Pharmacokinetics and Pharmacodynamics of the BACE1 Inhibitor Verubecestat (MK-8931) in Healthy Japanese Adults: A Randomized, Placebo-Controlled Study.

ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of ß-amyloid (Aß) peptides and is considered a potential treatment target for Alzheimer's disease (AD). To support Japan's participation in the global clinical development program, we characterized the safety, pharmacokinetics (PKs), and pharmacodynamics of the BACE1 inhibitor verubecestat (MK-8931) in 24 healthy Japanese adults in a two-part, single-center, randomized, placebo-controlled phase I trial (protocol MK-8931-007) and compared the results with historical data from non-Japanese subjects. Both single (20, 100, and 450 mg) and multiple (80 and 150 mg once daily for 14 days) doses of verubecestat were well tolerated. Verubecestat's PK profile was similar in Japanese and non-Japanese subjects. Verubecestat also reduced mean cerebrospinal fluid concentrations of the Aß proteins Aß40, Aß42, and soluble ß fragment of amyloid precursor protein; the level of reduction was comparable between Japanese and non-Japanese subjects. These results support the continued global development of verubecestat as a potential disease-modifying agent for Japanese and non-Japanese subjects who are at risk for developing AD.

Treatments for Hypertension in Type 2 Diabetes-Non-pharmacological and Pharmacological Measurements.

Obesity, hypertension, obesity-related hypertension such as hypertension with diabetes are growing health problems. Obesity, hypertension and diabetes are important, independent risk factors for the onset and development of cardiovascular diseases. Hypertension in obesity is characterized by stimulation of the renin-angiotensin-aldosterone system (RAAS), elevated sympathetic activity, insulin resistance and selective leptin resistance. It is known that these characteristics, even in isolation, constitute risk factors for cardiovascular disease onset and progression. Therefore, pharmacological treatments should be selected based on favourable effects on insulin resistance, stimulated RAAS and sympathetic nervous systems.

The effects of dietary weight loss on indices of norepinephrine turnover: modulatory influence of hyperinsulinemia.

OBJECTIVES: This study was conducted to examine (1) the effects of dietary weight loss on indices of norepinephrine (NE) turnover and (2) whether baseline hyperinsulinemia modulates sympathetic neural adaptations. METHODS: Obese individuals aged 56 ± 1 year, BMI 32.5 ± 0.4 kg/m(2) , with metabolic syndrome, underwent a 12-week hypocaloric diet (HCD, n = 39) or no treatment (n = 26). Neurochemical measurements comprised arterial dihydroxyphenylalanine (DOPA), 3,4-dihydroxyphenylglycol (DHPG), and NE concentrations, the steady-state ratio of [3H]-DHPG to [3H]-NE, as an index of neuronal uptake, and calculated whole-body plasma NE clearance and spillover rates. RESULTS: Body weight decreased by -7.4 ± 0.5% in HCD group (P < 0.001) and was accompanied by reductions in DOPA, NE, and DHPG averaging -14 ± 5% (P = 0.001), -23 ± 4% (P <0.001), and -5 ± 4% (P = 0.03), respectively. NE spillover rate decreased by -88 ± 39 ng/min (P = 0.01), whereas neuronal uptake and NE plasma clearance were unchanged. Despite similar weight loss, hyperinsulinemic subjects exhibited greater reductions in NE and NE spillover rate, compared to normoinsulinemic subjects (group by time interaction P < 0.05). CONCLUSIONS: Weight loss is associated with down-regulation of sympathetic nervous activity but no overall alteration in disposition indices. Hyperinsulinemic subjects derive a greater sympathoinhibitory benefit during weight loss.

Different mechanisms in weight loss-induced blood pressure reduction between a calorie-restricted diet and exercise.

The present study compared the effectiveness of a mild calorie-restricted diet (D) alone, exercise (EX) alone and a combination of D+EX on weight loss-induced blood pressure (BP) reduction over 24 weeks. We focussed especially on the relationship between sympathetic nervous activity, as indicated from measures of plasma norepinephrine (NE), and insulin resistance (homeostasis model of insulin resistance, HOMA-IR). The three groups each comprised 30 obese, hypertensive men. Body mass index (BMI), fat mass, waist-to-hip ratio, BP, plasma NE and HOMA-IR were measured every 2 weeks during the first 4 weeks and subsequently every 4 weeks for the next 20 weeks. All basal parameters were similar among the three groups. At 24 weeks, the combination group with D+EX comprised a significantly higher prevalence of normotensive subjects than the D alone or EX alone group (P<0.05). In the D alone group, plasma NE was decreased significantly at 2 weeks, reductions in BMI, fat mass and BP were observed at 8 weeks, and waist-to-hip ratios and HOMA-IR were decreased at 12 weeks. In comparison, in the EX alone group, significant reductions of fat mass and HOMA-IR were observed at 4 weeks. Plasma NE and HOMA-IR were reduced at 8 weeks while decreases in BP were detected at 12 weeks. In the D+EX group, significant reductions in plasma NE were observed at 2 weeks followed by significant decreases in BMI, fat mass, waist-to-hip ratio, BP levels and HOMA-IR at 4 weeks. The magnitudes of reductions of all parameters were greatest in the D+EX group. These results demonstrate that D+EX exerts a stronger ameliorative effect on weight loss, weight loss-induced BP reduction, normalization of BP, sympathetic activation and insulin resistance compared with D or EX alone. D and EX might, perhaps, exert different mechanisms on weight loss and weight loss-induced BP reduction; however, a combination of caloric restriction and exercise is preferred to control BP levels in obese hypertensive patients.

Effects of weight loss on renal function in overweight Japanese men.

Obesity is known as an independent risk factor for renal injury. Sympathetic nerve activation may have an important role of the pathogenesis of obesity, and hypertension may underpin the development of cardiovascular events. In the present study, we evaluated the effects of weight loss (WL) on renal function, especially focusing on sympathetic nervous activity. In 154 overweight or obese Japanese men (89 normotensive and 65 untreated mild hypertensive subjects), body weight, body mass index (BMI), total body fat mass, blood pressure (BP), serum creatinine, blood urea nitrogen, creatinine clearance (CCr) (calculated with the Cockcroft-Gault equation) and plasma norepinephrine (NE) were measured before and after a 12-month period of WL with a mild caloric-restricted diet and exercise. A significant WL was defined as 10% or more WL compared with the entry period. In total, 97 (63.0%) subjects succeeded in significant (by 14.3%) WL at 12 months, and 57 subjects (37.0%) did not succeed in significant WL but they lost 7.7% weight. At entry, levels of plasma NE, serum creatinine and fat mass were significantly lower and CCr was greater in the group with a significant WL compared with those without WL. BMI, total body fat mass and plasma NE significantly decreased, and CCr increased with WL. At both baseline and at the 12-month period, fat mass and plasma NE negatively correlated with CCr and positively correlated with creatinine at each time point. Changes in fat mass and plasma NE over 12 months correlated with changes in creatinine, and only changes in fat mass negatively correlated with changes in CCr. Basal fat mass and plasma NE correlated positively with serum creatinine at 12 months and negatively with CCr at the same time point. In multiple regression analyses, basal plasma NE and fat mass were significant determinants of serum creatinine levels and CCr at 12 months. In conclusion, WL improved renal function (as evident from measures of creatinine and CCr) in overweight individuals. Basal plasma NE levels and total body fat mass could be predictors for improvement in renal function associated with WL. Suppression of sympathetic nervous activation associated with WL may have a role in the ameliorative effects on renal function.

Relationships of adrenoceptor polymorphisms with obesity.

Obesity, hypertension, and type 2 diabetes are rapidly growing public health problems. Heightened sympathetic nerve activity is a well-established observation in obesity, hypertension, and type 2 diabetes. Human obesity, hypertension, and diabetes have strong genetic as well as environmental determinants. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity are mainly mediated via the ß2, and ß3-adrenergic receptors in humans. Further, ß2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. ß-adrenoceptor polymorphisms have also been associated with adrenoceptor desensitization, increased adiposity, insulin resistance, and enhanced sympathetic nervous activity. Many epidemiological studies have shown strong relationships between adrenoceptor polymorphisms and obesity, but the observations have been discordant. This paper will discuss the current topics involving the influence of the sympathetic nervous system and ß2- and ß3-adrenoceptor polymorphisms in obesity.

Exercise augments weight loss induced improvement in renal function in obese metabolic syndrome individuals.

OBJECTIVE: Metabolic syndrome (MetS) obesity is an independent risk factor for chronic kidney disease. This study was conducted to examine the effects of lifestyle interventions on renal parameters and putative metabolic, neuroadrenergic and hemodynamic mediators of renal injury. METHODS: Untreated men and women (mean age 55 ± 1 years; BMI 32.7 ± 0.6 kg/m) without pre-existing renal dysfunction, who fulfilled MetS criteria were randomized to dietary weight loss (WL, n = 13), weight loss combined with aerobic exercise (WL + EX, n = 13), or no treatment (control, n = 12). Estimated glomerular filtration rate (eGFR), 24 h urinary albumin excretion, plasma renin activity (PRA), muscle sympathetic nerve activity (MSNA), baroreflex sensitivity (BRS), anthropometric, metabolic and fitness variables were measured at baseline and week 12. RESULTS: Body weight decreased by -8.2 ± 0.8% in the WL and -10.7 ± 0.9% in the WL + EX groups (both P < 0.001). Fitness (maximal oxygen consumption) increased by 15 ± 5% and BRS by 5.5 ± 2.4 ms/mmHg in the WL + EX group only (P < 0.05). Serum creatinine decreased by -8.1 ± 4.8%, (WL, P = 0.016) and -14.9 ± 3.0% (WL + EX, P < 0.001). Estimated GFR increased commensurately but the increment was greater in the WL + EX group (P = 0.04). Albuminuria (P < 0.05) and MSNA (P < 0.001) decreased similarly in both groups, whereas PRA, high sensitivity C-reactive protein, uric acid and DBP decreased only in the WL + EX group (all P < 0.05). CONCLUSION: Moderate weight loss in obese MetS patients is associated with a reduction in albuminuria and an improvement in eGFR which is augmented by exercise co-intervention.

The effects of weight loss versus weight loss maintenance on sympathetic nervous system activity and metabolic syndrome components.

CONTEXT: Sympathetic nervous system (SNS) overactivity participates in both the pathogenesis and adverse clinical complications of metabolic syndrome (MetS) obesity. OBJECTIVE: We conducted a prospective lifestyle intervention trial to compare the effects of active weight loss and extended weight loss maintenance on SNS function and MetS components. METHODS: Untreated subjects (14 males, four females; mean age, 53 ± 1 yr; body mass index, 30.9 ± 0.9 kg/m(2)) who fulfilled Adult Treatment Panel III criteria were randomized to 12-wk hypocaloric diet alone (n = 8) or together with aerobic exercise training (n = 10). This was followed by a 4-month weight maintenance period. Measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine kinetics, substrate oxidation by indirect calorimetry, baroreflex sensitivity, plasma renin activity (PRA), and MetS components were performed. RESULTS: Body weight decreased by 9.3 ± 0.8% at wk 12 (P < 0.001), and this was maintained. During active weight loss, norepinephrine spillover rate decreased by 23 ± 16% (P = 0.004), MSNA by 25 ± 3 bursts per 100 heartbeats (P < 0.001), and PRA by 0.25 ± 0.09 ng/ml · h (P = 0.007), whereas baroreflex sensitivity increased by 5.2 ± 2.2 msec/mm Hg (P = 0.005). After weight maintenance, beneficial effects of weight loss on norepinephrine spillover rate were preserved, whereas PRA and MSNA rebounded (by 0.24 ± 0.11 ng/ml · h, P = 0.02; and 20 ± 5 bursts/100 heartbeats, P = 0.0003), and baroreflex sensitivity was attenuated. CONCLUSIONS: Divergent effects of successful weight loss maintenance on whole-body norepinephrine spillover rate and MSNA suggest organ-specific differentiation in SNS adaptation to weight loss under conditions of negative vs. stable energy balance.

Roles of beta2- and beta3-adrenoceptor polymorphisms in hypertension and metabolic syndrome.

Hypertension, diabetes mellitus (especially type 2 diabetes mellitus), metabolic syndrome and obesity are rapidly growing public health problems. Sympathetic nerve activation is observed in obesity, hypertension and diabetes mellitus, which have strong genetic as well as environmental determinants. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of catecholamines in obesity have been mainly mediated via the ß2- and ß3-adrenergic receptors in humans. Further, ß2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphistns of the ß-adrenoceptor gene have been shown to alter the function of several adrenoceptor subtypes and thus to modify the response to catecholamine. ß2-adrenoceptor polymorphisms (Arg16Gly, Gln27Glu, and Thr164Ile) have been studied in relation to hypertension. Genetic variations in the ß3-adrenoceptor (i.e. Try64Arg variant) are also associated with both obesity and hypertension. However, the precise relationships of the polymorphisms of ß2- and ß3-adrenoceptor genes with sympathetic nervous system activity, hypertension, and metabolic syndrome have not been fully clarified. This paper will discuss the current topics involving the influence of the sympathetic nervous system and ß2- and ß3- adrenoceptor polymorphisms in hypertension and metabolic syndrome.

The role of sympathetic nervous activity in renal injury and end-stage renal disease.

Sympathetic nervous system hyperactivity is observed in patients with renal injury, renovascular hypertension, chronic kidney disease (CKD) and end-stage renal disease (ESRD). Elevated sympathetic activity is of prognostic relevance in that plasma norepinephrine concentrations predict survival and the incidence of cardiovascular events in patients with ESRD, as well as future renal injury in normotensive healthy subjects with renal function in the normal range. Renal injury, CKD and ESRD are often associated with obesity, and its common sequelae hypertension and diabetes. In fact, hypertension and diabetes mellitus are the main causes of ESRD in western societies and together account for approximately more than 50% of ESRD incidence in the United States and Japan. Obesity also leads to increases in the incidence of cardiovascular diseases. Several clinical and epidemiological studies have clearly documented that heightened sympathetic nervous activity has an important role in the onset and maintenance of obesity and hypertension. Elevated sympathetic nervous activity may actually represent an important mechanism contributing to the onset and maintenance of renal injury at least in part through its concomitant adverse effects on obesity and hypertension. Understanding the contribution of sympathetic nervous hyperactivity to the onset and maintenance of renal injury might aid in the prevention and treatment of renal injury, CKD and ESRD. Very recently, renal sympathetic denervation was shown to be a potentially novel therapeutic strategy in resistant hypertension. In addition, renin-angiotensin system inhibitors are recommended as the initial therapy because of their renal protective effect, especially in hypertensive patients with type 2 diabetes or with proteinuria. The purpose of this review is to provide an overview of our current knowledge on the relationships between sympathetic nerve activity and renal function to further our understanding of the precise roles of sympathetic nerve activity in renal injury, particularly in the context of obesity and hypertension. These insights may be useful to improve prevention and treatment of renal injury in these patients.

Cardiovascular and renal complications of type 2 diabetes in obesity: role of sympathetic nerve activity and insulin resistance.

Overweight and obesity is a growing "world-wide epidemic problem". Because as many as, two-thirds of the adult population and a growing number of children are overweight. The prevalence of diabetes, especially type 2 diabetes and hypertension have significantly increased with the prevalence of obesity. Obesity accompanying type 2 diabetes and hypertension are known to be closely linked with insulin resistance and elevated sympathetic nervous activity. It has been well documented that obesity, hypertension, and diabetes are high risk factors for subsequent cardiovascular and renal complications. Many patients are both diabetic and hypertensive, while they are obese, but not all diabetic patients have hypertension, indicating that insulin resistance is not only a mechanism for blood pressure elevation in diabetic-hypertensive patients. Several investigators have reported that sympathetic nervous activation relates to cardiovascular complications in patients with hypertension, diabetes, and obesity, and that sympathetic nerve activity accompanying insulin resistance is closely linked with left ventricular hypertrophy in healthy subjects. In addition, sympathetic nerve activation may predict future renal injury in healthy normotensive subjects. These findings suggest that elevated sympathetic nerve activity associated with insulin resistance may contribute to the onset and maintenance of cardiovascular and renal complications in diabetes, and hypertension in obesity. Further, genetic polymorphisms of the beta2- and beta3-adrenoceptor gene have been associated with type-2 diabetes and insulin resistance in many epidemiological studies and might be another factor responsible for the close relationship between insulin resistance and heightened sympathetic nerve activity. Thus, focusing on the interactions between insulin resistance, sympathetic nervous activity and beta-adrenoceptor polymorphisms might help in understanding the precise relationships between insulin resistance and sympathetic nerve activity in type 2 diabetes and obesity-related hypertension. The purpose of this article is to provide a synthesis of the current findings on the mechanisms of the onset and maintenance of cardiovascular and renal complications in obesity, diabetes and hypertension. A better understanding of the relationships of sympathetic nervous system activity and insulin resistance might help with the clinical treatment of diabetes and hypertension in obesity. Further, to clarify the pathogenesis and mechanisms of the association between obesity, diabetes, and hypertension may lead to reductions in cardiovascular and renal risk.

Sympathetic neural adaptation to hypocaloric diet with or without exercise training in obese metabolic syndrome subjects.

OBJECTIVE: Sympathetic nervous system (SNS) overactivity contributes to the pathogenesis and target organ complications of obesity. This study was conducted to examine the effects of lifestyle interventions (weight loss alone or together with exercise) on SNS function. RESEARCH DESIGN AND METHODS: Untreated men and women (mean age 55 +/- 1 year; BMI 32.3 +/- 0.5 kg/m(2)) who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated to either dietary weight loss (WL, n = 20), dietary weight loss and moderate-intensity aerobic exercise (WL+EX, n = 20), or no treatment (control, n = 19). Whole-body norepinephrine kinetics, muscle sympathetic nerve activity by microneurography, baroreflex sensitivity, fitness (maximal oxygen consumption), metabolic, and anthropometric measurements were made at baseline and 12 weeks. RESULTS: Body weight decreased by -7.1 +/- 0.6 and -8.4 +/- 1.0 kg in the WL and WL+EX groups, respectively (both P < 0.001). Fitness increased by 19 +/- 4% (P < 0.001) in the WL+EX group only. Resting SNS activity decreased similarly in the WL and WL+EX groups: norepinephrine spillover by -96 +/- 30 and -101 +/- 34 ng/min (both P < 0.01) and muscle sympathetic nerve activity by -12 +/- 6 and -19 +/- 4 bursts/100 heart beats, respectively (both P < 0.01), but remained unchanged in control subjects. Blood pressure, baroreflex sensitivity, and metabolic parameters improved significantly and similarly in the two lifestyle intervention groups. CONCLUSIONS: The addition of moderate-intensity aerobic exercise training to a weight loss program does not confer additional benefits on resting SNS activity. This suggests that weight loss is the prime mover in sympathetic neural adaptation to a hypocaloric diet.

Weight loss may reverse blunted sympathetic neural responsiveness to glucose ingestion in obese subjects with metabolic syndrome.

OBJECTIVE: The purpose of this study was to examine the effects of weight loss on sympathetic nervous system responsiveness to glucose ingestion in obese subjects with metabolic syndrome, in whom such responses are reportedly blunted. RESEARCH DESIGN AND METHODS: Thirty four subjects, 19 insulin resistant and 15 insulin sensitive and aged 55 +/- 1 years (mean +/- SE) with BMI 31.6 +/- 0.6 kg/m2, who fulfilled the Adult Treatment Panel III criteria for metabolic syndrome participated. Simultaneous measurements of whole-body norepinephrine spillover rate, calf blood flow, and intra-arterial blood pressure were made at times 0, 30, 60, 90, and 120 min postglucose (75 g). The experiment was repeated after a 3-month hypocaloric diet with or without an exercise program. RESULTS: Body weight decreased by 8.1 +/- 0.9 and 8.4 +/- 1.1 kg and resting norepinephrine spillover by 94 +/- 31 and 166 +/- 58 ng/min (all P < or = 0.01) in insulin-resistant and insulin-sensitive subjects, respectively. Weight loss was accompanied by a marked increase in sympathetic responsiveness after glucose but only in insulin-resistant subjects. In this subgroup, comparative increases in norepinephrine spillover rates at baseline and after weight loss averaged -3 +/- 25 versus 73 +/- 24 ng/min at 30 min (P = 0.039), 36 +/- 21 versus 115 +/- 28 ng/min at 60 min (P = 0.045), 9 +/- 21 versus 179 +/- 50 ng/min at 90 min (P < 0.001), and 40 +/- 48 versus 106 +/- 39 ng/min at 120 min (P = 0.24). CONCLUSIONS: Weight loss reverses blunted sympathetic responsiveness to glucose ingestion in insulin-resistant subjects with metabolic syndrome, which is relevant to postprandial energy utilization and body weight homeostasis.

Blunted sympathetic neural response to oral glucose in obese subjects with the insulin-resistant metabolic syndrome.

BACKGROUND: Glucose ingestion stimulates sympathetic nervous system (SNS) activity in lean subjects, whereas blunted responses have been reported in the obese. OBJECTIVE: The objective was to investigate the impact of insulin resistance on the SNS response to oral glucose. DESIGN: Nineteen insulin-resistant (IR) and 12 insulin-sensitive (IS) obese subjects with the metabolic syndrome and matched for age, sex, and blood pressure participated. Simultaneous measurements of muscle sympathetic nerve activity (MSNA) by microneurography, whole-body norepinephrine spillover rate, cardiac baroreflex sensitivity (BRS), calf blood flow, and arterial blood pressure were made at baseline and 30, 60, 90, and 120 min after a 75-g glucose load. RESULTS: IR subjects had a higher insulin area under the curve from 0 to 120 min (AUC(0-120): 13,468 +/- 677 compared with 6399 +/- 612 mU/L . min; P < 0.001), glucose AUC(0-120) (P < 0.05), and resting MSNA (41 +/- 3 compared with 31 +/- 3 bursts/min; P = 0.03) than did IS subjects. MSNA and the norepinephrine spillover rate increased from baseline (by 29 +/- 7% and 40 +/- 13%, respectively; P < or = 0.001 for both) in IS subjects after the glucose load. In contrast, there was a blunted and delayed sympathetic response in IR subjects. Cardiac BRS and diastolic blood pressure decreased, whereas calf blood flow increased after the glucose load and by a similar magnitude in both groups (P < 0.01). Body mass index, abdominal fat, and insulin AUC(0-120) were independent (inverse) predictors of the SNS response. CONCLUSIONS: IR subjects with the metabolic syndrome have a blunted SNS response to oral glucose compared with IS subjects with the metabolic syndrome, which is related to central adiposity and the insulin response but not to differences in skeletal muscle vasodilation or BRS.

Leptin-receptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic nerve activation in a Caucasian male population.

Leptin plays a key role in the regulation of body weight through the sympathetic nervous system; however, the contributions of leptin-receptor polymorphisms to obesity and sympathetic nerve activity have not been fully clarified. In the present study, we examined the relationships between leptin-receptor polymorphisms, plasma leptin and whole-body norepinephrine (NE) spillover as an index of sympathetic nerve activity in a Caucasian male cohort. In 129 young healthy normotensive men with a wide range of body mass index (BMI) (19.4-39.5 kg/m(2)), we measured leptin-receptor polymorphisms (Gln223Arg, Lys656Asn, and Lys109Arg), plasma leptin levels, whole-body NE spillover, whole-body NE clearance, BMI and blood pressure (BP) levels in the supine position after overnight fasting. Overweight-obese (BMI>or=25 kg/m(2)) subjects had significantly greater BMI, BP levels, plasma leptin and whole-body NE spillover compared to lean (BMI<25 kg/m(2)) subjects, but the NE clearance was similar. Overweight-obese subjects had significantly higher frequencies of the Arg223 allele and the Arg223 homozygous allele of Gln223Arg and the Asn656 allele of Lys656Asn compared to lean subjects. Subjects carrying the Arg223 homozygous or the Asn656 allele had higher levels of plasma leptin, BMI, waist circumference, and waist-to-hip ratio, but significantly less whole-body NE spillover, especially when they were also overweight-obese. BP levels and whole-body NE clearance were similar between subjects with and without the Arg223 homozygous or Asn656 allele. No differences were found in the distributions of the Arg109 allele of Lys109Arg polymorphism between nonobese and overweight-obese subjects. In addition, BMI, BP, plasma leptin levels, whole-body NE spillover and whole-body NE clearance were similar between those with and without the Arg109 allele. Together, these findings demonstrate that leptin-receptor polymorphisms were related to the incidence of obesity in a Caucasian male population. These polymorphisms were accompanied by high plasma leptin levels (leptin resistance) and lower whole-body plasma NE spillover (blunted sympathetic nerve activity). We therefore hypothesize that leptin-receptor play a role in the development of obesity through leptin resistance and blunted leptin-mediated sympathetic nerve activity.

High plasma norepinephrine levels associated with beta2-adrenoceptor polymorphisms predict future renal damage in nonobese normotensive individuals.

Renal injury is common in obesity and hypertension. In the present study, we examined relationships between renal function alterations, plasma norepinephrine (NE), and beta2-adrenoceptor polymorphisms in a longitudinal design over 5 years. In 219 nonobese, normotensive men with entry-normal renal function, we measured serum blood urea nitrogen (BUN), creatinine, creatinine clearance, plasma NE, homeostasis model assessment of insulin resistance (HOMA-IR), body mass index (BMI), total body fat mass, and blood pressure (BP) annually for 5 years. beta2 (Arg16Gly, Gln27Glu)-adrenoceptor polymorphisms were determined. The subjects were stable in body weight and BP (<10%) for 5 years. High plasma NE was defined as > or =mean+1 SD at entry. Thirty-seven subjects had entry-high plasma NE and 182 were entry-normal. Entry-high plasma NE subjects had significantly greater total body fat mass and plasma NE and significantly lower creatinine clearance at entry and throughout the study. Increases in BMI, fat mass, BP, plasma NE, BUN, and creatinine, as well as the reduction in creatinine clearance in the 5 years, were significantly greater in entry-high NE subjects. These subjects had significantly higher frequencies of the Gly16 allele of beta2-adrenoceptor polymorphisms. Throughout the study, subjects carrying the Gly16 allele had higher plasma NE, HOMA-IR, and fat mass, and significantly greater reductions in creatinine clearance. Plasma NE at entry was a determinant variable for changes in BUN, creatinine, and creatinine clearance over the 5-year period in multiple regression analysis. In conclusion, high plasma NE at entry, associated with the Gly16 allele of the beta2-adrenoceptor polymorphisms, predict renal function deterioration (seen in elevations of BUN and creatinine and reduction of creatinine clearance) over a 5-year period accompanying further heightened sympathetic nerve activity and deterioration of insulin resistance.