Diabetes in Asians: The ‘Thin Outside, Fat Inside’ (TOFI) phenotype

As a pharmacist and Certified Diabetes Educator, I see a lot of people with diabetes. Most of my patients these days are Asian as well, because I speak fluent Cantonese and a decent amount of Mandarin. A question that comes up a lot is, “I have a pretty active lifestyle, I am reasonably fit and I don’t eat or drink sugary things like pop or juice—so why do I have diabetes?”For reference, these individuals are visually quite lean, their BMI is around 23-24.5 and they walk or hike most days of the week. We know that as BMI increases, the risk of type 2 diabetes goes up as well but a BMI of 23-24.5 still falls within the normal/healthy weight category—so how does that make any sense?The answer is not so simple. In fact, there are a number of factors that increase the risk of diabetes, such as aging, genetics, body fat and low muscle mass. As we get older, the cells in our body become less sensitive to insulin (the hormone that helps cells take in sugar from the bloodstream). We also lose muscle which means we dispose of even less sugar, AND our pancreas begins to lose the ability to produce insulin.If you have a first-degree family member with diabetes, your risk increases twofold. If this family member developed diabetes before the age of 40, your risk is actually 7-9 times higher.1,2Now let’s talk about fat.TOFI—Thin Outside, Fat InsideA common phenotype in Asians is TOFI— Thin on the Outside, Fat on the Inside. This means the individual is visually thin because they have very little subcutaneous fat but they actually carry a lot of visceral fat (and possibly ectopic fat as well).3For reference, visceral fat is fat that surrounds the organs in the intra-abdominal cavity and ectopic fat is fat found inside organs that are not meant to store fat. Normally when you eat more calories than you burn, excess energy is stored in the form of triglycerides in subcutaneous adipose tissue.It has been hypothesized that Asians have impaired subcutaneous adipose tissue (SAT) storage, meaning there is a limit to how much fat can be stored subcutaneously. Once that limit is reached, excess fat “spills over” into other sites—typically the visceral and ectopic depots.Visceral fat can surround organs in the intra-abdominal cavity, such as the pancreas, liver and intestines, while a classic example of ectopic fat is fat in the liver—commonly known as fatty liver.So how would you know If you have a lot of visceral or ectopic fat?Measures like Body Mass Index (BMI) and Waist Circumference (WC) can help screen for individuals who may have elevated visceral and/or ectopic fat, but unless you complete an MRI or a CT scan, there’s no definitive way to determine the amount and its distribution inside the body.However, there ARE some body-fat scales at gyms and medical clinics that estimate visceral fat. There is also a device called a FibroScan that uses ultrasound-based technology to detect fatty liver.So what does TOFI have to do with diabetes? It’s actually the accumulation of visceral and/or ectopic fat that induces insulin resistance and elevates diabetes risk3,4,5. Large population studies have shown that visceral fat is strongly linked to insulin resistance and a higher risk of dysglycemia (abnormal blood sugar).Visceral fat is metabolically active and releases:Pro-inflammatory cytokines that disrupt insulin signalling in liver and muscle, resulting in insulin resistance3,5. Some of these cytokines (IL-6, TNF-a) also inhibit the production of adiponectin, a hormone produced by subcutaneous fat thatimproves insulin sensitivitypreserves beta cell functionlowers fasting glucoseprevents ectopic fat buildupreduces inflammation andprotects against diabetes and cardiovascular disease3Free-fatty acids that drain into the liver, leading to:fatty liverincreased glucose output from the liveroverproduction of lipid particles (VLDL)elevated triglyceridesand eventually hepatic insulin resistance3.Ectopic fat, on the other hand, can accumulate inside organs such as the liver, muscle and pancreas. And actually, Asian or not, individuals with type 2 diabetes generally have more ectopic fat, particularly in the liver.6 Fat inside the liver impairs insulin signaling, resulting in hepatic insulin resistance and increased glucose production.6 That is what leads to elevated fasting blood sugars.In Asians, hepatic fat is more strongly associated with the progression of prediabetes to diabetes than visceral fat alone.7,8,9 South Asians in particular have been shown to have higher hepatic and intramuscular fat and lower lean mass compared with other ethnic groups too.8How about fat inside skeletal muscle? Fat in this compartment actually disrupts the muscle’s ability to take up glucose from the bloodstream. Asians are particularly vulnerable because lower muscle mass and intramuscular fat deposition translates to a reduced ability to burn fat. As a result, fat accumuates in the muscle, driving even more insulin resistance.10Then there is fat in the pancreas, which contributes to beta-cell dysfunction and impaired insulin secretion. Even in individuals without diabetes, higher pancreatic fat is associated with poorer insulin secretion.BMI and Asian cut-offsTOFI is the reason why the regular BMI cutoffs are not fully applicable to Asians because type 2 diabetes often occurs at a lower BMI.4 The World Health Organization (WHO) defines overweight as a BMI of 25.0-29.9kg/m2 and obesity as a BMI of ≥30kg/m2.BUT many Asian countries have revised their obesity criteria based on the growing evidence that metabolic risk is elevated at a much lower BMI. For example, early studies in Hong Kong Chinese patients found that diabetes and cardiometabolic risks started to increase at a BMI of 23 kg/m2, while other studies reported a threshold in the range of 22-25kg/m2.4The KSSO (Korean Society for the Study of Obesity) found the risk of type 2 diabetes, dyslipidemia and hypertension increased linearly as BMI rose from 23 to 25.11 Compared with individuals of normal weight (BMI of 18.5-22.9), a BMI of 23-24.9 was associated with:a 2.4-fold increase in the risk of type 2 diabetesa 1.2-fold increase in the risk of a heart attacka 1.2-fold increase in the risk of ischemic stroke.In patients with a BMI range of 25-29.9, those risks increased even more— 1.6-fold, 1.6-fold and 6.5-fold, respectively.11Yikes.Level of risk and BMIA multiethnic cohort study on Canadians in Ontario found that a BMI of 30kg/m2 in Caucasian subjects was associated with the same incidence of diabetes as a BMI of 25kg/m2 in Chinese subjects and 24kg/m2 in South Asians.4 The conclusion is that diabetes develops earlier, at a higher rate and at much lower BMI levels in Asians compared to Caucasian subjects.Multiethnic studies have found that at any given BMI, Asians have more visceral adiposity (that is, about 3-8% more body fat) compared to Caucasians, and it is this visceral fat that confers the additional metabolic risk.4Compared to Caucasians, the body fat percentage was found to be:5-7% higher in Indian men8% higher in Indian women5% higher in Indonesian menand 7% higher in Indonesian.10And that’s not all—if you’re Asian, even modest weight gain significantly increases your risk of diabetes. A 5-kg increase in body weight raises the risk of diabetes by 84% in Asians, compared with 44% in Hispanic, 38% in African American, and 37% in Caucasian.4What about waist circumference?Waist circumference (WC) is a simple and inexpensive tool for assessing abdominal obesity. As the WC goes up, the cardiometabolic risk increases as well. In the United States and Canada, a WC ≥ 102 cm (in men) or ≥ 88 cm (in women) indicates an increased risk of visceral adiposity.13However, these standard cutoffs underestimate the risk in Asians, so as expected, the thresholds are lower. Under the Obesity Canada guidelines, the recommended cutoffs for South Asians, Southeast Asians and East Asians is lower:≥ 85 cm in menand ≥ 75 cm in womenYou may also see ≥90cm in men and ≥80cm in women in guidelines endorsed by various international organizations and societies.12While visceral fat isn’t directly visible—because it could be deep inside the abdomen wrapped around internal organs—central obesity is a strong external sign that visceral fat is present, especially if the individual is lean elsewhere. As visceral fat increases, it occupies more space within the abdominal cavity, increasing intra-abdominal pressure and causing the abdominal wall to protrude outward.Enough about fat—let's talk about muscleCompared with Caucasians, Asians are more likely to have lower muscle mass. One study examining muscle mass in middle-aged and older Korean adults found that a low muscle mass index (MMI) was strongly associated with the incidence of diabetes independent of obesity, and that having sufficient muscle mass may even confer a protective effect in those with a high BMI.14 Other studies have similarly reported that low muscle mass was associated with insulin resistance, dysglycemia and pre-diabetes.14,15And it actually makes a lot of sense if you think about it. Skeletal muscle is a metabolically active organ, accounting for about 30% of the resting metabolic rate and disposing of about 80% of blood glucose after eating.14,15 Having less muscle means having a lower capacity to take up and store glucose—so where does the excess glucose go? It ends up getting stored in the ectopic and visceral fat depots.In other words, low muscle mass prediposes you to accumulating more harmful fat, which then drives insulin resistance and dysglycemia.Does reducing visceral and ectopic fat improve diabetes?Yes. A reduction in visceral and/or ectopic fat is associated with improved insulin sensitivity and better pancreatic beta-cell function.16,17 This is also why a 10-15% reduction in body weight early in type 2 diabetes can induce remission.17 There are a number of lifestyle interventions that can reduce visceral and ectopic fat such as exercise, a hypocaloric diet or a combination of diet and exercise.One study found that 12-14 weeks of diet-induced and exercise-induced weight loss produced similar reductions in abdominal obesity and visceral fat.18 In fact, a 7% reduction in body weight was associated with a 25% reduction in visceral fat.18Another study of previously sedentary postmenopausal women (mixed race but predominantly Caucasian) showed that 200 minutes per week of moderate-intensity exercise consisting of both aerobic exercise and resistance training — resulted in a 4.2% loss of total body fat and a 6.9% loss of intra-abdominal fat.19So what types of exercise are best?Exercise promotes muscle fat oxidation (burning fat for energy), which means less fat gets diverted to visceral fat depots. Technically, aerobic exercise, resistance training and combined aerobic + resistance training have all been shown to be effective at reducing visceral and ectopic fat in patients with type 2 diabetes.20And while reductions in visceral and subcutaneous fat are closely linked to overall weight loss, a decrease in hepatic fat can occur independently of significant weight changes.20Aeroboic exercises are activities that increase your heart rate and involve large muscle groups — for example, biking, hiking, dancing and brisk walking. Some studies suggest that aerobic exercise may be more superior than combined exercise in reducing ectopic fat, particularly hepatic fat, and that resistance training alone doesn’t produce much change in visceral fat.20,25 Other studies, however, have found that combined aerobic and resistance is more effective than either type of exercise alone at reducing visceral fat.20This makes a lot of sense because while aerobic exercise reduces body fat, resistance training increases muscle mass. So if you are currently doing only aerobic exercise, I strongly encourage incorporating some resistance training as well to help preserve or build muscle mass. Keep in mind that exercise can and should produce some weight loss — and that usually means a combination of both muscle and fat. Resistance training helps to prevent some of that muscle loss.There are many benefits to combined aerobic and resistance training. Most of them are pretty well known —such as improved cardiovascular health (including blood pressure and lipid profile) and mental health — but there is one that is less obvious: bone health.Did you know that having type 2 diabetes is associated with a higher risk of osteoporosis and fractures? Lifetime fracture risk is about 40-70% higher in those with type 2 diabetes.21 Chronic hyperglycemia impairs bone remodeling and damages bone-forming cells, called osteoblasts, which leads to more porous, weaker bones. Combination exercise programs that include resistance training are encouraged because they help maintain bone and muscle mass and improve balance.One study also suggests that frequency matters as well—ideally 30-60 minute sessions at least 3 times a week for at least 10 months.22 This is consistent with the recommendations made by the following organizations:Diabetes Canada (DC): 150 minutes of moderate-to-vigorous intensity aerobic exercise PLUS 2 to 3 sessions of resistance training per week.23American Gastroenterological Association (AGA): 150-300 minutes of moderate intensity exercise or 75-150 minutes of vigorous-intensity aerobic exercise per week. Resistance training can complement aerobic exercise, but should not replace it.24An exercise worth mentioning also is HIIT—High Intensity Interval Training, which has been shown to reduce visceral fat. HIIT is a type of exercise that alternates between short bursts of very intense activity and periods of rest or low-intensity recovery. An example would be a 30 second sprint (or fast cycling, fast stair climbing, burpees, etc.) followed by 90 seconds of slow walking, repeated 8-10 rounds.Most studies on HIIT have focussed on visceral fat, so data on ectopic fat reduction (like hepatic fat) is still quite limited.25 HIIT is thought to produce favourable changes in visceral fat by enhancing basal metabolic rate and post-exercise oxygen consumption more than moderate-intensity continuous aerobic exercise in those with a high BMI.25Interestingly, a meta-analysis found that HIIT running was more effective than HIIT cycling at reducing visceral AND total fat mass, while HIIT cycling was more effective at reducing total abdominal fat mass.26 This is likely because running builds larger muscle mass compared with cycling, and the type of muscle contractions involved in running stimulates greater fat oxidation at the same relative intensity.Additionally, post-exercise oxygen consumption is about 37% higher after a running session than after a cycling session.26While HIIT is generally considered safe and well-tolerated, it may not be appropriate for individuals who:have uncontrolled type 2 diabetes or uncontrolled hypertensionhave had a recent cardiac eventare not accustomed to moderate- or vigorous-intensity exerciseBefore beginning any intense exercise program, it’s best to undergo an evaluation first —especially if there are any cardiac concerns.Ok, so what about diet?To be fair, this topic deserves a post of its own (and will be a future article). However, what I can tell you now is that short-term studies on low-calorie and low-carb diets have shown reductions in visceral and liver fat. In contrast, ketogenic diets without calorie restriction generally did not show much effect.Please remember to consult a healthcare provider for an assessment before starting any diet, as some approaches may not be appropriate for everyone and long-term data are still quite limited.If you have higher than normal visceral and/or ectopic fat, should you avoid fats?People tell me all the time they “can’t eat fat” because they already have elevated body fat. You do not need to avoid ALL dietary fats. Remember—there are good fats and bad fats. Most major organizations organizations, including the American Gastroenterological Association and Diabetes Canada, recommend limiting saturated fat, avoiding trans fat and prioritizing unsaturated fats from plant or marine sources (such as olive oil, nuts, seeds and fatty fish).24Saturated fat—such as that found in red meat or processed meats—is positively associated with an accumulation of visceral and ectopic fat, so it should be minimized. Studies have show that unsaturated fats (plant oils, nuts, seeds, fish) are inversely associated with liver fat, visceral fat and intramuscular fat because they are preferentially oxidized for energy and do not activate the lipotoxic pathways that divert storage to visceral and ectopic depots.27An important dietary pattern to highlight is the Mediterranean diet, which has been shown to be beneficial in the treatment and management of many metabolic conditions including cardiovascular disease, diabetes and fatty liver. It emphasizes daily consumption of fresh vegetables, fruit, legumes, minimally processed whole grains, fish and omega-3 fatty acids such as olive oil, nuts, and seeds as primary fat sources, with limited intake of dairy, red meat and processed meat.24Remember, though, that any excess calories—whether from fat, carbs or protein—can ultimately be converted into visceral fat or ectopic fat if your energy intake exceeds what your body can use! The key point is: don’t eat excess calories.SummaryAsians generally have a lower BMI, but at the same BMI as Caucasians, they tend to have lower muscle mass and higher amounts of visceral and ectopic fat (Remember TOFI - Thin Outside, Fat Inside)BMI and Waist Circumference cutoffs for defining metabolic risk are lower for AsiansAccumulation of visceral and ectopic fat drives insulin resistance and pancreatic beta-cell dysfunctionIt’s not just about body fat — low muscle mass is also strongly associated with diabetes. Maintaining or increasing muscle mass helps reduce insulin resistance (and is protective against osteoporosis)Aim for at least 150 minutes of moderate-to-vigorous intensity aerobic exercise PLUS 2 to 3 sessions of resistance training per weekCombined aerobic and resistance training is more effective than either exercise alone for reducing visceral fat, but aerobic exercise may be more effective than combined training for reducing liver fatResistance training alone is likely not very effective for reducing visceral fatHIIT, like aerobic exercise, is effective for visceral fat; data on ectopic reduction is limited.A calorie deficit can help reduce visceral and ectopic fatYou do NOT need to avoid ALL dietary fats — limit saturated fat, avoid trans fat and prioritize unsaturated fats from plant and marine sourcesExcess calories from any macronutrient (fat, carbs or protein) can still be converted into visceral or ectopic fatA Mediterranean diet is beneficial for managing and treating many metabolic conditions, including cardiovascular disease, diabetes, and fatty liver.Lysa Leong, BSc(Pharm), PharmD, CDE is a Vancouver pharmacist and host of The Cheerful Pharmacist podcast. 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Diabetes in Asians: The ‘Thin Outside, Fat Inside’ (TOFI) phenotype

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