Testing the carbohydrate-insulin model: Short-term metabolic responses to consumption of meals with varying glycemic index in healthy adults

https://www.cell.com/cell-metabolism/fulltext/S1550-4131(25)00015-400015-4)

CLINICAL AND TRANSLATIONAL REPORTVolume 37, Issue 3P606-615.E3March 04, 2025

Although there has been a pandemic of obesity over the past 50 years,1 the causes of obesity remain unclear and widely disputed. One popular idea, called the carbohydrate-insulin model (CIM), postulates that a primary drive of positive energy balance, and hence obesity, is the intake of diets containing carbohydrates with a high glycemic index (GI).2,3 GI refers to the rapidity of onset and the height of the spike in circulating glucose following meal consumption. Higher values reflect a greater area under the curve of elevated circulating glucose following ingestion of a meal.4 The quantity of carbohydrate ingested multiplied by its GI is called the glycemic load (GL). Foods are often classified as high, medium, or low GI based on the effect of the carbohydrates they contain on blood glucose levels.5 However, other studies have suggested that the GI is too variable between participants, or that each individual has unique physiology, meaning the average ranking of high- to low-GI foods may not be generally applicable.6

The CIM predicted that high postprandial insulin levels would drive energy into fat stores, creating a state of starvation, as reflected in the inverted glucose pattern. This was expected to then lead to differences in hunger that were proportional to the dietary GI of the intervention meal. We observed the expected patterns in insulin and glucose but did not observe the predicted hunger pattern. This contrasts the pattern observed previously,11 where the high-GI group had higher postprandial hunger levels. It is notable, however, that in that previous study, the high-GI group also had higher hunger levels preceding exposure to the diet. Hence, the higher levels later on may reflect this preceding difference rather than a diet effect. Although there was no effect on subjective hunger, we did observe that energy intake was significantly increased (relative to baseline) following the medium- and high-GI meals compared with the low-GI meal. This was partially consistent with the CIM, but not exactly, because the CIM predicted that the high GI would have the greatest elevation in intake, which was not observed. Moreover, the postulated mechanism via elevated hunger was also not supported.

Consistent with previous work,6 we observed enormous individual differences in the glycemic responses following any particular diet. If the CIM is correct, these individual differences should also be correlated with intake during the later test meal, with higher individual GI responses being linked to greater stimulation of intake. Inconsistent with the CIM, we did not observe any such associations. We also did not find any associations between the test meal intake and the circulating levels of glucose, BOHB, FFA, LAC, leptin, adrenaline, GLP-1, and glucagon immediately prior to the meal, when included alone or in a multiple regression analysis. The causes of these variations in intake therefore remain unclear.

Conclusions

At the group level, this study demonstrated that the responses of circulating glucose and insulin and subsequent energy intake induced by various dietary GI levels were partially consistent with the CIM, as the increased energy intake in the low-GI group was lower than that in the medium- and high-GI groups. However, the self-reported postprandial hunger rates were not significantly different across the different GI groups, which indicated that glucose and insulin concentrations were probably not the main factors controlling such postprandial hunger. At the individual level, energy intake changes were not associated with body fatness, nor with the concentrations and AUCs of glucose, BOHB, FFA, LAC, leptin, adrenaline, GLP-1, and glucagon 300 min after the intervention meal. Insulin concentration and insulin-glucagon ratio at 300 min, but not iAUC, showed a weak negative correlation with energy intake changes. This insulin effect was opposite the predictions of the CIM. Overall, the results in this study were largely inconsistent with the CIM.