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. 2022 Dec;236(4):e13884.
doi: 10.1111/apha.13884. Epub 2022 Sep 12.

The impact of macronutrient composition on metabolic regulation: An Islet-Centric view

Klinsmann Carolo Dos Santos  1   2 , Camilla Olofsson  3 , João Paulo M C M Cunha  2 , Fiona Roberts  2 , Sergiu-Bogdan Catrina  3   4 , Malin Fex  2 , Neda Rajamand Ekberg  3   4 , Peter Spégel  1
Affiliations

The impact of macronutrient composition on metabolic regulation: An Islet-Centric view

Klinsmann Carolo Dos Santos et al. Acta Physiol (Oxf). 2022 Dec.

Abstract

Aim: The influence of dietary carbohydrates and fats on weight gain is inconclusively understood. We studied the acute impact of these nutrients on the overall metabolic state utilizing the insulin:glucagon ratio (IGR).

Methods: Following in vitro glucose and palmitate treatment, insulin and glucagon secretion from islets isolated from C57Bl/6J mice was measured. Our human in vivo study included 21 normoglycaemia (mean age 51.9 ± 16.5 years, BMI 23.9 ± 3.5 kg/m2 , and HbA1c 36.9 ± 3.3 mmol/mol) and 20 type 2 diabetes (T2D) diagnosed individuals (duration 12 ± 7 years, mean age 63.6 ± 4.5 years, BMI 29.1 ± 2.4 kg/m2 , and HbA1c 52.3 ± 9.5 mmol/mol). Individuals consumed a carbohydrate-rich or fat-rich meal (600 kcal) in a cross-over design. Plasma insulin and glucagon levels were measured at -30, -5, and 0 min, and every 30 min until 240 min after meal ingestion.

Results: The IGR measured from mouse islets was determined solely by glucose levels. The palmitate-stimulated hormone secretion was largely glucose independent in the analysed mouse islets. The acute meal tolerance test demonstrated that insulin and glucagon secretion is dependent on glycaemic status and meal composition, whereas the IGR was dependent upon meal composition. The relative reduction in IGR elicited by the fat-rich meal was more pronounced in obese individuals. This effect was blunted in T2D individuals with elevated HbA1c levels.

Conclusion: The metabolic state in normoglycaemic individuals and T2D-diagnosed individuals is regulated by glucose. We demonstrate that consumption of a low carbohydrate diet, eliciting a catabolic state, may be beneficial for weight loss, particularly in obese individuals.

Keywords: alpha cell; beta cell; glucagon; insulin; insulin/glucagon ratio.

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Conflict of interest statement

The authors have no conflict of interest to declare.

Figures

FIGURE 1
FIGURE 1
Alterations in insulin and glucagon secretion and the insulin:glucagon ratio (IGR) in islets from 10‐ to 16‐week‐old female mice elicited by glucose (Glc) and palmitate (FA) were examined according to a face‐centred central composite design. (A) Schematic representation of the face‐centred central composite design. Blue squares indicate the experiments that are conducted and include orthogonal experiments (corners), star‐point experiments (on the sides) and centre‐point experiments (centre) conducted in the experimental space, ranging from 0 to 0.25 mM palmitate and 1 to 16.7 mM glucose. Variables are scaled to +1 (16.7 mM glucose or 0.5 mM palmitate), −1 (1 mM glucose or 0.25 mM palmitate), and 0 (8.85 mM glucose or 0.125 mM palmitate). Hence, an experiment conducted with Glc‐ and Fa+ involves islets exposed to 1 mM glucose and 0.25 mM palmitate. (B) Glucagon and insulin secretion and the IGR for the experiments indicated in (A). Plots show the median, with boxes covering the first‐to‐third quartile, whiskers indicating 1.5 times the interquartile range, and dots show experimental results outside this range. Response surfaces for (C) insulin, (D) glucagon, and (E) the IGR derived from linear models (~Glc + FA + Glc*Glc + FA*FA + Glc*FA). Equations fitted from the data and used to produce the surface plots are given in Table 1
FIGURE 2
FIGURE 2
Meal‐elicited variation in blood glucose levels. Trajectories of glucose in individuals with type 2 diabetes (T2D) and without diabetes (ND) after consumption of a carbohydrate‐rich meal (carbohydrate) and a fat‐rich meal (fat). Thin black lines indicate trajectories for individual study participants, and black triangles and the thick black line indicate the mean and the grey shaded area the confidence interval. Right: Fitted values from linear mixed‐effects models. p‐values given below the graph; t, time; m, meal (carbohydrate or fat); g, group (T2D or ND); and x, interaction meal*group
FIGURE 3
FIGURE 3
Meal‐elicited trajectories of hormones and the insulin:glucagon ratio (IGR). (A) Left: Trajectories of insulin in individuals with type 2 diabetes (T2D) and without diabetes (ND) after consumption of a carbohydrate‐rich meal (carbohydrate) and a fat‐rich meal (fat). Thin black lines indicate trajectories for individual study participants, black triangles and the thick black line indicate the mean, and grey shaded area the confidence interval. Right: Fitted values from linear mixed‐effects models. p‐values given below the graph; t, time; m, meal (carbohydrate or fat); g, group (T2D or ND); x, interaction meal*group. (B) Data for glucagon and (C) data for the IGR, illustrated as outlined in (A)
FIGURE 4
FIGURE 4
Influence of HbA1c and BMI on the meal elicited response in insulin:glucagon ratio (IGR). The meal‐elicited increase in IGR is substantially higher for both a carbohydrate‐rich meal (A) and a fat‐rich meal (B) in normoglycaemic obese individuals as compared to leaner individuals. No such association is observed for individuals with type 2 diabetes (T2D). (C) The relative increase in the IGR response for a carbohydrate‐rich meal as compared to a fat‐rich meal depends on the BMI, but not on the glycaemic state of the individual. The meal elicited response in the IGR depends on the HbA1c in individuals with T2D for the carbohydrate‐rich meal (D), but not for the fat‐rich meal (E). The relative increase in the IGR response for a carbohydrate‐rich meal decreases with HbA1c among individuals diagnosed with T2D. ΔIGR = IGR at 60 min – IGR at baseline (−30 min). ΔΔIGR = ΔIGR for carbohydrate‐rich meal – ΔIGR for fat‐rich meal. Data analysed using multilinear regression. p‐values given above the graph; BMI; g, group (T2D or ND); x, interaction BMI*group
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