It is estimated that, by 2030, 550 million people will have type 2 diabetes (T2DM) and about half will be unaware of this fact. A similar number are estimated to be at future risk of developing T2DM.1,2 The majority of new cases are due to an increase in affluence leading to chronic energy imbalance with increasing energy intake and decreasing levels of exercise, resulting in obesity. However, recent evidence suggests that the type of calories (energy) consumed can result in vastly different outcomes. The epidemic of T2DM worldwide has been correlated with a dramatic rise in obesity, but the link between the two may be more complex than it seems.
Body mass index (BMI), which has been used both clinically and epidemiologically to determine the extent of obesity, does not fully characterize the biology of excess adiposity. Fat depots can be divided into subcutaneous and visceral or fat stored in and around the internal organs and muscle. Visceral adipose tissue appears to be a better predictor of metabolic risk factors than BMI, but is difficult to measure.3 Waist circumference, which measures both subcutaneous and visceral adipose tissue, may be a better predictor of metabolic risk, including T2DM and cardiovascular disease (3).
The rise in obesity and T2DM is linked to a dramatic increase in dietary sugar intake over the last 100 years, particularly table sugar (sucrose) and high-fructose corn syrup (HFCS). Consumption in the USA increased by more than 1000% between 1970 and 1990.4 Fructose is a major component of both table sugar and HFCS and has unique biochemical, metabolic and endocrine responses that differentiate it from glucose.
Dysregulation in Complex Neurophysiological Pathways Affects Satiety
Increasing evidence suggests that fructose affects the balance of complex neurophysiological pathways, including hormonal secretions from adipocytes (leptin), pancreatic islets (insulin and amylin) and the gastrointestinal tract (ghrelin). Thus, it interferes with satiety signals and may contribute to the increase in visceral fat deposition associated with T2DM.
Fructose has a similar calorific value to glucose, but is distinct from glucose in that it doesn’t induce an insulin response or pass through the blood brain barrier to trigger a neurophysiological satiety response.5 These significant biochemical differences have a number of knock on effects.
A lack of insulin response results in decreased leptin secretion from adipocytes.6 Leptin is a key appetite-regulating hormone with influence on food intake and energy expenditure.7 Reduced insulin and leptin production contributes to increased food intake (energy), weight gain and obesity.5,8 Amylin, a pancreatic hormone co-secreted with insulin, is also known for its role as a satiation hormone in the control of food intake.9
Ghrelin has been the focus of significant research into its potent effects on stimulating food intake in animals and humans.10 An increase in insulin and glucose after a meal has been shown to decrease circulating ghrelin.11 However, fructose fails to suppress ghrelin secretion, thus contributing to decreased satiety and increased food intake.8
A cluster of metabolic risk factors known as metabolic syndrome has been shown to increase the chances of developing T2DM, cardiovascular problems and stroke. These risk factors include obesity, particularly excess body fat around the waist and internal organs; high blood pressure; high fasting blood glucose (insulin resistance); and high triglycerides with low HDL cholesterol.
Hepatic metabolism of fructose and glucose are initially different. Unlike glucose, hepatic fructose metabolism is not regulated by energy status (ATP and citrate). This results in unregulated hepatic uptake of fructose, a depletion of inter-cellular phosphate and increases in toxic uric acid.12 Unregulated fructose hepatic metabolism also results in increased hepatic lipogenesis with resulting postprandial elevations in triglyceride levels in both normal and overweight individuals.5,8 Triglyceride clearance (mitochondrial oxidation) might also be negatively affected by reduced insulin and leptin levels and decreased insulin sensitivity.5,8
Studies have also shown that a high fructose diet results in significant increases in abdominal and ectopic fat, which is fat stored in and around internal organs and muscle.13 Lipid accumulation in skeletal muscle and liver has also been associated with insulin resistance, an early hallmark of T2DM. As cells are overwhelmed by triglycerides, the intermediates of lipid metabolism, such as diacylglycerol and acyl-CoA, interfere with key proteins within the insulin-signaling pathway in these tissues.14 Initially, muscle and hepatic insulin resistance is overcome by increased insulin production by the pancreas, resulting in hyperinsulinaemia. Eventually, pancreatic failure may occur, resulting in reduced insulin production and insulin dependent diabetes.15