Introduction
Obesity and physical inactivity are major risk factors for type 2 diabetes mellitus. Obesity has been linked to the accumulation of ectopic fat in different organs, such as the heart, muscle, liver and pancreas [
1]. Although ectopic fat in the liver and its association with metabolic disorders has been extensively studied [
2], less is known about the role of fatty pancreas despite its clinical significance [
3,
4]. A growing amount of evidence suggests that fatty pancreas is more frequently observed in individuals with impaired glucose tolerance [
5‐
9]. Therefore, approaches to maintain a normal pancreatic fat content could reduce the risk of metabolic diseases and type 2 diabetes.
Insulin resistance and dysfunction of the pancreatic beta cells characterise type 2 diabetes and are already present before hyperglycaemia develops [
10,
11]. A relationship between pancreatic fat and impaired beta cell function has been shown in some [
6,
12] but not all [
13‐
15] studies. A recent study showed that pancreatic fat content decreased after bariatric surgery, with normalisation of the first-phase insulin response, only in individuals with type 2 diabetes despite similar weight losses in type 2 diabetic participants and individuals with normal glucose tolerance, suggesting that fatty pancreas associates with type 2 diabetes [
9]. It currently remains unclear whether pancreatic fat accumulation causes beta cell dysfunction and consequently type 2 diabetes, or whether fatty pancreas and type 2 diabetes are independent consequences of obesity [
4].
Regular exercise training has a major role in the prevention of type 2 diabetes [
16]. It has recently been shown that both moderate-intensity continuous training (MICT) as well as different high-intensity interval training (HIIT) regimes can improve beta cell function in insulin resistance [
17‐
21]. However, the effects of exercise training on pancreatic fat content are unknown, although it has been speculated that lifestyle modifications targeted at decreasing pancreatic fat could improve glycaemic control [
22].
To study the effects of short-term exercise training on the pancreas, we recruited healthy middle-aged men as well as men and women with prediabetes or type 2 diabetes. The aims of the present study were to investigate (1) whether 2 weeks of exercise training would have similar effects on pancreatic fat content and beta cell function in healthy and prediabetic or type 2 diabetic men, and (2) whether the effects of sprint interval training (SIT) and MICT would differ in prediabetic or type 2 diabetic men and women. We previously showed that 2 weeks of either SIT or MICT decreased intrathoracic fat in both healthy and prediabetic or type 2 diabetic men [
23]. We therefore hypothesised that pancreatic fat would decrease by exercise training similarly in healthy and prediabetic or type 2 diabetic participants.
Discussion
The present study shows for the first time that exercise training decreases pancreatic fat content regardless of baseline glucose tolerance. Both SIT and MICT reduced pancreatic fat, especially in individuals with fatty pancreas, underlining the beneficial effect of exercise training for those at risk of type 2 diabetes. Decreased pancreatic fat was not associated with changes in pancreatic metabolism or beta cell function.
At baseline, pancreatic fat content was higher in prediabetic or type 2 diabetic men than healthy men, which is consistent with previous studies [
5‐
8], although a conflicting report also exists [
35]. Whereas pancreatic fat was positively associated with BMI, body fat and visceral fat in all male participants, these associations were lost when considering only those who had prediabetes or type 2 diabetes. Furthermore, pancreatic fat correlated positively with fasting glucose, ISR
basal and ISR
total in all men, but not in prediabetic or type 2 diabetic participants. Previous studies have reported conflicting results with regards to the association between pancreatic fat and BMI, some reporting a positive correlation [
5,
7,
12,
35] and others reporting no significant correlation [
6,
22]. The association between pancreatic fat and beta cell function is equally unclear. Studies addressing mainly non-diabetic individuals have reported no association between these variables [
13‐
15], whereas other studies have shown that the association is different in normoglycaemic and prediabetic or type 2 diabetic individuals [
6,
12]. Beta cell functional variables have been shown to have distinct patterns of decrease when spanning the range from normoglycaemic obese individuals to those with overt type 2 diabetes [
36], and even beta cell defects in impaired fasting glucose and impaired glucose tolerance are different [
37]. Therefore, it may be that different factors affect pancreatic fat accumulation during normoglycaemia, impaired glucose tolerance and full-blown type 2 diabetes [
6,
9,
22]. These discrepancies highlight the fact that more research is needed to better understand the causes and consequences of fatty pancreas.
Just 2 weeks of exercise training decreased pancreatic fat similarly in healthy and prediabetic or type 2 diabetic men. A cross-sectional study investigating eight monozygotic young adult male twin pairs with different fitness levels reported no difference in pancreatic fat between more and less active twins [
38]. However, even the healthy participants in the present study had relatively low physical fitness and high BMI, which may explain why such a short training intervention decreased pancreatic fat in the present study. Pancreatic fatty acid uptake and insulin-stimulated glucose uptake as well as fasting serum NEFA concentration were similar in healthy and prediabetic or type 2 diabetic men at baseline and remained unchanged by training. Hence, substrate uptake does not seem to explain the baseline difference between the groups or the observed decrease in pancreatic fat after exercise training. However, we measured fatty acid uptake in the fasting state, and it is possible that fat accumulation may occur during the postprandial period. A subgroup comparison between prediabetic and type 2 diabetic men (ESM Table
1) suggests that glucose uptake may be different during the progression of type 2 diabetes. Moreover, sex may also affect pancreatic metabolism (ESM Table
2). However, the small number of participants in the subgroup comparisons limits the interpretation of the findings. Further studies spanning the range from obesity to overt type 2 diabetes could shed more light on the question of whether there is a distinct pattern in pancreatic metabolism when type 2 diabetes progresses, and whether it is related to the accumulation of pancreatic fat.
When dividing the men according to low (≤6.2%) and high (>6.2%) baseline pancreatic fat content [
22], exercise training decreased pancreatic fat by 31% in those men who had fatty pancreas to start with. The result that as little as 2 weeks of exercise has a marked impact on those individuals with fatty pancreas is clinically significant, as ectopic fat accumulation is recognised as a major factor in the development of type 2 diabetes [
3,
4,
22].
The effects of exercise training on beta cell function have been previously studied in obese, prediabetic or type 2 diabetic individuals using a disposition index as the measure of beta cell function. Regardless of the different exercise modes (HIIT, MICT or functional high intensity training [CrossFit]) used in different studies, all have reported an increased disposition index after the training intervention, and hence inferred that training improves beta cell function [
17‐
21]. However, as the disposition index may be biased [
39], we studied beta cell function using several model-based variables. At baseline, ISR
total was higher in prediabetic or type 2 diabetic men than healthy men. This reflects higher glucose levels and the reciprocal relationship between insulin sensitivity and insulin secretion, implying that reduced insulin sensitivity is compensated by increased ISR [
40] until glucotoxicity becomes too great for beta cells to compensate sufficiently [
41]. After exercise training, ISR
basal decreased in prediabetic or type 2 diabetic men, while ISR
early increased only in healthy men. When considering all prediabetic or type 2 diabetic participants (men and women), differences in these variables after SIT and MICT were not significant (
p = 0.082 and
p = 0.056 for time, respectively). On the other hand, whole-body insulin sensitivity increased similarly in both groups. The increase in ISR
early in healthy men may be a response to improved glucose sensitivity in the muscles, whereas prediabetic or type 2 diabetic individuals may compensate improved whole-body insulin sensitivity by maintaining or decreasing insulin secretion, which was already increased at baseline. A similar compensatory decrease in insulin secretion in overweight adults after training has previously been reported [
21]. When normalising early ISR for glucose concentration, it decreased similarly in healthy and prediabetic or type 2 diabetic men. A corresponding decrease was observed in rate sensitivity, probably due to improved whole-body insulin sensitivity.
The potentiation of insulin secretion was impaired in prediabetic or type 2 diabetic men compared with healthy men at baseline. Our finding is in line with previous studies, which have reported blunted and delayed potentiation in diabetic individuals using a multiple meal test [
42] as well as a decreased potentiation factor ratio in diabetic individuals compared with non-diabetic control participants [
6]. Exercise training might normalise potentiation in prediabetic or type 2 diabetic men towards that of the healthy men (Fig.
3b;
p = 0.083), suggesting that exercise training may improve the ability of beta cells to read potentiating signals, such as incretins and neural signals. However, further work is necessary to explore this.
Over the past few years, numerous studies have elucidated the effects of HIIT, or its special case SIT, in both healthy and type 2 diabetic participants, and have concluded that HIIT is at least as beneficial as the more traditional MICT in improving glycaemic control and maximal exercise capacity [
43‐
45]. With regards to prediabetic or type 2 diabetic men and women in the present study, SIT and MICT had a different effect only on
\( \overset{\cdot }{V}{\mathrm{O}}_{2\mathrm{peak}} \), which increased only after SIT, as discussed in our previous report [
25]. The changes observed in all the other variables investigated in the present study, including increased whole-body insulin sensitivity, decreased pancreatic fat content, improved potentiation and decreased ΔISR
0-30/ΔG
0-30, were similar for both training modes. To conclude, both SIT and MICT can be used to improve the metabolic health of prediabetic or type 2 diabetic individuals.
The present study is not, however, without limitations. The number of participants was relatively small, although similar sample sizes have previously been used in exercise training studies with a technically demanding study design. In addition, the dropout rate was relatively high. The prediabetic or type 2 diabetic participants comprised a rather heterogeneous group containing both men and women, some with prediabetes and others with type 2 diabetes, but the number of each was too small to fully address the differences between the subgroups. It has been shown that pancreatic function differs during prediabetes and overt type 2 diabetes [
36]. However, in the prediabetic and type 2 diabetic men in the present study, pancreatic function and responses to exercise were quite similar, probably because the individuals with type 2 diabetes had been relatively recently diagnosed (median duration of type 2 diabetes 4 years). Also, the oral hypoglycaemic medication taken by the participants with type 2 diabetes was interrupted for 2 days before the pre- and post-measurement PET scans. However, measuring glucose and fatty acid uptake as well as pancreatic fat content were unsuccessful in some participants (Table
1), and the heterogeneity of the prediabetic or type 2 diabetic individuals may have affected the results relating to pancreatic metabolism.
Using
1H MRS to measure pancreatic fat content cannot distinguish intracellular fat accumulation in beta cells from adipose tissue infiltration. Since pancreatic islets containing beta cells cover only around 2% of the pancreatic mass, most of the fat detected by MRS probably lies outside the islets. While the main deposition of fat in the human pancreas remains unclear, it has been suggested that
1H MRS measurement of triacylglycerols in the whole pancreas represents a surrogate marker for islet lipids [
3]. In addition, individuals with type 2 diabetes have been shown to have a lower pancreatic volume than healthy individuals [
46], making voxel placement more challenging. In the present study, the voxel placement within the body of pancreas was carefully ensured by axial, sagittal and coronal directions of investigation.
Finally, this study was designed to investigate the early-phase responses to exercise training. Lim et al studied the effects of dietary energy restriction in type 2 diabetes at different time points over 8 weeks, showing that although liver fat content decreased rapidly, the decrease in pancreatic fat content and improvement in beta cell function took longer to occur [
47]. Therefore, the lack of association between changes in pancreatic fat content and beta cell function in the present study may be due to the short time course of the exercise intervention, and longer exercise interventions will be needed to investigate the functional effect of decreased pancreatic fat.