Examining the association between depression and obesity during a weight management programme.

The prevalence of depression in those with obesity is reported to be as high as double that in individuals of normal weight. There is potentially a bi-directional relationship between obesity and depression. Some research has suggested that depression results in weight gain and obesity, and other studies have suggested that those with obesity are more likely to develop depression at a later stage. The aim of this study was to investigate the association of depression symptoms with weight change over a 12-month study. Seventy participants undertook a 3-month lifestyle (diet and exercise) weight loss intervention, and were followed up as part of a 12-month study. Participants completed the Beck Depression Inventory-II (BDI-II) and had their body weight measured throughout the study. Baseline body mass index (BMI) of participants (mean ± standard deviation [SD]) was 31.1 ± 3.9 kg m-2 , body weight was 89.4 ± 16.1 kg, and age was 45.4 ± 11.1 years; 63% of the cohort were female. The mean weight change from baseline to 3 months was -5.2% (±SD 4.3%), and from baseline to 12 months was -4.2% (±SD 6.1%). There was a significant decrease in BDI-II scores over the 12-month study, and a 1-unit decrease in BDI-II score was associated with a further decrease in body weight of -0.4%. The current study indicated that weight loss was associated with improvements in mood for non-clinically depressed individuals with obesity, and these improvements persisted during a period of 3-12 months of follow-up.

A randomized controlled trial to determine the efficacy of a high carbohydrate and high protein ready-to-eat food product for weight loss.

UNLABELLED: Incorporating meal replacements has been shown to produce a significantly greater weight loss than a conventional reduced calorie diet. Ready-to-eat conventional foods may also be effective in this role and provide additional benefit because of their palatability, acceptance and enjoyment and thus increase dietary compliance. This trial investigated the efficacy of a ready-to-eat food product (Vita-Weat biscuit) that is both high in carbohydrate and high in protein as part of a diet prescription for weight loss in an overweight and obese population group. A total of 76 participants were randomized to a 6-week weight loss intervention including the ready-to-eat food product (intervention group) or advice on the 'Australian Guide to Healthy Eating' (control group). Both groups lost approximately 2 kg weight which equated to a reduction in body mass index of 0.70 kg m(-2) . There was no significant difference in percentage weight loss from screening to 6 weeks between the two groups; mean difference for the intervention vs. CONTROL GROUP: -0.20% (95% confidence interval: -0.96, 1.36); P = 0.73. Both diets were nutritionally matched and well-accepted over the 6-week period. This study shows that the inclusion of a ready-to-eat food product can be included as part of a dietary programme to achieve a clinically significant weight loss over a short period. This may have benefit when incorporated into an individual's meal plan intermittently to assist weight control. It also provides support for current public health nutritional guidelines as the participants in this study following such advice were also successful in achieving a clinically meaningful weight loss.

Weight loss improves reproductive outcomes in obese women undergoing fertility treatment: a randomized controlled trial.

For women attempting pregnancy, obesity reduces fertility and is an independent risk factor for obstetric and neonatal complications. The aim of this evaluator-blinded, randomized controlled trial was to evaluate a weight loss intervention on pregnancy rates in obese women undertaking fertility treatment. Forty-nine obese women, aged ≤ 37 years, presenting for fertility treatment were randomized to either a 12-week intervention (n = 27) consisting of a very-low-energy diet for the initial 6 weeks followed by a hypocaloric diet, combined with a weekly group multidisciplinary programme; or a control group (n = 22) who received recommendations for weight loss and the same printed material as the intervention. Anthropometric and reproductive parameters were measured at baseline and at 12 weeks. The 22 women who completed the intervention had greater anthropometric changes (-6.6 ± 4.6 kg and -8.7 ± 5.6 cm vs. -1.6 ± 3.6 kg and -0.6 ± 6.3 cm) compared with the control group (n = 17; P < 0.001). The intervention group achieved a pregnancy rate of 48% compared with 14% (P = 0.007), took a mean two fertility treatment cycles to achieve each pregnancy compared with four in the control group (P = 0.002), and had a marked increase in the number of live births (44% vs. 14%; P = 0.02). A group weight loss programme, incorporating dietary, exercise and behavioural components, is associated with a significant improvement in pregnancy rates and live births in a group of obese women undergoing fertility treatment.

An intragastric balloon produces large weight losses in the absence of a change in ghrelin or peptide YY.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?: The development of obesity is a multi-factorial process that results in an alteration in the neuroendocrine hormones that help regulate appetite and body weight. Weight loss has been shown to alter this neuroendocrine balance so as to promote weight regain. An intragastric balloon is an effective method to achieve significant weight loss in obese patients and is well suited for those patients who are looking for an alternative to lifestyle modification alone, and those who are not ready or suitable for surgical intervention. Limited research has shown that the weight loss achieved with an intragastric balloon is mediated by altered secretion of the hormones that regulate appetite and weight. WHAT DOES THIS STUDY ADD?: There are currently limited data on the effects of intragastric balloons on appetite and weight-related hormones. In the current study, we have investigated a broad range of gut hormones and adipokines and their response to weight loss induced by differing methods, and the subsequent effect this may have on weight regain. This is an important research area as novel therapies and long-term strategies are needed to counteract the unfavourable changes to the neuroendocrine control of appetite and satiety associated with diet-induced weight loss. This study aims to determine the effect of weight loss achieved with different methods on fasting levels of appetite hormones. Sixty-six obese adults with metabolic syndrome were randomized to intragastric balloon (IGB) for 6 months, with a 12-month behavioural modification programme (IGB group, 'IGBG') or a 12-month behavioural modification programme alone (control group, 'CG'). Anthropometric assessments and blood samples were taken every 3 months and total ghrelin, peptide YY (PYY), adiponectin and leptin were measured. Significant weight-loss differences favouring the IGBG were evident between groups at all time points. Ghrelin increased when the IGB was in situ (+39.3 pmol L(-1) vs. baseline) and returned to baseline after its removal (-34.7 pmol L(-1) ). Adiponectin and PYY levels remained stable in the IGBG, with transient increases noted in the CG. There were no significant between-group differences for ghrelin, PYY or adiponectin. In the IGBG, despite a decrease in leptin at 6 months (-11.7 ng mL(-1) ), levels increased to baseline after IGB removal (-3.7 ng mL(-1) ). In summary, weight loss associated with the IGB did not alter fasting levels of PYY or adiponectin. There was a return of ghrelin and leptin levels to baseline values after IGB removal. No compensatory rise in ghrelin was evident in either group 12 months after initial weight reduction, suggesting that such treatment strategies may lead to better long-term sustainable weight loss.

The effect of dairy consumption on blood pressure in mid-childhood: CAPS cohort study.

BACKGROUND/OBJECTIVES: It has been postulated that a higher dairy consumption may affect blood pressure regulation. The aim of this study was to examine the association between dairy consumption and blood pressure in mid-childhood. SUBJECTS/METHODS: Subjects (n = 335) were participants of a birth cohort at high risk of asthma with information on diet at 18 months and blood pressure at 8 years. Multivariate analyses were used to assess the association of dairy consumption (serves) and micronutrient intakes (mg). In a subgroup of children (n = 201), dietary intake was also measured at approximately 9 years. RESULTS: Children in the highest quintile of dairy consumption at 18 months had lower systolic blood pressure (SBP) and diastolic blood pressure (DBP) at 8 years (2.5 mm Hg, P=0.046 and 1.9 mm Hg, P = 0.047, respectively) than those in the lowest quintiles. SBP was lowest among children in the highest quintiles of calcium, magnesium and potassium intakes. Significant negative linear trends were observed between SBP and intakes of dairy serves, calcium, magnesium and potassium. Furthermore, SBP and DBP were lowest in the group of children that consumed at least two dairy serves at both 18 months and the follow-up dietary data collection at 9 years, compared with all other children (SBP 98.7 vs 101.0 mm Hg, P = 0.07; and DBP 56.5 vs 59.3 mm Hg, P = 0.006, respectively). CONCLUSION: These results are consistent with a protective effect of dairy consumption in childhood on blood pressure at age 8 years.

The major plant-derived cannabinoid Δ(9)-tetrahydrocannabinol promotes hypertrophy and macrophage infiltration in adipose tissue.

Synthetic cannabinoid receptor agonists activate lipoprotein lipase and the formation of lipid droplets in cultured adipocytes. Here we extend this work by examining whether Δ(9)-tetrahydrocannabinol (THC), a major plant-derived cannabinoid, increases adipocyte size in vivo. Further, possibly as a consequence of hypertrophy, we hypothesize that THC exposure promotes macrophage infiltration into adipose tissue, an inflammatory state observed in obese individuals. Rats repeatedly exposed to THC in vivo had reduced body weight, fat pad weight, and ingested less food over the drug injection period. However, THC promoted adipocyte hypertrophy that was accompanied by a significant increase in cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) expression, an enzyme important in packaging triglycerides. We also showed that THC induced macrophage infiltration and increased expression of the inflammatory cytokine tumor necrosis factor alpha (TNF-α) in adipose tissue but did not induce apoptosis as measured by TUNEL staining. That THC increased adipocyte cell size in the absence of greater food intake, body weight and fat provides a unique model to explore mechanisms underlying changes in adipocyte size associated with a mild inflammatory state in fat tissue.

Anatomically specific patterns of glial activation in the periaqueductal gray of the sub-population of rats showing pain and disability following chronic constriction injury of the sciatic nerve.

Neuropathic pain conditions for which treatment is sought are characterized by complex behavioural disturbances, as well as "pain." Recent studies using chronic constriction injury of the sciatic nerve have shown that rats develop three distinct patterns of disability characterized by changes in social-interactions and sleep-wake cycle behaviours post-injury: (i) Persistent Disability, (ii) Transient Disability and (iii) No Disability. These patterns occur despite all rats showing identical levels of allodynia and hyperalgesia (i.e., pain). In rats, social-interactions and sleep-wake cycle behaviours are regulated in part, by neural networks, which converge on the periaqueductal grey (PAG). We sought therefore to identify neural adaptations in the PAG, 6 days following chronic constriction injury (CCI), the time at which rats in which disabilities persist are first distinguished from those without disabilities (i.e., No Disability and Transient Disability). GeneChips, RT-PCR and Western blotting revealed the select up-regulation in translation and transcription of glial fibrillary acidic protein (GFAP) and Vimentin in rats with Persistent Disability. Significant increases in GFAP immunoreactivity were localized histologically to the lateral and caudal ventrolateral columns of the PAG. This anatomically specific pattern of increased GFAP suggests activation of astrocytes by select neural pathways, which likely include afferents of both spinal and nucleus of the solitary tract (NTS) origin. The PAG columns in which astrocytes are activated play significant roles in modulating both social-interactions and the sleep-wake cycle. It is possible therefore that the persistent disabilities seen in a subgroup of CCI rats are in part a functional consequence of this specific pattern of astrocyte activation.

Effect of the glycemic index of carbohydrates on day-long (10 h) profiles of plasma glucose, insulin, cholecystokinin and ghrelin.

BACKGROUND: Low glycemic index (GI) carbohydrates have been linked to increased satiety. The drive to eat may be mediated by postprandial changes in glucose, insulin and gut peptides. OBJECTIVE: To investigate the effect of a low and a high GI diet on day-long (10 h) blood concentrations of glucose, insulin, cholecystokinin (CCK) and ghrelin (GHR). DESIGN: Subjects (n=12) consumed a high and a low GI diet in a randomized, crossover design, consisting of four meals that were matched for macronutrients and fibre, and differed only in carbohydrate quality (GI). Blood was sampled every 30-60 min and assayed for glucose, insulin, CCK and GHR. RESULTS: The high GI diet resulted in significantly higher glucose and insulin mean incremental areas under the curve (IAUC, P=0.027 and P=0.001 respectively). CCK concentration was 59% higher during the first 7 h of the low GI diet (394+/-95 pmol/l min) vs the high GI diet (163+/-38 pmol/l min, P=0.046), but there was no difference over 10 h (P=0.224). GHR concentration was inversely correlated with insulin concentration (Pearson correlation -0.48, P=0.007), but did not differ significantly between the low and high GI diets. CONCLUSIONS: Mixed meals of lower GI are associated with lower day-long concentrations of glucose and insulin, and higher CCK after breakfast, morning tea and lunch. This metabolic profile could mediate differences in satiety and hunger seen in some, but not all, studies.

Beta2-glycoprotein I inhibits vascular endothelial growth factor and basic fibroblast growth factor induced angiogenesis through its amino terminal domain.

BACKGROUND: Beta-2 glycoprotein I (beta(2)GPI) is a plasma glycoprotein which interacts with various proteins of the coagulation and fibrinolysis system. beta(2)GPI has recently been shown to have anti-angiogenic properties. OBJECTIVES: We undertook this study to investigate the specific domain of beta(2)GPI involved in the anti-angiogenic function and its effect on downstream signaling of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). METHODS: Various preparations of beta(2)GPI were used on human umbilical vein endothelial cells (HUVECs) in the absence or presence of VEGF and bFGF. The effect on HUVECs' proliferation, migration and tubule formation in Matrigel matrix was investigated. The effect of beta(2)GPI on the mRNA expression of VEGF receptors and phosphorylation of signaling molecules was also studied. RESULTS: beta(2)GPI is shown in this study to be an anti-angiogenic molecule in vitro by inhibiting VEGF and bFGF-induced proliferation, migration and papillary-like tubule formation of HUVECs. This inhibition was achieved by native, proteolytically clipped and domain deletion mutants, domain I-IV (DI-IV) but not domain II-V (DII-V) of beta(2)GPI. Native beta(2)GPI was found to downregulate the expression of the VEGF receptor KDR/Flk-1 on endothelial cells and to block the phosphorylation of VEGF's downstream effector molecules in the MAPK/ERK and PI3K/Akt/GSK3beta pathways. CONCLUSIONS: These results indicate that beta(2)GPI has anti-angiogenic functions which depend on the presence of domain I. This anti-angiogenic activity may have important implications for the therapeutic manipulation of angiogenesis in various disease states.

Is postprandial hypertriglyceridaemia in relatives of type 2 diabetic subjects a consequence of insulin resistance?

BACKGROUND: Higher postprandial triglyceride responses reported in first degree relatives of people with type 2 diabetes (REL) were postulated to be the result of an early, possibly intrinsic, defect in oral lipid handling. The postprandial triglyceride response to high fat meals (HFM) in normal subjects is reduced by the insulin response to dietary carbohydrate (CHO) in the meal. The aims of this study were to examine whether (1) insulin resistance is associated with an intrinsic defect in triglyceride handling in insulin-resistant REL and (2) insulin resistance is associated with altered triglyceride handling after HFM with high CHO content. MATERIALS AND METHODS: Postprandial responses to a HFM in normolipidaemic, normoglycaemic REL were compared with subjects without a family history of diabetes mellitus (CON). Over 6 h, the insulin, glucose, triglyceride and nonesterified fatty acid (NEFA) responses after a high fat (80 g fat), low CHO (HFM-LC; 20 g CHO, 4250 kJ) meal and a high fat, high CHO (HFM-HC; 100 g CHO, 5450 kJ) meal were examined. RESULTS: The 10 (7F/3M) REL were significantly more insulin-resistant, determined by glucose infusion during a hyperinsulinaemic euglycaemic clamp than the 10 (5F/5M) CON (glucose infusion rate 44.6 +/- 4.9 vs. 60.0 +/- 4.8 micromol min(-1) kg FFM(-1), P = 0.037). Subjects were similar for age and body mass index (BMI). The triglyceride increments after the HFM-LC were similar in both, peaking at 180-240 min (Delta0.77 +/- 0.11 mmol L(-1)), demonstrating no postprandial defect in REL, despite insulin resistance. There was a significantly lower postprandial triglyceride response in CON following the HFM-HC compared with the HFM-LC, but not in REL. In contrast, the higher insulin level during the HFM-HC was associated with significantly greater NEFA level suppression than in the HFM-LC (2.13 +/- 0.51 vs. 0.70 +/- 0.35 mmol L(-1), P = 0.03), only in the REL. CONCLUSIONS: These results are inconsistent with a primary aetiological role for postprandial hypertriglyceridaemia in already insulin resistant type 2 diabetic REL, but raise the possibility that this potentially atherogenic manifestation is secondary to insulin resistance lessening VLDL production and/or release from the liver.

Insulin determines leptin responses during a glucose challenge in fed and fasted rats.

OBJECTIVE: Leptin secretion has been shown to respond acutely to changes in blood glucose and insulin. Nutritional state also has a marked effect on both the level of circulating leptin protein and leptin gene expression. The aim of this study was to assess whether the prior nutritional state altered the leptin secretory response to an acute glucose challenge, and to determine potential mechanisms. DESIGN: Male fed or fasted rats (200-250 g) were administered a single intravenous glucose bolus (1, 4 or 7 g/kg). The serum leptin, glucose, insulin and free fatty acid responses were studied over the following 5 h. The level of leptin gene expression and leptin protein was then determined in the epididymal fat pads, and in fed and fasted untreated rats for basal comparison. RESULTS: Leptin secretion in response to glucose was suppressed in fasted rats following all glucose doses. The total leptin response was correlated with the total insulin response in all conditions (r = 0.85) and with the glucose response in fed rats (r = 0.69). Both leptin gene expression and leptin protein content were lower in basal fasted rats. Leptin gene expression and leptin protein content still remained lower 5 h following a glucose bolus but there was partial reversal of the effects of fasting following the 7 g/kg glucose dose. CONCLUSIONS: Leptin secretion in response to an intravenous glucose bolus was determined by the insulin response and was significantly suppressed in fasted compared to fed rats. In addition to differences in the total insulin response of the animals, lower leptin responses may be facilitated by lower levels of both leptin gene mRNA and pre-existing leptin protein in epididymal adipose tissue of fasted rats.

Student-designed enzyme-linked metabolite assay kits.

The extensive use of commercial kits in molecular biology and biochemistry has prompted us to design a series of practical sessions to help students become familiar with the uses and limitations of pre-packaged assay systems. To facilitate an understanding of these assay systems and to promote reflection on their appropriate use, students manufacture their own kit for one of four enzyme-linked metabolite assays. To do this they must investigate the role of each of the components in the assay, optimize the conditions where possible, check for cross reactivity, and then work this assay up for a few related "real" samples. Students make up all the buffers, the standard solution, instructions, and even the packaging. The kit is checked for accuracy by the producers, "marketed" to other students, and evaluated by their peers. By going through this process, students learn the benefits and pitfalls of commercial kits as well as reinforcing the basic principles of metabolite measurement and gaining experience with assay design, troubleshooting, and problem solving.

The postprandial response of adiponectin to a high-fat meal in normal and insulin-resistant subjects.

OBJECTIVE: Adiponectin is an adipose-specific protein with short-term effects in vivo on glucose and fatty acid levels. We studied the plasma concentration and the proteolytic activation status of adiponectin following the consumption of a high-fat, low-carbohydrate meal. DESIGN: Analysis of adiponectin concentration and polypeptide structure after consumption of a fat meal. SUBJECTS: Normal subjects (n=24) and first-degree relatives of patients with type II diabetes (n=20). MEASUREMENTS: All subjects had a normal fasting plasma glucose and glucose tolerance. Blood was collected for the determination of plasma insulin, adiponectin, triglyceride, and free fatty acids. Body composition was assessed with dual-energy X-ray absorptiometry and whole-body insulin sensitivity with a euglycaemic, hyperinsulinaemic clamp. Postprandial response over 6 h was determined for plasma adiponectin, glucose, insulin, triglyceride, and free fatty acids. Adiponectin was measured by commercial RIA and its polypeptide structure examined by Western blotting. RESULTS: The relatives were more insulin resistant and had increased adiposity compared with control subjects. There was no significant difference in postprandial response in fatty acids, triglyceride, or insulin between the groups. Postprandial levels of adiponectin measured by radioimmunoassay were not significantly different from fasting levels, and no breakdown products of adiponectin were detectable in postprandial samples by Western blotting. CONCLUSIONS: Levels of circulating adiponectin do not alter in response to a fat meal, despite evidence in mice that acute changes in adiponectin significantly affect postprandial fatty acid flux. Moreover, a fat meal challenge did not lead to significant activation of adiponectin by proteolytic conversion.

Effect of a series of novel sulphonylthioureas on glucose tolerance in the obese fa/fa Zucker rat.

1. The recent development of a series of novel KATP channel modulators, namely sulphonylthioureas and sulphonylureas, is thought to make improvements in potency and tissue selectivity compared with current sulphonylureas, such as glibenclamide, which shares a similar structure to the novel compounds. 2. These novel compounds were first examined for their effect on hyperglycaemia and glucose tolerance during an oral glucose tolerance test following 5 days administration in the lean fa/- and obese fa/fa Zucker rat (a model of insulin resistance). Comparisons with present antidiabetic agents, metformin and glibenclamide were performed. 3. Several compounds showed improvements in glucose tolerance compared with control and the primary structural prerequisites for the maintenance of this activity were investigated. Of most interest was compound 3-15 ((N-[(4-methylphenylsulphonyl]-N'-(2-ethoxypyrid-4-yl)thiourea; 0.1 mg/kg per day), which significantly improved glucose tolerance following 5 days administration in the fa/fa Zucker rat. This paralleled the improvement seen in metformin (300 mg/kg per day)-treated fa/fa rats, but compound 3-15 was up to 3000-fold more potent than metformin. 4. Obese fa/fa Zucker rats were then treated with compound 3-15 for 28 days to determine whether glycaemic control could be maintained over the longer term. 5. Compound 3-15 showed a significant improvement in glucose clearance and reduction in insulin concentration following 28 days treatment during an intravenous glucose tolerance test compared with untreated rats, without any change in the rate of weight gain. 6. The novel sulphonylthiourea 3-15 appears to improve glucose clearance during acute and chronic treatment in the fa/fa Zucker rat with no effect on the rate of weight gain. It is thought that compound 3-15 may be eliciting its actions by improving insulin sensitivity, but its effects on insulin secretion are still to be elucidated.

Metabolic consequences of a species difference in Gibbs free energy of Na+/Ca2+ exchange: rat versus guinea pig.

The Gibbs free energy of the sarcolemmal Na+/Ca2+ exchanger (DeltaG(Na/Ca)) determines its net Ca2+ flux. We tested the hypothesis that a difference of diastolic DeltaG(Na/Ca) exists between rat and guinea pig myocardium. We measured the suprabasal rate of oxygen consumption (VO2) of arrested Langendorff-perfused hearts of both species, manipulating DeltaG(Na/Ca) by reduction of extracellular Na+ concentration, [Na+](o). Hill equations fitted to the resulting VO2-[Na+](o) relationships yielded Michaelis constant (K(m)) values of 67 and 25 mM for rat and guinea pig, respectively. We developed and tested a simple thermodynamic model that attributes this difference of K(m) values to a 7.84 kJ/mol difference of DeltaG(Na/Ca). The model predicts that reversal of Na+/Ca2+ exchange, leading to diastolic Ca2+ influx, should occur at a value of [Na+](o) about three times higher in rat myocardium. We verified this quantitative prediction using fura 2 fluorescence to index intracellular Ca2+ concentration in isolated ventricular trabeculae at 37 degrees C. The postulated difference in free energy of Na+/Ca2+ exchange explains a number of reported disparities of Ca2+ handling at rest between rat and guinea pig myocardia.

High glycemic index starch promotes hypersecretion of insulin and higher body fat in rats without affecting insulin sensitivity.

In rats, prolonged feeding of high glycemic index (GI) starch results in basal hyperinsulinemia and an elevated insulin response to an intravenous glucose tolerance test (IVGTT). The aim of this study was to assess hepatic and peripheral insulin resistance (IR) using euglycemic hyperinsulinemic clamps. Insulin sensitivity, epididymal fat deposition and fasting leptin concentrations were compared in rats fed isocalorically a low or high GI diet for 7 wk (45% carbohydrate, 35% fat and 20% protein as energy) or a high fat diet (20% carbohydrate, 59% fat and 21% protein as energy) for 4 wk so that final body weights were similar. At the end of the study, high GI rats had higher basal leptin concentration and epididymal fat mass than the low GI group, despite comparable body weights. High GI and high fat feeding both resulted in the higher insulin response during IVGTT, but impaired glucose tolerance was seen only in rats fed high fat. The GI of the diet did not affect basal and clamp glucose uptake or hepatic glucose output, but high fat feeding induced both peripheral and hepatic IR. The findings suggest that hypersecretion of insulin without IR may be one mechanism for increased fat deposition in rats fed high GI diets.

In vivo and in vitro suppression by leptin of glucose-stimulated insulin hypersecretion in high glucose-fed rats.

OBJECTIVES: Chronic feeding to rats of high glycaemic index (GI) diets results in the hypersecretion of insulin in response to an i.v. glucose load. The first aim of this study was to see if this exaggerated insulin response was accompanied by a hypersensitivity to glucose stimulation in isolated islets in vitro. The second aim was to see if the adipocyte factor, leptin, was able to alter insulin secretion in this model both in vivo and in vitro. DESIGN AND METHODS: Rats were fed for 6 weeks either a high GI diet in which the carbohydrate component was mostly glucose (GLUC diet) or a low GI diet containing mostly amylose (AMOSE diet). Rats then underwent an i.v. glucose tolerance test (ivGTT) (1g/kg) with and without a prior infusion of leptin (133 microg/kg perh). Islets were then isolated from these rats and basal and glucose-stimulated insulin secretion (GSIS) measured in both the absence and presence (100ng/ml) of leptin. RESULTS AND CONCLUSIONS: Peak insulin response during the ivGTT was 3-fold greater in GLUC rats (P<0.001). Leptin had no effect on AMOSE rat insulin response but lowered the GLUC rat response to AMOSE rat levels. In vitro, basal insulin secretion was 4-fold greater in GLUC rats (P<0.05). At 20mmol/l glucose, there was no further increase in insulin secretion in GLUC rats but a 2-fold increase in AMOSE rats. Leptin had no effect on basal insulin secretion or GSIS in AMOSE rats but reduced basal insulin secretion and GSIS in GLUC rats. These results show insulin hypersecretion in high GI-fed rats may be reduced by leptin.

Strategies for building criticism skills in undergraduate biochemists.

This paper describes an easy method for empowering biochemistry students to think critically about research data. The technique encourages students to formulate their own opinions by removing the usually dominant 'expert' commentary. The exercise can be done individually or in very large groups, requires no specialist materials and confirmation that articulation and criticism skills have been learnt can be assessed under standard examination conditions. The skills learnt are not discipline specific and, as well as learning how best to read research papers, students also learn something about the research process.

Aging changes tissue-specific glucose metabolism in rats.

This study defines the tissue-specific changes in glucose metabolic flux that occur over time prior to the onset of whole-body insulin resistance in rats. Rats at 6 weeks of age were maintained on a high-carbohydrate diet for either 12 or 26 weeks, at which time euglycemic clamps were performed at basal and midphysiological plasma insulin concentrations. Following death, insulin-sensitive tissues were excised and frozen until assayed for the rate of glucose uptake, glycogenesis, and lipogenesis. Glucose metabolic flux, particularly through glycogenesis, was reduced between 18 and 32 weeks of age in all tissues except the adipose tissues. For example, the rate of glycogenesis in liver at 18 weeks (117+/-10 nmol glucose incorporated/min/g) was more than double that observed at 32 weeks (54+/-8 nmol glucose incorporated/min/g, P < .01). Despite this, animals in the 32-week group displayed no impairment in whole-body glucose disposal, due to compensatory glucose uptake in white adipose tissue (WAT) and increased glucose flux through lipogenesis in brown adipose tissue (BAT). At 32 weeks, the rate of glucose uptake in WAT (85.0+/-5.6 nmol 2-deoxy-D-glucose phosphate accumulated/min/g) was approximately double that at 18 weeks (46.6+/-5.6 nmol 2-deoxy-D-glucose phosphate accumulated/min/g) was approximately double that at 18 weeks (46.6+/-5.6 nmol 2-deoxy-D-glucose phosphate accumulated/min/g, P < .01). These changes in insulin responsiveness in adipose tissue of older animals may underlie the increased adiposity that is currently thought to be the causative factor in the development of age-related insulin resistance.

Development of insulin resistance in the rat is dependent on the rate of glucose absorption from the diet.

The effect of long-term consumption of diets of different carbohydrate composition was investigated be feeding rats for up to 52 wk on diets in which the carbohydrate was either glucose, amylose or amylopectin. A glucose-based diet was included to examine the relationship between the rate of carbohydrate absorption from the diet and the development of insulin resistance. Insulin sensitivity was assessed by subjecting animals to an intravenous glucose tolerance test (IVGTT). Amylopectin-fed animals became progressively insulin resistant from 12 to 26 wk of feeding. The area under the plasma insulin curves in response to a glucose load (IVGTT) for these animals rose progressively from 15.1 +/- 2.5 nmol/L.30 min at 8 wk to 45.8 +/- 3.5 nmol/L.30 min (P < 0.001) at 26 wk of feeding. Amylose-fed animals did not exhibit insulin resistance until 26 wk of feeding when insulin secretion in response to a glucose load was 28.3 +/- 0.9 vs. 14.6 +/- 3.2 nmol/L.30 min at 16 wk of feeding (P < 0.005). Glucose-fed animals displayed insulin resistance after only 8 wk of feeding. At this time, the area under their plasma insulin curves was almost double that for amylose- or amylopectin-fed animals (P < 0.001). We conclude that long-term consumption of a diet in which available carbohydrate is rapidly absorbed causes insulin resistance in rats. The more rapidly glucose is absorbed from the diet, the faster the insulin resistance develops.