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PubMed1980

Development of obesity in Zucker obese (fafa) rat in absence of hyperphagia.

The free-feeding, genetically obese rat is hyperphagic, hyperinsulinemic, and hypertriglyceridemic and has increased fat cell size and number compared to its lean littermate. These experiments demonstrate that, when fafa rats are prevented from expressing hyperphagia throughout life, the complete obese "syndrome" still develops. Furthermore, life-long food restriction does not prevent increased lipoprotein lipase in the fafa rat. The data support the concept that a peripheral metabolic adaptation, probably in lipid metabolism, results in preferential shunting of dietary substrate in the restricted obese rats to adipose tissue with concomitant decreases in other tissues.

Adipose Tissue↗
PubMed1998

Behavioral and endocrine traits of obesity-prone and obesity-resistant rats on macronutrient diets.

Patterns of eating behavior, body weight gain, and hormone changes were examined in normal-weight albino Sprague-Dawley rats on macronutrient diets. These diets consisted of either three separate jars with pure macronutrients, fat, carbohydrate and protein, from which to choose, or a single diet with different concentrations of fat and carbohydrate. Similar patterns on the choice-diet and single-diet paradigms were observed. During the first 7-10 days on these diets but not subsequently, the rats consuming a fat-rich diet exhibit significant hyperphagia, an increase in both total and fat intake that produces higher body weight gain. Compared with a 10% fat diet, a 30% fat diet is associated with a decline in insulin and corticosterone (CORT) levels, whereas a 60% fat diet produces an increase in circulating glucose. Levels of glucose are positively correlated with fat intake, and together these measures are consistently related to body fat. These relationships are most strongly expressed in rats that consume a fat-rich diet with >30% fat. Whereas insulin levels are also positively related to body fat, CORT is inversely related in these normal-weight subjects. In animals consuming a high-fat diet, a clear separation can be seen between "obesity-prone" (OP) rats with 100% greater body fat than "obesity-resistant" (OR) rats. The OP rats, which consume 15% more total calories, have significantly higher insulin and glucose levels. In animals that consume a diet with >30% fat, it is the OP but not the OR rats that exhibit a positive relation between fat intake, glucose levels, and body fat and reveal an additional association between carbohydrate intake, insulin, and body fat. Thus these rats on macronutrient diets exhibit distinct traits that relate behavior to hormone disturbances and adiposity and distinguish subjects that are prone vs. resistant to obesity.

Adipose Tissue↗
PubMed2003

Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset.

Rats selectively bred to develop diet-induced obesity (DIO) were compared with those bred to be diet resistant (DR) on a 31% fat high-energy diet with regard to their central leptin signaling and blood-brain barrier (BBB) transport. Peripheral leptin injection (15 mg/kg ip) into lean 4- to 5-wk-old rats produced 54% less anorexia in DIO than DR rats. DIO rats also had 21, 63, and 64% less leptin-induced immunoreactive phosphorylated signal transducer and activator of transcription 3 (pSTAT3) expression in the hypothalamic arcuate, ventromedial, and dorsomedial nuclei, respectively. However, hindbrain leptin-induced nucleus tractus solitarius pSTAT3 and generalized sympathetic (24-h urine norepinephrine) activation were comparable. Reduced central leptin signaling was not due to defective BBB transport since transport did not differ between lean 4- to 5-wk-old DIO and DR rats. Conversely, DIO leptin BBB transport was reduced when they became obese at 23 wk of age on low-fat chow or after 6 wk on high-energy diet. In addition, leptin receptor mRNA expression was 23% lower in the arcuate nuclei of 4- to 5-wk-old DIO compared with DR rats. Thus a preexisting reduction in hypothalamic but not brain stem leptin signaling might contribute to the development of DIO when dietary fat and caloric density are increased. Defects in leptin transport appear to be an acquired defect associated with the development of obesity and possibly age.

Aging↗
PubMed1980

Vagal mediation of hypothalamic obesity but not of supermarket dietary obesity.

In two independent experiments, complete subdiaphragmatic vagotomy did not prevent the development of the obesity that results from the addition of highly palatable foods to the diet of rats. The vagotomized animals exhibited only a 1-day delay in the onset of overeating, and this only when first exposed to the tasty diet. In independent tests of the functional completeness of the vagotomies, the vagotomized animals failed to overeat or gain excessive weight on a standard laboratory diet following bilaterally parasagittal hypothalamic knife cuts. Thus, hypothalamic knife-cut obesity requires the integrity of the vagus for its full expression, whereas dietary obesity does not.

Animals↗
PubMed1993

Skeletal muscle glucose metabolism in obesity-prone and obesity-resistant rats.

Ad libitum access to a high-fat (HF) diet produces a wide range of weight gain in rats. Rats most susceptible to weight gain on such a diet (obesity prone; OP) are more insulin resistant after 4-5 wk of diet exposure than are those most resistant (obesity resistant; OR) to weight gain. To investigate whether skeletal muscle glucose metabolism contributes to insulin resistance in this model, insulin-stimulated glucose metabolism was assessed in the perfused hindquarter of rats exposed to either a low-fat (LF, n = 6) or HF diet for 5 wk. Delineation of OP (n = 6) and OR (n = 6) rats was based on body weight gain. OP rats gained 60% more body weight while eating only 10% more energy than OR rats. Single-pass perfusions were carried out for 2 h in the presence of glucose, insulin, and [U-14C]glucose. Insulin-stimulated glucose uptake (mumol.100 g-1.min-1) was 14.2 +/- 0.9 in LF, 11.1 +/- 0.8 in OR, and 6.2 +/- 0.6 in OP. Glucose oxidation (mumol.100 g-1.min-1) was 1.7 +/- 0.3 and 1.2 +/- 0.3 in LF and OR, respectively, but was 0.2 +/- 0.1 in OP. Net glycogen synthesis was significantly reduced in OP compared with OR and LF despite similar glycogen synthase I activity. Muscle triglyceride concentration was not significantly different in OR and OP rats. These results demonstrate significant defects in skeletal muscle glucose uptake and disposal in rats most susceptible to HF diet-induced obesity. Clearly, the heterogeneous response to a HF diet involves not only body weight gain but also skeletal muscle fuel metabolism.

Animals↗
PubMed2003

Los function and obesity: the impact of untreated obesity, weight loss, and chronic gastric balloon distension.

BACKGROUND/AIMS: In obesity, many gastro-oesophageal reflux promoting factors are present. Weight reduction is advised to symptomatic overweight subjects. The aim of the present study was to investigate the influences of untreated obesity, weight loss, and chronic gastric balloon distension on the lower oesophageal sphincter (LOS) function. METHODS: Patients entering a randomized, double-blind, sham-controlled study of balloon treatment, consisting of 4 months of either sham balloon or balloon treatment followed by 4 months of balloon treatment. Manometry and 24-hour pH measurements were performed at the start of the study and after 13 and 26 weeks. RESULTS: Before treatment, LOS dysfunction was present in 7 of 32 patients (21.9%). Increased upright and supine reflux was present in 8 patients (25%). Sham treatment resulted in a weight loss of 9.7% with improved LOS function (a significant 0.6-cm increase in LOS length and a non-significant 2.6 mm Hg higher LOS pressure) and in a significantly decreased upright reflux (acid reflux time decreasing from 8.0 to 5.5% and number of meal-related and postprandial reflux episodes decreasing from 49 to 32). These improved values deteriorated after 4 months of balloon placement, with significantly increasing total, upright, and supine reflux to 7.5, 7.6, and 6.7% of the time, respectively, with oesophageal lesions after an overall 17.8% weight loss. Four months of balloon treatment induced a similar weight loss (9.9%) with significantly increased supine reflux from 1.6 to 6.7% of the time. After a second 4-month balloon period and an overall 13.8% weight loss, LOS and reflux values returned towards baseline values. A comparison of both groups demonstrated the adverse effects of balloon positioning after a period of substantial sham-induced weight loss. CONCLUSIONS: Impaired LOS function and increased gastro-oesophageal reflux were observed in one quarter of the untreated obese subjects. Weight loss ameliorated manometry and pH values, but subsequent balloon positioning tended to counteract these beneficial changes. In patients on balloon treatment from the start, adverse effects seemed to wear off with prolonged treatment.

Double-Blind Method↗
PubMed1997

Lisinopril versus hydrochlorothiazide in obese hypertensive patients: a multicenter placebo-controlled trial. Treatment in Obese Patients With Hypertension (TROPHY) Study Group.

Because obesity-associated hypertension has unique hemodynamic and hormonal profiles, certain classes of antihypertensive agents may be more effective than others as monotherapy. Thus, we compared the efficacy and safety of the angiotensin-converting enzyme inhibitor lisinopril and the diuretic hydrochlorothiazide in a 12-week, multicenter, double-blind trial in 232 obese patients with hypertension. Patients with an office diastolic pressure between 90 and 109 mm Hg were randomized to treatment with daily doses of lisinopril (10, 20, or 40 mg), hydrochlorothiazide (12.5, 25, or 50 mg), or placebo. Mean body mass indexes were similar for all patients. At week 12, lisinopril and hydrochlorothiazide effectively lowered office diastolic (-8.3 and -7.7 versus -3.3 mm Hg, respectively; P<.005) and systolic (-9.2 and -10.0 versus -4.6 mm Hg, respectively; P<.05) pressures compared with placebo. Ambulatory blood pressure monitoring confirmed that lisinopril and hydrochlorothiazide effectively lowered 24-hour blood pressure compared with placebo (P<.001). Significant dose-response differences were observed between treatments. Sixty percent of patients treated with lisinopril had an office diastolic pressure <90 mm Hg compared with 43% of patients treated with hydrochlorothiazide (P<.05). Responses to therapies differed with both race and age. Neither treatment significantly affected insulin or lipid profiles; however, plasma glucose increased significantly after 12 weeks of hydrochlorothiazide therapy compared with lisinopril (+0.31 versus -0.21 mmol/L; P<.001). Hydrochlorothiazide also decreased serum potassium levels by 0.4 mmol/L from baseline. In conclusion, lisinopril was as effective as hydrochlorothiazide in treating obese patients with hypertension. Treatment with angiotensin-converting enzyme inhibitors may show greater efficacy as monotherapy at lower doses compared with thiazide diuretics, may have a more rapid rate of response, and may offer advantages in patients at high risk of metabolic disorders.

Adult↗
PubMed1990

Impact of obesity on insulin action in volunteers with normal glucose tolerance: demonstration of a threshold for the adverse effect of obesity.

We examined whether obesity must first exceed a critical threshold before it begins to impair insulin action in volunteers with normal glucose tolerance. Forty-nine healthy volunteers, whose ideal body weight ranged from 80-240%, underwent euglycemic clamps during sequential insulin infusions of 0.4, 1.0, and 10 mU/kg.min. Insulin sensitivity was assessed by estimation of the plasma insulin concentration that produced half-maximal glucose disposal (EC50). Glucose disposal during the highest insulin infusion was used as an index of maximal insulin responsiveness. There was a significant correlation between body mass index and insulin sensitivity (EC50) best fitted by a straight line that broke at a body mass index of 26.8 kg/m2 (P less than 0.05). Below this breakpoint (26.8 kg/m2), there was no significant correlation (r = 0.1), whereas above the breakpoint there was a strong positive correlation (r = 0.8; P less than 0.001) between EC50 and body mass index. In contrast, insulin responsiveness was not significantly correlated with body mass index (r = 0.1). We conclude that insulin sensitivity for glucose disposal is impaired in human subjects with normal glucose tolerance who exceed a critical threshold of obesity, which corresponds to an ideal body weight of 120%. This threshold is consistent with the nonlinear (J-shaped) relationship between obesity and its other adverse health consequences, and may have important implications for desirable weight goals.

Adult↗
PubMed2006

Isomer-specific anti-obese and hypolipidemic properties of conjugated linoleic acid in obese OLETF rats.

Conjugated linoleic acid (CLA), a mixture of positional and geometric isomers of linoleic acid, has attracted considerable attention because of its potentially beneficial biologic effects both in vitro and in vivo. Our results clearly show the specific action of the 10trans,12cis-CLA isomer against hyperlipidemia and obesity in obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats. After 2 weeks of feeding with 10t,12c-CLA, but not 9cis,11trans-CLA, abdominal adipose tissue weight and serum and hepatic lipid levels in OLETF rats were lower than those in linoleic acid-fed rats. These effects were attributable to suppressed fatty acid synthesis and enhanced fatty acid beta oxidation in the liver on a 10t,12c-CLA diet. Additionally, we showed that mRNA expression of fatty acid synthase, carnitine palmitoyltransferase, leptin, and sterol regulatory element binding protein-1 was also regulated by 10t,12c-CLA. We suppose that 10t,12c-CLA reveals hypolipidemic and anti-obese activity through the alteration of mRNA expressions in the liver and white adipose tissue.

Adipose Tissue↗
PubMed1998

Leptin levels in non-obese and obese children and young adults with type 1 diabetes mellitus.

OBJECTIVE: To evaluate serum leptin levels in children and young adults with type 1 (insulin-dependent) diabetes mellitus and to investigate whether they are different in prepuberty, puberty and young adulthood. DESIGN: Three groups of diabetics (prepubertal, pubertal and young adults) subdivided into obese and non-obese were studied. Three groups of healthy subjects matched for sex, age and body mass index served as controls. RESULTS: Diabetic patients had serum leptin concentrations similar to those of controls in all three groups. A small non-significant increase in leptin from the prepubertal to the young adult age group for both diabetics and controls was found. A significant association of serum leptin level with body mass index (P < 0.001), female sex (P < 0.001) and age (P < 0.01) in both the diabetic and control group was present. Insulin-dependent diabetes was not associated with higher leptin concentration. CONCLUSIONS: Serum leptin concentrations are similar in diabetic patients and healthy controls. The association between obesity and leptin concentration was similar in the diabetic and non-diabetic subjects. Type 1 diabetes mellitus does not modify serum leptin concentration.

Adolescent↗
PubMed2003

Physiological difference between dietary obesity-susceptible and obesity-resistant Sprague Dawley rats in response to moderate high fat diet.

The primary aim of the present study was to define central and peripheral physiological differences between dietary obesity-susceptible (DOS) and obesity-resistant (DOR) outbred Sprague Dawley (SD) rats when given a moderate high fat diet containing 32.34% of energy as a fat. After a 9-week feeding period, the DOS-SD rats consumed significantly more feed (11.1%) and had higher abdominal (39.9%) and epididymal (27.5%) fat pads than the DOR-SD rats. In addition, serum leptin and insulin levels were significantly increased in the DOS-SD rats compared with those in the DOR-SD rats. However, we did not observe significant differences in serum triglyceride, cholesterol and glucose. No differences in hypothalamic OB-Ra and Rb mRNA expressions were found between the two groups. In contrast, arcuate NPY immunohistochemical expression was much higher in the DOS-SD rats than in the DOR-SD rats, though NPY expression in the supraoptic and paraventricular nuclei was not different between the two phenotypes. In peripheral tissues, the DOS-SD rats showed noticeably increased acetyl CoA carboxylase (ACC) mRNA expression in the liver, not epididymal fat. However, Western blot of peroxisomal proliferator activated factor gamma (PPAR gamma) in the liver and epididymal fat was not different between the two phenotypes of SD rats. It was concluded that different body weight phenotypes within outbred SD population responded differently to the development of dietary induced obesity via altered anabolic features in the hypothalamus and liver.

Acetyl-CoA Hydrolase↗
PubMed2003

[Treatment of obesity: the need to target attention on high-risk patients characterized by abdominal obesity].

Abdominal obesity is associated with metabolic abnormalities, increasing the risk of type 2 diabetes and coronary artery disease (CAD). The Quebec Cardiovascular Survey demonstrated that the atherogenic metabolic triad (AMT) present in abdominally obese (AO) males increases the risk of CAD 20-fold over the course of 5 years. An early detection algorithm was developed to identify individuals presenting these atherogenic abnormalities. It was found that the association of large waist circumference (WC) and moderate hypertriglyceridemia (the "hypertriglyceridemic waist", or HW) could adequately identify a significant portion of individuals with the AMT. It is important to note that even in the absence of classic risk factors, abdominally obese patients can present increased risk of CAD if they have HW. Finally, it has been suggested that the risk of developing an acute coronary syndrome in AO patients is not always related to the degree of coronary stenosis, and the patient s atherothrombotic/inflammatory profile should be taken into account in evaluating risk. Stabilization of the atherosclerotic plaque would become a legitimate therapeutic objective, and more feasible for prevention of CAD, in AO patients.

Abdomen↗
PubMed2004

Characterization of the resistance to the anorectic and endocrine effects of leptin in obesity-prone and obesity-resistant rats fed a high-fat diet.

Leptin produced by adipocytes controls body weight by restraining food intake and enhancing energy expenditure at the hypothalamic level. The diet-induced increase in fat mass is associated with the presence of elevated circulating leptin levels, suggesting the development of resistance to its anorectic effect. Rats, like humans, show different susceptibility to diet-induced obesity. The aim of the present study was to compare the degree of leptin resistance in obesity-prone (OP) vs obesity-resistant (OR) rats on a moderate high-fat (HF) diet and to establish if the effects of leptin on hypothalamo-pituitary endocrine functions were preserved. Starting from 6 weeks after birth, male Sprague-Dawley rats were fed on either a commercial HF diet (fat content: 20% of total calorie intake) or a standard pellet chow (CONT diet, fat content: 3%). After 12 weeks of diet, rats fed on HF diet were significantly heavier than rats fed on CONT diet. Animals fed on HF diet were ranked according to body weight; the two tails of the distribution were called OP and OR rats respectively. A polyethylene cannula was implanted into the right ventricle of rats 1 week before central leptin administration. After 12 weeks of HF feeding, both OR and OP rats were resistant to central leptin administration (10 mug, i.c.v.) (24 h calorie intake as a percent of vehicle-treated rats: CONT rats, 62 [50; 78]; OR, 93 [66; 118]; OP, 90 [70; 120] as medians and 95% confidence intervals (CIs) of six rats for each group). Conversely, after 32 weeks of diet both OR and OP rats were partially responsive to 10 mug leptin i.c.v. as compared with CONT rats (24 h calorie intake as a percent of vehicle-treated rats: CONT rats, 60 [50; 67]; OR, 65 [50; 80]; OP, 80 [60; 98] as medians and 95% CIs of six rats for each group); the decrease of food intake following 200 mug leptin i.p. administration was similar in all the three groups (calorie intake as a percent of vehicle-treated rats: 86 [80; 92] as median and 95% CI). The long-term intake of HF diet caused hyperleptinemia, hyperinsulinemia and higher plasma glucose levels in OP rats as compared with CONT rats. Plasma thyroxine (T4) was lower in all the rats fed the HF diet as compared with CONT. i.c.v. administration of leptin after 32 weeks of diet restored normal insulin levels in OP rats. Moreover, leptin increased plasma T4 concentration and strongly enhanced GH mRNA expression in the pituitary of OP as well as OR rats (180+/-10% vs vehicle-treated rats). In conclusion, long-term intake of HF diet induced a partial central resistance to the anorectic effect of leptin in both lean and fat animals; the neuroendocrine effects of leptin on T4 and GH were preserved.

Animals↗
PubMed2006

Breast-feeding and risk for childhood obesity: does maternal diabetes or obesity status matter?

OBJECTIVE: We sought to evaluate whether maternal diabetes or weight status attenuates a previously reported beneficial effect of breast-feeding on childhood obesity. RESEARCH DESIGN AND METHODS: Growing Up Today Study (GUTS) participants were offspring of women who participated in the Nurses' Health Study II. In the present study, 15,253 girls and boys (aged 9-14 years in 1996) were included. Maternal diabetes and weight status and infant feeding were obtained by maternal self-report. We defined maternal overweight as BMI > or = 25 kg/m2. Childhood obesity, from self-reported height and weight, was based on the Centers for Disease Control and Prevention definitions as normal, at risk for overweight, or overweight. Maternal status categories were nondiabetes/normal weight, nondiabetes/overweight, or diabetes. Logistic regression models used generalized estimating equations to account for nonindependence between siblings. RESULTS: For all subjects combined, breast-feeding was associated with reduced overweight (compared with normal weight) in childhood. Compared with exclusive use of formula, the odds ratio (OR) for exclusive breast-feeding was 0.66 (95% CI 0.53-0.82), adjusted for age, sex, and Tanner stage. Results did not differ according to maternal status (nondiabetes/normal weight OR 0.73 [95% CI 0.49-1.09]; nondiabetes/overweight 0.75 [0.57-0.99]; and diabetes 0.62 [0.24-1.60]). Further adjustment for potential confounders attenuated results, but results remained consistent across strata of maternal status (P value for interaction was 0.50). CONCLUSIONS: Breast-feeding was inversely associated with childhood obesity regardless of maternal diabetes status or weight status. These data provide support for all mothers to breast-feed their infants to reduce the risk for childhood overweight.

Adolescent↗
PubMed1993

Effect of dehydroepiandrosterone on neurotransmitter levels and appetite regulation of the obese Zucker rat. The Obesity Research Program.

The obese Zucker rat is a model of youth-onset obesity associated with hyperphagia. In this study, dehydroepiandrosterone's effect at decreasing food intake and body weight in the obese Zucker rat was investigated. Rats were treated with a dehydroepiandrosterone-supplemented diet (0.0, 0.06, 0.15, 0.3, or 0.6%) for 7 days. The 0.3 and 0.6% treatment groups showed a dramatic decrease in daily food intake, which was evident the 1st day. In addition to the reduction in food intake, body weight changes also were affected significantly in the high-dose treatment groups. The possibility that these dehydroepiandrosterone-induced changes were correlated to perturbations in central neurotransmitter levels associated with appetite control was investigated. The hypothalamus, frontal cortex, striatum, and hippocampus of dehydroepiandrosterone-treated animals were assayed for neurotransmitters known to have inhibitory or stimulatory effects on feeding behavior (serotonin, dopamine, norepinephrine, and epinephrine). Significant differences from steroid-free controls were noted only in the levels of hypothalamic serotonin in animals treated with dehydroepiandrosterone. Serotonin in the hypothalamus has been shown to decrease feeding behavior. The magnitude of dehydroepiandrosterone's effect on hypothalamic serotonin correlated with its effect on feeding behavior. Thus, dehydroepiandrosterone may reduce hyperphagia by altering hypothalamic levels of serotonin.

Androgens↗
PubMed2004

XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients.

OBJECTIVE: It is well established that the risk of developing type 2 diabetes is closely linked to the presence and duration of overweight and obesity. A reduction in the incidence of type 2 diabetes with lifestyle changes has previously been demonstrated. We hypothesized that adding a weight-reducing agent to lifestyle changes may lead to an even greater decrease in body weight, and thus the incidence of type 2 diabetes, in obese patients. RESEARCH DESIGN AND METHODS: In a 4-year, double-blind, prospective study, we randomized 3,305 patients to lifestyle changes plus either orlistat 120 mg or placebo, three times daily. Participants had a BMI >/=30 kg/m2 and normal (79%) or impaired (21%) glucose tolerance (IGT). Primary endpoints were time to onset of type 2 diabetes and change in body weight. Analyses were by intention to treat. RESULTS: Of orlistat-treated patients, 52% completed treatment compared with 34% of placebo recipients (P < 0.0001). After 4 years' treatment, the cumulative incidence of diabetes was 9.0% with placebo and 6.2% with orlistat, corresponding to a risk reduction of 37.3% (P = 0.0032). Exploratory analyses indicated that the preventive effect was explained by the difference in subjects with IGT. Mean weight loss after 4 years was significantly greater with orlistat (5.8 vs. 3.0 kg with placebo; P < 0.001) and similar between orlistat recipients with impaired (5.7 kg) or normal glucose tolerance (NGT) (5.8 kg) at baseline. A second analysis in which the baseline weights of subjects who dropped out of the study was carried forward also demonstrated greater weight loss in the orlistat group (3.6 vs. 1.4 kg; P < 0.001). CONCLUSIONS: Compared with lifestyle changes alone, orlistat plus lifestyle changes resulted in a greater reduction in the incidence of type 2 diabetes over 4 years and produced greater weight loss in a clinically representative obese population. Difference in diabetes incidence was detectable only in the IGT subgroup; weight loss was similar in subjects with IGT or NGT [correction].

Adult↗
PubMed2000

Acceleration of the development of diabetes in obese diabetic (db/db) mice by nicotinamide: a comparison with its antidiabetic effects in non-obese diabetic mice.

Destruction of pancreatic beta cells has been implicted in the progression to hyperglycemia in type 1 diabetes. While there is evidence of beta-cell loss in type 2 diabetes, its contribution to the development of the diabetic state is undecided. Nicotinamide has defensive effects against toxic insults to the pancreatic islets and confers protection in both human and animal models of type 1 diabetes, but its effects on type 2 diabetes are less well documented. This report describes a comparison of the outcome of chronic oral administration of nicotinamide on the development of diabetes in obese diabetic (db/db) and non-obese diabetic (NOD) mice models of type 2 and type 1 diabetes, respectively. Nicotinamide was administered in the diet (5 g/kg diet) for 12 (db/db) or 24 (NOD) weeks. Over the 12 weeks of the study, control diabetic (db/db) mice became progressively more hyperglycemic and glycosuric, while serum and pancreatic insulin levels decreased compared with those on day 0. In mice treated with nicotinamide, there was a pronounced acceleration in the development of hyperglycemia and glycosuria, as well as a decrease in pancreatic insulin levels, compared with time-matched controls. In addition, the morphology of the pancreatic islets of nicotinamide-treated diabetic (db/db) mice showed an enhanced islet disorganization. By comparison, in NOD mice, nicotinamide prevented the decline in serum and pancreatic insulin levels and maintained normal islet architecture and insulin content. Our data shows that in contrast to its preventative effects on the development of autoimmune diabetes in NOD mice, chronic nicotinamide administration to obese diabetic (db/db) mice markedly accelerated the progression of diabetes. The results of our study caution against the use of nicotinamide in insulin-resistant states, such as type 2 diabetes.

Animals↗
PubMed2001

Plasma beta-endorphin levels in obese and non-obese patients with polycystic ovary disease.

The aim of this study was to determine the influence of body weight on circulating plasma levels of beta-endorphin and insulin in women with polycystic ovary disease (PCOD), as well as the correlation between the plasma levels of beta-endorphin and insulin. One-hundred and sixty-seven consecutive subjects with PCOD were recruited, 117 of whom had normal weight (body mass index (BMI) < 25) while 50 were obese (BMI > 25). A venous blood sample was taken and plasma concentrations of beta-endorphin, insulin, gonadotropins, prolactin, progesterone, 17 beta-estradiol, estrone, androgens, dehydroepiandrosterone sulfate and sex hormone-binding globulin (SHBG) were measured. Mean beta-endorphin and insulin plasma levels were significantly higher (p < 0.05) in obese PCOD women than in non-obese ones. Correlation analysis showed a positive association between insulin and beta-endorphin, beta-endorphin and BMI (and weight), insulin and BMI (and weight), and a negative correlation was found between insulin and SHBG. A weak association was found between beta-endorphin and luteinizing hormone (LH) in peripheral plasma. Stratified and linear regression analysis showed that plasma beta-endorphin concentrations correlate more with BMI than with insulinemia.

Adolescent↗