Immunoglobulin G-mediated food intolerance and metabolic syndrome influence the occurrence of reflux esophagitis in Helicobacter pylori-infected patients

BACKGROUND Reflux esophagitis has an increasing prevalence and complex and diverse symptoms.Identifying its risk factors is crucial to understanding the etiology,prevention,and management of the disease.The occurrence of reflux esophagitis may be associated with food reactions,Helicobacter pylori(H.pylori)infection,and metabolic syndromes.AIM To investigate the risk factors for reflux esophagitis and analyze the effects of immunoglobulin(Ig)G-mediated food intolerance,H.pylori infection,and metabolic syndrome on reflux esophagitis.METHODS Outpatients attending the Second Medical Center of the PLA General Hospital between 2017 and 2021 were retrospectively enrolled.The patients’basic information,test results,gastroscopy results,H.pylori test results,and IgG-mediated food intolerance results were collected.Multivariate logistic regression analysis was used to analyze risk factors for reflux esophagitis.Statistical mediation analysis was used to evaluate the effects of IgG-mediated food intolerance and metabolic syndrome on H.pylori infection affecting reflux esophagitis.RESULTS A total of 7954 outpatients were included;the prevalence of reflux esophagitis,IgG-mediated food intolerance,H.pylori infection,and metabolic syndrome were 20.84%,61.77%,35.91%,and 60.15%,respectively.Multivariate analysis showed that the independent risk factors for reflux esophagitis included IgG-mediated food intolerance(OR=1.688,95%CI:1.497-1.903,P<0.00001)and metabolic syndrome(OR=1.165,95%CI:1.030-1.317,P=0.01484),and the independent protective factor for reflux esophagitis was H.pylori infection(OR=0.400,95%CI:0.351-0.456,P<0.00001).IgG-mediated food intolerance had a partially positive mediating effect on H.pylori infection as it was associated with reduced occurrence of reflux esophagitis(P=0.0200).Metabolic syndrome had a partially negative mediating effect on H.pylori infection and reduced the occurrence of reflux esophagitis(P=0.0220).CONCLUSION Patients with IgG-mediated food intolerance and metabolic syndrome were at higher risk of developing reflux esophagitis,while patients with H.pylori infection were at lower risk.IgG-mediated food intolerance reduced the risk of reflux esophagitis pathogenesis in patients with H.pylori infection;however,metabolic syndrome increased the risk of patients with H.pylori infection developing reflux esophagitis.

Food intolerance and the few-foods(or oligoantigenic)diet in children with attention-deficit hyperactivity disorder

The hypothesis that some children with attention-deficit hyperactivity disorder(ADHD)may show sensitivity or allergic reactions to various food items has led to the development of the the few-foods(or oligoantigenic)diet.The rationale of the diet is to eliminate certain foods from the diet in order to exclude potential allergens contained either naturally in food or in artificial ingredients with allergenic properties.The oligoantigenic diet attempts to identify individual foods to which a person might be sensitive.First,ADHD symptoms are monitored while multiple foods are excluded from the diet.Subsequently,if symptoms remit,foods are re-introduced,while observing the individual for the return of symptoms.An advantage of the oligoantigenic diet is that it can be tailored to the individual.A growing body of evidence suggests that behavioral symptoms of subgroups of children with ADHD may benefit from the elimination of certain foods.The effect sizes of an oligoantigenic diet regarding improvement of ADHD symptoms have been found to be medium to large.Available evidence suggests that the investigation of the role of food hypersensitivities in ADHD is a promising avenue worthy of further exploration.Further large-scale,randomized controlled studies including assessment of long-term outcome are therefore warranted.

Risk Factors of Enternal Nutrition Intolerance in Septic Patients:A Case-control Study

Objective:This study aimed to investigate the incidence of enteral nutrition intolerance(ENI)in patients with sepsis and explore potential risk factors.Methods:A case-control study was conducted in patients with sepsis who were receiving enteral nutrition(EN)at a tertiary hospital in China.The included patients were divided into the ENI group and the non-ENI group.Univariate and multivariate analyses were performed to identify the risk factors for ENI.Results:A total of 859 patients were included in the study.Among them,288(33.53%)patients experienced symptoms of ENI,including diarrhea,vomiting,bloating,and gastric retention.Logistic regression analysis revealed that the Acute Physiology and Chronic Health Evaluation H(APACHE H)score,thoracocentesis,and usage of cardiotonic drugs(namely,inotropes)were independent predictors of the ENI.Conclusion:The incidence of ENI is relatively high in patients with sepsis,especially in those who have higher APACHE H scores,have undergone thoracocentesis,and have received inotropes.

Summary of the Best Evidence for Tube Feeding Intolerance in Critically Ill Children

Objective:To summarize the evidence of tube feeding intolerance in critically ill children,aiming to provide evidence-based information for clinical nursing staff.Methods:Evidence search was done in Chinese and English databases to guide network and professional associations at home and abroad.The search time limit was from January 2014 to January 2024,nearly 10 years of relevant literature,mainly including guidelines,consensus,expert advice,best practice,evidence summary,system evaluation,and meta-analysis.Literature quality evaluation and evidence extraction were independently performed by two researchers.Results:This paper included 13 articles,including three guidelines,three systematic evaluations,three expert opinions,and four expert consensus.Twenty-six pieces of evidence were summarized from 10 aspects of feeding intolerance definition,team building,nutritional assessment,nutritional preparation,feeding protocol,feeding route,feeding management,pipeline management,gastric residual volume,and drug application.Conclusion:This paper summarized the evidence of tube feeding intolerance in critically ill children,which can provide evidence-based information for clinical practice.The abdominal signs should be closely observed when evaluating feeding intolerance,focusing on the prevention and reduction of feeding interruption.

Alcohol intolerance and myalgic encephalomyelitis/chronic fatigue

BACKGROUND The literature is mixed about the occurrence of alcohol intolerance among patients with myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS).Surveys that asked respondents with ME/CFS whether they experienced alcohol intolerance within a recent time frame might produce inaccurate results because respondents may indicate that the symptom was not present if they avoid alcohol due to alcohol intolerance.AIM To overcome this methodologic problem,participants in the current study were asked whether they have avoided alcohol in the past 6 mo,and if they had,how severe their alcohol intolerance would be if they were to drink alcohol.METHODS The instrument used was a validated scale called the DePaul symptom questionnaire.Independent t-tests were performed among the alcohol intolerant or not alcohol intolerant group.The alcohol intolerant group had 208 participants,and the not alcohol intolerant group had 96 participants.RESULTS Using specially designed questions to properly identify those with alcohol intolerance,those who experienced alcohol intolerance vs those who did not experience alcohol intolerance experienced more frequent/severe symptoms and domains.In addition,using a multiple regression analysis,the orthostatic intolerance symptom domain was related to alcohol intolerance.CONCLUSION The findings from the current study indicated that those with ME/CFS are more likely to experience alcohol intolerance.In addition,those with this symptom have more overall symptoms than those without alcohol intolerance.

Sunitinib for Taiwan Residents patients with gastrointestinal stromal tumor after imatinib treatment failure or intolerance

AIM:To report preliminary results of the efficacy and safety of sunitinib in the management of Taiwan Residents gastrointestinal stromal tumors (GIST) patients facing imatinib mesylate (IM) intolerance or failure.METHODS:Between 2001 and May 2010,199 Taiwan Residents patients with metastatic GIST were treated at Chang Gung Memorial Hospital.Among them,23 (11.6%) patients receiving sunitinib were investigated.RESULTS:Sixteen male and 7 female patients with a median age of 59 years (range:24-83 years) received sunitinib.Twenty-two GIST patients changed to sunitinib because of IM failure and 1 because of intolerance.The median duration of sunitinib administration was 6.0 mo (range:2-29 mo).The clinical benefit was 65.2% [2 complete response (CR),4 partial response (PR),and 9 stationary disease (SD);15/23].In 12 patients harboring mutations of the kit gene at exon 11,the clinical benefit rate (CR,PR,and SD) was 75.0% and 6 patients with tumors containing kit exon 9 mutations had a clinical benefit of 50.0% (not significant,P=0.344).The progression free survival (PFS) and overall survival (OS) did not differ between patients whose GISTs had wild type,KIT exon 9,or KIT exon 11 mutations.Hand-foot syndrome was the most common cause of grade Ⅲ adverse effect (26.1%),followed by anemia (17.4%),and neutropenia (13.0%).During the median 7.5-mo follow-up after sunitinib use,the median PFS and OS of these 23 GIST patients after sunitinib treatment were 8.4 and 14.1 mo,respectively.CONCLUSION:Sunitinib appears to be an effective treatment for Taiwan Residents with IM-resistant/intolerant GISTs and induced a sustained clinical benefit in more than 50% of Taiwan Residents advanced GIST patients.

Development of a prediction model for enteral feeding intolerance in intensive care unit patients:A prospective cohort study

BACKGROUND Enteral nutrition(EN)is essential for critically ill patients.However,some patients will have enteral feeding intolerance(EFI)in the process of EN.AIM To develop a clinical prediction model to predict the risk of EFI in patients receiving EN in the intensive care unit.METHODS A prospective cohort study was performed.The enrolled patients’basic information,medical status,nutritional support,and gastrointestinal(GI)symptoms were recorded.The baseline data and influencing factors were compared.Logistic regression analysis was used to establish the model,and the bootstrap resampling method was used to conduct internal validation.RESULTS The sample cohort included 203 patients,and 37.93%of the patients were diagnosed with EFI.After the final regression analysis,age,GI disease,early feeding,mechanical ventilation before EN started,and abnormal serum sodium were identified.In the internal validation,500 bootstrap resample samples were performed,and the area under the curve was 0.70(95%CI:0.63-0.77).CONCLUSION This clinical prediction model can be applied to predict the risk of EFI.

Exercise intolerance in heart failure with preserved ejection fraction： more than a heart problem

Heart failure （HF） with preserved ejection fraction （HFpEF） is the most common form of HF in older adults, and is increasing in preva- lence as the population ages. Furthermore, HFpEF is increasing out of proportion to HF with reduced EF （HFrEF）, and its prognosis is worsening while that of HFrEF is improving. Despite the importance of HFpEF, our understanding of its pathophysiology is incomplete, and optimal treatment remains largely undefined. A cardinal feature of HFpEF is reduced exercise tolerance, which correlates with symptoms as well as reduced quality of life. The traditional concepts of exercise limitations have focused on central dysfimction related to poor cardiac pump function. However, the mechanisms are not exclusive to the heart and lungs, and the understanding of the pathophysiology of this dis- ease has evolved. Substantial attention has focused on defining the central versus peripheral mechanisms underlying the reduced functional capacity and exercise tolerance among patients with HF. In fact, physical training can improve exercise tolerance via peripheral adaptive mechanisms even in the absence of favorable central hemodynamic function. In addition, the drug trials performed to date in HFpEF that have focused on influencing cardiovascular function have not improved exercise capacity. This suggests that peripheral limitations may play a significant role in HF limiting exercise tolerance, a hallmark feature of HFpEF.

Pharmacological therapy of feed intolerance in the critically ills

Feed intolerance in the setting of critical illness is associated with higher morbidity and mortality,and thusrequires promptly and effective treatment. Prokineticagents are currently considered as the first-line therapygiven issues relating to parenteral nutrition and post-pyloric placement. Currently,the agents of choice areerythromycin and metoclopramide,either alone or incombination,which are highly effective with relativelylow incidence of cardiac,hemodynamic or neurologicaladverse effects. Diarrhea,however,can occur in up to 49% of patients who are treated with the dual prokinetic therapy,which is not associated with Clostridiumdifficile infection and settled soon after the cessation ofthe drugs. Hence,the use of prokinetic therapy over along period or for prophylactic purpose must be avoided,and the indication for ongoing use of the drug(s)must be reviewed frequently. Second line therapy,suchas total parenteral nutrition and post-pyloric feeding,must be considered once adverse effects relating theprokinetic therapy develop.

Brain-derived neurotrophic factor inhibits glucose intolerance after cerebral ischemia

Brain-derived neurotrophic factor is associated with the insulin signaling pathway and glucose me- tabolism. We hypothesized that expression of brain-derived neurotrophic factor and its receptor may be involved in glucose intolerance following ischemic stress. To verify this hypothesis, this study aimed to observe the changes in brain-derived neurotrophic factor and tyrosine kinase B receptor expression in glucose metabolism-associated regions following cerebral ischemic stress in mice. At day 1 after middle cerebral artery occlusion, the expression levels of brain-derived neurotrophic factor were significantly decreased in the ischemic cortex, hypothalamus, liver, skeletal muscle, and pancreas. The expression levels of tyrosine kinase B receptor were decreased in the hypothalamus and liver, and increased in the skeletal muscle and pancreas, but remained unchanged in the cortex Intrahypothalamic administration of brain-derived neurotrophic factor （40 ng） suppressed the de- crease in insulin receptor and tyrosine-phosphorylated insulin receptor expression in the liver and skeletal muscle, and inhibited the overexpression of gluconeogenesis-associated phosphoenolpy- ruvate carboxykinase and glucose-6-phosphatase in the liver of cerebral ischemic mice. However, serum insulin levels remained unchanged. Our experimental findings indicate that brain-derived neurotrophic factor can promote glucose metabolism, reduce gluconeogenesis, and decrease blood glucose levels after cerebral ischemic stress. The low expression of brain-derived neurotrophic factor following cerebral ischemia may be involved in the development of glucose intolerance.

Hydrogen breath test for the diagnosis of lactose intolerance,is the routine sugar load the best one?

AIM: To evaluate the prevalence of lactose intolerance (LI) following a load of 12.5 g in patients diagnosed as high-grade malabsorbers using the hydrogen breath test (HBT)-25.METHODS: Ninety patients showing high-grade malabsorption at HBT-25 were submitted to a second HBT with a lactose load of 12.5 g.Peak hydrogen production,area under the curve of hydrogen excretion and occurrence of symptoms were recorded.RESULTS: Only 16 patients (17.77%) with positive HBT-25 proved positive at HBT-12.5.Hydrogen production was lower as compared to HBT-25 (peak value 21.55 parts per million (ppm) ± 29.54 SD vs 99.43 ppm ± 40.01 SD; P < 0.001).Symptoms were present in only 13 patients.The absence of symptoms during the high-dose test has a high negative predictive value (0.84) for a negative low-dose test.The presence of symptoms during the first test was not useful for predicting a positive low-dose test (positive predictive value 0.06-0.31).CONCLUSION: Most patients with a positive HBT-25 normally absorb a lower dose of lactose and a strict lactose restriction on the basis of a "standard" HBT is,in most instances,unnecessary.Thus,the 25 g lactose tolerance test should probably be substituted by the 12.5 g test in the diagnosis of LI,and in providing dietary guidelines to patients with suspected lactose malabsorption/intolerance.

Adalimumab induction therapy for ulcerative colitis with intolerance or lost response to infliximab: An open-label study

AIM: To evaluate the efficacy of adalimumab induction therapy in patients with ulcerative colitis who previously responded to infliximab and then lost response or became intolerant. METHODS: Ten patients with ulcerative colitis were enrolled in a 4-wk open-label trial. The patients received a loading dose of 160 mg adalimumab at wk 0 followed by 80 mg at wk 2. The primary efficacy measure was clinical improvement at wk 4, as defined by a decrease in clinical activity index (CAI) of more than 4. RESULTS: Four of 10 patients (40%) benefited from subsequent adalimumab therapy; one patient achieved remission (CAI < 4) and 3 had clinical improvement at wk 4. 6 patients had no response (60%); 2 of 6 (33.3%) subsequently underwent colectomy. This was accompanied by a decrease in median CRP concentration from 16.8 mg/mL at baseline to 3.85 mg/mL at wk 4, excluding two patients who underwent colectomy after two infusions of adalimumab. Among the 6 patients with severe colitis (CAI > 12) at baseline, none achieved remission and only one patient had clinical improvement at wk 4. CONCLUSION: The small advantage of adalimumab in patients with mild to moderate ulcerative colitis and lost response or intolerance to infliximab needs to be confirmed in randomised, double-blind, placebo- controlled trials.

Glucose intolerance and diabetes mellitus in ulcerative colitis: Pathogenetic and therapeutic implications

Diabetes mellitus is one of the most frequent co-morbidities of ulcerative colitis patients.The epidemiological association of these diseases suggested a genetic sharing and has challenged gene identification.Diabetes co-morbidity in ulcerative colitis has also relevant clinical and therapeutic implications,with potential clinical impact on the follow up and outcome of patients.These diseases share specific complications,such as neuropathy,hepatic steatosis,osteoporosis and venous thrombosis.It is still unknown whether the coexistence of these diseases may increase their occurrence.Diabetes and hyperglycaemia represent relevant risk factors for postoperative complications and pouch failure in ulcerative colitis.Medical treatment of ulcerative colitis in patients with diabetes mellitus may be particularly challenging.Corticosteroids are the treatment of choice of active ulcerative colitis.Their use may be associated with the onset of glucose intolerance and diabetes,with difficult control of glucose levels andwith complications in diabetic patients.Epidemiologic and genetic evidences about diabetes co-morbidity in ulcerative colitis patients and shared complications and treatment of patients with these diseases have been discussed in the present review.

Lactose malabsorption and intolerance: What should be the best clinical management?

Lactose malabsorption (LM) is the incomplete hydrolysis of lactose due to lactase deficiency, which may occur as a primary disorder or secondary to other intestinal diseases. Primary adult-type hypolactasia is an autosomal recessive condition resulting from the physiological decline of lactase activity. Different methods have been used to diagnose LM. Lactose breath test represents the most reliable technique. A recent consensus conference has proposed the more physiological dosage of 25 g of lactose and a standardized procedure for breath testing. Recently a new genetic test, based on C/T13910 polymorphism, has been proposed for the diagnosis of adult-type hypolactasia, complementing the role of breath testing. LM represents a wellknown cause of abdominal symptoms although only some lactose malabsorbers are also intolerants. Diagnosing lactose intolerance is not straightforward. Many non-malabsorber subjects diagnose themselves as being lactose intolerant. Blind lactose challenge studies should be recommended to obtain objective results. Besides several studies indicate that subjects with lactose intolerance can ingest up to 15 g of lactose with no or minor symptoms. Therefore a therapeutic strategy consists of a lactose restricted diet avoiding the nutritional disadvantages of reduced calcium and vitamin intake. Various pharmacological options are also available. Unfortunately there is insufficient evidence that these therapies are effective. Further double-blind studies are needed to demonstrate treatment effectiveness in lactose intolerance.

Relation between Stress Conditions, Uncertainty and Incongruity Intolerance, Rigidity and Mental Health: Experimental Demonstrations

An innovative critique of existing studies on creativity has revealed the opportunity of distinguishing between different varieties of creative tasks, and namely creativity for “Continuity”, “Opposition” and “Detachment”, considering relations between products and perceived models. This theoretical contribution has led to a specific evaluation procedure: the COD Creativity test. Considering the influences of dynamic processes on creative processes, it is worth experimentally studying the effects of short-term stress or comfort treatments. The similarities and differences between various existing studies are examined. A non-invasive but effective procedure, compared to classic techniques, is described: the “drawing recall” of stressful or relaxing real experiences, accompanied by detailed evaluations of the emotional sphere. In a specific investigation, creativity turned out to be significantly lower after acute stress with respect to comfort treatment. In conclusion, the cognitive, decisional and activity processes involved in creativity operations can be considered as strictly reflecting emotional dynamic processes, as well as the experiences gained during the stress or comfort treatments. Results are explained considering the role of conflict overload in stress as a factor of incongruity and uncertainty intolerance, inhibiting the production of bizarre and unusual ideas and configurations, and thus reducing essential aspects relevant to the evaluation of creativity levels. From clinical point of view, we underline that decades of research has generally shown that being more rigid is associated with poorer mental health. Our experimental study gives confirmation of the link between stress and intolerance of uncertainty and incongruity;this correlation could augment the negative impact of stressors on anxiety levels. In summary, people with high level of intolerance of uncertainty and, generally, with high level of intolerance of incongruity, develop mental rigidity, and this traits constellation represent a risk for mental health.

Adult hereditary fructose intolerance

Hereditary fructose intolerance(HFI) is an underrecognized,preventable life-threatening condition.It is an autosomal recessive disorder with subnormal activity of aldolase B in the liver,kidney and small bowel.Symptoms are present only after the ingestion of fructose,which leads to brisk hypoglycemia,and an individual with continued ingestion will exhibit vomiting,abdominal pain,failure to thrive,and renal and liver failure.A diagnosis of HFI was made in a 50-year-old woman on the basis of medical history,response to fructose intolerance test,demonstration of aldolase B activity reduction in duodenal biopsy,and molecular analysis of leukocyte DNA by PCR showed homozygosity for two doses of mutant gene.HFI may remain undiagnosed until adult life and may lead to disastrous complications following inadvertent fructose or sorbitol infusion.Several lethal episodes of HFI following sorbitol and fructose infusion have been reported.The diagnosis can only be suspected by taking a careful dietary history,and this can present serious complications.

Milk Consumption and Lactose Intolerance in Adults

Objective To investigate relations between milk consumption and lactose intolerance （LI） in adults and to explore the effect of milk consumption on lactase activity.Methods Total of 182 subjects aged 20‐70 years were recruited and interviewed by questionnaires,and their accumulative cow＇s milk intake （AMI） was calculated.LI was evaluated by hydrogen breath test （HBT）.Results A negative correlation was found between AMI and severity of observed LI symptom （r=-0.2884;P0.05）.Binary logistic regression analysis showed a negative correlation between LI and duration and frequency of milk consumption （OR,0.317 and 0.465,respectively;both P0.05） and a positive correlation between LI and amount of milk consumed per sitting （OR,6.337;P0.05）.Conclusion LI is related to various milk consumption behaviors.Most Chinese adults with LI may tolerate moderate milk consumption 160 mL.

Women with overweight, mixed hyperlipidemia, intolerance to glucose and diastolic hypertension

Primarily healthy women who attended a practice of General Medicine were examined and coded data were evaluated using two statistical methods (n = 248, aged 36 ± 14 years). It was found that participants with LDL-related (mixed) hyperlipidemia showed higher blood pressure, a higher proportion of alcohol problems and/or smoking compared to normolipidemic women (p ≤ 0.05). These hyperlipidemic women who reported alcohol problems and/or smoking more often showed proteinuria and/or hematuria, rise of LDL/HDL, critical fasting blood glucose and lower HDL-cholesterol compared to hyperlipidemic women reporting healthy lifestyle (p ≤ 0.05). Likewise, high triglycerides were associated with rise of blood pressure and intolerance to glucose (p ≤ 0.05) and also with elevated total cholesterol. Alcohol-related hypertriglyceridemia overlapped with diastolic hypertension, rise of body weight and urine pathology, lowering of HDL-cholesterol and critical fasting blood glucose. The motivating message was that women with mixed hyperlipidemia and healthy lifestyle had functionally renal endothelium and healthy HDL-related baseline measures. Altogether, LDL-related hyperlipidemia and/or high triglycerides were correlated with diastolic hypertension whereby critical alcohol consumption declined renal endothelium and lowered HDL-cholesterol implicating baseline strategies to neutralize early risk factors.

Children with lysinuric protein intolerance: Experience from a lower middle income country

BACKGROUND Lysinuric protein intolerance(LPI)is an inborn error of metabolism consequential to recessive mutations in the SLC7A7 gene.The metabolic imbalance in absorption and excretion of dibasic amino acids is considered the basis of LPI.The disease results from protein intolerance with signs and symptoms oscillating from cerebral impairment,respiratory involvement,renal failure and autoimmune complications.AIM To determine biochemical and clinical presentation of cases with biochemical picture suggestive of LPI in Pakistani children.METHODS The study was conducted at the Biochemical Genetic Lab,Department of Pathology and Laboratory Medicine,AKU Plasma,and urine amino acid quantification data from January 2013 to October 2018 was included in this study.The amino acids were analyzed by high performance liquid chromatography.Prestructured requisition forms were used to obtain the clinicopathological data.Statistical analysis was done by Microsoft Excel 2017.RESULTS A total of 6 patients were recognized.All the patients were male(100%).The mean age was 24 mo±10 d.All the patients had low plasma concentration of lysine,ornithine and arginine,whereas increased levels of lysine,ornithine and arginine in urine were observed in 2 patients.History of consanguineous marriage was present in all patients(100%).The most observed clinical symptom was feeding difficulty followed by failure to thrive(83.3%)and developmental delay(66.6%).Hepatomegaly was present in all patients(100%).No mutation analysis was done.CONCLUSION This study portrays the biochemical and clinical spectrum of LPI in Pakistan.Although clinical manifestations appeared in the first 2 years of life,most of them suffered a delay in undergoing diagnostic workup.

Maternal inheritance of glucose intolerance via oocyte TET3 insufficiency

Diabetes mellitus is prevalent among women of reproductive age,and many women are left undiagnosed or untreated1.Gestational diabetes has profound and enduring effects on the long-term health of the offspring2,3.However,the link between pregestational diabetes and disease risk into adulthood in the next generation has not been sufficiently investigated.Here we show that pregestational hyperglycaemia renders the offspring more vulnerable to glucose intolerance.