficiency in normal human subjects.

A subclinical vitamin K deficiency was induced in 32 healthy subjects (four groups of eight males and females) aged 20-40 and 60-80 yr residing in the Metabolic Research Unit of the Human Nutrition Research Center on Aging at Tufts University. Volunteers were initially fed (4 d) a baseline-period diet containing the recommended daily allowance for vitamin K which is equivalent to 80 micrograms/d of phylloquinone (vitamin K1). During the baseline period various parameters of vitamin K nutritional status were monitored. The baseline period was followed by a 13-d depletion period during which the subjects were fed a very low vitamin K1 diet (approximately 10 micrograms/d). After depletion, the subjects entered a 16-d repletion period (four stages lasting 4 d each) during which time they were repleted with 5, 15, 25, and 45 micrograms of vitamin K1 per day. Vitamin K1 depletion dramatically and significantly decreased plasma vitamin K1 levels (P < 0.0001) in both elderly and young groups to values 13-18% of day 1 (elderly 0.22 nM, young 0.14 nM). Repleting the subjects with up to 45 micrograms of vitamin K1 per day failed, in the case of the young subjects, to bring plasma vitamin K1 levels back into the normal range. Dietary vitamin K1 restriction induced different responses in the urinary excretion of gamma-carboxyglutamic acid between the young and the elderly subjects with values decreasing significantly (P < 0.03) in the young while remaining unchanged in the elderly. The vitamin K1 depletion period had no significant effect on either prothrombin and activated partial thromboplastin times, or Factor VII and protein C (as determined by antigenic and functional assays). By using a monoclonal antibody, decarboxy prothrombin was found to increase slightly but significantly in both groups (P < 0.05) as a consequence of the low vitamin K1 diet. This study clearly shows that a diet low in vitamin K1 can result in a functional subclinical deficiency of vitamin K (decreased urinary gamma-carboxyglutamic acid excretion) without affecting blood coagulation.     

Multiorgan insulin sensitivity in lean and obese subjects

OBJECTIVE

To provide a comprehensive assessment of multiorgan insulin sensitivity in lean and obese subjects with normal glucose tolerance.

RESEARCH DESIGN AND METHODS

The hyperinsulinemic-euglycemic clamp procedure with stable isotopically labeled tracer infusions was performed in 40 obese (BMI 36.2 ± 0.6 kg/m², mean ± SEM) and 26 lean (22.5 ± 0.3 kg/m²) subjects with normal glucose tolerance. Insulin was infused at different rates to achieve low, medium, and high physiological plasma concentrations.

RESULTS

In obese subjects, palmitate and glucose R_a in plasma decreased with increasing plasma insulin concentrations. The decrease in endogenous glucose R_a was greater during low-, medium-, and high-dose insulin infusions (69 ± 2, 74 ± 2, and 90 ± 2%) than the suppression of palmitate R_a (52 ± 4, 68 ± 1, and 79 ± 1%). Insulin-mediated increase in glucose disposal ranged from 24 ± 5% at low to 253 ± 19% at high physiological insulin concentrations. The suppression of palmitate R_a and glucose R_a were greater in lean than obese subjects during low-dose insulin infusion but were the same in both groups during high-dose insulin infusion, whereas stimulation of glucose R_d was greater in lean than obese subjects across the entire physiological range of plasma insulin.

CONCLUSIONS

Endogenous glucose production and adipose tissue lipolytic rate are both very sensitive to small increases in circulating insulin, whereas stimulation of muscle glucose uptake is minimal until high physiological plasma insulin concentrations are reached. Hyperinsulinemia within the normal physiological range can compensate for both liver and adipose tissue insulin resistance, but not skeletal muscle insulin resistance, in obese people who have normal glucose tolerance.Obesity is associated with a constellation of metabolic alterations that are risk factors for coronary heart disease, including diabetes, dyslipidemia, and nonalcoholic fatty liver disease (1). It is likely that insulin resistance in specific organ systems, namely adipose tissue, liver, and skeletal muscle, is involved in the pathogenesis of these metabolic abnormalities (2,3). The effect of insulin resistance on daily glucose and free fatty acid (FFA) metabolism in obese people who do not have diabetes is unclear, however, because it is possible that hyperinsulinemia associated with obesity can overcome the defect in insulin action and normalize metabolic function. In fact, data from large studies have demonstrated that basal plasma glucose and FFA concentrations in obese people are not different than those in lean subjects (4). Accordingly, it is possible that many obese people have multiorgan insulin resistance and are at increased risk for development of metabolic diseases even when basal glucose and FFA concentrations are normal.The assessment of insulin action is complex because insulin has multiple metabolic functions that differ across organ systems and require different doses of insulin to achieve maximal effects (5). A multistage hyperinsulinemic-euglycemic clamp procedure (HECP), conducted in conjunction with isotopically labeled tracer infusions to measure substrate kinetics, can be used to determine simultaneously insulin action in the liver (suppression of glucose R_a into plasma), muscle (stimulation of glucose R_d from plasma), and adipose tissue (suppression of adipose tissue triglyceride lipolysis; i.e., glycerol and palmitate R_a into plasma).The primary purpose of the current study was to further understand the potential insulin-related metabolic dysfunction associated with obesity by providing a comprehensive assessment of multiorgan insulin sensitivity across a physiological range of plasma insulin concentrations in lean and obese subjects through the use of a multistage HECP in conjunction with stable isotopically labeled glucose, palmitate, and glycerol tracer infusions. Only subjects who had normal fasting plasma glucose concentrations and who did not have impaired glucose tolerance or diabetes were included in this study to eliminate the potential confounding influences of basal hyperglycemia and diabetes therapy on the assessment of insulin action. Most obese people do not have impaired glucose tolerance or diabetes, so our group represents the majority of the obese population (4). We hypothesized that hepatic glucose production and adipose tissue lipolytic rate are much more sensitive to insulin than is muscle glucose uptake. Basal hyperinsulinemia and physiological increases in plasma insulin concentration in obese subjects with normal glucose tolerance should therefore be able to overcome insulin resistance in the liver and adipose tissue but not skeletal muscle, resulting in normal rates of endogenous glucose production (EGP) and lipolysis but not glucose disposal.     

Lifestyle modification and endothelial function in obese subjects

The metabolic syndrome is a cluster of metabolic and vascular abnormalities that include central obesity, insulin resistance, hyperinsulinemia, glucose intolerance, hypertension, dyslipidemia, hypercoagulability and an increased risk of coronary and cerebral vascular disease. These metabolic and vascular abnormalities are the main cause of cardiovascular mortality in western societies. Endothelial dysfunction, an early step in the development of atherosclerosis, has been reported in obese nondiabetic individuals and in patients with Type 2 diabetes. It has also been observed in individuals at high risk for Type 2 diabetes, including those with impaired glucose tolerance and the normoglycemic first-degree relatives of Type 2 diabetic patients. Recent evidence points to adipocytes as a complex and active endocrine tissue whose secretory products, including free fatty acids and several cytokines (i.e., leptin, adiponectin, tissue necrosis factor-alpha, interleukin-6, and resistin) play a major role in the regulation of human metabolic and vascular biology. These adipocytokines have been claimed to be the missing link between insulin resistance and cardiovascular disease. Interventions designed to improve endothelial and/or adipose-tissue functions may reduce cardiovascular events in obese individuals with either the metabolic syndrome or Type 2 diabetes. Lifestyle modification in the form of caloric restriction and increased physical activity are the most common modalities used for treating those individuals at risk and is unanimously agreed to be the initial step in managing Type 2 diabetes. Several recent studies have demonstrated favorable impacts of lifestyle modifications in improving endothelial function and insulin sensitivity, in addition to altering serum levels of adipocytokines and possibly reducing cardiovascular events. This review discusses current knowledge of the role of lifestyle modifications in ameliorating cardiovascular risk in obese subjects with either the metabolic syndrome or Type 2 diabetes.     

Lifestyle modification and endothelial function in obese subjects

The metabolic syndrome is a cluster of metabolic and vascular abnormalities that include central obesity, insulin resistance, hyperinsulinemia, glucose intolerance, hypertension, dyslipidemia, hypercoagulability and an increased risk of coronary and cerebral vascular disease. These metabolic and vascular abnormalities are the main cause of cardiovascular mortality in western societies. Endothelial dysfunction, an early step in the development of atherosclerosis, has been reported in obese nondiabetic individuals and in patients with Type 2 diabetes. It has also been observed in individuals at high risk for Type 2 diabetes, including those with impaired glucose tolerance and the normoglycemic first-degree relatives of Type 2 diabetic patients. Recent evidence points to adipocytes as a complex and active endocrine tissue whose secretory products, including free fatty acids and several cytokines (i.e., leptin, adiponectin, tissue necrosis factor-α, interleukin-6, and resistin) play a major role in the regulation of human metabolic and vascular biology. These adipocytokines have been claimed to be the missing link between insulin resistance and cardiovascular disease. Interventions designed to improve endothelial and/or adipose-tissue functions may reduce cardiovascular events in obese individuals with either the metabolic syndrome or Type 2 diabetes. Lifestyle modification in the form of caloric restriction and increased physical activity are the most common modalities used for treating those individuals at risk and is unanimously agreed to be the initial step in managing Type 2 diabetes. Several recent studies have demonstrated favorable impacts of lifestyle modifications in improving endothelial function and insulin sensitivity, in addition to altering serum levels of adipocytokines and possibly reducing cardiovascular events. This review discusses current knowledge of the role of lifestyle modifications in ameliorating cardiovascular risk in obese subjects with either the metabolic syndrome or Type 2 diabetes.     

Mechanism of mammalian cell lysis mediated by peptide defensins. Evidence for an initial alteration of the plasma membrane.

Defensins induce ion channels in model lipid bilayers and permeabilize the membranes of Escherichia coli. We investigated whether similar membrane-active events occur during defensin-mediated cytolysis of tumor cells. Although defensin-treated K562 targets did not release chromium-labeled cytoplasmic components for 5-6 h, they experienced a rapid collapse (within minutes) of the membrane potential, efflux of rubidium, and influx of trypan blue. Defensin treatment also blunted the subsequent acidification response induced by nigericin, thereby further supporting the notion of enhanced transmembrane ion flow during exposure. These initial effects on the plasma membrane were not sufficient for subsequent lysis; a second phase of injury was required which involved the continued presence of defensin. The rapid membrane permeabilization phase was inhibited by azide/2-deoxyglucose, cytochalasin B, and increased concentrations of extracellular potassium and was unaffected by actinomycin-D, cycloheximide, and varying the calcium concentration. In contrast, the second phase was unaffected by cytochalasin B, inhibited by azide/2-deoxyglucose, enhanced by actinomycin D and cycloheximide, and varied with calcium concentration. These results indicate the initial adverse effect of defensins on mammalian cells occurs at the cell membrane. It is possible that the second phase of injury is mediated intracellularly by defensin that has been internalized through this leaky membrane.