Fermentation of undigested carbohydrate produces short-chain fatty acids (SCFA), some of which have been shown to reduce hepatic glucose production (HGP) in animals. The aim of this study was to ...examine whether carbohydrate fermentation decreases HGP in man. Ten healthy subjects consumed 90-g carbohydrate portions of either brown rice or barley for dinner in random order 1 week apart. The following morning, glucose kinetics were measured basally and during an oral glucose tolerance test (OGTT). HGP was calculated as the difference between the total rate of glucose appearance (calculated from % enrichment of 6,6 dideuterated glucose 6,6 D2 glucose) and the rate of appearance of gut-derived glucose (calculated from 6-3H glucose in the glucose drink). To detect fermentation, breath H2 content was measured by end-expiratory sampling of alveolar air. Significantly more breath H2 was produced after barley consumption (24 +/- 4 v 4 +/- 1 ppm, P < .001), indicating that barley contains more fermentable carbohydrate than rice. Glucose tolerance improved after the barley meal, with the peak OGTT plasma glucose concentration being 0.7 mmol/L lower than that after the rice meal (7.7 +/- 0.4 v 8.4 +/- 0.3 mmol/L, P < .05). This was primarily due to a 30% reduction in HGP (area under the curve, 909 +/- 116 v 1,295 +/- 157 mumol/kg; P < .01). No difference in the rates of glucose disappearance or gut glucose absorption was observed. However, serum free fatty acid (FFA) concentrations were significantly reduced the morning after the barley meal. In summary, carbohydrate fermentation enhances the suppression of HGP and FFA levels by oral glucose in man.
Fructose-1,6-Bisphosphatase Overexpression in Pancreatic β-Cells Results in Reduced Insulin Secretion
A New Mechanism for Fat-Induced Impairment of β-Cell Function
Melkam Kebede 1 ,
Jenny Favaloro 1 ...,
Jenny E. Gunton 2 3 ,
D. Ross Laybutt 2 ,
Margaret Shaw 1 ,
Nicole Wong 1 ,
Barbara C. Fam 1 ,
Kathryn Aston-Mourney 1 ,
Christian Rantzau 1 ,
Anthony Zulli 1 ,
Joseph Proietto 1 and
Sofianos Andrikopoulos 1
1 Department of Medicine, Heidelberg Repatriation Hospital, University of Melbourne, Heidelberg Heights, Victoria, Australia
2 Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
3 Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia
Corresponding author: Sofianos Andrikopoulos, sof{at}unimelb.edu.au
Abstract
OBJECTIVE— Fructose-1,6-bisphosphatase (FBPase) is a gluconeogenic enzyme that is upregulated in islets or pancreatic β-cell lines exposed
to high fat. However, whether specific β-cell upregulation of FBPase can impair insulin secretory function is not known. The
objective of this study therefore is to determine whether a specific increase in islet β-cell FBPase can result in reduced
glucose-mediated insulin secretion.
RESEARCH DESIGN AND METHODS— To test this hypothesis, we have generated three transgenic mouse lines overexpressing the human FBPase (huFBPase) gene specifically
in pancreatic islet β-cells. In addition, to investigate the biochemical mechanism by which elevated FBPase affects insulin
secretion, we made two pancreatic β-cell lines (MIN6) stably overexpressing huFBPase.
RESULTS— FBPase transgenic mice showed reduced insulin secretion in response to an intravenous glucose bolus. Compared with the untransfected
parental MIN6, FBPase-overexpressing cells showed a decreased cell proliferation rate and significantly depressed glucose-induced
insulin secretion. These defects were associated with a decrease in the rate of glucose utilization, resulting in reduced
cellular ATP levels.
CONCLUSIONS— Taken together, these results suggest that upregulation of FBPase in pancreatic islet β-cells, as occurs in states of lipid
oversupply and type 2 diabetes, contributes to insulin secretory dysfunction.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 28 March 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted March 23, 2008.
Received September 17, 2007.
DIABETES
Obesity is a complex and multifactorial chronic disease with genetic, environmental, physiological and behavioural determinants that requires long-term care. Obesity is associated with a broad range ...of complications including type 2 diabetes, cardiovascular disease, dyslipidaemia, metabolic associated fatty liver disease, reproductive hormonal abnormalities, sleep apnoea, depression, osteoarthritis and certain cancers. An algorithm has been developed (with PubMed and Medline searched for all relevant articles from 1 Jan 2000–1 Oct 2021) to (i) assist primary care physicians in treatment decisions for non-pregnant adults with obesity, and (ii) provide a practical clinical tool to guide the implementation of existing guidelines (summarised in Appendix 1) for the treatment of obesity in the Australian primary care setting.
Treatment pathways should be determined by a person’s anthropometry (body mass index (BMI) and waist circumference (WC)) and the presence and severity of obesity-related complications. A target of 10–15% weight loss is recommended for people with BMI 30–40 kg/m2 or abdominal obesity (WC > 88 cm in females, WC > 102 cm in males) without complications. The treatment focus should be supervised lifestyle interventions that may include a reduced or low energy diet, very low energy diet (VLED) or pharmacotherapy. For people with BMI 30–40 kg/m2 or abdominal obesity and complications, or those with BMI > 40 kg/m2 a weight loss target of 10–15% body weight is recommended, and management should include intensive interventions such as VLED, pharmacotherapy or bariatric surgery, which may be required in combination. A weight loss target of > 15% is recommended for those with BMI > 40 kg/m2 and complications and they should be referred to specialist care. Their treatment should include a VLED with or without pharmacotherapy and bariatric surgery.
Summary Low-carbohydrate “ketogenic” diets have increased in popularity over recent years as a means of weight loss. Published studies of these diets have been highly heterogeneous, and it remains ...unclear to what degree dietary carbohydrate intake must be restricted in order to induce ketosis. Despite concern that they are often relatively high in fat, ketogenic low-carbohydrate diets have been generally shown to compare favourably with low-fat diets in terms of weight loss and improvements in triglyceride and high-density lipoprotein levels. This review includes a brief overview of ketone body metabolism, and summarises the literature regarding the safety and efficacy of ketogenic diets for weight loss.
Objectives We sought to determine whether an obesity paradox exists in the contemporary era of percutaneous coronary intervention (PCI) and to explore potential clinical factors that might ...contribute. Background Previous studies have suggested that overweight and obese patients might have better outcomes after PCI than patients with a normal or low body mass index (BMI); however this “obesity paradox” remains poorly understood. Methods We evaluated 4,762 patients undergoing PCI between April 1, 2004 and September 30, 2007, enrolled in the MIG (Melbourne Intervention Group) registry. Patients were classified as underweight, normal, overweight, class I obese, and class II to III obese, BMI <20, 20 to 25, 25.1 to 30, 30.1 to 35, and >35 kg/m2 , respectively. We compared in-hospital, 30-day, and 12-month outcomes. Results As BMI increased from <20 to >35 kg/m2 , there was a statistically significant, linear reduction in 12-month major adverse cardiac events (MACE) (21.4% to 11.9%, p = 0.008) and mortality (7.6% to 2.0%, p < 0.001). Obesity was, with multivariate analysis, an independent predictor of reduced 12-month MACE and showed a trend for reduced 12-month mortality. At 12 months, obese patients had higher use of aspirin, clopidogrel, beta-blockers, renin-angiotensin system blockers and statins. Conclusions Compared with normal-weight individuals, overweight and obese patients had lower in-hospital and 12-month MACE and mortality rates after PCI. Moreover, obese patients had a higher rate of guideline-based medication use at 12 months, which might in part explain the obesity paradox seen after PCI.
Obesity susceptibility in humans and in rodent strains varies in response to the consumption of high-energy density (HED) diets. However, the exact mechanism(s) involved in this susceptibility ...remain(s) unresolved. The aim of the present study was to gain greater insight into this susceptibility by using C57BL/6J (B6) mice that were separated into obesity-prone (diet-induced obese (DIO)) and obesity-resistant (diet-induced resistant (DR)) groups following an HED diet for 6 weeks. Physiological, biochemical and gene expression assessments of energy balance were performed in the DIO and DR mice on an HED diet and chow-fed mice. The increased weight gain of the DIO mice as compared to the DR mice was associated with increased energy intake and higher plasma leptin and adiponectin levels but not with reduced physical activity or resting energy expenditure. Hypothalamic Pomc gene expression was elevated, but there were no changes in Npy or Agrp expression. Adipose tissue leptin and adiponectin gene expression were significantly reduced in the DIO group as compared to the DR group. Interestingly, ileum expression of G protein-coupled receptor (Gpr) 40 (Gpr40) was significantly increased, whereas Gpr120, Gpr119, Gpr41, and glucagon-like peptide 1 (Glp1) were reduced. Contrastingly, the lower weight gain of the DR group was associated with elevated adipose tissue leptin and adiponectin gene expression, but there were no differences in plasma hormone or hypothalamic gene expression levels as compared to chow-fed mice. Therefore, the present data demonstrate that susceptibility and resistance to diet-induced weight gain in B6 mice appears to be predominantly driven by peripheral rather than hypothalamic modifications, and changes in gut-specific receptors are a potentially important contributor to this variation.
Pharmacotherapy for obesity IOANNIDES-DEMOS, Lisa L; PROIETTO, Joseph; MCNEIL, John J
Drugs (New York, N.Y.),
01/2005, Letnik:
65, Številka:
10
Journal Article
Recenzirano
Pharmacotherapy for the management of obesity is primarily aimed at weight loss, weight loss maintenance and risk reduction, and has included thyroid hormone, amphetamines, phentermine, amfepramone ...(diethylpropion), phenylpropanolamine, mazindol, fenfluramines and, more recently, sibutramine and orlistat. These agents decrease appetite, reduce absorption of fat or increase energy expenditure. Primary endpoints used to evaluate anti-obesity drugs most frequently include mean weight loss, percentage weight loss and proportion of patients losing >or=5% and >or=10% of initial bodyweight. Secondary endpoints may include reduction in body fat, risk factors for cardiovascular disease and the incidences of diseases such as diabetes mellitus. Most pharmacotherapies have demonstrated significantly greater weight loss in patients on active treatment than those receiving placebo in short-term (<or=1 year) randomised controlled trials of pharmacological treatment in conjunction with a calorie-controlled diet or lifestyle intervention. The evidence of long-term efficacy is limited to sibutramine (2 years) and orlistat (4 years). These are the only drugs currently approved for the long-term management of obesity in adults. Sibutramine recipients randomised following 6 months' treatment to either sibutramine or placebo demonstrated significantly better weight maintenance at 2 years than those taking placebo (p<0.001), with >or=10% loss of initial bodyweight in 46% of patients. For patients taking orlistat, weight loss was 2.2 kg greater than those on placebo at 4 years (p<0.001), with significantly more patients achieving >or=10% loss of initial bodyweight (26.2% and 15.6%, respectively; p<0.001). Other drugs that have been evaluated for weight loss include ephedrine, the antidepressants fluoxetine and bupropion, and the antiepileptics topiramate and zonisamide. Two clinical trials with fluoxetine both reported no significant difference in weight loss compared with placebo at 52 weeks. Clinical trials evaluating ephedrine, bupropion, topiramate and zonisamide have demonstrated significantly greater weight loss than placebo but have been limited to 16-26 weeks' treatment. A major obstacle to the evaluation of the clinical trials is the potential bias resulting from low study completion rates. Completion rates varied from 52.8% of phentermine recipients in a 9-month study, to 40% of fenfluramine recipients in a 24-week comparative study with phentermine and 18% of amfepramone recipients in a 24-week study. One-year completion rates range from 51% to 73% for sibutramine and from 66% to 85% for orlistat. Other potential sources of bias include run-in periods and subsequent patient selection based on compliance or initial weight loss. Several potential new therapies targeting weight loss and obesity through the CNS pathways or peripheral adiposity signals are in early phase clinical trials. Over the next decade the drug treatment of obesity is likely to change significantly because of the availability of new pharmacotherapies to regulate eating behaviours, nutrient partitioning and/or energy expenditure.
It is often stated, "the faster you lose weight, the faster it is regained ". A review of existing literature does not support such a statement--indeed if anything the reverse is true. The origins of ...this erroneous view are the misconceptions that weight regain is a simple matter of bad dietary and social habits and that it takes time to change these, that physiological adaptations to rapid weight loss are different to those of gradual weight loss and that weight regain is simply due to a return to old habits. Indeed there are many advantages to rapid weight loss achieved with the use of a modern very low energy diet, including the fact that rapid weight loss is a motivating factor, that the mild ketosis that occurs not only suppresses hunger, but also slows protein loss and that adherence is easier with a structured dietary regime. VLEDs are dietary preparations that provide all nutritional requirements together with between 1845 and 3280 KJ (450 and 800 Kcal) per day. An individual takes this meal replacement three times daily as a substitute for breakfast, lunch and dinner. In addition, a bowl of non-starchy vegetables once daily provides some fibre and helps to satisfy the social aspect of eating. A teaspoon of oil on the vegetables contracts the gall bladder to minimise the risk of gall stone formation. Since weight loss, at whatever rate, results in physiological adaptations leading to weight regain, careful attention must be paid to the period after the VLED regime is completed. Lifestyle modification, diet and exercise are instituted optimally with behaviour modification. If, despite the subject's best efforts, weight regain occurs, an appetite suppressant is advisable to help control the drive to eat.
Elevated levels of tumor necrosis factor (TNFα) are implicated in the development of insulin resistance, but the mechanisms mediating these chronic effects are not completely understood. We ...demonstrate that TNFα signaling through TNF receptor (TNFR) 1 suppresses AMPK activity via transcriptional upregulation of protein phosphatase 2C (PP2C). This in turn reduces ACC phosphorylation, suppressing fatty-acid oxidation, increasing intramuscular diacylglycerol accumulation, and causing insulin resistance in skeletal muscle, effects observed both in vitro and in vivo. Importantly even at pathologically elevated levels of TNFα observed in obesity, the suppressive effects of TNFα on AMPK signaling are reversed in mice null for both TNFR1 and 2 or following treatment with a TNFα neutralizing antibody. Our data demonstrate that AMPK is an important TNFα signaling target and is a contributing factor to the suppression of fatty-acid oxidation and the development of lipid-induced insulin resistance in obesity.
Aims/hypothesis
This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in ...individuals with obesity (BMI ≥30 kg/m
2
) and type 2 diabetes (HbA
1c
53–97 mmol/mol 7–11% and fasting glucose <15.6 mmol/l).
Methods
Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug.
Results
In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was −3.1 ± 1.2% with placebo (
n
= 22) vs −13.5 ± 1.1% and −12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (
n
= 25;
n
= 19;
p
< 0.0001). The change in HbA
1c
(baseline 67 mmol/mol 8.3%) was −6.6 ± 2.2 mmol/mol (−0.6 ± 0.2%) with placebo vs −21.9 ± 2.2 mmol/mol (−2.0 ± 0.2%) or −21.9 ± 3.3 mmol/mol (−2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (
p
< 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism.
Conclusions/interpretation
MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA
1c
.
Trial registration:
ClinicalTrials.gov
NCT02324491
Funding:
The study was funded by Zafgen, Inc.
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