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Nature Reviews. Neuroscience Mar 2019Alzheimer disease (AD) is a major cause of age-related dementia. We do not fully understand AD aetiology and pathogenesis, but oxidative damage is a key component. The... (Review)
Review
Alzheimer disease (AD) is a major cause of age-related dementia. We do not fully understand AD aetiology and pathogenesis, but oxidative damage is a key component. The brain mostly uses glucose for energy, but in AD and amnestic mild cognitive impairment glucose metabolism is dramatically decreased, probably owing, at least in part, to oxidative damage to enzymes involved in glycolysis, the tricarboxylic acid cycle and ATP biosynthesis. Consequently, ATP-requiring processes for cognitive function are impaired, and synaptic dysfunction and neuronal death result, with ensuing thinning of key brain areas. We summarize current research on the interplay and sequence of these processes and suggest potential pharmacological interventions to retard AD progression.
Topics: Alzheimer Disease; Animals; Brain; Disease Progression; Glucose Intolerance; Glycolysis; Humans; Oxidative Stress
PubMed: 30737462
DOI: 10.1038/s41583-019-0132-6 -
American Journal of Obstetrics &... May 2022Patients with gestational diabetes mellitus are at increased risk for type 2 diabetes mellitus or glucose intolerance postpartum compared with those without diabetes... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with gestational diabetes mellitus are at increased risk for type 2 diabetes mellitus or glucose intolerance postpartum compared with those without diabetes mellitus.
OBJECTIVE
We aimed to evaluate the association between early gestational diabetes mellitus and postpartum dysglycemia compared with gestational diabetes mellitus diagnosed by routine screening in a cohort of patients with obesity.
STUDY DESIGN
This was a secondary analysis of a randomized controlled trial of patients with obesity and singleton, nonanomalous gestations that compared early gestational diabetes mellitus screening at 14 to 20 weeks of gestation with routine screening at 24 to 28 weeks of gestation. Patients were included in this analysis if they were diagnosed with gestational diabetes mellitus at the primary study site. The primary outcome was postpartum dysglycemia, defined as any abnormality on 2-hour oral glucose tolerance test 6 weeks postpartum or clinical diagnosis based on hyperglycemia requiring pharmacotherapy after delivery with deferred glucose tolerance test. Maternal characteristics and outcomes were compared in bivariable analysis, and logistic regression estimated the association between early gestational diabetes mellitus and postpartum dysglycemia.
RESULTS
Of 119 patients included in this analysis, 30 were diagnosed by screening at <20 weeks of gestation and 89 at 24 to 28 weeks of gestation. Patients were overall similar in baseline characteristics. Patients with early gestational diabetes mellitus were more likely to have postpartum dysglycemia than those with gestational diabetes mellitus diagnosed with routine screening (36.7% vs 14.6%; odds ratio, 3.38; 95% confidence interval, 1.31-8.73). Most patients with early gestational diabetes mellitus who had postpartum dysglycemia were diagnosed clinically (n=7/11), whereas none of the patients with gestational diabetes mellitus established by routine testing were diagnosed with postpartum dysglycemia clinically. All (100%) patients with early gestational diabetes mellitus who completed a postpartum glucose tolerance test had dysglycemia compared with only 45% of patients with gestational diabetes mellitus diagnosed on routine screening. The proportion of patients who followed up for postpartum visits and the timing of follow-up were similar between groups. Postpartum glucose tolerance test completion was low but also similar between groups.
CONCLUSION
Although postpartum glucose tolerance test completion is low, patients with gestational diabetes mellitus before 20 weeks of gestation, seem to be at higher risk for postpartum dysglycemia than those with gestational diabetes mellitus diagnosed at routine screening in a cohort of patients with obesity. Larger studies are needed to confirm these findings, but postpartum follow-up and diabetes mellitus testing may be even more important to improve long-term health in patients with early gestational diabetes mellitus.
Topics: Diabetes Mellitus, Type 2; Diabetes, Gestational; Female; Glucose Intolerance; Humans; Obesity; Postpartum Period; Pregnancy
PubMed: 35272093
DOI: 10.1016/j.ajogmf.2022.100609 -
Nutrients Nov 2019(1) Background: Eating is fundamental to survival. Animals choose when to eat depending on food availability. The timing of eating can synchronize different organs and... (Review)
Review
(1) Background: Eating is fundamental to survival. Animals choose when to eat depending on food availability. The timing of eating can synchronize different organs and tissues that are related to food digestion, absorption, or metabolism, such as the stomach, gut, liver, pancreas, or adipose tissue. Studies performed in experimental animal models suggest that food intake is a major external synchronizer of peripheral clocks. Therefore, the timing of eating may be decisive in fat accumulation and mobilization and affect the effectiveness of weight loss treatments. (2) Results: We will review multiple studies about the timing of the three main meals of the day, breakfast, lunch and dinner, and its potential impact on metabolism, glucose tolerance, and obesity-related factors. We will also delve into several mechanisms that may be implicated in the obesogenic effect of eating late. Conclusion: Unusual eating time can produce a disruption in the circadian system that might lead to unhealthy consequences.
Topics: Adipose Tissue; Animals; Blood Glucose; Breakfast; Circadian Rhythm; Feeding Behavior; Female; Glucose Intolerance; Humans; Lunch; Male; Meals; Melatonin; Obesity; Weight Loss
PubMed: 31684003
DOI: 10.3390/nu11112624 -
Metabolism: Clinical and Experimental Aug 2016The exposure of hepatocytes to high concentrations of lipids and carbohydrates and the ensuing hepatocellular injury are termed lipotoxicity and glucotoxicity,... (Review)
Review
The exposure of hepatocytes to high concentrations of lipids and carbohydrates and the ensuing hepatocellular injury are termed lipotoxicity and glucotoxicity, respectively. A common denominator is metabolic derangement, especially in regards to intracellular energy homeostasis, which is brought on by glucose intolerance and insulin resistance in tissues. In this review, we highlight the lipids and carbohydrates that provoke hepatocyte injury and the mechanisms involved in lipotoxicity and glucotoxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment. Through upregulation of proteins involved in various pathways including PKR-like ER kinase (PERK), CCAAT/enhancer-binding homologous protein (CHOP), c-Jun NH2-terminal kinase-1 (JNK), Bcl-2 interacting mediator (BIM), p53 upregulated modulator of apoptosis (PUMA), and eventually caspases, hepatocytes in lipotoxic states ultimately undergo apoptosis. The protective role of certain lipids and possible targets for pharmacological therapy are explored. Finally, we discuss the role of high fructose and glucose diets in contributing to organelle impairment and poor glucose transport mechanisms, which perpetuate hyperglycemia and hyperlipidemia by shunting of excess carbohydrates into lipogenesis.
Topics: Endoplasmic Reticulum Stress; Glucose Intolerance; Humans; Insulin Resistance; JNK Mitogen-Activated Protein Kinases; Mitochondria; Non-alcoholic Fatty Liver Disease; Oxidative Stress; Signal Transduction; Transcription Factor CHOP
PubMed: 26997538
DOI: 10.1016/j.metabol.2016.02.014 -
The New England Journal of Medicine May 2001Type 2 diabetes mellitus is increasingly common, primarily because of increases in the prevalence of a sedentary lifestyle and obesity. Whether type 2 diabetes can be... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Type 2 diabetes mellitus is increasingly common, primarily because of increases in the prevalence of a sedentary lifestyle and obesity. Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known.
METHODS
We randomly assigned 522 middle-aged, overweight subjects (172 men and 350 women; mean age, 55 years; mean body-mass index [weight in kilograms divided by the square of the height in meters], 31) with impaired glucose tolerance to either the intervention group or the control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity. An oral glucose-tolerance test was performed annually; the diagnosis of diabetes was confirmed by a second test. The mean duration of follow-up was 3.2 years.
RESULTS
The mean (+/-SD) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group (P<0.001 for both comparisons between the groups). The cumulative incidence of diabetes after four years was 11 percent (95 percent confidence interval, 6 to 15 percent) in the intervention group and 23 percent (95 percent confidence interval, 17 to 29 percent) in the control group. During the trial, the risk of diabetes was reduced by 58 percent (P<0.001) in the intervention group. The reduction in the incidence of diabetes was directly associated with changes in lifestyle.
CONCLUSIONS
Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects.
Topics: Diabetes Mellitus, Type 2; Diet, Fat-Restricted; Dietary Fiber; Exercise; Female; Glucose Intolerance; Glucose Tolerance Test; Humans; Incidence; Life Style; Male; Middle Aged; Obesity; Risk; Weight Loss
PubMed: 11333990
DOI: 10.1056/NEJM200105033441801 -
The Journal of Clinical Endocrinology... Aug 2020Consuming calories later in the day is associated with obesity and metabolic syndrome. We hypothesized that eating a late dinner alters substrate metabolism during sleep... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Consuming calories later in the day is associated with obesity and metabolic syndrome. We hypothesized that eating a late dinner alters substrate metabolism during sleep in a manner that promotes obesity.
OBJECTIVE
The objective of this work is to examine the impact of late dinner on nocturnal metabolism in healthy volunteers.
DESIGN AND SETTING
This is a randomized crossover trial of late dinner (LD, 22:00) vs routine dinner (RD, 18:00), with a fixed sleep period (23:00-07:00) in a laboratory setting.
PARTICIPANTS
Participants comprised 20 healthy volunteers (10 male, 10 female), age 26.0 ± 0.6 years, body mass index 23.2 ± 0.7 kg/m2, accustomed to a bedtime between 22:00 and 01:00.
INTERVENTIONS
An isocaloric macronutrient diet was administered on both visits. Dinner (35% daily kcal, 50% carbohydrate, 35% fat) with an oral lipid tracer ([2H31] palmitate, 15 mg/kg) was given at 18:00 with RD and 22:00 with LD.
MAIN OUTCOME MEASURES
Measurements included nocturnal and next-morning hourly plasma glucose, insulin, triglycerides, free fatty acids (FFAs), cortisol, dietary fatty acid oxidation, and overnight polysomnography.
RESULTS
LD caused a 4-hour shift in the postprandial period, overlapping with the sleep phase. Independent of this shift, the postprandial period following LD was characterized by higher glucose, a triglyceride peak delay, and lower FFA and dietary fatty acid oxidation. LD did not affect sleep architecture, but increased plasma cortisol. These metabolic changes were most pronounced in habitual earlier sleepers determined by actigraphy monitoring.
CONCLUSION
LD induces nocturnal glucose intolerance, and reduces fatty acid oxidation and mobilization, particularly in earlier sleepers. These effects might promote obesity if they recur chronically.
Topics: Adolescent; Adult; Blood Glucose; Cross-Over Studies; Fatty Acids, Nonesterified; Feeding Behavior; Female; Glucose Intolerance; Healthy Volunteers; Humans; Hydrocortisone; Insulin; Male; Meals; Obesity; Oxidation-Reduction; Polysomnography; Sleep; Time Factors; Triglycerides; Young Adult
PubMed: 32525525
DOI: 10.1210/clinem/dgaa354 -
Signal Transduction and Targeted Therapy Mar 2023Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen has been proven to be the first-line...
Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen has been proven to be the first-line chemotherapy for several solid tumors in clinics, however, its therapeutic role in NAFLD has never been elucidated before. In vitro experiments, tamoxifen protected hepatocytes against sodium palmitate-induced lipotoxicity. In male and female mice fed with normal diets, continuous tamoxifen administration inhibited lipid accumulation in liver, and improved glucose and insulin intolerance. Short-term tamoxifen administration largely improved hepatic steatosis and insulin resistance, however, the phenotypes manifesting inflammation and fibrosis remained unchanged in abovementioned models. In addition, mRNA expressions of genes related to lipogenesis, inflammation, and fibrosis were downregulated by tamoxifen treatment. Moreover, the therapeutic effect of tamoxifen on NAFLD was not gender or ER dependent, as male and female mice with metabolic disorders shared no difference in response to tamoxifen and ER antagonist (fulvestrant) did not abolish its therapeutic effect as well. Mechanistically, RNA sequence of hepatocytes isolated from fatty liver revealed that JNK/MAPK signaling pathway was inactivated by tamoxifen. Pharmacological JNK activator (anisomycin) partially deprived the therapeutic role of tamoxifen in treating hepatic steatosis, proving tamoxifen improved NAFLD in a JNK/MAPK signaling-dependent manner.
Topics: Animals; Female; Male; Mice; Fatty Liver; Glucose Intolerance; Inflammation; Insulin Resistance; Tamoxifen; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinases
PubMed: 36864030
DOI: 10.1038/s41392-022-01299-y -
American Journal of Physiology.... Jan 2008Insulin resistance contributes to the pathophysiology of diabetes and is a hallmark of obesity, metabolic syndrome, and many cardiovascular diseases. Therefore,... (Review)
Review
Insulin resistance contributes to the pathophysiology of diabetes and is a hallmark of obesity, metabolic syndrome, and many cardiovascular diseases. Therefore, quantifying insulin sensitivity/resistance in humans and animal models is of great importance for epidemiological studies, clinical and basic science investigations, and eventual use in clinical practice. Direct and indirect methods of varying complexity are currently employed for these purposes. Some methods rely on steady-state analysis of glucose and insulin, whereas others rely on dynamic testing. Each of these methods has distinct advantages and limitations. Thus, optimal choice and employment of a specific method depends on the nature of the studies being performed. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. The hyperinsulinemic euglycemic glucose clamp and the insulin suppression test directly assess insulin-mediated glucose utilization under steady-state conditions that are both labor and time intensive. A slightly less complex indirect method relies on minimal model analysis of a frequently sampled intravenous glucose tolerance test. Finally, simple surrogate indexes for insulin sensitivity/resistance are available (e.g., QUICKI, HOMA, 1/insulin, Matusda index) that are derived from blood insulin and glucose concentrations under fasting conditions (steady state) or after an oral glucose load (dynamic). In particular, the quantitative insulin sensitivity check index (QUICKI) has been validated extensively against the reference standard glucose clamp method. QUICKI is a simple, robust, accurate, reproducible method that appropriately predicts changes in insulin sensitivity after therapeutic interventions as well as the onset of diabetes. In this Frontiers article, we highlight merits, limitations, and appropriate use of current in vivo measures of insulin sensitivity/resistance.
Topics: Animals; Blood Glucose; Glucose Clamp Technique; Glucose Intolerance; Homeostasis; Humans; Insulin Resistance; Models, Biological
PubMed: 17957034
DOI: 10.1152/ajpendo.00645.2007 -
Frontiers in Endocrinology 2020Half of the patients with phaeochromocytoma have glucose intolerance which could be life-threatening as well as causing postoperative hypoglycemia. Glucose intolerance... (Review)
Review
Half of the patients with phaeochromocytoma have glucose intolerance which could be life-threatening as well as causing postoperative hypoglycemia. Glucose intolerance is due to impaired insulin secretion and/or increased insulin resistance. Impaired insulin secretion is caused by stimulating adrenergic α2 receptors of pancreatic β-cells and increased insulin resistance is caused by stimulating adrenergic α1 and β3 receptors in adipocytes, α1 and β2 receptors of pancreatic α-cells and skeletal muscle. Furthermore, different affinities to respective adrenergic receptors exist between epinephrine and norepinephrine. Clinical studies revealed patients with phaeochromocytoma had impaired insulin secretion as well as increased insulin resistance. Furthermore, excess of epinephrine could affect glucose intolerance mainly by impaired insulin secretion and excess of norepinephrine could affect glucose intolerance mainly by increased insulin resistance. Glucose intolerance on paraganglioma could be caused by increased insulin resistance mainly considering paraganglioma produces more norepinephrine than epinephrine. To conclude, the difference of actions between excess of epinephrine and norepinephrine could lead to improve understanding and management of glucose intolerance on phaeochromocytoma.
Topics: Adrenal Gland Neoplasms; Animals; Glucose Intolerance; Humans; Paraganglioma; Pheochromocytoma
PubMed: 33324347
DOI: 10.3389/fendo.2020.593780 -
Physiology & Behavior Apr 2018Some aspects of glucose homeostasis are regulated differently in males and females. This review discusses the most fundamental gender differences in glucose homeostasis... (Review)
Review
Some aspects of glucose homeostasis are regulated differently in males and females. This review discusses the most fundamental gender differences in glucose homeostasis and diabetes. These include the prevalence of impaired fasting glucose and impaired glucose tolerance, the prevalence and incidence of type 2 and type 1 diabetes, and the sex-specific effects of testosterone and estrogen deficiency and excess. These gender-specific differences in glucose homeostasis represent a source of factors that should be studied to develop gender-based therapeutic avenues for diabetes.
Topics: Blood Glucose; Diabetes Mellitus; Female; Glucose Intolerance; Homeostasis; Humans; Male; Sex Characteristics
PubMed: 28843891
DOI: 10.1016/j.physbeh.2017.08.016