Effects of Exercise on Insulin Resistance

EFFECTS OF EXERCISE ON INSULIN RESISTANCE

INTRODUCTION

Insulin resistance (IR) is identified as an impaired biologic response to insulin stimulation of target tissues, primarily liver, muscle, and adipose tissue¹. Glucose uptake by the muscle is impaired which results in a compensatory increase in beta cell insulin production and hyperinsulinemia. The metabolic consequences of insulin resistance can result in hyperglycemia, hypertension, dyslipidemia, visceral adiposity, hyperuricemia, elevated inflammatory markers, endothelial dysfunction, and a prothrombic state. Progression of insulin resistance can lead to metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and type 2 diabetes mellitus. It most commonly occurs in association with obesity but may result from multiple other underlying causes, which include stress, medications, pregnancy, lipodystrophy, insulin antibodies, genetic defects in insulin signal pathways and blocking autoantibodies against the insulin receptor².

There are three primary sites of IR which are muscle, liver, and adipose tissue. IR is proposed to begin in muscle tissue with immune-mediated inflammatory changes and excess free fatty acids, causing ectopic lipid deposition. When the muscle glucose uptake is impaired, excess glucose returns to the liver increasing de novo lipogenesis (DNL) and circulating free fatty acids, which would further contribute to ectopic fat deposition and IR¹. Common presentations in which IR is observed are the following; a) asymptomatic patients with obesity, hypertension, or hyperlipidemia, b) those with metabolic syndrome, c) prediabetes or T2D. d) Those with a symptomatic micro-vascular disease, e) polycystic ovarian syndrome (PCOS). IR can be managed by various ways which include firstly, lifestyle intervention; dietary modification and physical activity, secondly, pharmacological interventions for blood glucose management (metformin, Glucagon-like peptide one inhibitors, sodium-glucose cotransporter-2 inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, insulin therapy), thirdly, surgical intervention; bariatric surgery improves insulin sensitivity by excessive weight loss.

Insulin sensitivity (SI) illustrates how sensitive the body is to the effects of insulin. One who is insulin sensitive would require smaller amounts of insulin to lower blood glucose levels than someone who has low sensitivity. People with low SI are referred to as Insulin resistant and would require larger amounts of insulin to keep the blood glucose stable. Poor SI would lead to elevated blood glucose, impaired glycemic control, a risk of β cell failure and development of Type 2 diabetes (T2D). SI can be measured via various methods which include: a) measuring fasting insulin concentrations (elevated fasted insulin >25mIU/L indicates poor SI), b) oral glucose tolerance testing (OGTT) c) hyperinsulinaemic-euglycaemic clamp, d) hyperglycaemic clamp, e) homeostatic model assessment of IR (HOMA-IR), f) HOMA-β, g) quantitative insulin sensitivity check index (QUICKI)³ . Physical activity performed on a regular basis would reduce the risks of IR, metabolic syndrome and T2D, and there would be an improvement in SI in those who are IR with exercise. The primary purpose of this review paper is to summarise the effects of exercise on IR. This paper will overview the effects of exercise, diet and combined effects both exercise and diet on IR.

Effects of Exercise on IR

Physical activity improves both calorie expenditure and SI in muscle tissue. It has both long-term and short-term effects on SI. Single exercise bouts produce immediate effects and may last up to 72 hours post-exercise while regular bouts of exercise produce long-term chronic improvement. In already trained individuals, optimal SI and glycemic control are promoted as a result of individual exercise bouts. A single bout of exercise produces an acute increase in glucose uptake into the skeletal muscle, both during exercise and for some hours post-exercise. Improvements in SI during exercise are associated with an increase in activity of AMPK which leads to deactivation of TCB1D4, thus promoting GLUT4 translocation to the cell membrane and thereby increasing glucose uptake. Increase in glycogen synthase activity due to exercise, has been proposed as a factor that increases SI. Another factor which improves SI,  as a result of exercise, is increased in skeletal muscle capillarization³.

Exercise type and intensity

1. Aerobic Exercise (AE)

Moderate AE improves SI and other markers of glycaemic control. (30 min or more, 3 or more times a week for 8 weeks).³ Improvements in HOMA-IR, fasting plasma insulin and fasting glucose has also been observed following 8 weeks of aerobic training (30 min walking, 3 times a week). It has also been suggested that changes in β cell function as a result of training maybe a fundamental determinant of training-induced improvements in glycaemic control. A probable dose response reports additional benefits from higher exercise doses with increases in SI, and improved β cell function.

2. High-Intensity Interval Training (HIIT)

HIIT has been demonstrated to induce significant increases in GLUT 4 protein. Interval training is beneficial in patients with both High and low HOMA. It could also be a more effective preventive exercise regimen for asymptomatic healthy individuals. HIIT has shown to improve SI in a shorter duration along with a greater adherence. It may be unsuitable for individuals with a risk of cardiovascular conditions.

3. Functional High Intensity Training (FHIT)

FHIT has found to increase SI. It significantly reduces fat mass, diastolic blood pressure (DBP), blood lipids, and metabolic syndrome z-score. This type of training also increases basal fat oxidation and high molecular mass adiponectin which correlated in the change of SI. FHIT has proven to be an effective means of improving SI and reducing cardio-metabolic risk factors in patients with T2D. It also provides a time efficient method for reducing the metabolic burden of T2D.⁴

4. Resistance Exercise (RE)

RE has shown to improve indicators of glycemic control in various populations. Increase in GLUT4 concentration and translocation and enhancement of SI has also been seen. It has been suggested that these changes may be due to increases in muscle mass as well as qualitative changes in the muscle.³

5. AE+RE

A combination of both types of exercise is more effective on IR than performing them individually and would also have additional benefits. Better metabolic outcomes have been observed when both the exercise was combined. Also both improves hepatic fat content and SI.³

Exercise alone without weight loss

Exercise training without weight loss may augment glucose disposal stimulated by insulin, however, after cessation of exercise IR generally returns to baseline which indicates that activities without weight loss predominantly affects variations in glycogen stores and glycogen synthase activity. Changes in body composition variable i.e. fat mass, visceral and subcutaneous adipose tissue and body fat percentage are influenced as a result of exercise in the absence of weight loss which may lead to enhancements in insulin-stimulated glucose disposal. Significant reductions in intra-abdominal fat and subcutaneous fat were observed in an aerobic exercise intervention without weight loss. Improvements in VO2 peak have also been observed which partially supported improvements in free fatty acid mobilization and oxidation. Reduction in waist circumference and associated increases in mitochondrial density has been observed in an aerobic exercise training which started at a moderate intensity and progressed to a vigorous intensity. Improvements in plasma glucose and reductions in gynoid fat, leg fat and leptin has been found on the same subjects⁵.

Exercise with Weight loss

Weight loss due to exercise is accompanied by reductions in visceral adipose tissue (VAT), which seem to drive improvements in IR. Benefits of vigorous exercise promotes significant weight loss enhanced SI and β cell function. Also slight but significant reductions in body weight may mitigate IR. Both aerobic and resisted exercises would reduce weight or fats mass and affect IR if done with sufficient stimulus. A 10% reduction in body weight has an intense effect on IR following an intervention.  The volume of exercise to achieve weight loss is large and requires 60min/day or more when one relies on exercise alone as a strategy to lose weight. Exercise-induced weight loss reduces adiposity and systemic IR more effectively than calorie restriction alone.

Effects of Diet alone

To reduce weight or adipose tissue a large volume of exercise is required which might be difficult, therefore dietary modification is commonly implemented and utilized to reduce IR. Dietary modifications would be beneficial in a population who are unable to perform exercises, i.e. geriatric population, neuropathic patients, individuals with foot ulcers and heart disease.⁶

1. Effects of low fat diet

Low fat diet has shown to reduce weight in overweight individuals.⁷ However other restricted diets have found to be more effective in achieving a long-term weight loss in obese people.⁸ IR individuals usually have a difficulty in adhering to low fat diets in the longer term.⁹

2. Effects of high fiber diets

The bulking effect of low energy food to the diet and the slowing of gastric emptying and absorption of carbohydrate and fat contents add to the beneficial effects of fiber intake. It is also assumed that this type of diet increases satiety and influences efforts to lose weight.¹⁰ However, many studies have not specified the type of fiber consumed and some have reported only moderate effects on weight loss.

3. Effects of low glycemic index (GI) diets

Some studies have shown positive effects of low glycaemic diets on weight loss in overweight individuals than other diets. However, some did not show any benefit of low versus high GI diet on weight loss. Effects of low GI diet remain inconclusive due to fewer numbers of participants and short duration of available studies.

4. Effects of low carbohydrate high protein diet. (LCHP)

Compared to low fats diet, diets with increased protein content have found to be more effective in achieving weight loss, in the short term.¹¹ Carbohydrate restriction and increased protein content is a common concept. A moderate LCHP diet appears to have beneficial effects on blood lipids, body composition, and weight loss.⁸ Dietary protein has a higher satiating effect compared to other micronutrients, thus having better weight loss in low carbohydrate diets. Increased thermogenesis as a result of a high protein diet further leads to favourable effects on body weight. It also increases lean mass and reduces fat mass in obese people.

Combined effects of diet and exercise

Combination of diet and exercise is more effective than diet alone in improving SI.³ A low calorie diet following exercise training reported beneficial effects on HOMA-IR and more weight reduction. Improved SI was observed in a group of aerobic exercise and caloric restriction. Similar results were seen with resistance training but long-term effects were observed with aerobic training. Weight loss as a result of both calorie restriction and exercise may improve muscle metabolism while reducing adiposity. Improved mitochondrial oxidative capacity as a result of increased mitochondrial density was also observed. A greater reduction in total abdominal fat has been observed in the combined group. Both interventions used together provide a powerful tool for weight reduction and management, and an effective mechanism to improve glucose metabolism.

Summary

References

1. Insulin Resistance – StatPearls – NCBI Bookshelf. Available at: https://www.ncbi.nlm.nih.gov/books/NBK507839/. (Accessed: 7th November 2018)

2. Genetic syndromes of severe insulin resistance. – PubMed – NCBI. Available at: https://www.ncbi.nlm.nih.gov/pubmed?term=21536711. (Accessed: 7th November 2018)

3. Update on the effects of physical activity on insulin sensitivity in humans. – PubMed – NCBI. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28879026. (Accessed: 7th November 2018)

4. Fealy, C. E. et al. Functional high-intensity exercise training ameliorates insulin resistance and cardiometabolic risk factors in type 2 diabetes. Exp. Physiol. 103, 985–994 (2018).

5. Exercise Training and Insulin Resistance: A Current Review. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625541/. (Accessed: 7th November 2018)

6. Pi-Sunyer, F. X. Weight loss in type 2 diabetic patients. Diabetes Care 28, 1526–1527 (2005).

7. Astrup, A., Grunwald, G. K., Melanson, E. L., Saris, W. H. & Hill, J. O. The role of low-fat diets in body weight control: a meta-analysis of ad libitum dietary intervention studies. Int. J. Obes. Relat. Metab. Disord. J. Int. Assoc. Study Obes. 24, 1545–1552 (2000).

8. Weickert, M. O. Nutritional Modulation of Insulin Resistance. Scientifica 2012, (2012).

9. McClain, A. D., Otten, J. J., Hekler, E. B. & Gardner, C. D. Adherence to a low-fat vs. low-carbohydrate diet differs by insulin resistance status. Diabetes Obes. Metab. 15, 87–90 (2013).

10. Weickert, M. O. & Pfeiffer, A. F. H. Metabolic effects of dietary fiber consumption and prevention of diabetes. J. Nutr. 138, 439–442 (2008).

11. Malik, V. S. & Hu, F. B. Popular weight-loss diets: from evidence to practice. Nat. Clin. Pract. Cardiovasc. Med. 4, 34–41 (2007).