CVD, including atherosclerosis, hypertension, myocardial infarction, stroke and heart failure, affect about 10 % of young and middle-aged (<65 years) and about 30 % of older (≥65 years) adults and are the leading causes of mortality, accounting for >25 % of all deaths(1–Reference Blackwell and Villarroel3). More than 80 % of CVD-related deaths are due to IHD and stroke(Reference Blackwell and Villarroel3). The prevalence of CVD is closely linked to the prevalence of obesity because obesity is commonly associated with metabolic abnormalities that are important risk factors for CVD, including insulin resistance, pre-diabetes, and type-2 diabetes (T2D), atherosclerotic dyslipidaemia, endothelial dysfunction and hypertension(Reference Klein, Wadden and Sugerman4–Reference Nordestgaard, Benn and Schnohr13). Insulin is a key regulator of glucose and lipid metabolism and also regulates sympathetic nerve activity and endothelial function; accordingly, resistance to the effects of insulin is a key pathogenic mechanism involved in CVD(Reference Laakso and Kuusisto14). In addition, increases in plasma glucose and TAG per se are directly involved in causing the cellular pathogenic changes associated with hypertension and atherosclerosis(Reference Reusch and Wang15,Reference Miller, Stone and Ballantyne16) .
Premenopausal women have a more beneficial traditional CVD risk profile (lower fasting plasma glucose(Reference Menke, Rust and Savage17–Reference Flanagan, Holt and Owens22) and less atherogenic lipid profile, characterised by lower plasma TAG and Apo-B containing particles, higher HDL-cholesterol, and more large and fewer small HDL particles(Reference Magkos, Mohammed and Mittendorfer19,Reference Pascot, Lemieux and Bergeron23) ) and a lower absolute risk for CVD than men. The observed sex differences in the metabolic CVD risk profile are attributed to the sex hormone milieu, particularly the protective effect of oestradiol, but it is becoming clear that chronological age per se has a major and possibly greater influence on cardiometabolic function in women than menopause(Reference Wang, Magkos and Mittendorfer24–Reference Matthews, Crawford and Chae28). In addition, the relative risk for CVD associated with hyperglycaemia and dyslipidaemia is several-fold higher in women than in men(Reference Castelli5,Reference Abdel-Maksoud, Eckel and Hamman7,Reference Kannel and McGee10,Reference Wei, Gaskill and Haffner12,Reference Peters, Huxley and Woodward29–Reference Sone, Tanaka and Tanaka33) . A meta-analysis of sixty four studies, including a total of 858 507 people, found the relative risk for CVD associated with T2D is about 45 % greater in women than in men(Reference Peters, Huxley and Woodward29); another, smaller meta-analysis, which focused on young and middle-aged (<60 years) adults only, found the relative risk for CVD associated with T2D is approximately three times as high in women than men(Reference Kalyani, Lazo and Ouyang30). Moreover, women with atherosclerotic dyslipidaemia (hypertriglyceridaemia and/or low HDL-cholesterol) have a two to four times greater risk for CVD than women with normal plasma lipids whereas atherosclerotic dyslipidaemia increases the risk for CVD by only 25–50 % in men(Reference Castelli5,Reference Abdel-Maksoud, Eckel and Hamman7) . The reasons for the sex differences in absolute CVD risk and CVD risk associated with increased glucose and TAG concentrations are unclear but could be related to differences in the mechanisms that cause hyperglycaemia and dyslipidaemia in men and women, which could influence the pathogenic processes involved in CVD. For example, the CVD risk associated with increased plasma TAG concentration is not simply determined by the total amount of TAG but dependent on the number of circulating TAG-containing lipoprotein particles at any given TAG concentration (i.e. lots of small TAG-poor v. few large, TAG-rich particles), and the T2D risk associated with impaired glucose tolerance depends on the shape of the plasma glucose profile after glucose ingestion, which is likely determined by variations in insulin secretion, plasma clearance and target tissue action(Reference Stock34–Reference Trico, Natali and Arslanian40). In the present paper, we will review and highlight important differences in insulin kinetics and action, basal and postprandial glucose and lipid metabolism and myocardial substrate use between men and women.
Regulation of plasma glucose and TAG concentrations
Plasma glucose concentration is maintained by a balance between hepatic, and to a lesser extent, renal glucose production, meal glucose appearance in plasma and tissue glucose uptake. Insulin is a major regulator of endogenous glucose production and tissue glucose uptake (see(Reference Petersen and Shulman41–Reference Petersen, Vatner and Shulman43) for excellent and detailed reviews). Insulin suppresses endogenous glucose production, both by acting directly on hepatocytes, and indirectly by inhibiting glucagon production and adipose tissue lipolysis(Reference Petersen, Vatner and Shulman43). Endogenous glucose production is very sensitive to the inhibitory effect of insulin and small increases in plasma insulin above basal values are sufficient to completely suppress it(Reference Kolterman, Insel and Saekow44–Reference Rizza, Mandarino and Gerich46). Insulin stimulates tissue (predominantly muscle) glucose uptake in a dose-dependent manner and the maximal stimulatory effect of insulin on glucose disposal far exceeds the normal postprandial rise in plasma insulin(Reference Kolterman, Insel and Saekow44). Insulin is also a potent inhibitor of adipose tissue lipolysis and fatty acid release into plasma, and small increases in plasma insulin above basal values are sufficient to completely suppress it(Reference Conte, Fabbrini and Kars45,Reference Jensen and Nielsen47,Reference Jensen, Caruso and Heiling48) . Insulin also regulates hepatic TAG synthesis and secretion, both directly and indirectly by regulating adipose tissue lipolysis. Insulin stimulates hepatic de novo lipogenesis (DNL), inhibits VLDL-particle (Apo-B-100) and TAG secretion, and regulates the availability of adipose-derived fatty acids for hepatic TAG synthesis(Reference Petersen and Shulman41,Reference Sparks, Sparks and Adeli49) . In healthy people, insulin secretion, plasma insulin clearance and insulin sensitivity are tightly coordinated and both insulin secretion and insulin clearance often change simultaneously in opposite directions to compensate for changes in insulin sensitivity; relative insulin insufficiency due to an imbalance among insulin secretion, plasma clearance and sensitivity causes an increase in plasma glucose, fatty acid and TAG concentrations, and ultimately pre-diabetes, T2D and atherosclerotic dyslipidaemia(Reference Kim and Reaven50–Reference Kahn, Prigeon and McCulloch52).
Basal plasma glucose concentration and flux in men and women
Plasma glucose concentration after an overnight fast is generally slightly (about 10 %) lower in women than in men(Reference Menke, Rust and Savage17–Reference Flanagan, Holt and Owens22,Reference Arner and Ryden53) , but it is unclear whether this is due to less glucose production or more efficient plasma clearance in women than in men. The results from studies that evaluated basal endogenous glucose production are equivocal. In most studies basal endogenous glucose production, expressed per kg body weight or per kg fat-free mass, was not different in men and women, irrespective of adiposity status and age(Reference Hoeg, Sjoberg and Jeppesen54–Reference Yeo, Hays and Dennis62). However, in some studies, basal endogenous glucose production, expressed per kg body weight or fat-free mass was less(Reference Anderwald, Gastaldelli and Tura18,Reference Honka, Latva-Rasku and Bucci63) and in others it was greater(Reference Basu, Dalla Man and Campioni64,Reference Tran, Jacot-Descombes and Lecoultre65) in women compared with age-matched men. The reasons for the differences in results among studies are unclear but are likely related to differences in the prevailing plasma insulin concentration (because insulin is a potent inhibitor of endogenous glucose production(Reference Conte, Fabbrini and Kars45)) and the duration of fasting, which affects hepatic glucose production differently in men and women(Reference Mittendorfer, Horowitz and Klein55,Reference Soeters, Sauerwein and Groener66) .
Basal plasma NEFA concentration and flux in men and women
Plasma NEFA concentration after an overnight fast is generally greater in women than men(Reference Arner and Ryden53,Reference Karpe, Dickmann and Frayn67–Reference Mittendorfer, Yoshino and Patterson69) . The difference in NEFA concentration is largely due to the greater fat mass relative to fat-free mass, not differences in adipose tissue lipolytic activity and/or plasma clearance rate (reviewed later), in women than in men. We measured NEFA appearance rate in plasma, an index of adipose tissue lipolytic activity(Reference Mittendorfer, Liem and Patterson70), in lean, overweight and obese (including severely obese) men and women and found basal NEFA appearance rate in plasma, is directly related to fat mass, and the relationship between fat mass and NEFA appearance in plasma is not different in men and women(Reference Mittendorfer, Magkos and Fabbrini68). However, NEFA appearance rate in relationship to fat-free mass, or unit of plasma volume, or resting energy expenditure is approximately 50 % greater in women than in men(Reference Mittendorfer, Magkos and Fabbrini68,Reference Nielsen, Guo and Albu71,Reference Magkos, Patterson and Mohammed72) because women have more fat mass than men for any given amount of fat-free mass(Reference Gallagher, Heymsfield and Heo73), and fat-free mass is the primary determinant of resting energy expenditure(Reference Oshima, Miyauchi and Kawano74,Reference Cunningham75) .
Insulin action on glucose metabolism in men and women
Potential sex differences in insulin action on glucose metabolism have been evaluated by using the homoeostasis model assessment of insulin resistance (e.g.(Reference Guerra, Fuentes and Delgado-Guerra76,Reference Sung, Choi and Gwon77) ), the oral glucose tolerance test (OGTT) (e.g.(Reference Anderwald, Gastaldelli and Tura18,Reference Sumner, Kushner and Sherif78,Reference Faerch, Pacini and Nolan79) ), the intravenous glucose tolerance test (IVGTT) (e.g.(Reference Clausen, Borch-Johnsen and Ibsen21,Reference Flanagan, Holt and Owens22) ) and the gold-standard hyperinsulinaemic-euglycaemic clamp technique, with or without simultaneous glucose tracer infusion (e.g.(Reference Anderwald, Gastaldelli and Tura18,Reference Jensen and Nielsen47,Reference Hoeg, Sjoberg and Jeppesen54,Reference Ter Horst, Gilijamse and de Weijer57,Reference Frias, Macaraeg and Ofrecio58,Reference Chan, Chooi and Ding80– Reference Nuutila, Knuuti and Maki83)). We focus on the results from studies that used the hyperinsulinaemic-euglycaemic clamp procedure in conjunction with glucose tracers (stable isotope- or radio-labelled) to distinguish the effects of insulin on glucose production and glucose disposal (not those that only report the M-value, i.e. the glucose infusion rate during the clamp) and those that used the arterio-venous balance technique or dynamic positron emission tomography imaging to provide a direct measure of tissue glucose uptake rates. The homoeostasis model assessment of insulin resistance and the IVGTT-derived insulin sensitivity indices do not provide direct information about the effect of insulin on organ-specific glucose kinetics and the OGTT provides a standard 75 g dose of glucose to subjects regardless of body size, which makes the interpretation of the results difficult because women are generally smaller than men(Reference Faerch, Pacini and Nolan79,Reference Rathmann, Strassburger and Giani84,Reference Sicree, Zimmet and Dunstan85) .
Insulin action on endogenous glucose production
Endogenous glucose production is very sensitive to changes in plasma insulin and even small increases in plasma insulin concentration above values observed after an overnight fast can almost completely inhibit it(Reference Conte, Fabbrini and Kars45,Reference DeFronzo, Jacot and Jequier86) . A study that used a relatively low-dose insulin infusion rate that sub-maximally suppressed endogenous glucose production found endogenous glucose production was more sensitive to the inhibitory effect of insulin in women than men (greater relative suppression in women)(Reference Ter Horst, Gilijamse and de Weijer57). Several other studies evaluated the effects of higher (near maximally suppressive) doses of insulin on endogenous glucose production and found near maximally suppressed endogenous glucose production rates were not different in men and women(Reference Anderwald, Gastaldelli and Tura18,Reference Hoeg, Sjoberg and Jeppesen54,Reference Frias, Macaraeg and Ofrecio58) .
Insulin action on glucose disposal
Comparing whole body glucose disposal rates in men and women is difficult because of differences in body size and body composition in men and women. In healthy lean men, skeletal muscle accounts for the majority (>75 %) of whole body insulin-stimulated glucose disposal(Reference DeFronzo, Jacot and Jequier86,Reference Yki-Jarvinen, Young and Lamkin87) . However, both muscle and adipose tissue are highly sensitive to insulin(Reference Dadson, Landini and Helmio88–Reference Williams, Price and Kelley90) and insulin-stimulated tissue glucose uptake rates in various adipose tissue depots range from 25 to >50 % the rates measured in muscle(Reference Honka, Latva-Rasku and Bucci63). Accordingly, the contribution of adipose tissue to total (whole body) glucose disposal depends on a person's adiposity. Whole body insulin-stimulated glucose disposal rate expressed per kg fat-free or lean body mass and adjusted for plasma insulin concentration was often not different in men or age-matched (young or older) women(Reference Jensen and Nielsen47,Reference Ter Horst, Gilijamse and de Weijer57,Reference Boirie, Gachon and Cordat81) but glucose uptake rate per leg lean mass (arterio-venous-balance technique) or uptake into muscle (assessed by using dynamic positron emission tomography imaging) was greater in lean women than in lean age-matched men(Reference Hoeg, Sjoberg and Jeppesen54,Reference Hoeg, Roepstorff and Thiele82,Reference Nuutila, Knuuti and Maki83) .
NEFA-induced insulin resistance of glucose metabolism in men and women
Plasma NEFA are important negative regulators of insulin action in liver and muscle. An experimentally-induced (intravenous lipid and heparin infusion) increase in plasma NEFA concentration before and during a hyperinsulinaemic-euglycaemic clamp impairs insulin action in liver and muscle in a dose-dependent manner(Reference Boden, Chen and Ruiz91–Reference Belfort, Mandarino and Kashyap94). The adverse effect of NEFA on insulin action lasts for almost 4 h after cessation of lipid infusion(Reference Gormsen, Nielsen and Jessen95). The observed greater insulin sensitivity of both endogenous glucose production(Reference Ter Horst, Gilijamse and de Weijer57) and muscle glucose disposal(Reference Hoeg, Sjoberg and Jeppesen54,Reference Hoeg, Roepstorff and Thiele82,Reference Nuutila, Knuuti and Maki83) in women compared with men is therefore intriguing considering basal NEFA release from adipose tissue in relationship to fat-free mass is markedly greater in women than in men(Reference Mittendorfer, Magkos and Fabbrini68,Reference Nielsen, Guo and Albu71,Reference Magkos, Patterson and Mohammed72) . Several studies therefore tested the susceptibility of men and women to NEFA-induced insulin resistance. In some studies, women were less susceptible to NEFA-induced insulin resistance of glucose disposal(Reference Hoeg, Sjoberg and Jeppesen54,Reference Frias, Macaraeg and Ofrecio58) , whereas others reported no sex difference in NEFA-mediated insulin resistance(Reference Belfort, Mandarino and Kashyap94,Reference Vistisen, Hellgren and Vadset96) ; however, this could have been due to statistical power because a trend for a lower impairment in women than in men (46 v. 60 % impairment) was observed(Reference Vistisen, Hellgren and Vadset96). Only one study evaluated the effect of increased plasma NEFA concentration on insulin-mediated suppression of endogenous glucose production and found NEFA impaired it similarly in men and women(Reference Frias, Macaraeg and Ofrecio58).
Insulin action on adipose tissue lipolysis in men and women
Adipose tissue is very sensitive to the antilipolytic effect of insulin(Reference Jensen, Caruso and Heiling48), so even small differences in plasma insulin concentration can have marked effects on NEFA appearance in plasma. The results from studies that evaluated the effect of sex on insulin-mediated suppression of NEFA release into the circulation are inconsistent and difficult to interpret because different doses of insulin were used and plasma insulin concentrations were either not reported or markedly (about 30 %) different in men and women(Reference Jensen and Nielsen47,Reference Shadid, Kanaley and Sheehan97,Reference Millstein, Pyle and Bergman98) . However, one of these studies evaluated the dose–response relationship between plasma insulin concentration and NEFA rate of appearance in plasma in lean and overweight and obese men and women and found the half-maximum effective insulin concentration was not different in men and women but greater in obese than non-obese subjects(Reference Jensen and Nielsen47), suggesting no sex differences in insulin sensitivity of adipose tissue lipolysis but obesity-associated insulin-resistance in both men and women.
Insulin secretion in men and women
A large cohort study that included 380 healthy young subjects found plasma C-peptide concentration (an index of insulin secretion) after an overnight fast was greater in women than men(Reference Clausen, Borch-Johnsen and Ibsen21). Potential sex differences in glucose-stimulated insulin secretion have been evaluated by using both IVGTT and OGTT. During the IVGTT, a body weight-adjusted dose of glucose is provided, whereas the same standard dose of glucose (75 g) is given to everyone during the OGTT, which makes the interpretation of the results from OGTT difficult, because women are generally smaller than men(Reference Faerch, Pacini and Nolan79,Reference Rathmann, Strassburger and Giani84,Reference Sicree, Zimmet and Dunstan85) . The acute C-peptide response to an intravenous glucose challenge was not different in men and age-matched women(Reference Clausen, Borch-Johnsen and Ibsen21), but the acute insulin response was greater in women than men(Reference Clausen, Borch-Johnsen and Ibsen21,Reference Flanagan, Holt and Owens22) , suggesting similar glucose-induced insulin secretion but impaired insulin clearance in women compared with men (reviewed in more detail later). The interpretation of the results from studies that evaluated insulin secretion after mixed meal ingestion(Reference Basu, Dalla Man and Campioni64,Reference Chan, Chooi and Ding80) is complicated because different meals were used in different studies and meal energy and carbohydrate contents were not always adjusted for differences in body weight and energy expenditure in men and women. One study provided a body weight adjusted meal (41·84 kJ/kg and 1·2 g dextrose/kg) to both young and older men and women(Reference Basu, Dalla Man and Campioni64) and found the early rise in plasma C-peptide was not different in women and men, but women had slightly higher C-peptide concentrations during the later postprandial period (about 60 min after starting the meal).
Insulin clearance in men and women
The effect of sex on plasma insulin clearance is unclear because of conflicting results from different studies. A study that used the hyperinsulinaemic-euglycaemic pancreatic clamp technique in conjunction with arterial and hepatic vein blood sampling in young and older adults found whole body insulin clearance was greater in women than in men, and this was due to greater non-splanchnic insulin clearance in women whereas hepatic/splanchnic insulin clearance was lower in women than in men(Reference Jensen, Nielsen and Gupta99). Another study reported impaired steady-state insulin clearance during a hyperinsulinaemic-euglycaemic clamp in women compared with men, but insulin clearance was calculated as the insulin infusion rate divided by plasma insulin concentration(Reference Chan, Chooi and Ding80), which ignores residual endogenous insulin secretion during the clamp(Reference Waldhausl, Gasic and Bratusch-Marrain100). Studies that used a mathematical modelling approach to estimate whole body and regional plasma insulin clearance after mixed meal ingestion found postprandial non-splanchnic insulin clearance was greater in young Caucasian women than in men and splanchnic insulin clearance was significantly less or tended to be less in women than in men(Reference Basu, Dalla Man and Campioni64); however, in young Asian and older Caucasian subjects, plasma insulin clearance rates were not different in women and men(Reference Basu, Dalla Man and Campioni64,Reference Chan, Chooi and Ding80) . Data obtained during an IVGTT suggest impaired insulin clearance in women compared with men because the acute C-peptide response, which provides a measure of insulin secretion, was not different in men and women but insulin concentration was greater in women than in men(Reference Clausen, Borch-Johnsen and Ibsen21).
Postprandial glucose kinetics in men and women
Postprandial glucose kinetics in young and older men and women were evaluated by using a triple tracer mixed meal metabolic testing protocol(Reference Basu, Dalla Man and Campioni64). The meal provided 41·84 kJ/kg and contained 1·2 g dextrose/kg. Endogenous glucose production was rapidly and nearly completely suppressed during the first 60 min after meal ingestion and then returned to basal values in both men and women (both young and old). However, meal glucose appearance in plasma was faster in women than in men (both young and old). Differences in glucose absorption in men and women have also been observed during an OGTT(Reference Anderwald, Gastaldelli and Tura18), but the results cannot be directly compared with the meal test or among men and women because both men and women received 75 g glucose during the OGTT, so women received much more glucose relative to their body weight and metabolic rate than men.
Postprandial fatty acid kinetics in men and women
Postprandial endogenous and meal fatty acid appearance in plasma in men and pre-menopausal women has been evaluated by using a dual tracer (oral and intravenous) mixed meal testing protocol(Reference Jensen101). Meal ingestion suppressed the NEFA rate of appearance in plasma rapidly and nearly completely for almost 4 h in both men and women whereas meal-derived fatty acid appearance in plasma tended to be greater in men than in women(Reference Jensen101). Postprandial lipaemia and the organ distribution and metabolic fate of NEFA entering the systemic circulation from adipose tissue lipolysis and meals are markedly different in men and pre-menopausal women. After an overnight fast, a smaller proportion of plasma NEFA flux is oxidised to CO2 in women than in men(Reference Koutsari, Basu and Rizza102), even though women convert plasma NEFA more rapidly to readily oxidised ketones(Reference Marinou, Adiels and Hodson103). The greater non-oxidative disposal of NEFA in women appears to be targeted to adipose tissue because a greater proportion of both plasma NEFA and meal-derived fatty acids are stored in subcutaneous adipose tissue in women than in men (about 25 v. ≤10 %, respectively) whereas uptake into liver, muscle and visceral fat after mixed or high fat meal ingestion is not different in men and women(Reference Santosa, Hensrud and Votruba104–Reference Votruba and Jensen108). The postprandial increase in plasma TAG after consuming a mixed or high fat meal is less in women than in men, even though the same amount of meal fat is oxidised in women and men(Reference Votruba and Jensen108–Reference Pramfalk, Pavlides and Banerjee110) and less meal fat is cleared by splanchnic tissues in women than in men(Reference Nguyen, Hernandez Mijares and Johnson111). The difference in postprandial lipaemia between women and men was observed regardless of whether or not the meal was adjusted for individual subject's energy needs and therefore smaller relative to body weight in men than women. These results suggest markedly impaired peripheral TAG clearance after meal intake in men compared with women. In addition, it was found that adding carbohydrates to an oral lipid load decreased postprandial lipaemia in women but not in men(Reference Knuth, Remias and Horowitz112). The differences in postprandial lipid metabolism in men and pre-menopausal women are at least in part due to differences in the sex hormone milieu(Reference Westerveld, Kock and van Rijn113–Reference van Beek, de Ruijter-Heijstek and Erkelens115). However, an independent effect of chronological age on postprandial lipaemia has also been observed and it was as pronounced, if not more pronounced than that of menopause(Reference Jackson, Abraham and Smith25). Moreover, subcutaneous adipose tissue fatty acid storage is even greater in postmenopausal than premenopausal women(Reference Santosa and Jensen116), suggesting the observed sexual dimorphism in adipose tissue fatty acid storage is not due to differences in female sex steroids.
Basal hepatic lipid metabolism in men and women
In a series of studies, we evaluated VLDL-TAG and VLDL-Apo-B-100 kinetics by using stable isotope labelled tracer techniques in conjunction with compartmental modelling analysis in lean and obese men and women. The results from these studies revealed that a person's sex affects the kinetics of both the particle (Apo-B-100) per se and the TAG moiety of particles, often independently suggesting differences in the lipid load of particles. The differences between men and women are not only due to differences in the sex hormone milieu and are dependent on subjects' adiposity status. We found: (i) lean young women produce fewer but TAG-richer VLDL particles than men(Reference Mittendorfer, Yoshino and Patterson69,Reference Magkos, Patterson and Mohammed72,Reference Mittendorfer, Patterson and Klein117) , (ii) ovarian hormone deficiency after menopause increases VLDL-TAG but not VLDL-Apo-B-100 (VLDL particle) secretion rate(Reference Magkos, Fabbrini and Mohammed118), (iii) testosterone treatment has no effect on VLDL-TAG and VLDL-Apo-B-100 kinetics, but oestradiol given to postmenopausal women with obesity stimulates VLDL-TAG plasma clearance(Reference Wang, Smith and Patterson119,Reference Smith, Reeds and Okunade120) , (iv) increased VLDL-TAG concentrations in obese compared with lean men results from over-secretion of VLDL-TAG whereas increased VLDL-TAG concentrations in obese compared with lean women results in part from VLDL-TAG over-secretion but mostly from impaired VLDL-TAG removal from plasma(Reference Mittendorfer, Yoshino and Patterson69,Reference Mittendorfer, Patterson and Klein117) and (v) obese women, but not obese men, are resistant to the inhibitory effects of combined hyperglycaemia–hyperinsulinaemia on hepatic VLDL-TAG secretion whereas no differences in the hyperglycaemia–hyperinsulinaemia induced suppression of VLDL-TAG secretion was observed in lean men and women(Reference Mittendorfer, Patterson and Klein121). A higher VLDL-TAG secretion rate in women with abdominal obesity compared with lean women was also observed by others(Reference Hodson, Banerjee and Rial122) and was mostly due to an increase in the secretion of large and to a lesser extent small VLDL (50 and 12 % increase, respectively). The VLDL-TAG plasma clearance rate in that study was also about 15–20 % less in obese compared with lean women, but the difference did not reach statistical significance(Reference Hodson, Banerjee and Rial122). In addition, it was found that menopause increased hepatic TAG secretion specifically in the small VLDL fraction, and decreased or tended to decrease the secretion of both small and large VLDL particles(Reference Hodson, Banerjee and Rial122). The observed differences in the VLDL-TAG secretion rate between men and women are most likely due to differences in the incorporation of systemic plasma fatty acids into VLDL-TAG(Reference Magkos, Patterson and Mohammed72), rather than differences in hepatic DNL(Reference Pramfalk, Pavlides and Banerjee110).
Effect of fructose ingestion on hepatic de novo lipogenesis in men and women
Fructose stimulates hepatic DNL and high fructose consumption is associated with hepatic steatosis and hypertriglyceridaemia(Reference Pinnick and Hodson123–Reference Schwarz, Noworolski and Erkin-Cakmak125). Consumption of a high- compared with a low-fructose drink (containing 100 g sugar with either 60 or 20 % fructose) significantly increased postprandial hepatic DNL in women (peak DNL about 20 % v. about 7 %) but not in men (about 7 % after both meals)(Reference Low, Cornfield and Charlton126). This suggests women are more susceptible to fructose-induced hepatic steatosis and non-alcoholic fatty liver disease. It is worth noting that the stimulatory effect of fructose on DNL is most likely a secondary phenomenon because very little fructose is directly converted to fatty acids and fructose-to-fatty acid conversion was only observed in men but not in women(Reference Tran, Jacot-Descombes and Lecoultre65). This is consistent with recent findings that suggest fructose metabolism occurs predominantly in the small intestine, where it is converted to glucose, lactate and glycerol(Reference Jang, Hui and Lu127).
Myocardial substrate utilisation in men and women
A series of elegant studies that used dynamic positron emission tomography imaging have demonstrated marked differences in myocardial substrate use in men and women. Myocardial oxygen consumption is greater in healthy lean women than healthy lean men and women's hearts use less glucose and fewer dietary fatty acids as a source of energy than men(Reference Kunach, Noll and Phoenix106,Reference Peterson, Soto and Herrero128,Reference Peterson, Herrero and Coggan129) . Obesity reduces myocardial glucose uptake and oxidation in men, but not in women(Reference Peterson, Herrero and Coggan129). Insulin-stimulated myocardial glucose uptake rate, conversely, is not different in healthy young men and women(Reference Nuutila, Knuuti and Maki83). These findings could have important clinical implications, because myocardial perfusion and fuel use are directly linked with cardiac function(Reference Mather and DeGrado130,Reference Abel, O'Shea and Ramasamy131) .
Conclusion
There are marked differences in many aspects of glucose and lipid metabolism in men and women. Women compared with men: (i) are more sensitive to the inhibitory effect of insulin on glucose production and the stimulatory effect of insulin on muscle glucose disposal, (ii) have greater adipose tissue NEFA release relative to fat-free mass and resting energy and are less susceptible to the adverse effect of NEFA on insulin action in muscle, (iii) have altered meal glucose absorption kinetics, possibly due to different gastric emptying rates(Reference Hutson, Roehrkasse and Wald132), (iv) have greater basal and postprandial non-oxidative fatty acid disposal and fatty acid storage in adipose tissue and reduced postprandial lipaemia and (v) are more susceptible to fructose-induced DNL. Moreover, hepatic and plasma lipid metabolism is markedly affected by sex and the observed metabolic differences between men and women depend on subjects' adiposity and age. Conversely, no major differences between men and women have been observed for the antilipolytic effect of insulin and acute glucose-induced insulin secretion. The effect of sex on plasma insulin clearance is unclear because of conflicting results from different studies. We conclude that sex needs to be considered when interpreting data reported in the literature and planning new studies. Carefully designed studies are needed to determine the mechanisms responsible for the observed sexual dimorphism in metabolism and to disentangle the effects of chronological and biological (pre/post menopause) age on metabolism in women.
Financial Support
The authors received salary support from NIH grants DK115400, DK121560, DK56341 (Washington University School of Medicine Nutrition and Obesity Research Center), and UL1 TR000448 (Washington University School of Medicine Clinical Translational Science Award), a grant from the American Diabetes Association (ICTS 1-18-ICTS-119) and the Atkins Obesity Award while working on this manuscript.
Conflict of Interest
None.
Authorship
The authors were jointly responsible for all aspects of preparation of this paper.
