King Grub
2018-01-05, 13:00
BACKGROUND:
A fundamental precept of the carbohydrate–insulin model of obesity is that insulin secretion drives weight gain. However, fasting hyperinsulinemia can also be driven by obesity-induced insulin resistance. We used genetic variation to isolate and estimate the potentially causal effect of insulin secretion on body weight.
METHODS:
Genetic instruments of variation of insulin secretion [assessed as insulin concentration 30 min after oral glucose (insulin-30)] were used to estimate the causal relationship between increased insulin secretion and body mass index (BMI), using bidirectional Mendelian randomization analysis of genome-wide association studies. Data sources included summary results from the largest published metaanalyses of predominantly European ancestry for insulin secretion (n = 26037) and BMI (n = 322154), as well as individual-level data from the UK Biobank (n = 138541). Data from the Cardiology and Metabolic Patient Cohort study at Massachusetts General Hospital (n = 1675) were used to validate genetic associations with insulin secretion and to test the observational association of insulin secretion and BMI.
RESULTS:
Higher genetically determined insulin-30 was strongly associated with higher BMI (β = 0.098, P = 2.2 × 10−21), consistent with a causal role in obesity. Similar positive associations were noted in sensitivity analyses using other genetic variants as instrumental variables. By contrast, higher genetically determined BMI was not associated with insulin-30.
CONCLUSIONS:
Mendelian randomization analyses provide evidence for a causal relationship of glucose-stimulated insulin secretion on body weight, consistent with the carbohydrate–insulin model of obesity.
For most of the past 40 years, high dietary fat was considered a primary cause of obesity. Recently, attention has focused instead on foods with a high glycemic load (1), including fast-digesting carbohydrates like refined grains, potato products, and added sugars.
According to the carbohydrate–insulin model (1–5), a high glycemic load diet—by increasing insulin secretion—alters substrate partitioning toward fat deposition and promotes weight gain. This hypothesis has received support from mechanistic studies of metabolic fuels (6), translational research (7), observational studies (8, 9), and clinical trials (10). Consistent with prediction, several systematic reviews and metaanalyses have shown that lower-carbohydrate diets are superior to low-fat diets for weight loss (11–14). In particular, individuals with high insulin secretion appear particularly responsive to dietary carbohydrate content (8–10, 15).
Despite these findings, the carbohydrate–insulin model remains controversial in the absence of definitive metabolic studies. Results of recent feeding studies examining the effect of dietary composition on energy expenditure are variable, showing advantages (16, 17), disadvantages (18), or no effect of a lower-carbohydrate diet compared with a lower-fat diet (19, 20). However, these short protocols (some with duration of ≤1 week) may reflect short-term phenomena—specifically metabolic adaptations to higher fat intake (21–23)—rather than long-term effects of macronutrient composition on body composition.
Mendelian randomization offers a complementary approach to previous research on this topic, with the opportunity to examine relationships for longer than can be achieved in interventional trials, and is theoretically less susceptible to certain biases such as confounding and reverse causation present in conventional observational analyses. In Mendelian randomization, genetic predictors of an exposure of interest are used to assess the causal association between that exposure and an outcome (24). To clarify the causal direction of relationships between 2 observed traits (e.g., insulin secretion and obesity), a bidirectional strategy using a set of genetic instruments for each trait can be used (25).
A recent Mendelian randomization analysis (26) cast doubt on the carbohydrate–insulin model, finding no evidence for a causal relationship between fasting insulin and body mass index (BMI)7. However, in the carbohydrate–insulin model, it is insulin secretion in response to carbohydrate, not fasting insulin, that influences weight gain, in part because the latter is strongly confounded by insulin resistance (5). Indeed, insulin resistance in adipose tissue protects against weight gain, as demonstrated by the fat-specific insulin receptor knockout mouse model (27). Therefore, we selected genetic variants identified by large genome-wide association studies associated with glucose-stimulated insulin secretion, not fasting insulin, to more appropriately test the carbohydrate–insulin model.
Genetic Evidence That Carbohydrate-Stimulated Insulin Secretion Leads to Obesity. Clinical Chemistry, January 2018.
http://clinchem.aaccjnls.org/content/64/1/192
A fundamental precept of the carbohydrate–insulin model of obesity is that insulin secretion drives weight gain. However, fasting hyperinsulinemia can also be driven by obesity-induced insulin resistance. We used genetic variation to isolate and estimate the potentially causal effect of insulin secretion on body weight.
METHODS:
Genetic instruments of variation of insulin secretion [assessed as insulin concentration 30 min after oral glucose (insulin-30)] were used to estimate the causal relationship between increased insulin secretion and body mass index (BMI), using bidirectional Mendelian randomization analysis of genome-wide association studies. Data sources included summary results from the largest published metaanalyses of predominantly European ancestry for insulin secretion (n = 26037) and BMI (n = 322154), as well as individual-level data from the UK Biobank (n = 138541). Data from the Cardiology and Metabolic Patient Cohort study at Massachusetts General Hospital (n = 1675) were used to validate genetic associations with insulin secretion and to test the observational association of insulin secretion and BMI.
RESULTS:
Higher genetically determined insulin-30 was strongly associated with higher BMI (β = 0.098, P = 2.2 × 10−21), consistent with a causal role in obesity. Similar positive associations were noted in sensitivity analyses using other genetic variants as instrumental variables. By contrast, higher genetically determined BMI was not associated with insulin-30.
CONCLUSIONS:
Mendelian randomization analyses provide evidence for a causal relationship of glucose-stimulated insulin secretion on body weight, consistent with the carbohydrate–insulin model of obesity.
For most of the past 40 years, high dietary fat was considered a primary cause of obesity. Recently, attention has focused instead on foods with a high glycemic load (1), including fast-digesting carbohydrates like refined grains, potato products, and added sugars.
According to the carbohydrate–insulin model (1–5), a high glycemic load diet—by increasing insulin secretion—alters substrate partitioning toward fat deposition and promotes weight gain. This hypothesis has received support from mechanistic studies of metabolic fuels (6), translational research (7), observational studies (8, 9), and clinical trials (10). Consistent with prediction, several systematic reviews and metaanalyses have shown that lower-carbohydrate diets are superior to low-fat diets for weight loss (11–14). In particular, individuals with high insulin secretion appear particularly responsive to dietary carbohydrate content (8–10, 15).
Despite these findings, the carbohydrate–insulin model remains controversial in the absence of definitive metabolic studies. Results of recent feeding studies examining the effect of dietary composition on energy expenditure are variable, showing advantages (16, 17), disadvantages (18), or no effect of a lower-carbohydrate diet compared with a lower-fat diet (19, 20). However, these short protocols (some with duration of ≤1 week) may reflect short-term phenomena—specifically metabolic adaptations to higher fat intake (21–23)—rather than long-term effects of macronutrient composition on body composition.
Mendelian randomization offers a complementary approach to previous research on this topic, with the opportunity to examine relationships for longer than can be achieved in interventional trials, and is theoretically less susceptible to certain biases such as confounding and reverse causation present in conventional observational analyses. In Mendelian randomization, genetic predictors of an exposure of interest are used to assess the causal association between that exposure and an outcome (24). To clarify the causal direction of relationships between 2 observed traits (e.g., insulin secretion and obesity), a bidirectional strategy using a set of genetic instruments for each trait can be used (25).
A recent Mendelian randomization analysis (26) cast doubt on the carbohydrate–insulin model, finding no evidence for a causal relationship between fasting insulin and body mass index (BMI)7. However, in the carbohydrate–insulin model, it is insulin secretion in response to carbohydrate, not fasting insulin, that influences weight gain, in part because the latter is strongly confounded by insulin resistance (5). Indeed, insulin resistance in adipose tissue protects against weight gain, as demonstrated by the fat-specific insulin receptor knockout mouse model (27). Therefore, we selected genetic variants identified by large genome-wide association studies associated with glucose-stimulated insulin secretion, not fasting insulin, to more appropriately test the carbohydrate–insulin model.
Genetic Evidence That Carbohydrate-Stimulated Insulin Secretion Leads to Obesity. Clinical Chemistry, January 2018.
http://clinchem.aaccjnls.org/content/64/1/192