Metformin is the most widely prescribed drug for patients with type 2 diabetes mellitus and the first‐line pharmacological option as supported by multiple international guidelines, yet a rather large ...proportion of patients cannot tolerate metformin in adequate amounts because of its associated gastrointestinal (GI) adverse events (AEs). GI AEs typically encountered with metformin therapy include diarrhoea, nausea, flatulence, indigestion, vomiting and abdominal discomfort, with diarrhoea and nausea being the most common. Although starting at a low dose and titrating slowly may help prevent some GI AEs associated with metformin, some patients are unable to tolerate metformin at all and it may also be difficult to convince patients to start metformin again after a bout of GI AEs. Despite this clinical importance, the underlying mechanisms of the GI intolerance associated with metformin are poorly known. In the present review, we discuss: the epidemiology of metformin‐associated GI intolerance and its underlying mechanisms; genotype variability and associated factors affecting metformin GI intolerance, such as comorbidities, co‐medications and bariatric surgery; clinical consequences and therapeutic strategies to overcome metformin GI intolerance. These strategies include appropriate titration of immediate‐release metformin, use of extended‐release metformin, the promise of delayed‐release metformin and gut microbiome modulators, as well as alternative pharmacological therapies when metformin cannot be tolerated at all. Given the available data, all efforts should be made to maintain metformin before considering a shift to another drug therapy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The worldwide epidemic of obesity and insulin resistance favors nonalcoholic fatty liver disease (NAFLD). Insulin resistance (IR) in the adipose tissue increases lipolysis and the entry of ...nonesterified fatty acids (NEFAs) in the liver, whereas IR‐associated hyperinsulinemia promotes hepatic de novo lipogenesis. However, several hormonal and metabolic adaptations are set up in order to restrain hepatic fat accumulation, such as increased mitochondrial fatty acid oxidation (mtFAO). Unfortunately, these adaptations are usually not sufficient to reduce fat accumulation in liver. Furthermore, enhanced mtFAO without concomitant up‐regulation of the mitochondrial respiratory chain (MRC) activity induces reactive oxygen species (ROS) overproduction within different MRC components upstream of cytochrome c oxidase. This event seems to play a significant role in the initiation of oxidative stress and subsequent development of nonalcoholic steatohepatitis (NASH) in some individuals. Experimental investigations also pointed to a progressive reduction of MRC activity during NAFLD, which could impair energy output and aggravate ROS overproduction by the damaged MRC. Hence, developing drugs that further increase mtFAO and restore MRC activity in a coordinated manner could ameliorate steatosis, but also necroinflammation and fibrosis by reducing oxidative stress. In contrast, physicians should be aware that numerous drugs in the current pharmacopoeia are able to induce mitochondrial dysfunction, which could aggravate NAFLD in some patients. (Hepatology 2013;58:1497–1507)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Aims/hypothesis
Recent evidence suggests that oxidative stress may contribute to the pathogenesis of type 2 diabetes. The diet, and especially fruit and vegetables, contains a variety of compounds ...with antioxidant activity, which may have cumulative/synergistic antioxidant effects. The total antioxidant capacity, an index derived from dietary intake, is a single estimate of antioxidant capacity from all dietary antioxidants. The main aim of this study was to investigate the relationship between total antioxidant capacity and risk of type 2 diabetes.
Methods
Among 64,223 women (mean age 52 ± 7 years) from the French E3N-European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, 1751 women had validated type 2 diabetes during 15 years of follow-up. The total antioxidant capacity was estimated with the ferric ion-reducing antioxidant power (FRAP) method. Adjusted Cox proportional hazards regression models were used to calculate HRs and 95% CIs for the associations between total antioxidant capacity and type 2 diabetes risk, adjusted for potential confounders.
Results
In multivariable models, higher levels of total antioxidant capacity were associated with a lower risk of type 2 diabetes. Compared with women in the lowest quintile, women in the third, fourth and fifth quintiles for total antioxidant capacity had HRs of 0.74 (95% CI 0.63, 0.86), 0.70 (95% CI 0.59, 0.83) and 0.73 (95% CI 0.60, 0.89), respectively. The inverse association between total antioxidant capacity and risk of type 2 diabetes was linear up to values of 15 mmol/day, after which the effect reached a plateau.
Conclusions/interpretation
Our findings suggest that the total antioxidant capacity may play an important role in reducing the risk of type 2 diabetes in middle-aged women. More studies are warranted to better understand the biological mechanisms underlying this inverse association.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aims/hypothesis
Diet is one of the main lifestyle-related factors that can modulate the inflammatory process. Surprisingly the dietary inflammatory index (DII) has been little investigated in ...relation to type 2 diabetes, and the role of BMI in this relationship is not well established. We studied this association and the role of BMI in the inflammatory process in a large population-based observational study.
Methods
A total of 70,991 women from the E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l’Education Nationale) cohort study were followed for 20 years. Incident type 2 diabetes cases were identified using diabetes-specific questionnaires and drug reimbursement insurance databases, and 3292 incident cases were validated. The DII was derived from a validated food frequency questionnaire. Multivariable Cox regression models estimated HRs and 95% CIs between DII and incident type 2 diabetes. Interactions were tested between DII and BMI on incident type 2 diabetes and a mediation analysis of BMI was performed.
Results
Higher DII scores, corresponding to a higher anti-inflammatory potential of the diet, were associated with a lower risk of type 2 diabetes. Compared with the 1st quintile group, women from the 2nd quintile group (HR 0.85 95% CI 0.77, 0.94) up to the 5th quintile group (HR 0.77 95% CI 0.69, 0.85) had a lower risk of type 2 diabetes before adjustment for BMI. There was an interaction between DII and BMI on type 2 diabetes risk (
p
Interaction
< 0.0001). The overall association was partly mediated by BMI (58%).
Conclusions/interpretation
Our findings suggest that a higher anti-inflammatory potential of the diet is associated with a lower risk of type 2 diabetes, and the association may be mediated by BMI. These results may improve our understanding of the mechanisms underlying the role of diet-related anti-inflammation in the pathogenesis of type 2 diabetes in women. Further studies are warranted to validate our results and evaluate whether the results are similar in men.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Aims/hypothesis
The objective of this study was to evaluate the relationship of ABO blood type (A, B, AB and O), Rhesus factor (positive or negative) and a combination of the two (ABO × Rhesus) with ...type 2 diabetes mellitus risk.
Methods
In total, 82,104 women from the large prospective E3N cohort were followed between 1990 and 2008. Multivariate Cox regression models were used to estimate HRs and 95% CIs.
Results
Those with either the A (HR 1.10 95% CI 1.02, 1.18) or B (HR 1.21 95% CI 1.07, 1.36) group were at increased risk of type 2 diabetes mellitus compared with those with the O group. The association with the AB group did not reach statistical significance (HR 1.17 95% CI 0.99, 1.39). There was no difference in type 2 diabetes mellitus risk between Rhesus positive and negative groups (HR 0.96 95% CI 0.88, 1.05). When the universal donors (O
−
) were taken as the reference category, we observed an increased risk for both A
+
(HR 1.17 95% CI 1.02, 1.35) and A
−
(HR 1.22 95% CI 1.03, 1.45) individuals. The greatest increase in risk was seen for those with the B
+
blood group (HR 1.35 95% CI 1.13, 1.60). We also observed a greater type 2 diabetes mellitus risk for those with the AB
+
group (HR 1.26 95% CI 1.02, 1.57). Adjustment for fasting plasma glucose and lipid concentrations in a case–control subsample did not alter the associations.
Conclusions/interpretation
This study suggests that people with the O blood type have a lower risk of developing type 2 diabetes mellitus. Therefore, blood group should be investigated in future clinical and epidemiological studies on diabetes, and further pathophysiological research is needed to determine why individuals with blood type O have a lower risk of type 2 diabetes mellitus.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background There is limited evidence as to whether the metabolic syndrome (MetS) is associated with depression or anxiety and, if so, whether this association is gender-specific. This study ...investigated in each gender whether the MetS is associated with anxiety or depression and whether these relationships are independent of age, obesity, smoking status, socioeconomic factors, and lifestyle. Methods Metabolic syndrome (American Heart Association/National Heart, Lung, and Blood Institute criteria), depression, and anxiety (Hospital Anxiety and Depression Scale) were assessed in 1598 subjects at risk of cardiovascular disease. Results In both men and women, the MetS was associated with an increased prevalence of depression but not anxiety. The number of components of the MetS increased with increasing levels of depression but not anxiety. This association between the MetS and depressive symptoms was independent of age, smoking status, socioeconomic factors, and lifestyle. The relationship was observed across body mass index categories and was independent of anxiety. Conclusions The MetS is associated with depression and depressive symptoms but not anxiety irrespective of gender and overweight/obesity status in subjects at risk of cardiovascular disease. These findings suggest a potential importance of screening for depression in patients with the MetS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Experimental evidence suggests that developmental exposure to persistent organic pollutants (POP) and to some non persistent pesticides may disrupt metabolic regulation of glucose metabolism and ...insulin secretion, and thereby contribute to the current epidemic of obesity and metabolic disorders. Quasi-experimental situations of undernutrition in utero have provided some information. However, the evidence in humans concerning the role of the prenatal environment in these disorders is contradictory, and little is known about long-term outcomes, such as type 2 diabetes, of prenatal exposure.
Our aim was to evaluate the effects of prenatal exposure to POP and organophosphate pesticides on fetal markers of glucose metabolism in a sample of newborns from the Pelagie mother–child cohort in Brittany (France).
Dialkylphosphate (DAP) metabolites of organophosphate pesticides were measured in maternal urine collected at the beginning of pregnancy. Cord blood was assayed for polychlorinated biphenyl congener 153 (PCB153), p,p′-dichlorodiphenyl dichloroethene (DDE) and other POP. Insulin and adiponectin were determined in cord blood serum (n=268).
A decrease in adiponectin and insulin levels was observed with increasing levels of DDE, but only in girls and not boys. Adiponectin levels were not related to the concentrations of other POP or DAP metabolites. Decreasing insulin levels were observed with increasing PCB153 concentrations. Insulin levels increased with DAP urinary levels. Additional adjustment for BMI z-score at birth modified some of these relations.
Our observations bring support for a potential role of organophosphate pesticides and POP in alterations to glucose metabolism observable at birth.
•Insulin and adiponectin were determined in cord blood serum.•Adiponectin and insulin decreased with higher DDE levels in cord blood among girls.•Insulin levels decreased with increasing PCB153 concentrations in cord blood.•Insulin levels increased with organophosphate metabolites in maternal urine.•Exposure to pesticides and PCBs may induce early alterations of glucose metabolism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Introduction People living with HIV (PLWH) live longer and face new health challenges resulting from the confluence of chronic HIV infection and the natural effect of aging and ...comorbidities. However, there is a dearth of information on the long-term impact of HIV infection on the health and wellbeing of PLWH in sub-Saharan Africa. This research aimed to fill this gap by reporting on physical, functional and social outcomes among PLWH treated at a referral center in Abidjan, Ivory Coast, and comparing them with those of a control group. Methods Body composition, functional capacity, sarcopenia, limitations in daily activities and social participation were assessed among 300 PLWH (aged ≥ 30 years) and 200 uninfected adults of similar age and sex. The associations between these outcomes and participants’ socioeconomic characteristics, HIV history and physical activity level were assessed using generalized additive models adjusted for age and sex. Results The median age was 51 years, and the median antiretroviral therapy duration was 15 years. Compared to controls, PLWH reported higher levels of physical activity ( p < 0.0001). They had a lower muscle index (adjusted p < 0.0001) and grip strength (adjusted p < 0.0001) but achieved similar performance on the 6-min walk test (6MWT, p = 0.2). Among PLWH, physical activity level was positively associated with better performance in the 6MWT ( p = 0.006) and greater hand grip strength ( p = 0.04). The difference in physical performance according to the level of physical activity appeared mainly after the age of 60. PLWH reported similar rates of activity limitations ( p = 0.8), lower depression levels and greater scores for social functioning ( p = 0.02). Conclusion In this study, PLWH achieved high levels of physical activity, which may explain why they maintained good physical performance and social functioning despite having a higher risk of sarcopenia. These results have important implications for resource-limited health systems and show avenues for chronic care models. Trial registration This study was registered on the ClinicalTrials.gov website (NCT05199831, first registration the 20/01/2022).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims/hypothesis
The objective of this study was to evaluate the prospective relationship between dietary acid load, assessed with both the potential renal acid load (PRAL) and the net endogenous acid ...production (NEAP) scores, and type 2 diabetes risk.
Methods
A total of 66,485 women from the E3N-EPIC cohort were followed for incident diabetes over 14 years. PRAL and NEAP scores were derived from nutrient intakes. HRs for type 2 diabetes risk across quartiles of the baseline PRAL and NEAP scores were estimated with multivariate Cox regression models.
Results
During follow-up, 1,372 cases of incident type 2 diabetes were validated. In the overall population, the highest PRAL quartile, reflecting a greater acid-forming potential, was associated with a significant increase in type 2 diabetes risk, compared with the first quartile (HR 1.56, 95% CI 1.29, 1.90). The association was stronger among women with BMI <25 kg/m
2
(HR 1.96, 95% CI 1.43, 2.69) than in overweight women (HR 1.28, 95% CI 1.00, 1.64); statistically significant trends in risk across quartiles were observed in both groups (
p
trend
< 0.0001 and
p
trend
= 0.03, respectively). The NEAP score provided similar findings.
Conclusions/interpretation
We have demonstrated for the first time in a large prospective study that dietary acid load was positively associated with type 2 diabetes risk, independently of other known risk factors for diabetes. Our results need to be validated in other populations, and may lead to promotion of diets with a low acid load for the prevention of diabetes. Further research is required on the underlying mechanisms.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We aimed to estimate the prevalence of depressive disorder in people living with HIV (PLWH) and evaluate its association with non-HIV-specific and HIV-specific factors in PLWH and in PLWH compared to ...the general population (GP). We used cross-sectional data from the QuAliV study, conducted within the ANRS-CO3 Aquitaine-AQUIVIH-NA cohort of PLWH in Nouvelle-Aquitaine (2018-2020), and a nationally-representative survey in the GP (EHIS-ESPS, 2014-2015), we included all participants aged ≥ 18 years old who had completed the Patient Health Questionnaire-8 (PHQ-8). Depressive disorder was defined as Patient Health Questionnaire-8 score greater or equal to 10. Its association with non-HIV-specific (demographic, socio-economic, behavioral, health status), HIV-specific factors (immuno-viral markers, antiretrovirals, level of perceived HIV-stigma), and HIV-status was assessed using Poisson regression models with robust variance in women and men separately. We included 914 PLWH (683 men/231 women). More than one in five PLWH had depressive disorder. It was strongly associated with being younger and experiencing severe pain in both sexes. Unemployment in women, being single, and lack of family ties in men were also associated with depressive disorder. More than 30% of our sample reported HIV-stigma, with a dose-response relationship between level of perceived HIV-stigma and depressive disorder. The crude prevalence of depressive disorder was 2.49 (95%CI 1.92-3.22) and 4.20 (95%CI 3.48-5.05) times higher in women and men living with HIV respectively compared to GP counterparts and 1.46 (95%CI 1.09-1.95) and 2.45 (95%CI 1.93-3.09) times higher after adjustment for non-HIV specific factors. The adjusted prevalence ratio of depressive disorder was not significantly different in HIV-stigma free women, but remained twice as high in HIV-stigma free men. The prevalence of depressive disorder compared to the GP tended to decrease with age in PLWH. Excess depressive disorder remains a major concern in PLWH. Our findings reaffirm the importance of regular screening. Tackling social inequalities and HIV-stigma should be prioritized to ensure that PLWH achieve good mental as well as physical health outcomes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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