Sex differences in metabolic regulation and diabetes susceptibility

Tramunt, Blandine; Smati, Sarra; Grandgeorge, Naia; Lenfant, Françoise; Arnal, Jean‐François; Montagner, Alexandra; Gourdy, Pierre

doi:10.1007/s00125-019-05040-3

Cited by 528 publications

(481 citation statements)

References 65 publications

(84 reference statements)

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“…Contrary findings between men and women could be explained by sex differences in T2D susceptibility (153) . Pre-menopausal women are less susceptible to T2D than men, partly explained by difference in sex steroid hormones (153) .…”

Section: Low-carbohydrate Diets Hba1c Level and Incident Type 2 Diabcontrasting

confidence: 58%

Low and reduced carbohydrate diets: challenges and opportunities for type 2 diabetes management and prevention

2020

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Low-carbohydrate diets (LCD) have been promoted for weight control and type 2 diabetes (T2D) management, based on an emerging body of evidence, including meta-analyses with an indication of publication bias. Proposed definitions vary between 50 and 130 g/d, or <10 and <40 % of energy from carbohydrate, with no consensus on LCD compositional criteria. LCD are usually followed with limited consideration for other macronutrients in the overall diet composition, introducing variance in the constituent foods and in metabolic responses. For weight management, extensive evidence supports LCD as a valid weight loss treatment, up to 1–2 years. Solely lowering carbohydrate intake does not, in the medium/long term, reduce HbA1c for T2D prevention or treatment, as many mechanisms interplay. Under controlled feeding conditions, LCD are not physiologically or clinically superior to diets with higher carbohydrates for weight-loss, fat loss, energy expenditure or glycaemic outcomes; indeed, all metabolic improvements require weight loss. Long-term evidence also links the LCD pattern to increased CVD risks and mortality. LCD can lead to micronutrient deficiencies and increased LDL-cholesterol, depending on food selection to replace carbohydrates. Evidence is limited but promising regarding food choices/sources to replace high-carbohydrate foods that may alleviate the negative effects of LCD, demanding further insight into the dietary practice of medium to long term LCD followers. Long-term, high-quality studies of LCD with different food sources (animal and/or plant origins) are needed, aiming for clinical endpoints (T2D incidence and remission, cardiovascular events, mortality). Ensuring micronutrient adequacy by food selection or supplementation should be considered for people who wish to pursue long-term LCD.

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Section: Low-carbohydrate Diets Hba1c Level and Incident Type 2 Diabcontrasting

confidence: 58%

Low and reduced carbohydrate diets: challenges and opportunities for type 2 diabetes management and prevention

2020

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“…It is also possible that TCDD may interfere with sex hormones, specifically estrogen, leading to sex-specific changes in metabolism. Indeed, diabetes prevalence is generally higher in men than women, which has been attributed to a protective role of estrogen on body composition and glucose homeostasis 43 . Previous studies have reported crosstalk between AhR and estrogen signaling 44 , although the role of AhR in metabolism is complex and not fully understood 45 .…”

Section: For Schematic Timeline) (Ae) Average Islet Area (B-df-h)mentioning

confidence: 99%

Long-term metabolic consequences of acute dioxin exposure differ between male and female mice

Hoyeck

Blair

Ibrahim

et al. 2020

Sci Rep

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epidemiological studies have consistently shown an association between exposure to environmental pollutants and diabetes risk in humans. We have previously shown that direct exposure of mouse and human islets (endocrine pancreas) to the highly persistent pollutant TCDD (2,3,7,8-tetrachlorodibenzop-dioxin) causes reduced insulin secretion ex vivo. Furthermore, a single high-dose of TCDD (200 µg/kg) suppressed both fasting and glucose-induced plasma insulin levels and promoted beta-cell apoptosis after 7 days in male mice. The current study investigated the longer-term effects of a single high-dose TCDD injection (20 µg/kg) on glucose metabolism and beta cell function in male and female C57Bl/6 mice. TCDD-exposed males displayed modest fasting hypoglycemia for ~4 weeks post-injection, reduced fasting insulin levels for up to 6 weeks, increased insulin sensitivity, decreased beta cell area, and increased delta cell area. tcDD-exposed females also had long-term suppressed basal plasma insulin levels, and abnormal insulin secretion for up to 6 weeks. Unlike males, TCDD did not impact insulin sensitivity or islet composition in females, but did cause transient glucose intolerance 4 weeks post-exposure. our results show that a single exposure to dioxin can suppress basal insulin levels longterm in both sexes, but effects on glucose homeostasis are sex-dependent. Diabetes mellitus is one of the leading causes of death worldwide, and its prevalence is increasing at alarming rates 1. Type 2 diabetes (T2D) is the most common form of diabetes, and is characterized by chronic hyperglycemia, peripheral insulin resistance, and insufficient insulin production by pancreatic beta cells 2. The rapid increase in diabetes incidence worldwide cannot be accounted for by genetics and lifestyle alone, suggesting that other environmental factors are likely contributing to diabetes etiology. In particular, epidemiological studies have reported an association between exposure to persistent organic pollutants (POPs) and increased diabetes incidence 3,4. However, while epidemiological studies can uncover correlative associations, basic research in model systems is required to investigate causation. Generally, POPs are lipophilic chemicals that resist degradation, leading to widespread global dispersion, bioaccumulation, and long-term release into the environment 5. Dioxins and dioxin-like compounds are a broad class of POPs that activate the aryl hydrocarbon receptor (AhR), which induces a variety of target genes, including cytochrome P450 (Cyp)1a1 and Cyp1a2. Although CYP enzymes are essential for xenobiotic metabolism, CYP-mediated substrate oxidation can also generate highly reactive intermediate metabolites that cause oxidative stress and DNA/protein damage 6. Our lab has shown that CYP1A enzymes are inducible and functional in human and mouse pancreatic islets, and that these enzymes remain active for at least two weeks following a single acute exposure to the classic dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 7. These data indic...

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“…Conversely, a higher rate of NAFLD was found among the postmenopausal women (5-7). In agreement with this nding, sex differences also exist in the risk factors, such as obesity and type 2 diabetes (8,9). Biological sex differences are exhibited in many physiological phenomenon, including fat distribution, triglyceride storage in liver and muscle (10), fatty acid and glucose metabolism (11), etc.…”

Section: Introductionmentioning

confidence: 54%

Sex Differences in Dietary Copper-Fructose Interaction-Induced Alterations of Gut Microbial Activity are Not Correlated to Hepatic Steatosis

Song

Fang

et al. 2020

Preprint

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Abstract Background: Inadequate copper intake and increased fructose consumption represent two important nutritional problems in the US. Diet copper-fructose interactions alter gut microbial activity and contribute to the development of nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine whether dietary copper-fructose interactions alter gut microbial activity in a sex-differential manner, and whether sex differences in gut microbial activity are associated with sex differences in hepatic steatosis. Methods: Male and female weanling Sprague-Dawley (SD) rats were fed ad libitum with an AIN-93G purified rodent diet with defined copper content for 8 weeks. The copper content is 6mg/kg and 1.5mg/kg in adequate copper diet (CuA) and marginal copper diet (CuM), respectively. Animals had free access to either deionized water or deionized water containing 10% fructose (F) (w/v) as the only drink during the experiment. Body weight, calorie intake, plasma ALT, AST and liver histology were evaluated. Fecal microbial contents were analyzed by 16S rRNA sequencing. Fecal and cecal short chain fatty acids (SCFAs) were determined by gas chromatography-mass spectrometry (GC-MS).Results: Male and female rats exhibit similar trends of changes in the body weight, body weight gain and calorie intake in response to dietary copper and fructose, with a generally higher level in male rats. Several female rats in CuAF group developed mild steatosis, while no obvious steatosis was observed in male rats fed with CuAF or CuMF. Fecal 16S rRNA sequencing analysis revealed distinct alterations of the gut microbiome in male and female rats. Linear discriminant analysis (LDA) effect size (LEfSe) identified sex-specific abundant taxa in different groups. Further, total SCFAs, as well as, butyrate were decreased in a more pronounced manner in female CuMF rats than in male rats. Of note, the decreased SCFAs are concomitant with the reduced SCFA producers, but not correlated to hepatic steatosis. Conclusions: Our data demonstrated sex differences in the alterations of gut microbial activities and hepatic steatosis in response to dietary copper-fructose interaction in rats. Tissue-specific responses to dietary copper and fructose likely contribute to the sex differences in gut microbial activity and metabolic phenotype.

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Sex differences in metabolic regulation and diabetes susceptibility

Cited by 528 publications

References 65 publications

Low and reduced carbohydrate diets: challenges and opportunities for type 2 diabetes management and prevention

Low and reduced carbohydrate diets: challenges and opportunities for type 2 diabetes management and prevention

Long-term metabolic consequences of acute dioxin exposure differ between male and female mice

Sex Differences in Dietary Copper-Fructose Interaction-Induced Alterations of Gut Microbial Activity are Not Correlated to Hepatic Steatosis

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