Biomedical subjects

Hanno Pijl

Publications and source records attributed to Hanno Pijl.

35 records · Page 2Linked to original sources

PubMed2003

Reduced dopaminergic tone in hypothalamic neural circuits: expression of a "thrifty" genotype underlying the metabolic syndrome?

The thrifty genotype hypothesis postulates that the genetically determined ability to grow obese and insulin resistant in times of food abundance confers a survival advantage in times of famine. Obviously, this ability poses a major health threat in modern times, where food is always available in large quantities. In the last 10-15 years, many genes encoding pathways that orchestrate energy balance and fuel flux have been discovered. This paper summarizes the evidence that diminished dopaminergic tone in hypothalamic nuclei contributes to the "thrifty" genotype/phenotype. Reduced dopaminergic neurotransmission in the suprachiasmatic nucleus of seasonally obese animals appears to drive noradrenalin and NPY mediated transmissions in other nuclei to induce the obesity syndrome at the appropriate time of year. Treatment with dopamine D(2) receptor agonists can fully reverse the metabolic syndrome in these animals. Similar mechanisms are operative in non-seasonal obese animal models. In man, treatment with dopamine D(2) receptor antagonists induces obesity and type 2 diabetes mellitus, whereas dopamine D(2) receptor activation ameliorates the metabolic profile in obese nondiabetic and diabetic humans. Various loss of function mutations of the dopamine D(2) receptor gene are associated with overweight in humans. In concert, the data support the notion that diminution of dopaminergic (dopamine D(2) receptor mediated) transmission in relevant hypothalamic nuclei sets the stage for efficient partitioning of ingested nutrients to contribute to a phenotype that is not so thrifty anymore.

Animals↗

PubMed2003

Overexpression of APOC1 in obob mice leads to hepatic steatosis and severe hepatic insulin resistance.

Obese obob mice with strong overexpression of the human apolipoprotein C1 (APOC1) exhibit excessive free fatty acid (FFA) and triglyceride (TG) levels and severely reduced body weight (due to the absence of subcutaneous adipose tissue) and skin abnormalities. To evaluate the effects of APOC1 overexpression on hepatic and peripheral insulin sensitivity in a less-extreme model, we generated obob mice with mild overexpression of APOC1 (obob/APOC1(+/-)) and performed hyperinsulinemic clamp analysis. Compared with obob littermates, obob/APOC1(+/-) mice showed reduced body weight (-25%) and increased plasma levels of TG (+632%), total cholesterol (+134%), FFA (+65%), glucose (+73%), and insulin (+49%). Hyperinsulinemic clamp analysis revealed severe whole-body and hepatic insulin resistance in obob/APOC1(+/-) mice and, in addition, increased hepatic uptake of FFA and hepatic TG content. Treatment of obob/APOC1(+/-) mice with rosiglitazone strongly improved whole-body insulin sensitivity as well as hepatic insulin sensitivity, despite a further increase of hepatic fatty acid (FA) uptake and a panlobular increase of hepatic TG accumulation. We conclude that overexpression of APOC1 prevents rosiglitazone-induced peripheral FA uptake leading to severe hepatic steatosis. Interestingly, despite rosiglitazone-induced hepatic steatosis, hepatic insulin sensitivity improves dramatically. We hypothesize that the different hepatic fat accumulation and/or decrease in FA intermediates has a major effect on the insulin sensitivity of the liver.

Animals↗

PubMed2003

The decline in plasma leptin in response to calorie restriction predicts the effects of adjunctive leptin treatment on body weight in humans.

BACKGROUND: Plasma leptin levels decline in response to food restriction. We hypothesized that the magnitude of this decline would predict the amount of weight lost in response to exogenous leptin administration. METHODS: Thirty obese subjects were mildly energy-restricted for 21 days. Subsequently, they were randomized to receive either recombinant human leptin [rL, 10 mg s.c. once (n=15) or twice (n=6) daily] or placebo (n=9) as an adjunct to the dietary measures for 12 weeks. RESULTS: Weight loss amounted to 2.8+/-1.1, 5.2+/-0.9, and 7.9+/-1.4 kg (mean+/-standard error) (p=0.035 vs. placebo) in placebo, rL once daily, and rL b.i.d. treated subjects, respectively. The reduction in plasma leptin concentrations during the initial 21 days was positively correlated with the loss of body weight following leptin treatment (r(2)=0.24, p=0.04). Plasma leptin concentration prior to the initiation of rL therapy was inversely associated with the amount of body weight lost in response to intervention (r(2)=0.36, p=0.003). CONCLUSION: Leptin administration counteracts the adaptations that are actuated by the drop in leptin concentrations and thereby disrupts energy balance to promote weight loss.

Journal Article↗

PubMed2003

Rosiglitazone improves muscle insulin sensitivity, irrespective of increased triglyceride content, in ob/ob mice.

The present study was performed to examine the effects of rosiglitazone treatment on tissue-specific insulin sensitivity. Therefore, we used obese, insulin-resistant ob/ob mice and measured the effects of rosiglitazone treatment on insulin sensitivity and simultaneously tissue-specific uptake of glucose and free fatty acids (FFA) under hyperinsulinemic euglycemic clamp conditions. Rosiglitazone treatment resulted in significantly higher body weight and decreased plasma levels of glucose, insulin, and triglyceride (TG). Glucose tolerance, as well as insulin sensitivity, was improved upon rosiglitazone treatment, as assessed by glucose tolerance and insulin sensitivity tests. Hyperinsulinemic euglycemic clamps showed increased glucose infusion rates with increased whole body insulin sensitivity. Rosiglitazone treatment resulted in increased glucose uptake by cardiac and skeletal muscle under hyperinsulinemic euglycemic clamp conditions, while no differences were observed in FA uptake. Measurement of TG content showed that rosiglitazone treatment resulted in decreased TG content of cardiac muscle, but increased TG content of skeletal muscle. We conclude that rosiglitazone treatment leads to strong improvement of insulin sensitivity, irrespective of increased muscle TG content, in ob/ob mice.

Animals↗

PubMed2003

Hypocretin deficiency in narcoleptic humans is associated with abdominal obesity.

OBJECTIVE: To determine the prevalence of obesity among patients with narcolepsy, to estimate associated long-term health risks on the basis of waist circumference, and to distinguish the impact of hypocretin deficiency from that of increased daytime sleepiness (i.e., reduced physical activity) on these anthropometric measures. RESEARCH METHODS AND PROCEDURES: A cross-sectional, case-control study was conducted. Patients with narcolepsy (n = 138) or idiopathic hypersomnia (IH) (n = 33) were included. Age-matched, healthy members of the Dutch population (Monitoring Project on Risk Factors for Chronic Diseases and Doetinchem Project; n = 10,526) were used as controls. BMI and waist circumference were determined. RESULTS: Obesity (BMI > or = 30 kg/m(2)) and overweight (BMI 25 to 30 kg/m(2)) occurred more often among narcolepsy patients [prevalence: 33% (narcoleptics) vs. 12.5% (controls) and 43% (narcoleptics) vs. 36% (controls), respectively; both p < 0.05]. Narcoleptics had a larger waist circumference (mean difference 5 +/- 1.4 cm, p < 0.001). The BMI of patients with IH was significantly lower than that of narcolepsy patients (25.6 +/- 3.6 vs. 28.5 +/- 5.4 kg/m(2); p = 0.004). DISCUSSION: Overweight and obesity occur frequently in patients with narcolepsy. Moreover, these patients have an increased waist circumference, indicating excess fat storage in abdominal depots. The fact that patients with IH had a lower BMI than narcoleptics supports the notion that excessive daytime sleepiness (i.e., inactivity) cannot account for excess body fat in narcoleptic patients.

Abdomen↗

PubMed2003

Blunted lipolytic response to fasting in abdominally obese women: evidence for involvement of hyposomatotropism.

BACKGROUND: Abdominal obesity is associated with a blunted lipolytic response to fasting that may contribute to the preservation of adipose tissue mass. OBJECTIVE: To further explore the pathophysiology of blunted lipolysis during fasting in obesity, we simultaneously measured lipolysis and distinct neuroendocrine regulatory hormones in abdominally obese and normal-weight (NW) women. DESIGN: Eight abdominally obese [x +/- SD body mass index (BMI; in kg/m(2)): 32.1 +/- 2.6] and 6 NW (BMI: 22.7 +/- 1.5) women were studied during the last 8 h of a 20-h fast. The glycerol appearance rate and the serum and plasma concentrations of insulin, leptin, cortisol, and growth hormone were measured regularly. RESULTS: At 13 h of fasting, the mean (+/-SD) glycerol appearance rate corrected for fat mass was greater in NW women than in obese women (7.2 +/- 1.0 and 5.1 +/- 0.6 micro mol.kg(-1).min(-1), respectively; P = 0.001). After a 20-h fast, lipolysis increased to 8.9 +/- 1.5 mmol.kg(-1).min(-1) in NW women (23%), whereas it did not change significantly in obese women (-2%). Fasting decreased insulin concentrations by approximately 30% in both groups, but it did not induce significant changes in leptin concentrations. Mean cortisol concentrations and urinary catecholamine excretion were comparable in both groups. However, mean plasma growth hormone concentrations were higher in NW women than in obese women (1.81 +/- 0.98 compared with 0.74 +/- 0.52 mU/L; P = 0.046). The relative change in lipolysis tended to correlate with mean plasma growth hormone concentrations (r = 0.515, P = 0.059). CONCLUSION: Abdominal obesity-associated hyposomatotropism may be involved in the blunted increase in lipolysis during fasting.

Abdomen↗

PubMed2003

A fish oil diet does not reverse insulin resistance despite decreased adipose tissue TNF-alpha protein concentration in ApoE-3*Leiden mice.

Dietary interventions with fish oil have been found to protect against the development of high-fat diet-induced insulin resistance and to decrease the expression of tumor necrosis factor (TNF)-alpha. However, the effect of fish oil administration on preexisting insulin resistance is subject to debate. In the present study, we examined the mechanism by which fish oil affects preexisting insulin resistance. High fat diet-induced insulin-resistant ApoE*3-Leiden transgenic mice were treated for 10 wk as follows: 1) high fat diet (control group), 2) high fat diet with 3 g/100 g fish oil and 3) high fat diet but food intake restricted to 75% of the ad libitum food intake. We measured plasma glucose, insulin, free fatty acids (FFA) and triglyceride (TG) levels throughout the study. After the 10-wk dietary intervention period we performed hyperinsulinemic euglycemic analyses and measured insulin sensitivity and FFA turnover. Furthermore, we then determined the VLDL-TG production rate and TNF-alpha protein expression in white adipose tissue (WAT). Compared with control mice, the insulin sensitivity of mice treated with fish oil was not affected, whereas it was improved (P < 0.05) for energy-restricted mice. FFA turnover was unaffected in both fish oil-treated and energy-restricted mice. Compared with controls, hepatic VLDL-TG production was lower (P < 0.05) with fish oil feeding but greater with energy restriction (P < 0.05). Interestingly, the level of TNF-alpha protein in WAT was lower (P < 0.05) in both groups. We conclude that partial replacement of saturated fat by fish oil does not improve preexisting high fat diet-induced insulin resistance, although it lowers TNF-alpha protein levels in WAT.

Adipose Tissue↗

PubMed2003

Contribution of fatty acids released from lipolysis of plasma triglycerides to total plasma fatty acid flux and tissue-specific fatty acid uptake.

There is controversy over the extent to which fatty acids (FAs) derived from plasma free FAs (FFAs) or from hydrolysis of plasma triglycerides (TGFAs) form communal or separate pools and what the contribution of each FA source is to cellular FA metabolism. Chylomicrons and lipid emulsions were labeled with [(3)H]triolein, injected into mice, and appearance in plasma of [(3)H]oleic acid was estimated, either through a steady-state approach or by compartmental modeling. [(14)C]oleic acid was included to trace plasma FFA. Eighty to 90% of triglyceride (TG) label was recovered in plasma, irrespective of tracer method or TG source. The contribution of TG lipolysis to total plasma FA turnover was 10-20%. After infusion of [(3)H]TG and [(14)C]FA, the retention of these labels varied substantially among liver, adipose tissue, and skeletal and heart muscle. Retention of TG label changed during fasting in the same direction as lipoprotein lipase (LPL) activity is regulated. We propose a model that reconciles the paradoxical 80-90% loss of TG label into plasma with LPL-directed differential uptake of TGFA in tissues. In this model, TGFAs mix locally at the capillaries with plasma FFAs, where they would lead to an increase in the local FA concentration, and hence, FA uptake. Our data indicate that a distinction between TG-derived FA and plasma FFA cannot be made.

Adipose Tissue↗

PubMed2002

Somatotropic axis in hypocretin-deficient narcoleptic humans: altered circadian distribution of GH-secretory events.

Narcolepsy is a sleep disorder caused by impaired hypocretin (orexin) neurotransmission. Growth hormone (GH) secretion may be altered in narcolepsy for various reasons. Slow-wave sleep episodes, which are closely associated with GH-secretory events, are more randomly dispersed over 24 h in narcoleptics. Furthermore, hypocretins may inhibit pituitary GH release. We assessed the function of the somatotropic axis in narcolepsy by deconvolving 24-h (10-min sampling interval) plasma GH concentration profiles in seven hypocretin-deficient narcoleptic patients and in seven healthy controls matched for age, sex, and body weight. Both basal and pulsatile GH secretion rate and secretagogue-induced GH release were similar in patients and controls. However, narcoleptics secreted approximately 50% of their total production during the daytime, whereas controls secreted only 25% during the day. Also, the GH output pattern of narcoleptics was significantly less regular. We propose that hypocretin deficiency disrupts the circadian distribution of hypothalamic GH-releasing hormone release in narcoleptic patients to simultaneously cause daytime GH release and promote their propensity to fall asleep during the day.

Adult↗

PubMed2002

Modeling the influence of growth hormone on lipolysis.

Lipolysis (the breakdown of fat) is generally estimated using stable isotopes, where the rate of appearance (Ra) of glycerol is calculated using Steele's equations. These equations are based on single-compartment differential equations for tracer and tracee where rate of change is approximated by the change in concentration from one time point to the next. We demonstrate an alternative approach to estimate metabolic processes, and to determine relationships between hormones and their actions. Growth hormone (GH) or saline was administered in a double-blind randomized crossover design to eight normal weight (NW) and eight obese (OB) subjects, and differences in the effects of GH on lipolysis were investigated. The relationship between the plasma GH concentration and glycerol Ra (as an index of lipolysis) was described using PK/PD modeling. The model incorporated the plasma GH, glycerol and D5-glycerol concentration profiles, and two sequential effect compartments to account for the delay in response. The estimated time-profile of glycerol Ra was compared with estimates obtained using Steele's equations. NONMEM (Version V) FOCE was used for parameter estimation, four differential equations were used, and glycerol and D5-glycerol were estimated simultaneously. The model adequately described both primary variables (glycerol) and derived variables (glycerol Ra as obtained using Steele's equations). Modeling allowed the assessment of potential differences in GH sensitivity in the two groups, and indicated the importance of GH in lipolysis.

Cross-Over Studies↗

PubMed2002

Ghrelin and the hyposomatotropism of obesity.

OBJECTIVE: Human obesity is characterized by growth hormone (GH) deficiency, which appears primarily related to a central pattern of obesity and is reverted on weight loss. As yet, the metabolic basis of the GH deficiency remains to be elucidated. The recently discovered endogenous ligand for the GH secretagogue receptor, ghrelin, stimulates GH secretion when administered to rodents or healthy humans. It may thus be hypothesized that low ghrelin levels underlie the hyposomatropism in obesity. RESEARCH METHODS AND PROCEDURES: We have tested this hypothesis in individuals with widely varying body mass and fat distribution and evaluated whether the improved GH concentrations on weight loss are associated with enhanced ghrelin levels. RESULTS: Both plasma GH and ghrelin levels were reciprocally related with body mass index (r = -0.67, p < 0.001). However, whereas 24-hour GH secretion was negatively related to the visceral fat area (r = -0.72, p < 0.01), ghrelin levels showed a positive relationship with the visceral fat area (r = 0.49, p < 0.02). Weight loss resulted in increased GH secretion (median 24-hour GH area under the curve: 1983 vs. 4024 mU/day before and after weight loss, respectively; p < 0.01) but did not affect ghrelin levels. No relationship could be found between GH and ghrelin plasma levels in obese subjects when comparing diurnal concentration profiles. DISCUSSION: We showed that plasma ghrelin and GH levels are both reciprocally related with body mass index, but no causative relationship could be demonstrated between low ghrelin levels and the hyposomatropism in human obesity.

Adult↗

PubMed2002

A low-fat diet has a higher potential than energy restriction to improve high-fat diet-induced insulin resistance in mice.

Previous studies have shown that energy restriction (ER) or low-fat (LF) diets have beneficial effects on high-fat (HF) diet-induced obesity and non-insulin-dependent diabetes. However, comparison between ER and low-fat diet regarding the effect on insulin resistance and lipid metabolism has not been reported. After inducing insulin resistance by HF feeding for 20 weeks, male C57BL/6J mice were divided into 3 groups. For a period of 12 weeks, group 1 received energy restriction (70% of ad libitum, HF diet), group 2 LF diet, and group 3 maintained on HF diet. Body weight and energy intake were reduced equally in ER and LF feeding. Plasma insulin levels were decreased on LF feeding, but were unchanged on ER, when compared with HF feeding. Glucose tolerance and insulin sensitivity tests revealed that insulin sensitivity was improved more efficiently by LF feeding than on ER. Plasma triglyceride (TG) levels were lower on LF feeding compared with ER and HF feeding. Measurement of hepatic very low-density lipoprotein (VLDL)-TG production revealed a lower production after LF diet feeding or ER compared with HF diet feeding. In summary, our data show that LF diet has a higher potential than ER to improve HF diet-induced insulin resistance, and that there is an association between improvement of insulin resistance and decrease of TG levels.

Animals↗

PubMed2002

Increase in daily LH secretion in response to short-term calorie restriction in obese women with PCOS.

We hypothesized that short-term calorie restriction would blunt luteinizing hormone (LH) hypersecretion in obese women with polycystic ovary syndrome (PCOS) and thereby ameliorate the anovulatory endocrine milieu. To test this hypothesis, 15 obese patients with PCOS and nine age- and body mass index-matched healthy women underwent 24-h blood sampling to quantitate plasma LH, leptin, and insulin levels. PCOS subjects were prescribed a very low caloric liquid diet (4.2 MJ/day) for 7 days and were then resampled. Basal and pulsatile LH secretion was threefold higher in PCOS subjects, but plasma insulin and leptin levels were not different in the calorie-replete state. Contrary to expectation, calorie restriction enhanced basal and pulsatile LH secretion even further. As expected, plasma glucose, insulin, and leptin concentrations decreased by 18, 75, and 50%, respectively. Serum total testosterone concentration fell by 23%, whereas serum estrone, estradiol, sex hormone-binding globulin (SHBG), and androstenedione concentrations remained unchanged. Enhanced LH secretion in the presence of normal metabolic and hormonal adaptations to calorie restriction points to anomalous feedback control of pituitary LH release in PCOS.

Adult↗

PubMed2002

Low amplitude and disorderly spontaneous growth hormone release in obese women with or without polycystic ovary syndrome.

Obesity is associated with considerably reduced plasma GH concentrations, which may contribute to anovulation in (obese) women with polycystic ovary disease (PCOS). This clinical investigation was undertaken to establish whether the GH release process is deranged in obese women with PCOS and, if so, whether the observed anomalies are features of the syndrome or a sequel of body fat accretion. To this end we sampled 24-h plasma GH concentration profiles at 10-min intervals in 15 obese PCOS patients [mean age, 29 yr (range, 20-38); percent body fat, 47 +/- 5.2%], 15 equally obese controls with regular menstrual cycles [age, 34 yr (range, 20-44); percent body fat, 48 +/- 4.9%], and 15 healthy age-matched lean controls [age, 34 yr (range, 21-45); percent body fat, 29 +/- 9.0%]. Compared with lean controls, obese PCOS patients exhibited a greater than 60% reduction in basal and a greater than 75% reduction in pulsatile and total daily GH secretion due to a 2.7-fold attenuation of burst mass and a lesser (1.4-fold) slowing of GH pulse frequency. The mean +/- SEM number of statistically significant GH peaks was 13.9 +/- 1.2/24 h, the endogenous GH half-life was 14.1 +/- 0.4 min, basal GH secretion was 5.0 +/- 0.7 mU/liter.24 h, and total secretion was 61.4 +/- 9.6 mU/liter.24 h in obese women with PCOS. None of these parameters differed from those in the body mass index-matched controls. The approximate entropy ratio was significantly increased in obese women (both PCOS and controls), indicating greater irregularity of the GH release process. Total GH secretion in patients and the two control groups correlated strongly and negatively with percent body fat (r = -0.775; P < 10(-8)). Serum concentrations of IGF-I and IGF-binding protein-3 were higher in patients with PCOS than in obese controls (P = 0.03 and P = 0.02, respectively), but the IGF-1/IGF-binding protein-3 ratio was equivalent in all three study groups. In conclusion, the profoundly reduced and irregular GH release in obese women with PCOS appears to be a corollary of body fat accretion and not of the syndrome per se.

Adult↗

PubMed2002

Growth hormone blunts protein oxidation and promotes protein turnover to a similar extent in abdominally obese and normal-weight women.

Abdominally obese individuals have reduced 24-h plasma GH concentrations. Their normal plasma IGF-I levels may reflect GH hypersensitivity. Alternatively, obesity-associated hyposomatotropism may cause less biological effect in target tissues. We therefore determined whole-body responsiveness to the anabolic effects of GH in abdominally obese (OB) and normal weight (NW) premenopausal women. A 1-h iv infusion of GH or placebo was randomly administered to six NW (body mass index, 21.1 +/- 1.9 kg/m(2)) and six OB (body mass index, 35.5 +/- 1.5 kg/m(2)) women in a cross-over design. Endogenous insulin, glucagon and GH secretion was suppressed by infusion of somatostatin. Whole-body protein turnover was measured using a 10-h infusion of [(13)C]-leucine. GH administration induced a similar plasma GH peak in NW and OB women (49.8 +/- 10.4 vs. 45.1 +/- 5.6 mU/liter). GH, compared with placebo infusion, increased nonoxidative leucine disposal, P < 0.0001) and endogenous leucine appearance (R(a), P = 0.0004) but decreased leucine oxidation (P = 0.0051). All changes were similar in both groups. Accordingly, whole-body GH responsiveness, defined as the maximum response of nonoxidative leucine disposal, leucine R(a), and oxidation per unit of GH, was not different in OB and NW women (0.25 +/- 0.18 vs. 0.19 +/- 0.17 micro mol/kg.h, 0.21 +/- 0.23 vs. 0.13 +/- 0.17 micro mol/kg.h, and -0.10 +/- 0.08 vs. -0.08 +/- 0.05 micro mol/kg.h, respectively). These results indicated that whole-body tissue responsiveness to the net anabolic effect of GH is similar in OB and NW women. Hence, we inferred that hyposomatotropism may promote amino acid oxidation and blunt protein turnover in abdominal obesity. However, hyposomatotropism cannot account for all anomalous features of protein metabolism in abdominally obese humans.

Abdomen↗

PubMed2002

Hyposomatotropism blunts lipolysis in abdominally obese women.

Abdominal obesity is associated with reduced 24-h plasma GH concentrations. It is unclear whether hyposomatotropism in abdominally obese humans is compensated by up-regulation of GH receptor sensitivity or causes less biological effect in target tissues. We, therefore, determined the responsiveness of adipose tissue to the lipolytic action of GH in abdominally obese (OB) and normal weight (NW) postmenopausal women. An iv bolus of recombinant human GH or placebo was randomly administered to eight NW [body mass index (BMI): 22.2 +/- 1.6 kg/m(2)] and eight abdominally OB (BMI: 32.1 +/- 2.6 kg/m(2)) women. Lipolysis was measured by infusion of D5-glycerol and modeled as a function of plasma GH concentrations to describe adipose tissue responsiveness. Similar plasma GH concentration peaks ( approximately 20 mU/liter) were achieved by GH injection in both groups. During placebo conditions, the average plasma GH level was significantly lower in OB compared with NW women (0.74 +/- 0.52 vs. 2.08 +/- 1.18 mU/liter, P = 0.023). Adipose tissue responsiveness, expressed as glycerol rate of appearance per kilogram of fat mass per unit plasma GH concentration was not different in both groups (NW: 1.06, OB: 0.68, P > 0.05). These results suggest that hyposomatotropism in abdominally obese individuals is not compensated by increased adipose tissue responsiveness to GH bio-action and, therefore, blunts lipolysis in these individuals.

Abdomen↗

PubMed2002

Modulation of monoaminergic neural circuits: potential for the treatment of type 2 diabetes mellitus.

A plethora of data from experimental animals provide strong support for the concept that reduced dopaminergic neuronal activity and enhanced noradrenergic tone in specific hypothalamic nuclei are involved in the pathogenesis of the metabolic syndrome. The available information on these neurotransmitter systems in insulin-resistant humans with obesity is in keeping with the postulate that analogous mechanisms may underlie their adverse metabolic profile. Treatment with bromocriptine, which has dopaminergic (D2 receptor agonist) and sympatholytic (alpha2-adrenoceptor agonistic and an alpha1-adrenoceptor antagonistic) actions, can reverse the metabolic anomalies in a variety of obese mammalian species. Combined D1/D2 receptor activation appears to exert even more powerful effects on fuel metabolism in various animal models of the metabolic syndrome. The currently available data on the metabolic effects of bromocriptine in humans with obesity and type 2 diabetes mellitus point in the same direction. Bromocriptine favorably affects glucose metabolism and various other components of the metabolic syndrome simultaneously to ameliorate the risk of damage to eyes, neural tissue, kidneys and the cardiovascular system in patients with type 2 diabetes mellitus. Moreover, a substantial number of studies indicate that bromocriptine lowers blood pressure in animals and humans with hypertension via its sympatholytic capacities. However, the effects of bromocriptine alone are relatively modest, the metabolic mechanism of action in humans remains uncertain, and the long-term efficacy and safety profiles of this compound are unknown. It seems important to seek for ways to boost the action of bromocriptine, by combining dopaminergic D2 and D1 receptor activation, for example. Notably, there is no antidiabetic drug that acts through central (dopaminergic) mechanisms. This novel approach may, therefore, result in synergistic actions with other available agents to favorably impact the risk of tissue damage in patients with type 2 diabetes mellitus.

Animals↗