|Year : 2021 | Volume
| Issue : 1 | Page : 10-17
Potential role of yoga in management of the ominous octet: Adding a new facet to type 2 diabetes management and prevention
Venugopal Vijayakumar1, Ramesh Mavathur2, Nagarathna Raguram2, Harish Ranjani3, Ranjit Mohan Anjana4, Viswanathan Mohan4
1 Department of Yoga, Govt. Yoga & Naturopathy Medical College, Chennai, India; Department of Yoga and Physical Activity, Madras Diabetes Research Foundation, Chennai, India
2 Department of Yoga and Life sciences, Swami Vivekananda Yoga Anusandhana Samsthana (S-VYASA University), Bengaluru, India
3 Translational Research Department, Madras Diabetes Research Foundation, Chennai, India
4 Madras Diabetes Research Foundation & Dr. Mohan’s Diabetes Specialities Centre, Chennai, India
|Date of Submission||05-Feb-2018|
|Date of Decision||23-Mar-2018|
|Date of Acceptance||09-Apr-2018|
|Date of Web Publication||25-Dec-2020|
Dr. Venugopal Vijayakumar
4, Conran Smith Road, Gopalapuram, Chennai - 600 086, Tamil Nadu.
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Vijayakumar V, Mavathur R, Raguram N, Ranjani H, Anjana RM, Mohan V. Potential role of yoga in management of the ominous octet: Adding a new facet to type 2 diabetes management and prevention. J Diabetol 2021;12:10-7
|How to cite this URL:|
Vijayakumar V, Mavathur R, Raguram N, Ranjani H, Anjana RM, Mohan V. Potential role of yoga in management of the ominous octet: Adding a new facet to type 2 diabetes management and prevention. J Diabetol [serial online] 2021 [cited 2021 May 9];12:10-7. Available from: https://www.journalofdiabetology.org/text.asp?2021/12/1/10/304358
| Introduction|| |
The prevalence and incidence of diabetes mellitus is increasing worldwide at an alarming pace. The number of adults with diabetes was 194 million in 2006 and was predicted to reach 333 million by 2025. But already, an estimated 425 million adults have diabetes and another 352.1 million adults have impaired glucose tolerance (IGT).
Our knowledge and understanding of the pathophysiology of type 2 diabetes mellitus (T2DM) is ever expanding. The two common pathophysiological abnormalities observed in T2DM are insulin resistance and impaired β-cell function. The pathophysiology of T2DM is believed to commence with insulin resistance, which leads to glucotoxicity and decreased β-cell function. However, according to the ‘β-cell centric’ approach, β-cell dysfunction is the primary defect in T2DM which in turn leads to insulin resistance. Apart from insulin resistance (in muscles and liver) and β-cell dysfunction, the ‘ominous octet’ model of DeFronzo refers to the involvement of brain, adipose tissue, gastrointestinal hormones, kidney and α-cells in the pathophysiology of T2DM and emphasises the need for a multiple drug combination to rectify the underlying pathophysiological defects and not simply aim at reducing the HbA1C levels.
A recent systematic review demonstrated that lifestyle interventions are better at reducing the incidence of T2DM than usual medical care in populations across different ethnicities and cultures., Lifestyle interventions are also effective in secondary prevention of diabetes as shown in the Da Qing study, where participants in the lifestyle group had a 47% lower risk of diabetic retinopathy at 20-year follow-up. Dietary modifications and exercise recommendations are the conventional lifestyle interventions recommended for the prevention and management of T2DM. Increase in moderate physical activity is associated with multiple benefits such as, improved insulin sensitivity, better glycemic control, reduced body mass index, improvement in lipid profile and other risk factors associated with diabetes such as obesity and hypertension., However, physical exercise may need to be done with caution in patients with increased risk of cardiovascular events and comorbidities associated with microvascular and macrovascular complications such as diabetic neuropathy and proliferative retinopathy, which could worsen with intensive exercise programs. Although the beneficial effects of physical activity are well established, adherence rate remains poor, as patients seem not to engage in regular physical activities for different reasons.,, There is growing interest in alternative and holistic models to T2DM management which could possibly improve adherence.
Yoga is a mind/body practise based on traditional Indian philosophy, depicting the ideal way of life and is more than just a physical activity. In terms of energy expenditure, it is similar to mild-to-moderate intensity exercise. In addition to the physical movements (asanas), yoga commonly involves multiple other components such as controlled respiration (pranayama), relaxation and meditation (dhyana). Many studies are emerging on the benefits of yoga in various diseases. Findings from extensive studies suggest yoga to have multiple benefits in the etiopathogenesis of T2DM and associated complications such as improved glycemic control, lipid profile, improved cognition, nerve conduction velocity, weight loss, reduced inflammation,, oxidative stress, and cardiovascular risk factors in T2DM patients.,, Comparative studies on yoga versus exercise suggest that yoga is as effective if not superior to physical exercise in health-related outcome measures such as blood glucose, lipids, salivary cortisol and oxidative stress which are of greater significance in the primary and secondary prevention of T2DM, with additional benefits of improving subjective measures such as fatigue, sleep, pain and quality of life (QoL).,
The role of physical exercise as a part of the lifestyle intervention in the prevention and management of diabetes is well established. The current narrative review aims at exploring the ‘ominous octet’ involved in the etiopathogenesis of T2DM and the potential role of yoga in correcting these pathological defects for an effective primary and secondary prevention of T2DM [Figure 1].
|Figure 1: Pathways involved in the yogic management of type 2 diabetes mellitus|
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| Yogic Management of the Ominous Octet|| |
The defects in β-cell dysfunction primarily involve three components. First, the secretion timing disorder, where there is a reduction in the initial acute phase insulin release (AIR). Autonomic nervous system is attributed for >70% of the AIR. AIR is generally abolished by vagotomy in rats and by atropine in humans which is suggestive of the pivotal role of vagal activity in AIR. Second is the quantitative disorder, in which there is an increase or decrease in the second phase insulin release. Third, the qualitative disorder, in which there is an increase in the proinsulin-to-insulin ratio. An increase in the amount of proinsulin in circulation, which is attributed to the impaired cleavage capacity of the β-cells, is observed irrespective of the diabetes duration, suggesting that β-cell dysfunction need not necessarily occur after insulin resistance and might possibly precede the onset of clinically overt T2DM.
Patients with T2DM have higher levels of oxidative stress. Subtle increases in the physiological concentration of the reactive oxygen species (ROS) might mimic a number of insulin-like effects, including increase in glucose transporters (GLUT) translocation, lipogenesis, decreased lipolysis, and an increase in the glucose-stimulated insulin secretion. However, chronic oxidative stress and free radical damage observed in T2DM plays an important role in inducing β-cell dysfunction, as β-cells possess limited defence against excess ROS production due to low levels of ROS-detoxifying enzymes., Increase in oxidative stress leads to decreased transcription of the insulin gene by decreasing PDX1 and MafA binding., Similarly, protein misfolding and resultant ER stress in the human β-cells is a major pathophysiological event in T2DM which is also associated with oxidative stress.
Yoga studies showed a reduction in oxidative stress and increased anti-oxidant defence, by improving superoxide dismutase, glutathione, malondialdehyde, Vitamin C and Vitamin E profile., γ-aminobutyric acid (GABA) induces membrane depolarisation and proliferation in β-cells, and thus increases insulin secretion. A study comparing the effects of yoga with walking, found yoga to improve GABA levels better than walking. Yoga reduces sympathetic activation and enhances parasympathetic activity through direct stimulation of the vagus nerve., The positive impact of yoga on the autonomic nervous system would possibly help overcome insulin secretion timing disorder as well. With improved antioxidant defence, GABA secretion and autonomic balance, yoga appears to have the potential to play multiple roles in preserving β-cell function associated with T2DM and metabolic syndrome.
Skeletal muscle is one of the major sites for disposal of ingested glucose in healthy individuals with normal glucose tolerance. Postprandial hyperglycaemia induces insulin secretion and the resultant increase in plasma insulin concentration stimulates glucose uptake in skeletal muscles. Meanwhile, glucose uptake into skeletal muscles is stimulated through insulin-independent mechanisms as well, that are activated by muscle contractions, hypoxia and nitric oxide, all of which are shown to increase membrane translocation of glucose transporter 4 (GLUT 4)., In the insulin-resistant state (e.g., in T2DM and metabolic syndrome), the insulin-dependent glucose disposal in skeletal muscle is markedly impaired; however, the capacity for the insulin-independent Adenosine 5’-monophosphate-activated protein kinase (AMPK)-mediated glucose uptake is still intact in the muscle cells of patients with T2DM.
Yoga – asanas and pranayama have shown to improve insulin sensitivity in T2DM. Insulin sensitivity is found to be significantly higher in regular practitioners of yoga. The observed increase in glucose sensitivity could be attributed to the possible activation of AMPK through muscle contractions involved during yoga postures.
Adipose tissue and inflammation
Increase in the pro-inflammatory markers and decrease in the anti-inflammatory markers are often observed in T2DM and prediabetes. Adipocytes are now known to be the key regulators of glucose homeostasis. Adipokines play an integral role in the etiopathogenesis of T2DM and modulation of adipocytes could therefore be a useful therapeutic strategy in T2DM.
Reduction in the pro-inflammatory markers such as tumor necrosis factor α, interleukin-6, C-reactive protein (CRP) and high-sensitivity CRP, and increase in the anti-inflammatory markers such as adiponectin are consistently reported through various studies on yoga.,, Adiponectin activates AMP kinase of liver and thereby help reduce hepatic glucose production (HGP). Role of adiponectin on improving endothelial nitric oxide synthetase (eNOS) and resultant increase in endothelial nitric oxide production is well established,, which is beneficial in the prevention of neuropathy, cardiovascular complications and improve delayed wound healing in diabetes. A systematic review on the effect of exercise on adiponectin states that moderate-intensity exercise programs have significant impact on the adiponectin levels. This was ably supported by a study which found regular yoga practise to increase adiponectin levels.
In 1854, the renowned physiologist Claude Bernard observed that a lesion in the floor of fourth-cerebral ventricle could induce diabetes and postulated that brain plays a central role in glucose homeostasis and diabetes pathogenesis. The notion remained popular up until the discovery of insulin by Banting and Best in 1921, and the identification of liver, muscle and adipose tissue as the principal target organs of insulin on glucose metabolism. Furthermore, a strong evolutionary link is observed between neurons and the insulin-producing β-cells in various animals., Even in higher animals, the hypothalamus senses blood glucose levels, in a similar way as the β-cells.
The available literature clearly suggests a high degree of association between brain and glucose metabolism. There are many glucose-sensing neurons in the brain, particularly in hypothalamus (arcuate, ventromedial and paraventricular nuclei) which helps in systemic glucose homeostasis., Injecting smaller doses of glucose or insulin into these discrete areas of the brain can lower blood glucose levels and increase liver insulin sensitivity, independent of the amount of insulin in circulation. Administration of leptin into the third ventricle reverses insulin resistance and diabetes phenotypes in lipodystrophic mouse at doses too low to have any effect outside the brain and is ineffective otherwise when administered peripherally. Conversely, deletion of receptors for either insulin or leptin from certain specific hypothalamic neurons causes systemic insulin resistance and glucose intolerance, indicating the physiological role of these neurons on systemic glucose metabolism., brain-derived neurotrophic factor (BDNF) prevents apoptosis and preserves insulin-secreting capacity of β-cells. Similarly, serotonin is also reported to increase β-cell proliferation. Some yoga studies have reported improvement in the BDNF and serotonin levels following practise of yoga., Conversely, disturbances in the glucose metabolism also affect the brain. HbA1C of more than 7% increases the risk of developing mild cognitive impairment by 4-fold. T2DM is associated with a 1.5–2.5-fold increased risk of cognitive dysfunction., A cognitive decline is observed very early, during IGT and metabolic syndrome.,,
Bromocriptine is a sympatholytic D2-dopamine agonist approved for use as antihyperglycemic medication. The mechanism of action of which is attributed to its dopaminergic activity in the brain and subsequent inhibition of sympathetic tone, thereby improving both insulin release and insulin sensitivity. Yoga, in addition to reduction in the sympathetic tone and increase in parasympathetic tone, has also shown to increase dopamine levels. A landmark study in yoga demonstrated that meditation facilitates cortical plasticity, and regular practitioners of meditation are observed to have increased cortical thickness, especially in areas associated with somatosensory, cognitive and emotional processing. An improvement in cognitive brain functions of T2DM patients is also observed with regular yoga practise. Further studies on yoga had shown increased gray matter in the limbic system, cerebral lobes and cerebellum, improved cerebral blood flow and activation of midbrain close to the hypothalamus. Yoga, thus might play an important role in enhancing the brain regulated glucose homeostasis mechanism, possibly through hypothalamic–pituitary–adrenal axis and potentially improve cognitive dysfunction associated with T2DM, albeit, more studies are required.
Elevated glucagon levels and hyperfunction of α-cells were demonstrated in individuals with T2DM in 1970. Indeed, the importance of α-cells in diabetes was observed way back in 1947, when Rodriquez-Candela reported that alloxan-induced diabetes of dogs could be ameliorated by removal of pancreatic α-cell remnants. A more recent study with an animal model demonstrated that, even in complete insulin deficiency, blocking of glucagon action could possibly prevent the metabolic and clinical derangements seen in type 1 diabetic mice, highlighting the importance of glucagon suppression in the pathogenesis of diabetes. Elevated fasting plasma glucagon levels lead to increase in the HGP and decreased insulin sensitivity in animal models. Similarly, the capacity of the liver to synthesise triglycerides (which independently causes insulin resistance) is enhanced during stress which is partly due to the action of glucagon through the cyclic adenosine monophosphate pathway. GABA induces membrane hyperpolarisation in α-cells, resulting in suppression of glucagon secretion, and as mentioned earlier, yoga improves GABA levels.,
Glucagon-like peptide-1 (GLP-1) is a potent incretin hormone, acting more like a ‘master switch’ in glucose metabolism by operating through multiple pathways such as increased glucose uptake of muscle and liver, inhibiting glucagon secretion, while promoting insulin and somatostatin secretion and delayed gastric emptying. The gene encoding the GLP-1, the proglucagon gene has three known sites of expression, namely, α-cells, L cells of the large intestine and the nucleus tractus solitarius in the hindbrain, which is the nucleus of vagus nerve as well. The role of vagus in the regulation of GLP-1 secretion has been clearly demonstrated in animal model. Bilateral subdiaphragmatic vagotomy in conjunction with gut transection and selective hepatic branch vagotomy completely abolishes the fat-induced and exogenous GIP-induced GLP-1 release, respectively, while stimulation of the distal end of the celiac branch of the subdiaphragmatic vagus nerve significantly increases the release of GLP-1. GLP-1 inhibits gastric emptying and acts through the vagal afferent-mediated central mechanism, which could positively be influenced by yoga due to its known property of vagal activation. However, this is purely speculative based on the known effects of yoga on the autonomic nervous system and robust studies are needed to establish the impact of yoga specifically on GLP-1 secretion.
The liver is the major organ of glucose metabolism and HGP and the main source of fasting hyperglycaemia, contributing to approximately 80% of diurnal hyperglycemia in T2DM. An increase in the circulating blood glucose levels releases insulin and inhibit HGP, but this negative feedback is dysfunctional in T2DM. Increased flux of free fatty acids to liver and accumulation of liver fat are the major determinants of the decreased sensitivity of endogenous HGP to insulin. Glucagon, central nutrient and hormone-sensing in the hypothalamus, together plays a central role in regulating peripheral glucose homeostasis and mediate in the reduction of HGP through vagal nerve efferent signaling to the liver.
Various meta-analysis and systematic reviews on the effect of yoga on T2DM consistently report a higher reduction in the FPG (fasting plasma glucose) levels, than PPG (post-prandial plasma glucose) levels, which suggests a reduction in the HGP., Although the effect of yoga on HGP has not been measured directly so far, one could speculate that the aforementioned positive impact of yoga on glucagon and adiponectin would have an influence in reducing the HGP. An improvement in the lipid profile through yoga is attributed to the increased hepatic lipase activity, which affects the lipoprotein metabolism and increases uptake of triglycerides by adipose tissue.
The kidney plays an important role in regulating glucose homeostasis. The inhibition of renal glucose reabsorption is one of the novel and effective strategies in the management of T2DM. β-cell dysfunction could upregulate sodium-glucose cotransporter 2 (SGLT2) protein in the kidney of patients with T2DM. Both SGLT2 and glucose transporter 2 (GLUT2) are expressed more in the proximal convoluted tubules cells of T2DM patients than in healthy individuals, resulting in elevated renal glucose uptake and further worsening of hyperglycaemia. Hypothalamic pro-opiomelanocortin deficiency improves glucose tolerance in mouse models, by increasing glycosuria and reduced sympathetic nervous system (SNS) activity which is attributed to observed glycosuria and improved glucose tolerance. Likewise, the SNS activity reducing property of yoga might also help reduce renal glucose reabsorption, facilitating improved glucose tolerance and better glycemic control [Figure 2]. This is obviously an area for future yoga research.
|Figure 2: Summary of the hypothesised role of yoga in management of the ‘Ominous octet’ defects of diabetes (Adapted from Defronzo 2009)|
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| Other Physiological and Metabolic Effects of Yoga|| |
The blood glucose lowering effect of yoga could be attributed to the stretching and contraction movements often performed during physical asana postures in yoga, as muscle contraction improves glucose sensitivity and reduce blood glucose., However, randomised controlled trials (RCTs) done in the past have found yoga to be as effective if not superior to physical exercises,, and the benefits are not just restricted to the physical movements involved in yoga. For instance, yoga nidra (‘yogic sleep’) is a yogic technique which involves complete body relaxation without any physical movements. A 3-month study exploring the efficacy of yoga nidra in patients with T2DM found a significant reduction in the blood glucose levels when compared to the control group. The study indicated that the reduction in blood glucose might not only be due to the physical movements involved but also through a possible reduction in the stress hormones or due to increased vagal activity. Decreased vagal tone contributes to the etiopathogenesis of T2DM in multiple ways., Reduced breathing rate increases vagal activation and decreases the influence of sympathetic branch of the autonomic nervous system, measured by an increase in heart rate variability and baroreceptor sensitivity. Some studies report betterment of the complications associated with diabetes, like improved nerve conduction velocity, cognition, and QoL. Autonomic dysfunction associated with T2DM is reported to be stabilised following yoga., It is of interest that a couple of studies have reported a reduction in the medication score and insulin intake of T2DM patients,, suggesting a possible improvement in β-cell dysfunction, insulin resistance or any of the pathological abnormalities in the above-mentioned ominous octet, which was not observed with the control group on exercise-based lifestyle intervention. Thus, yoga shows promising insights of becoming an effective complementary therapy in the prevention and management of T2DM.
| Quality of Studies|| |
Methodological flaws and bias are being reported in the systematic reviews of the past, on yoga studies in patients with diabetes., Unlike drug trials, blinding might not be possible in yoga studies, providing a very low score while assessing the available RCT for bias. But still, high-quality RCTs, taking into account of the bias in study design, selection bias and publication bias are lacking and are very much essential to concretise the evidence available on the beneficial effects of yoga in diabetes. Meanwhile, the available evidence from RCTs and comparative studies are in line with the findings of nonrandomised and uncontrolled studies, thus indicative that the positive findings observed with yoga are not simply due to poor study design alone.
Admittedly, there are a few studies reporting yoga not to be beneficial as popularly ‘claimed’, on various dimensions of diabetes such as glycemic control, inflammation, and blood pressure. Looking into the methodologies of these studies, it was observed that the duration of yoga intervention given was either once or twice a week, in comparison with the other yoga trials where the participants generally practise yoga three to five times a week. Yoga is more a way of life, to be practised ideally every day for health and well-being. Even if considered as just a form of physical activity, it should be practised 5 days a week to get the desired benefits. Therefore, yoga might have a dose-dependent effect on glycemic control in T2DM. Future studies on yoga should be designed so as to remove the bias in methodology and reporting, with the recommended duration or ‘dosage’ of three to five times a week.
Cost-effectiveness of yoga interventions
A cost-effective and sustainable intervention for the primary and secondary prevention of diabetes would help increase the QoL, diabetes-free years of life, improved life expectancy, and on top, cost savings, reducing the economic burden in growing economy of many developing countries where the prevalence of T2DM is on the rise. Yoga would be one such cost-effective intervention where the cost involved is a onetime investment, where the patients learn yoga once under the direct supervision of a suitably qualified and experienced yoga professional and can practise on their own after getting sufficient training. Moreover, the adherence rate of yoga is found to be higher than other forms of physical activity, making it a more acceptable and simpler form of physical activity for T2DM.
| Future Directions|| |
Few advantages of using yoga as a form of physical activity in T2DM are the relatively low cardiovascular demands when compared to other forms of exercises. Low impact makes it an easier and more simpler physical activity to practicse for people who are contraindicative for exercise. Unlike many ‘traditional’ therapies, yoga may be applicable to a larger population of T2DM patients as it appears to be safe and inexpensive., The strength of most available research evidence on yoga is modest and necessitates more robust research design and unbiased reporting in the future. Nevertheless, the potential role of yoga in the primary and secondary prevention of T2DM is worth considering. Yoga could be a safe and cost-effective modality to prevent and manage T2DM.
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Conflicts of interest
There are no conflicts of interest.
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