Relationship between diet/exercise and pharmacotherapy to enhance the GLP‐1 levels in type 2 diabetes

Abstract The rapid rise in the prevalence of type 2 diabetes mellitus (T2DM) poses a huge healthcare burden across the world. Although there are several antihyperglycaemic agents (AHAs) available including addition of new drug classes to the treatment algorithm, more than 50% of patients with T2DM do not achieve glycaemic targets, suggesting an urgent need for treatment strategies focusing on prevention and progression of T2DM and its long‐term complications. Lifestyle changes including implementation of healthy diet and physical activity are cornerstones for the management of T2DM. The positive effects of diet and exercise on incretin hormones such as glucagon‐like peptide‐1 (GLP‐1) have been reported. We hypothesize an IDEP concept (Interaction between Diet/Exercise and Pharmacotherapy) aimed at modifying the diet and lifestyle, along with pharmacotherapy to enhance the GLP‐1 levels, would result in good glycaemic control in patients with T2DM. Consuming protein‐rich food, avoiding saturated fatty acids and making small changes in eating habits such as eating slowly with longer mastication time can have a positive impact on the GLP‐1 secretion and insulin levels. Further the type of physical activity (aerobic/resistance training), intensity of exercise, duration, time and frequency of exercise have shown to improve GLP‐1 levels. Apart from AHAs, a few antihypertensive drugs and lipid‐lowering drugs have also shown to increase endogenous GLP‐1 levels, however, due to quick degradation of GLP‐1 by dipeptidyl peptidase‐4 (DPP‐4) enzyme, treatment with DPP‐4 inhibitors would protect GLP‐1 from degradation and prolong its activity. Thus, IDEP concept can be a promising treatment strategy, which positively influences the GLP‐1 levels and provide additive benefits in terms of improving metabolic parameters in patients with T2DM and slowing the progression of T2DM and its associated complications.


| INTRODUC TI ON
Over the past three decades, the world has witnessed a rapid rise in the prevalence of type 2 diabetes mellitus (T2DM) and expected to have 629 million of diabetes patients with 20-79 years by 2045.
This pandemic of T2DM leads not only to health problem such as diabetic-related complications but also to economic burden which is estimated to be USD 776 billion by 2045 across the globe. 1 An ageing population, changes in lifestyle, dietary patterns, physical inactivity, obesity and stress are the major contributors for the rise in T2DM. Due to the chronic and progressive nature of the disease, undiagnosed or poorly managed T2DM can lead to increased morbidity and mortality.
Despite the availability of several AHAs and addition of new drug classes to the treatment algorithm, more than 50% of patients with T2DM do not achieve glycaemic targets, suggesting an urgent need for treatment strategies focusing on prevention and progression of T2DM and its long-term complications. 2,3 The updated treatment guidelines (2018) recommend making lifestyle changes in diet and physical activity as part of T2DM management.
Nutrition therapy with individualized meal plan including energy balance, eating patterns and macronutrient distribution and each nutrition is indicated based on patient's age, body weight, physical activity, baseline HbA1c levels and diabetic-related complications. 4 For exercise therapy, patients with T2DM are advised to do 150 min/wk of moderate-to-vigorous-intensity physical activity or 75 min/wk of vigorous-intensity exercise or interval training for a minimum of 3 d/wk to reduce the risk of T2DM-related complications. 4 Landmark studies, which are bases of the guideline, revealed the importance of lifestyle modification including diet and exercise for glycaemic control and prevention of diabetes-related complications. As intervention for diet, the DIRECT study indicated that Mediterranean and low-carbohydrate diets may be as effective as low-fat diets for glycaemic control. 5 There are several intervention studies focusing on exercise. The IDES study demonstrated that promoting physical activity with aerobic and resistance training improved HbA1c compared to exercise counselling alone. 6 In addition, the Diabetes Prevention Programme study has shown benefits of lifestyle intervention, at least 150 minutes of physical activity per week to achieve a 7% weight loss, in reducing the incidence of T2DM in subjects at risk of diabetes. 7 The Look AHEAD study demonstrated that intensive lifestyle intervention through both decreased caloric intake and increased physical activity focusing on weight loss did not reduce the rate of cardiovascular events in overweight or obese adults T2DM patients while achieved better glycaemic control compared to control group. 8 In the randomized Steno-2 study of 21 years follow-up, multifactorial intervention including lifestyle changes (diet, exercise and weight loss) and pharmacotherapy (control of blood glucose, blood pressure and lipid profile) has been shown to reduce the risk of not only microvascular but also macrovascular events in T2DM. 9 The benefits of an intensive multifactorial treatment approach on the risk of cerebrovascular events and macrovascular complications were demonstrated in Japanese patients in the J-DOIT3 trial. 10 Among the available oral AHAs, use of incretin-based therapies such as DPP-4 inhibitors has increased recently because of the good glycaemic control with a low risk of hypoglycaemia and weight neutrality associated with these drugs. In Japan, more than 70% of patients with T2DM are being treated with DPP-4 inhibitors and ~60% of drug-naïve patients receive DPP-4 inhibitors as the firstline treatment. 11 In view of recent reports demonstrating positive effects of nutrition and diet on incretin hormones such as GLP-1, 12 we hypothesize an IDEP (Interaction between Diet/Exercise and Pharmacotherapy) concept by comprehensive literature review. The IDEP concept is the active incretin hormone levels, especially GLP-1, can be enriched through modifications in the diet, physical exercise and pharmacotherapy, which is further protected from degradation by use of DPP-4 inhibitors, thereby offers good glycaemic control in patients with T2DM. In this review, we discuss the IDEP concept, focusing on whether diet, exercise and pharmacotherapy can affect GLP-1 secretion.

| IN CRE TIN HORMONE S
GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) are two physiologically important incretin hormones. While GLP-1 is released within minutes from enteroendocrine L cells by nutritional, hormonal, pharmacological and neural signals, GIP is produced in the duodenal K cells in the proximal small intestine. 13 GIP and GLP-1 stimulate pancreatic beta cells to induce insulin secretion. In detail, GIP and GLP-1 exert their effects by binding to their specific receptors, the GIP receptor and the GLP-1 receptor. Binding to each receptor activates and increases the level of intracellular cyclic adenosine monophosphate thereby activating protein kinase A (PKA) and exchange protein activated by cAMP2 (EPAC2). PKA and EPAC2 are involved in a wide variety of intracellular events including altered ion channel activity, elevated cytosolic calcium levels and enhanced exocytosis of insulin-containing granules, all of which contribute to stimulation of insulin section in a glucose-dependent manner. 14 Incretin effect accounts for approximately 50% to 70% of total insulin secretion in subjects with normal glucose tolerance; however, in patients with T2DM, the incretin effect is diminished and accounts only for 10% to 40% of insulin secretion. Whether or not the decreased incretin effect is due to T2DM itself, or due to decreased β cell function, remains unclear. 15 Of the two incretins, we focused on GLP-1 because it potentiates insulin secretion under hyperglycaemic conditions and reduces blood glucose levels in patients with T2DM along with inhibition of gastric emptying, food intake and glucagon secretion. 16 In addition to improved glycaemic control and preserving islet β cell mass, GLP-1 has demonstrated beneficial effects on such as cardiac function and atherosclerotic plaque. 17 Further, the effect of incretins is dependent on the serum level of the soluble DPP-4 enzyme. In obese patients with T2DM, the plasma DPP-4 activity is increased resulting in reduced incretin effect and thereby decreasing the efficacy of DPP-4 inhibitor therapy. 18,19 In addition, bariatric surgery aimed at weight loss in individuals with T2DM shown to alter GLP-1 dynamics resulting in improved secretory response to nutrient intake. This improved nutrient sensing could be due to the increased nutrient load into the jejunum, bypassing duodenum, because of the direct connection to the stomach. 20 The maximum utilization of GLP-1 could be achieved by the IDEP concept.

| ME THOD TO RE TRIE VE ARTI CLE S
We performed a narrative review as we had three topics integrated in one concept. We searched appropriate articles with the following terms: (Diet OR Food) AND type 2 diabetes AND

| D IE T THER APY
Diet therapy is important not only as a fundamental treatment for diabetes but as a method to induce GLP-1 which collaborates with pharmacotherapy for better glycaemic control. In the following section, we summarize nutrition, food, dietary patterns and a couple of ways to induce GLP-1 secretion.

| Carbohydrates
Glucose is a potent stimulus for the secretion of incretin hormones.
Intestinal glucose sensing is mainly facilitated by the sodium-dependent glucose transporter (SGLT1), which is present abundantly in the absorptive enterocytes and the apical membranes of L and K cells. 21 Apart from SGLT1, GLUT2 is essential for glucose sensing and thus plays a role in systemic glucose control. 22 In addition to SGLT1 and GLUT2, secretion of GLP-1 in response to glucose may be mediated, at least in part, by the sweet taste receptors (T1R2 + T1R3) 23 even though, unlike glucose, artificial sweeteners do not trigger insulin, GLP-1 or GIP release in human. 24 Sugars including galactose, maltose, sucrose, and 3-O-methyl-Dglucose (3OMG) and maltitol stimulate GLP-1 release, whereas fructose, fucose, mannose, xylose and lactose do not stimulate GLP-1 secretion. A little difference in the molecular structures of sugars could affect stimulation of GLP-1, however, the mechanism of action is unclear. 25 Further a non-caloric sweetener and rare sugar, D-allulose (D-psicose), induced GLP-1 release in animal models. 26

| Protein and amino acids
Peptide transporter-1 (PEPT1), calcium-sensing receptor (CaSR) and GPR-C6A, which are all highly expressed in L cells, are involved in GLP-1 release. 29 L-arginine, which acts as an insulin secretagogue, increases GLP-1 levels and improve glucose clearance as shown in a mouse study. 30 Similarly, glutamine stimulates GLP-1 secretion in murine GLUTag cells, and Na + -coupled amino acid transporters are thought to play an important role in GLP-1 secretion. 31 Amino acids such as glutamine, phenylalanine, tryptophan, asparagine, arginine and the di-peptide glycine-sarcosine trigger GLP-1 secretion through CaSR and PEPT1 receptors. 32,33

| Lipids
Lipids including monounsaturated fatty acids, α-linolenic acid and docosahexaenoic acid (DHA) act as potent stimulators for GLP-1 release from L cells. 34,35 Several G protein-coupled receptors (GPRs) including GPR40, GPR43, GPR119, GPR120 act as prime sensors for fats, and free fatty acid receptors (FFAR 1/3) play an important role in inducing GLP-1 release. GPR40 and GPR119 act synergistically and mediate the triglyceride (TG)-induced secretion of incretins, whereas GPR120 plays a minor role in the regulation of incretin secretion. 36,37 We summarized the effects of nutrition including carbohydrates, amino acids and lipids and the receptors involved in GLP-1 levels in vitro and in vivo in Table 1 53 Similarly, bread made from sourdough lowered GLP-1 response when compared with multigrain or sprouted grain bread in subjects at risk for glucose intolerance 54 (Table 2).

| Effect of a sequence of a dietary regimen intake on incretin secretion
The type of meal, sequence of meal intake and adjustment in calorie consumption can all play a role in maintaining postprandial glucose homoeostasis. It has been reported that consuming fish/meat before rice enhances GLP-1 secretion compared with consuming rice before fish/meat in both healthy subjects and in patients with T2DM which leads to amelioration of postprandial glucose excursion. 55 Similarly, a whey preload or protein drink before a meal resulted in increased insulin and GLP-1 secretion, and decreased gastric emptying, in patients with T2DM. 56,57 These results suggest that eating carbohydrates later in a meal after protein might be a good strategy to enhance secretion of GLP-1 and in regulating postprandial glucose.
In patients with T2DM, adjusting the calorie balance in each meal with a high-energy breakfast and low-energy dinner has been shown to increase GLP-1 levels, and decrease prandial hyperglycaemia compared to a high-energy dinner and lower-energy breakfast. 58 Therefore, a change in meal timing with regard to calorie consumption could beneficially modulate GLP-1 secretion.

| Effect of mastication frequency per mouthful and eating speed on incretin secretion
It has been reported that mastication frequency, eating speed and eating duration have an impact on incretin secretion. In healthy individuals, chewing 30-times per bite increased the endogenous GLP-1

| Effect of intermittent fasting vs continuous energy restriction on glycaemic control and incretin secretion
A recent report revealed that intermittent energy restriction is comparable for the reduction of HbA1c with continuous energy restriction in patients with type 2 diabetes. 62 While a report showed that

| Current situation of exercise therapy for T2DM
Lifestyle The timing of exercise, for example, after a meal was shown to be effective in reducing glucose and TG levels in obese patients with T2DM who were on standard treatment. The results showed that while resistance exercise before dinner improved postprandial glycaemic control, resistance exercise after dinner improved both postprandial glucose and TG elevation. 68 In addition, a recent report demonstrated that afternoon exercise is more efficacious than morning exercise at improving blood glucose in T2DM individuals. 69 Further, calorie restriction and exercise resulted in weight loss, and improved glucose regulation as well as incretin secretion in obese patients with T2DM, suggesting the beneficial effects of combining diet and exercise therapy. 70

| Muscle structure in T2DM
Better understanding of skeletal muscles in terms of type of muscle fibres, size, fibre colour, fatigue resistance, metabolism and insulin

| Myokine, muscle-derived interleukin-6 (IL-6) induces GLP-1 secretion
Skeletal muscle constitutes 30%−40% of body weight and glucose uptake by the skeletal muscles increases by up to 50-fold during exercise. As exercise-induced glucose uptake involves a complex molecular signalling that is different from insulin, the glucose uptake is preserved even in insulin-resistant muscle emphasizing the therapeutic potential of exercise in the management of chronic metabolic disease. 74 GLUT4 translocation during muscle contraction to sarcolemma and t-tubules is essential for exercise-induced glucose uptake.
Exercise stimulates glucose uptake through enhancing insulin sensitivity and responsiveness. Muscle contraction, muscle remodelling or exercise training produce several secretory factors such as proteins, growth factors and cytokines (also referred to as myokines) that exert beneficial effects of exercise. 75 Although the discovery and validation of myokines are underway, a well-known myokine, IL-6 plays an important role in accelerating glucose uptake independent of insulin and communicating with central and peripheral organs. 76 Both type I and type II fibres express the muscle-derived IL-6 during exercise, which enhances glucose uptake and fat oxidation through activation of AMP-kinase and/or phosphatidylinositol 3-kinase. 77 Findings from several studies reported the benefits of exercise on GLP-1 release (Table 3) However, more studies are required to elucidate the optimal exercise for T2DM.

| PHARMACOTHER APY
On top of diet and exercise, pharmacotherapy itself is critical to achieve good glycaemic control. In the meantime, there are several medications which induce GLP-1 not only lowering blood glucose level. In the following section, we summarize antihyperglycaemic agents, antidyslipidaemia agents and antihypertensive agents as GLP-1 inducers.

| Biguanides
Biguanides are oral medications that reduce plasma glucose via multiple mechanisms. 81 Advantages of metformin include its high efficacy, low cost, minimal hypoglycaemia risk. Gastrointestinal symptom and lactic acidosis are adverse events to be considered.
Several studies demonstrated the involvement of metformin either directly or indirectly in GLP-1 secretion ( 14 wk Active GLP-1↑ Improving insulin resistance metformin affects gut microbiota in diabetic treatment-naive T2DM patients which contributes to metformin's antidiabetic effect. 84 (Table 4).  (Table 4).

| Thiazolidinediones
Thiazolidinediones (TZDs) are oral medications that increase insulin sensitivity and are of high glucose-lowering efficacy. TZDs are associated with the best evidence among glucose-lowering medications for glycaemic durability. 81 Potential adverse effect of TZDs is regarding fluid retention and congestive heart failure, weight gain and bone fracture.
Insulin resistance is associated with impaired GLP-1 secretion.
Use of pioglitazone improved the insulin resistance developed in rats fed with a high-fat diet as well as increased GLP-1 secretion 92 (Table 4)

| Sulphonylureas
Sulphonylureas lower glucose by stimulating insulin secretion from pancreatic beta cells. 81 They are inexpensive, widely available and have high glucose-lowering efficacy. As adverse effects, sulphonylureas are associated with weight gain and risk for hypoglycaemia.
Sulphonylurea seems not affect the secretion of incretin. 93 Sulphonylurea could uncouple the glucose dependence of the insulinotropic effect of GLP-1. 94

| Antidyslipidaemia agents
There is evidence that the hypolipidaemic agent, atorvastatin, com-

| IDEP
After reviewing diet, exercise and pharmacotherapy, respectively, we move on to interaction among them. Diet and pharmacotherapy interaction is presented in Table 5.

| DISCUSS ION/CON CLUS IONS
Diet, exercise and diabetes education alongside pharmacotherapy are crucial for the optimal management of T2DM. Changing the diet regimen and including exercise intervention as part of T2DM management can improve glycaemic control and reduce treatment escalation of AHAs, which otherwise can lead to risk of developing potential adverse effects and puts excessive costs on health care. 108 The interaction between diet/exercise and pharmacotherapy is limited, and hence we attempted to summarize such studies in the present review.

ACK N OWLED G EM ENTS
Sponsorship and article processing charges for this study were  Kinsuke Tsuda has served as an advisory board member for Novartis and has received lecture fees from Novartis.

AUTH O R CO NTR I B UTI O N S
All the authors researched and analysed the data and were involved in drafting the outline, reviewed all the drafts and approved the final draft of the manuscript.

E TH I C A L A PPROVA L
Not applicable.

DATA AVA I L A B I L I T Y
All data are included within the manuscript.