A2 features Dr Nedic’s explanation about Stubborn Abdominal Fat …
THE DANGER OF ABDOMINAL OBESITY with an ‘Iceberg ’ of INSULIN RESISTANCE
Sly Nedic discusses insulin resistance, including its relationship with abdominal obesity, diagnosis, and lifestyle interventions
In an ageing population, the proportion of fat to body weight tends to increase, particularly in the midsection of the body. In the past we might have accepted these changes as an inevitable fact of ageing. However, we have begun to notice that as our abdominal waist grows, so do our health risks, and abdominal obesity has been a well-established risk factor for many detrimental diseases of which cardiometabolic syndrome is a leading condition. Abdominal adiposity positively correlates with visceral fat, which lies deeply within the abdominal cavity and pads the spaces between the abdominal organs. It is largely responsible for a metabolic effect on insulin resistance (IR), cardiometabolic syndrome, and type 2 diabetes. The International Diabetes Federation (IDF) revealed that type 2 diabetes currently affects 246 million people worldwide and is expected to affect 380 million by 2025. There is approximately 6 million undiagnosed cases in the US1.
Through extensive research on abdominal (central) adiposity and waist circumference, Table 1 has been established as part of the necessary criteria for the diagnosis of cardiometabolic syndrome (National Cholesterol Education (NCE) ATP III criteria, World Health Organization (WHO) criteria, IDF criteria). Abdominal obesity is still overlooked in many fields. It is often seen as an aesthetic problem and only treated as a subcutaneous fat problem, and treated with a variety of non-surgical aesthetic procedures and liposuction. Liposuction does not significantly alter the insulin sensitivity of the muscles, liver, or adipose tissues; does not significantly alter plasma concentrations of C-reactive protein (CRP), interleukin (IL)-6, tumour necrosis factor (TNF)-α, and adiponectin; and does not significantly affect other risk factors for coronary heart disease2. The risk of cardiometabolic syndrome remains the same regardless of subcutaneous fat removal as visceral fat remains intact.
Failure to diagnose IR in the younger population has a possible association with abdominal obesity (cardiometabolic syndrome is present in 6.7% of people aged 20–29 years and is increasing every year)3. Associated conditions of abdominal obesity and IR are usually treated by conventional medicine as isolated problems, such as hypertension, hyperlipidaemia, and type 2 diabetes. They are often all treated with conventional chronic medication without addressing the problem as a syndrome, holistically, taking into consideration inflammation, oxidation, and detoxyfication. Recent data suggests that people with hypertension have a two‑fold higher prevalence of diabetes and obesity, of which half are insulin resistant3. Measuring waist circumference as a first step, or referring patients with abdominal adiposity to a physician can help identify individuals with a high risk of IR. The IDF made the following recommendation in their 2006 worldwide consensus definition of metabolic syndrome: ‘With the metabolic syndrome driving the twin global epidemics of type 2 diabetes and CVD there is an overwhelming moral, medical, and economic imperative to identify those individuals with metabolic syndrome early, so that lifestyle interventions and treatment may prevent the development of diabetes and/or cardiovascular disease.
What is insulin resistance?
IR is a widely used clinical term. It is usually defined as a state characterised by the reduced glucose-lowering activity of insulin, but it can also be used as a shorthand label for a clinical syndrome encompassing significant pathologies of metabolic syndrome. Furthermore, cellular insensitivity to the action of insulin is also termed as IR. Insulin resistance means the cells of the body do not respond appropriately to insulin, owing to either direct insulin resistance at the cellular level or through the countering action of insulin by counter-regulatory hormones. Insulin is a gene expression modulator involved in many biochemical processes in the body, such as:
- Glucose metabolism and maintaining normal glucose homeostasis
- GFat mobilisation and synthesis
- GProtein metabolism
- GOxidative stress and inflammatory response
- GMitochondrial function
- GCytokine synthesis
- GAdrenal and sex hormone metabolism.
Insulin-resistant tissue, such as adipose and skeletal, will require higher insulin levels compared to insulin sensitive tissue, such as the heart, adrenals, and brain where hyperinsulinaemia can cause many adverse effects. Understanding the complex role of insulin in almost all tissues in our body will ultimately lead to an understanding of why IR involves such a variety of pathologies. Insulin-resistant/hyperinsulinaemic individuals who have adequate compensation of insulin production have been grouped into a syndrome called syndrome X, cardiometabolic syndrome, IR syndrome, or metabolic syndrome. This syndrome is defined as a cluster of signs and symptoms secondary to insulin resistance and the resulting hyperinsulinaemia. According to the IDF definition, for a person to be defined as having metabolic syndrome they must have abdominal obesity, defined as waist circumference with ethnic specific values (Table 1), plus any two of the four factors listed in Table 2 (if body mass index (BMI) is >30 kg/m2, central obesity can be assumed and waist circumference does not need to be measured)4. The following conditions are linked to the pathophysiology of insulin resistance, which is an independent predictor of age-related diseases:
- Type 2 diabetes
- Polycystic ovarian syndrome (PCOS)
- Non-alcoholic steatohepatitis (NASH)
- Cognitive decline — type 3 diabetes
- Erectile dysfunction
- Sleep apnoea
- Cancer (breast cancer, prostate cancer, colon cancer)
- End-stage renal disease (ESRD)
What are the causes of insulin resistance?
The accumulation of substrate
Simply put, years of excess intake of high glycaemic load (GL) carbohydrates and saturated fats found in the Western diet can overwhelm the biochemical pathways of energy production in the body. After a period of time the body is not able to keep up with the demand of processing all the energy molecules and energy is stored as fat and glycogen. At some point the cell is overwhelmed with excess energy molecules (end‑products and intermediary substrates) and will not allow further sugar or saturated fatty acid uptake. One of the ways in which the body blocks energy entrance is through down regulation of GLUT 4 transport within the muscle cell; therefore, glucose cannot be transported into the cells. In the early stages of IR, glucose is stored as glycerol (along with the excess fatty acids) in the fat cells rather than being metabolised and used for energy. If excess energy intake continues, the fat cells become saturated with energy and glucose, as well as the fatty acids being blocked from entering the fat cells. The circulating glucose is converted to lipids by the liver. This is a predominant pathway to increased triglyceride levels in insulin-resistant conditions.
Furthermore, overconsumption of calories with a high GL, and particularly the metabolism of lipids, leads to metabolic products that result in glycosylation and phosphorylation of the insulin receptor substrate (IRS) (Figure 1) on serine residues (serine 307), terminating the insulin signal.
Counter regulatory hormones over-powering insulin
Insulin’s natural activity is to store glucose, while the counter regulatory hormones (CRHs) (cortisol, human growth hormone (HGH), glucagon, and catecholamines) try to prevent fuel storage in order to keep glucose going to the brain. They attempt this through increased gluconeogenesis, glycogenolysis, and increased lipolysis, as well as limited glucose use. The escalating levels of CRHs start early in IR, as the counter regulatory hormones are the first to be released under stressful conditions. The more stresses that occur on a daily basis, such as nutritional, emotional, chemical, physical or hormonal, and the longer these stresses are present, will stimulate chronic release of higher levels of the CRHs. To maintain homeostasis of blood glucose levels in a chronic stressful environment (which is our everyday life), requires a shift in both the baseline and postprandial insulin levels. A point is reached at which the system starts to decompensate.
The pancreas cannot keep up production and secretion of insulin to counter the effects of the CRHs, and the metabolic derangement of metabolic syndrome becomes apparent as the four counter regulatory hormones over-power the insulin. Stress, primarily through hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, appears to contribute to the accumulation of visceral fat tissue and vice versa6. Therefore, cortisol is considered to be a silent killer in modern society. Recent data suggests that a number of neuroendocrine and inflammatory mechanisms are mobilised during chronic stress in the development of central obesity and metabolic syndrome7. Obesity itself seems to constitute a chronic stressful state and may cause HPA axis dysfunction. Obesity may be considered a systemic, low-grade, inflammatory condition with increased CRHs.
There has been more awareness with regard to the fact that IR is becoming more apparent at a younger age and it is no long a problem exclusively related to the older population. Sullivan presents one possible explanation: ‘It is theorised that the metabolic syndrome may be a manifestation of the profound mismatch between our present environment and previous circumstances that have molded evolutionary selection. Familiar transmissions and variations in different ethnic distributions suggest that IR is genetically predisposed. It is likely that impaired insulin action has been the result of a number of inherited mutations in a variety of genes each with minor effects. Baroni et al support this view: ‘Several studies indicate the possible role of mutations of the insulin receptor substrate-1 (IRS-1) gene in the pathogenesis of insulin-resistance and suggest a possible interaction between the IRS-1 gene and obesity, either by an effect on the development of obesity or by causing or aggravating the obesity-associated with insulin resistance’9. Recent data suggest that marked impairment in insulin signalling is happening in adipose tissue long before glucose intolerance in individuals with genetic predisposition for type 2 diabetes.
Persistent organic pollutants
A popular statement is that our genes have not changed, but our environment has and that is what creates an epidemic. It has been found that a strong dose–response relation exists between serum concentrations of six persistent organic pollutants and the prevalence of type 2 diabetes11. Persistent organic pollutants (POPs) have been associated with type 2 diabetes risk by increasing IR; POPs may interact with obesity to increase the risk of type 2 diabetes11. It has been postulated that some common dietary ingredients like mono-oleoyl glycerol, iron, and saccharin are capable of producing long term hyperinsulinaemia owing to their toxic activity on beta cells, which react with the hyper-production of insulin12. Similar activity was found from arsenic, leading to an increased mortality rate from cardiovascular disease and diabetes13. A recently published article stated that Bisphenol A (BPA), in connection with insulin, can accelerate the conversion of 3T3-L1 fibroblasts into adipocytes14. There is certainly enough scientific data to explain why IR is currently a global epidemic problem.
Inflammation (the link between abdominal obesity and IR)
Research has implicated dysregulated inflammatory processes in the development of IR and cardiometabolic syndrome. Some inflammation-induced cytokines have been shown to be expressed during IR and metabolic syndrome, and mainly produced by visceral fat (Figure 2)15. For example, cytokines such as IL-1β, TNF-α, and interferon-gamma (IFN-γ) have been shown to play a role in cytokine-induced beta cell dysfunction in diabetes, as long as they are under nuclear factor-κB (NF‑κB) control. Modalities that regulate NF-κB expression may be beneficial in reducing IR and new medical research is focusing more in that direction16–18. The majority of these inflammatory cytokines are produced in metabolically-active visceral fat. In fact, when visceral fat was extracted from aged rats accounting for approximately 18% of their total body fat, it decreased the expression of TNF-α and a delayed onset of diabetes was achieved19. New functional medicine approaches of cardiometabolic syndrome include necessary treatment of the underlying inflammation (Figure 3). Inflammation consequences mediated via inflammatory cytokines leading to increased cardiometabolic risks are:
- Endothelial dysfunction
- Disruption of nitric oxide (NO) synthesis
- Arterial plaque deposition
- Oxidative stress
- Mitochondrial suppression
- Islet cell abnormalities
- Reduced glucose tolerance
A number of scientific studies20–22 have proven that low vitamin D levels are associated with IR, and that vitamin D supplementation improved IR. There is an inverse correlation between 25-hydroxy vitamin D, metabolic syndrome, and diabetes. Optimal levels of vitamin D are essential for normal insulin release, glucose tolerance, and for the regulation of serum calcium and free fatty acid metabolism. Low vitamin D levels have been implicated in heart failure, myocardial dysfunction, and sudden cardiac death. The insulin receptor gene promoter has been found to be sensitive to vitamin D supplementation. These effects were accompanied by a normalisation of the number of insulin receptors without altering receptor affinity, but improving the insulin response to glucose transport in adipocytes20–22. Checking vitamin D levels is a necessary part of extensive work towards diagnosing IR
5-Hydroxytryptophan and serotonin connection with insulin resistance
A number of human studies with 5-hydroxytryptophan (5- HTP)23–25, the precursor of serotonin, have found to be beneficial in treating IR. A well-known mechanism for developing IR from overwhelming metabolic pathways with high carbohydrate diet can be counteracted with a low GL carbohydrate. The problem is that some individuals compulsively snack on carbohydrates with a significant GL, which increases tryptophan/serotonin in the brain, temporarily reducing anxiety and depression in these individuals. This also increases the release of insulin to a degree that eventually becomes pathological. Providing an alternative, non-insulin-driven way to increase brain serotonin with 5-HTP supplements may help reduce IR, especially by reducing carbohydrate intake and decreasing hyperinsulinaemia23. Some studies identified that serotonin receptor (5-HT) are a regulator of insulin secretion, and thereby contribute a function to the colocalisation of serotonin and insulin in pancreatic β-cells through the independent receptor signalling mechanism24. There are a number of mechanisms in which abnormal liver function in metabolic syndrome can cause disturbances in brain activity and mood. The liver enzyme tryptophan oxygenase is activated by gluconeogenesis and it converts tryptophan to kynurenine, which shifts away from making serotonin and into the pathway for making glucose. Replenishing serotonin with 5-HTP can stabilise mood in this condition.
Diagnosis of insulin resistance
It is imperative to make an early diagnosis before IR becomes decompensated. In fact, identifying cases where a disease is not yet apparent is important to prevent high mortality from cardiometabolic syndrome. Signs of IR could help to identify potential cases of an under-diagnosed condition. In personal history we are looking for the following signs: specific ethnicity (Hispanic, Native American, east Asian), hypoglycaemic episodes and carbohydrate cravings, obstructive sleep apnoea, history of gestational diabetes, and menstrual irregularities in females. A physical exam will find a range of ‘non-typical’ signs often presented as aesthetic concerns in aesthetic clinics, such as abdominal obesity, adult-onset acne, hirsutism, male pattern alopecia, gynaecomastia, and acanthosis nigricans. Nevertheless, each individual with abdominal obesity should have an initial check-up for IR: lipids level, fasting glucose, and HbA1c readings. A Norfolk cohort prospective study26 showed the concentration of HbA1c significantly predicted mortality, independent of other common risk factors — even below the threshold commonly accepted for diagnosis of diabetes. Excess mortality was associated with HbA1c concentrations above 5% and predictive value for total mortality was stronger than the one documented for cholesterol, BMI, and hypertenson26. HbA1c has been checked in conventional medicine only in patients already taking anti-diabetic medication, and not as an initial check. Checking lipid levels can give some very important insights, especially the triglyceride/high density lipoprotein (TG/HDL) ratio, which is a simple test for IR:
- TG/HDL ≤ 3.0 normal — no IR
- TG/HDL ≈ 5.0 — suggestive of IR
- TG/HDL ≥ 8.0 — diagnostic of IR.
With these three parameters in combination with hypertension in individuals with abdominal obesity, a practitioner should ask the following questions: ‘Is it IR at all?’ And, ‘Is it compensated or non-compensated?’ Additional tests such as fasting insulin/glucose, postprandial glucose, and postprandial insulin can then be ordered for the full evaluation of the condition. It is interesting to mention that high fasting insulin concentrations appear to be an independent predictor of ischaemic heart disease in men. Since IR has an effect on almost all tissues in the body through mitochondrial toxicity, endothelial toxicity, and endocrine deregulation, one can only imagine the variety of the additional tests to be done for accurate diagnosis: CRP, cortisol levels, thyroid function, liver function test, CVD profile, oestrogen, progesterone, testosterone, and insulinlike growth factor (IGF)-1.
Integrative medical approach in treating IR
An emerging body of evidence27–32 suggests that the best results are achieved if the treatments are started early while IR is still in the compensated phase and an integrative medical approach is applied as following:
- Lifestyle interventions: dietary changes and weight management; exercise; stress management; POPs management (smoking cession, organic food, and support liver detoxification)
- Macro- and micro-nutritional management
- Botanical and phytonutrient supplementation.
In a study of 3234 non-diabetic subjects with high postprandial glucose, the lifestyle intervention reduced the incidence of progression to diabetes by 58% versus the metformin reduction of 31% (compared with placebo)27, revealing the importance and superiority of lifestyle changes. Dietary changes are one of the most important long‑term interventions. Adequate carbohydrate intake with low GL, high fibre, and good fats are essential. Dietary GL is defined as the product of a food’s glycaemic index (GI) and its carbohydrate content. The GL allows the assessment of the quantity, as well as the quality of the carbohydrate intake in the diet. In some studies28 there was a significant negative relationship between serum HDL cholesterol concentration and the glycaemic index of the diet for both men and women. Dietary GL is a stronger predictor than dietary fat intake of serum HDL cholesterol concentration. A decrease of 8% HDL cholesterol is associated with a 12-unit increase in the GI.
There have been approximately 40 published studies examined GI on a variety of metabolic endpoints in a period from 1981–2002, of which 35 reported results support the use of the GI concept. Taken as a group, a reduction of the dietary GI by an average of 8–40 units reduced HbA1C by 9%, urinary C-peptide 20%, and triglycerides by 19%.29 Additional support shows that plasminogen activator inhibitor-1 (PAI-1) was normalised on the low GI diet, showing a 54% decrease compared to the high GI diet30. Low GL dietary suggestions for the long term management of IR are:
- Total glycaemic load < 80 daily
- Each meal should have a glycaemic load of 20 or less
- Each snack should have a glycaemic load of 10 or less.
The GI and GL values of over 750 foods have been determined. The physician must supply the patient with a list of low GL foods since these are the most important for reversing IR. It has been shown that low fibre is a risk factor for the development of type 2 diabetes31. The high fibre diet reduced total plasma cholesterol concentrations by 6.7%, triglyceride concentrations by 10.2%, and very lowdensity lipoprotein (VLDL) concentrations by 12.5% as well as 24-hour plasma glucose and insulin concentrations by 10% and 12%, respectively. The right balance of saturated, polyunsaturated, and monounsaturated fats is important both for the prevention and treatment of diabetes. Saturated fats should be less than 10% of total calories. Total fat intake should be less than 30%. There is no evidence that high monounsaturated fat diets stimulate weight gain in patients with type 2 diabetes given that energy intake is controlled.
Exercise has been advocated by conventional medicine in all patients with type 2 diabetes, but it is accepted as an early intervention for the prevention as well as treatment of IR. Meta-analysis on exercise in type 2 diabetes suggests exercise training will reduce HbA1c, even without a change in body weight32. Moderate, consistent aerobic exercise (increases resting metabolic rate and burns fat) and resistive exercise (increases muscle mass) are highly recommended. Nutrients known to modify insulin responsiveness at the cellular level are:
- Chromium 1000 mcg/day33
- Alpha-lipoic acid 600 mg34
- CoQ10 100–200 mg35,36
- Vitamin D 2000–4000 IU daily20
- Magnesium 200–400 mg37
- Vitamins C, E, and other antioxidants38
- Omega-3 fatty acids 2 g39
- Vanadium 1–2 mg long term
It is advisable to prescribe the above nutrients in modifying insulin responsiveness only in the case of underlying deficiencies. There is much evidence documenting nutrient deficiencies in a modern society diet41,42. Among US adults, 68% consume less than the recommended daily allowance (RDA) of magnesium, and 19% consume less than 50% of the RDA. Approximately 90% of the diets analysed were below the minimum suggested safe and adequate daily intake of 50 mg for chromium, and magnesium and vitamin C intakes were low in more than 50% of the sample. Vitamin D inadequacy has been reported in approximately 36% of otherwise healthy young adults in the US and up to 57% of general medicine inpatients. It is an even higher percentage in Europe, and more than 80% in South Africa.
Recommendations cover a range of different ingredients, including:
- Green tea Consume 200 mg or more daily. Green tea decreases glucose production in the liver, decreasing hyperglycaemia, and protects beta cells as a potent antioxidant
- Cinnamon Consume 1 g daily. Cinnamon increases insulin receptor ‘receptiveness’ in skeletal muscle, increases glucose uptake and use in a skeletal muscle, and decreases beta cell distraction
- Fenugreek Consume a somewhat impractical 15 g per day. Decreases small intestine digestion of polysaccharides
- American ginseng Decreases small intestine digestion of polysaccharides. Variable effects can be experienced depending on exact ginsenoside profile
- Banaba Positive action on insulin receptor or as alpha-amylase inhibitor, as well as increasing glucose uptake and use by skeletal muscle. The specific dose has currently not been studied
Methods to decrease visceral fat and lower Inflammation, include:
- Fish oils 2 g/daily
- Boswellia 400 mg three times per day
- Curcumin 300 mg twice per day
- CoQ10 100 mg daily
- A low GL Mediterranean diet.
The danger of abdominal fat has been well researched and has moved beyond the point of being seen as just an aesthetic problem. It correlates with visceral fat that is metabolically active and associated with IR. Reactive hyperinsulinaemia and underlying inflammation are involved in the cascade process of developing cardiovascular disease, type 2 diabetes, cancers, and PCOS, which are in alarming epidemic proportions. Focus should be on identifying individuals who are insulin-resistant for an aggressive targeted intervention, mostly through long-term lifestyle changes.