Mechanisms underlying the efficacy of a rodent model of vertical sleeve gastrectomy - A focus on energy expenditure.

OBJECTIVE: Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study was to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model. METHODS: Diet-induced obese male Sprague-Dawley rats were either sham-operated, underwent VSG surgery or were pair-fed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of chow-fed rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 14C-2-deoxy-d-glucose (14C-2DG). Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals. RESULTS: Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in chow-fed animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlighted a patent neural link between the gut and BAT that included groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus. CONCLUSIONS: Collectively, these data support a role for BAT in mediating the metabolic sequelae following VSG surgery, particularly the improvement in glucose regulation, and highlight the need to better understand the contribution from this tissue in human patients.

Neuroendocrine mechanisms underlying bariatric surgery: Insights from human studies and animal models.

Obesity has reached epidemic proportions and, to date, bariatric surgery remains the only effective treatment for morbid obesity in terms of its capacity to achieve durable weight loss. Bariatric surgery procedures, including Roux-en-Y gastric bypass (RYGB), adjustable gastric banding (AGB) and sleeve gastrectomy (SG), have been the primary procedures conducted over the past decade, with SG increasing in popularity over the past 5 years at the expense of both RYGB and AGB. Although these procedures were initially proposed to function via restrictive or malabsorptive mechanisms, it is now clear that profound physiological changes underlie the metabolic improvements in patients who undergo bariatric surgery. Data generated in human patients and animal models highlight the rapid and sustained changes in gut hormones that coincide with these procedures. Furthermore, recent studies highlight the involvement of the nervous system, specifically the vagus nerve, in mediating the reduction in appetite and food intake following bariatric surgery. What is unclear is where these pathways converge and interact within the gut-brain axis and whether vagally-mediated circuits are sufficient to drive the metabolic sequalae following bariatric surgery.

Anti-Obesity Effect of the CB2 Receptor Agonist JWH-015 in Diet-Induced Obese Mice.

The cannabinoid receptor 2 (CB2) is well known for its immune modulatory role. However, recent localisation of CB2 receptors in metabolically active tissue suggests that the CB2 receptor plays a significant role in energy homeostasis. This study was designed to investigate the impact of chronic CB2 receptor stimulation on food intake, body weight and mood. Lean male C57BL/6 mice were injected i.p. with the selective CB2 receptor agonist, JWH-015 (0.0, 1.0, 5.0 and 10.0 mg kg-1) to establish dose response parameters. Mice made obese following exposure to a diet consisting of 19.4 MJ/kg (4641 Kcal/kg) of energy (19.0% protein, 21.0% total fat, 4.7% crude fiber, and 4.7% AD fiber were given either vehicle or 10 mg/kg JWH-015. Impact on mood, food intake, body weight, plasma metabolites, expression of key metabolic proteins in the brown adipose tissue (BAT) and white adipose tissue (WAT), and markers of inflammation were measured. High dose (10 mg/kg) JWH-015 reduced food intake after 1, 2, 4, and 24 h in lean mice. When given to diet induced obese (DIO) mice, a 10 mg/kg dose of JWH-015 significantly reduced body weight compared to vehicle. This dose led to a shift in markers of lipid metabolism and inflammation in WAT consistent with lipolysis and improved immune response. Furthermore, JWH-015 (10 mg/kg) produced a transient reduction in food intake and significant reduction in fat mass and adipocyte cell size. Importantly, JWH-015 produced an anxiolytic response in the elevated plus maze while having no effect on immobility time in the forced swim test. It should be noted that though the 10 mg/kg dose produced positive effects on the obese state, the possibility that these effects are mediated via non-CB2 receptor mechanisms cannot be ruled out. These results demonstrate a role for CB2 receptors in modulating energy homeostasis and obesity associated metabolic pathologies in the absence of any adverse impact on mood.

Hypothalamic control of adipose tissue.

A detailed appreciation of the control of adipose tissue whether it be white, brown or brite/beige has never been more important to the development of a framework on which to build therapeutic strategies to combat obesity. This is because 1) the rate of fatty acid release into the circulation from lipolysis in white adipose tissue (WAT) is integrally important to the development of obesity, 2) brown adipose tissue (BAT) has now moved back to center stage with the realization that it is present in adult humans and, in its activated form, is inversely proportional to levels of obesity and 3) the identification and characterization of "brown-like" or brite/beige fat is likely to be one of the most exciting developments in adipose tissue biology in the last decade. Central to all of these developments is the role of the CNS in the control of different fat cell functions and central to CNS control is the integrative capacity of the hypothalamus. In this chapter we will attempt to detail key issues relevant to the structure and function of hypothalamic and downstream control of WAT and BAT and highlight the importance of developing an understanding of the neural input to brite/beige fat cells as a precursor to its recruitment as therapeutic target.

Anti-obesity effects of the combined administration of CB1 receptor antagonist rimonabant and melanin-concentrating hormone antagonist SNAP-94847 in diet-induced obese mice.

OBJECTIVE: Current anti-obesity monotherapies have proven only marginally effective and are often accompanied by adverse side effects. The cannabinoid 1 (CB1) receptor antagonist rimonabant, while effective at producing weight loss, has been discontinued from clinical use owing to increased incidence of depression. This study investigates the interaction between the cannabinoid and melanin-concentrating hormone (MCH) systems in food intake, body weight control, and mood. DESIGN: Lean male C57BL/6 mice were injected i.p. with rimonabant (0.0, 0.03, 0.3 and 3.0 mg kg(-1)) or the MCH1-R antagonist SNAP-94847 (0.0, 1.0, 5.0 and 10.0 mg kg(-1)) to establish dose response parameters for each drug. Diet-induced obese (DIO) mice were given either vehicle, sub-threshold dose of rimonabant and SNAP-94847 alone or in combination. Impact on behavioral outcomes, food intake, body weight, plasma metabolites and expression of key metabolic proteins in the brown adipose tissue (BAT) and white adipose tissue (WAT) were measured. RESULTS: The high doses of rimonabant and SNAP-94847 produced a reduction in food intake after 2 and 24 h. Combining sub-threshold doses of rimonabant and SNAP-94847 produced a significantly greater loss of body weight in DIO mice compared with vehicle and monotherapies. In addition, combining sub effective doses of these drugs led to a shift in markers of thermogenesis in BAT and lipid metabolism in WAT consistent with increased energy expenditure and lipolysis. Furthermore, co-administration of rimonabant and SNAP-94847 produced a transient reduction in food intake, and significantly reduced fat mass and adipocyte size. Importantly, SNAP-94847 significantly attenuated the ability of rimonabant to reduced immobility time in the forced swim test. CONCLUSION: These results provide proof of principle that combination of rimonabant and a MCH1 receptor antagonist is highly effective in reducing body weight below that achieved by rimonabant and SNAP-94847 monotherapies. In addition, the combination therapy normalizes the rimonabant-induced behavioral changes seen in the forced swim test.

Neural and humoral changes associated with the adjustable gastric band: insights from a rodent model.

BACKGROUND: Bariatric surgical procedures, including the laparoscopic adjustable gastric band (LAGB), are currently the only effective treatments for morbid obesity, however, there is no clear understanding of the mechanisms underpinning the efficacy of LAGB. The aim of this study is to examine changes in activation of the sensory neuronal pathways and levels of circulating gut hormones associated with inflation of an AGB. DESIGN AND RESULTS: The trajectory within the central nervous system of polysynaptic projections of sensory neurons innervating the stomach was determined using the transsynaptically transported herpes simplex virus (HSV). Populations of HSV-infected neurons were present in the brainstem, hypothalamus and cortical regions associated with energy balance. An elevation of Fos protein was present within the nucleus of the solitary tract, a region of the brainstem involved in the control of food intake, following acute and chronic band inflation. Two approaches were used to test (1) the impact of inflation of the band alone (on a standard caloric background) or (2) the impact of a standard caloric meal (on the background of the inflated band) on circulating gut hormones. Importantly, there was a significant elevation of glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) following oral gavage of a liquid meal in animals with pre-inflated bands. There was no impact of inflation of the band alone on circulating GLP-1, PYY or ghrelin in animals on a standard caloric background. CONCLUSION: These data are consistent with the notion that the LAGB exerts its effects on satiety, reduced food intake and reduced body weight by the modulation of both neural and hormonal responses with the latter involving an elevation of meal-related levels of GLP-1 and PYY. These data are contrary to the view that the surgery is purely 'restrictive'.

Postnatal overfeeding leads to obesity and exacerbated febrile responses to lipopolysaccharide throughout life.

The perinatal environment can be crucial for programming long-term physiology, including the mechanisms regulating body weight, and postnatal overfeeding can lead to obesity throughout life. Inflammation-related complications are of particular concern in the obese. However, little is known about how postnatal overfeeding contributes to changes in the ability to respond to inflammation. In the present study, we investigate changes in the febrile and neurochemical response to immune challenge with lipopolysaccharide (LPS), in juvenile and adult, male and female Wistar rats made obese by overfeeding during the postnatal period. We demonstrate that febrile responses to LPS are exacerbated in these rats, with peak core temperatures being up to 0.5 °C higher compared to those in controls, and this is associated with an enhanced pro-inflammatory cytokine profile and enhanced hypothalamic-pituitary-adrenal (HPA) axis activation. Plasma pro-inflammatory cytokines concentrations were approximately three-fold greater in neonatally overfed rats after LPS and there were approximately twice as many neurones activated in the paraventricular nucleus of the hypothalamus as in controls, with a prolonged corticosterone response. We also observed elevated expression of toll-like receptors (TLR) 2 and 4 in adipose tissue and greater inhibitory factor κB phosphorylation in these obese animals. Despite similar changes in expression of adipose TLR3, there was no corresponding alteration in the response to a viral mimetic that acts at this receptor. We suggest that an elevated febrile response to LPS therefore occurs in cases of obesity and this is associated with altered HPA axis function and enhanced TLR2/4 expression in adipose tissue and an up-regulated downstream pro-inflammatory cascade.

Brown adipose tissue thermogenesis heats brain and body as part of the brain-coordinated ultradian basic rest-activity cycle.

Brown adipose tissue (BAT), body and brain temperatures, as well as behavioral activity, arterial pressure and heart rate, increase episodically during the waking (dark) phase of the circadian cycle in rats. Phase-linking of combinations of these ultradian (<24 h) events has previously been noted, but no synthesis of their overall interrelationships has emerged. We hypothesized that they are coordinated by brain central command, and that BAT thermogenesis, itself controlled by the brain, contributes to increases in brain and body temperature. We used chronically implanted instruments to measure combinations of bat, brain and body temperatures, behavioral activity, tail artery blood flow, and arterial pressure and heart rate, in conscious freely moving Sprague-Dawley rats during the 12-h dark active period. Ambient temperature was kept constant for any particular 24-h day, varying between 22 and 27 degrees C on different days. Increases in BAT temperature (> or = 0.5 degrees C) occurred in an irregular episodic manner every 94+/-43 min (mean+/-SD). Varying the temperature over a wider range (18-30 degrees C) on different days did not change the periodicity, and neither body nor brain temperature fell before BAT temperature episodic increases. These increases are thus unlikely to reflect thermoregulatory homeostasis. Episodic BAT thermogenesis still occurred in food-deprived rats. Behavioral activity, arterial pressure (18+/-5 mmHg every 98+/-49 min) and heart rate (86+/-31 beats/min) increased approximately 3 min before each increase in BAT temperature. Increases in BAT temperature (1.1+/-0.4 degrees C) were larger than corresponding increases in brain (0.8+/-0.4 degrees C) and body (0.6+/-0.3 degrees C) temperature and the BAT episodes commenced 2-3 min before body and brain episodes, suggesting that BAT thermogenesis warms body and brain. Hippocampal 5-8 Hz theta rhythm, indicating active engagement with the environment, increased before the behavioral and autonomic events, suggesting coordination by brain central command as part of the 1-2 h ultradian basic rest-activity cycle (BRAC) proposed by Kleitman.

A rodent model of adjustable gastric band surgery-implications for the understanding of underlying mechanisms.

BACKGROUND: Bariatric surgery is currently the only anti-obesity therapy that can deliver weight loss of up to 20-30% of body weight. Laparoscopic adjustable gastric banding (LAGB) and Roux-en-y gastric bypass are the most commonly performed of these surgeries. The mechanisms by which LAGB initiates an increase in satiety remain completely unknown. The aim of this study is to establish a rodent model of adjustable gastric banding (AGB) that will enable investigation of these mechanisms. METHODS: Sprague-Dawley rats were implanted with adjustable gastric bands immediately below the gastro-esophageal junction around the glandular stomach. This band, as in humans, can be inflated via an exteriorized port resulting in an incremental impact on the stomach. RESULTS: Rats with an incremental inflation of the AGB showed a clear stepwise reduction in food intake and body weight. Normal food intake and body weight gain were restored with band deflation. Barium-assisted X-ray of the stomach showed the formation of a small gastric pouch proximal to the inflated band in a manner analogous to the human LAGB. CONCLUSIONS: This is the first animal model of the AGB that allows incremental inflation for optimal tightening of the band in the conscious animal with corresponding effects on food intake and body weight. This model will allow measurement of acute and chronic neural and hormonal changes following activation of the band in the conscious animal and will provide the potential to inform and improve surgical approaches that are at the forefront of obesity treatments.

Pelvi-ureteric junction obstruction by crossing renal vessels: clinical and imaging features.

OBJECTIVE: To present the characteristic clinical and imaging findings of pelvi-ureteric junction (PUJ) obstruction caused by crossing renal vessels (CRV), as it presents particular features within the spectrum of congenital hydronephrosis. PATIENTS AND METHODS: Between April 1982 and December 2000, 384 children underwent surgery for PUJ obstruction. In 71 (18.5%; mean age 8.5 years, range 2 months to 14 years; 49 aged> 5 years), the obstruction was caused by CRV. The data collected from the medical records of these patients were analysed for their clinical presentation and imaging findings, i.e. ultrasonography (US), intravenous urography (IVU) and diuretic renography. RESULTS: The main presenting symptom was recurrent renal colic (pain, nausea, vomiting) in 59%, followed by urinary infection (UTI) in 20%, gross haematuria in 11% and an incidental diagnosis in 10%. By contrast, in the 313 children with intrinsic PUJ obstruction, renal colic was present in only 10.5%. Moreover, from 1991 to 2000, when the use of prenatal US became widespread, hydronephrosis was detected prenatally in 42 of 212 children (20%) with intrinsic PUJ obstruction, but in only two of 31 (6%) with obstruction by CRV. However, in 10 children with CRV operated on during this period, prenatal US had shown mild hydronephrosis (< 15 mm), which during the follow-up decreased until the children became symptomatic after 5-9 years (eight renal colic, two UTI). US during acute symptoms showed significant hydronephrosis (> 25 mm), and colour Doppler US of two patients directly showed the CRV. In all 71 children with CRV obstruction diuretic IVU and renography during the acute symptoms had an obstructive pattern, and in 24 renal colic was reproduced during the examination. The differential kidney function was < 40% in 11 children who presented with UTI; two required nephrectomy and in the remaining 69 an Anderson-Hynes pyeloplasty, after which none had an episode of renal colic or UTI during a mean (range) follow-up of 10.2 (2-20) years. CONCLUSIONS: PUJ obstruction by CRV should be suspected in older children presenting with recurrent renal colic and hydronephrosis. Good kidney function is expected in most of these children, despite their age, because the vascular obstruction is intermittent. Mild prenatal hydronephrosis that could decrease postnatally does not exclude the possibility of vascular obstruction, which may later become symptomatic. Imaging (US, diuretic IVU and renography) during an episode of pain is essential and colour Doppler US could help to establish the diagnosis in these cases. Knowing that a child has a CRV is important for choosing an open surgical approach rather than endoscopic pyelotomy, to avoid potential complications

The long-term outcome of bilateral Cohen ureteric reimplantation under a common submucosal tunnel.

OBJECTIVE: To analyse the results of bilateral Cohen reimplantation under a common submucosal tunnel, over an 18-year period. PATIENTS AND METHODS: We retrospectively examined 102 children (35 boys and 67 girls, median age 5.5 years, range 0.5-13.5) who underwent bilateral antireflux ureteric reimplantation from 1983 to 2000 with a modified Cohen technique, re-implanting both ureters under a common submucosal tunnel in the mid-trigonal area, to treat primary vesico-ureteric reflux (VUR, 99 patients) or obstructive megaureter (three). The mean (range) follow-up was 10.6 (2-18) years. RESULTS: The operation was successful in 198 of 204 (97%) ureters. One patient had vesico-ureteric stenosis in one ureter and was re-operated successfully. In two ureters in two different patients there was transient stasis after surgery caused by oedema within the tunnel, which gradually resolved. Two ureters in two other patients had reflux after surgery, which resolved spontaneously after 12 and 24 months, respectively. A 6-month old baby had anuria after surgery because of acute compression of both ureters within a narrow tunnel; this patient was re-operated, the tunnel widened and the obstruction resolved. None of 82 patients who had reached school age by the time of their last follow-up showed signs of voiding dysfunction. CONCLUSIONS: The modified bilateral Cohen reimplantation with both ureters under a common submucosal tunnel offers very good long-term results in curing VUR or obstructive megaureter. Crossing one ureter upon the other within the tunnel does not predispose to long-term obstruction. From these results we recommend it as a reliable technique for surgically treating bilateral VUR or obstructive megaureter.

The role of strict metabolic control by insulin infusion on fibrinolytic profile during an acute coronary event in diabetic patients.

BACKGROUND: Many clinical and laboratory observations give support to the hypothesis that strict metabolic control by insulin infusion during acute coronary events may improve the ischemic damage and prognosis. HYPOTHESIS: We investigated the impact of intensive insulin treatment on fibrinolytic parameters during an acute ischemic myocardial event (unstable angina or acute myocardial infarction) in patients with type 2 diabetes mellitus. METHODS: The study group consisted of 48 type 2 diabetic patients, of whom 24 were randomized to conventional therapy plus intensive insulin treatment (Group 1) and 24 to conventional therapy only (Group 2). The two groups were comparable according to gender, age, body mass index, waist:hip ratio, duration of diabetes, previous antidiabetic treatment, type of ischemic events, concomitant therapy, and the classic risk factors for coronary disease. Insulin-treated patients were excluded from the study. Plasma levels of fibrinogen, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) were measured on admission and discharge. Fibrinogen (fibr) was measured using the photometric method. PAI-1 and t-PA were measured by enzyme-linked immunosorbent assays. RESULTS: T-PA increased in both groups during hospitalization (t-PA(admission) vs. t-PA(discharge): Group 1: 15.42 +/- 4.4 ng x ml(-1) vs. 21.2 +/- 5.74 ng x ml(-1), p = 0.000037; Group 2: 14.47 +/- 6.31 ng x ml(-1) vs. 19.18 +/- 6.88 ng x ml(-1), p = 0.001). On the other hand, fibr and PAI-1 levels increased remarkably in controls (Group 2, fibr(admission) vs. fibr(discharge): 2.98 +/- 1.04 g x l(-1) vs. 3.59 +/- 1.01 g x l(-1), p = 0.002, and PAI-1admission vs. PAI-1 discharge: 30.6 +/- 17.34 ng x ml(-1) vs. 40.62 +/- 23.48 ng x ml(-1), p = 0.003). This finding was not observed in the intensive insulin treatment group (Group 1, fibr(admission) vs. fibr(discharge): 2.87 +/- 0.73 g x l(-1) vs. 2.67 +/- 0.72 g x l(-1), p = 0.101, and PAI-1 admission vs. PAI-1 discharge: 30.75 +/- 15.81 ng x ml(-1) vs. 27.75 +/- 6.43 ng x ml(-1), p = 0.484). CONCLUSION: Intensive insulin treatment during an acute coronary event improves fibrinolytic profile in patients with diabetes mellitus. This is a possible mechanism for the reduced short- and long-term mortality in diabetic patients treated with intensive insulin treatment protocol.

Antiplatelet is superior to anticoagulant treatment after coronary stenting: fewer coronary and other events within 30 days after stenting.

Stent prosthesis is a high efficacious method with low complication rates. However, the ideal adjunctive therapy following stent implantation remains controversial. The authors compared the effectiveness and complication rates of aspirin-ticlopidine antiplatelet therapy vs. anticoagulant therapy with acenocoumarol within 30 days following stent prosthesis. They prospectively studied 404 patients following stent prosthesis while randomly receiving anticoagulant (Group A: 201 patients) vs. antiplatelet treatment (Group B: 203 patients). Groups A and B were similar in demographic data (age, gender), stent location, clinical presentation, indication of stenting, and type of implanted stent. Chi-square test, t test, and Wilcoxon test for two samples were used for statistical analysis of the results. Stent implantation was attempted in 434 cases. This was successful in 70/85 (82%) of the bailout, 122/135 (90%) of the suboptimal, and 212/214 (99%) of the elective cases. In 201 patients anticoagulant treatment with acenocoumarol was administered for 4 weeks (group A), while 203 received antiplatelet treatment with ticlopidine (group B). The need for reintervention was less and total cardiac events were fewer in group B than in group A: three (1.5%) and nine (4.4%) vs 18 (9%) and 29 (14.4%), p<0.0008 and p<0.006 respectively. Hemorrhagic complications and total noncardiac events were fewer in group B than in group A: six (3%) and six (3%) vs. 18 (9%) and 19 (9.5%), p<0.01 and p<0.007 respectively. The length of hospital stay was shorter in group B than in A, p<0.0001. In conclusion, in this study of intracoronary stenting the authors had a high success rate in 434 attempted cases. Antiplatelet therapy was accompanied by fewer cardiac and noncardiac 1 month events when compared with anticoagulant therapy, supporting its role as the adjunctive treatment of choice post-stenting for the time being.

Angiographic study of coronary artery disease in diabetic patients in comparison with nondiabetic patients.

Diabetes mellitus is known to be a major risk factor for the development of coronary artery disease (CAD). The aim of this study was to investigate angiographically the coronary arteries of diabetic persons, focusing on the type and distribution of CAD, sex differences in CAD anatomy, and the size of the coronary vessels. This was a randomized study and included two groups of patients with angiographically demonstrated CAD. Group A included 463 diabetics, aged 60.3 years, and Group B 210 nondiabetic patients, aged 58.5 years. The two groups were matched by age, sex, weight, and classic risk factors. The authors evaluated the regional location of CAD, left ventricular (LV) function, and the width of the lumen of coronary arteries. The diabetics had three-vessel disease more frequently (p<0.001) and one-vessel disease less frequently (p<0.001). The CAD was more extensive in Group A (mean 2.2 vessels, compared to 1.8 vessels in Group B, p<0.01). The right coronary artery was affected more often in diabetics (p<0.01), as was the anterior descending artery in three-vessel disease (p<0.05). The male diabetics had the same angiographic CAD severity as the females, although the latter had a better LV ejection fraction (p<0.05). The female diabetics < 55 years old had CAD findings comparable with those from women 4 years older in Group B. Diabetics show more diffuse and severe CAD than the general population. There are no sex-related differences in the severity of CAD.