Dr Aidin Rawshani
En bittersöt historia om socker, livsstil, miljö och okunskap
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The saga of diabetes is one of the most extraordinary examples of translational research. At the beginning of the twentieth century, diabetes was a rare but rapidly fatal childhood disease. Revolutionary discoveries during the first half of the century transformed it into a condition with which people could live for many years. By the end of the century, childhood diabetes was the second most common chronic disease of childhood but it would represent less than 10% of all cases of diabetes. Instead, the adult form of diabetes emerged as one of the most common and most serious diseases mankind has ever faced. A brief review of the history of diabetes is warranted, particularly as some facts are relevant to this thesis. The term diabetes mellitus was coined by the Greek physician Aretaeus (80-138 C.E.) to describe a rare condition characterized by sweet tasting and excessive urine accompanied by weight loss and fatigue. In 1776, Matthew Dobson confirmed elevated glucose levels in the urine of individuals with diabetes. Little did either of them know that the sweetness would bring about a very bitter taste for mankind in the twentieth century. Dramatic advances in the understanding of diabetes followed. Researchers deciphered gluconeogenesis,1 glycogenesis, glycogenolysis,2 hormones and enzymes involved in glucose metabolism.3,4 In 1889, Oskar Minkowski and Joseph von Merring performed pancreatectomies on dogs and observed that it caused fatal diabetes. They suspected that the pancreas was essential to glucose metabolism.5 Fredrick Banting and Charles Best discovered insulin in 1921 after treating diabetic dogs with an extract from the pancreas of healthy ones.6 They succeeded in purifying insulin from bovine pancreases the following year and thus created a life-saving treatment.7 A few decades later, the insulin gene was cloned and recombinant DNA technology made unlimited supply of insulin available.8 As outlined by Polonsky, the saga of diabetes is extraordinary and overflowing with discoveries, many of which have extended beyond diabetes. Female researchers – Dorothy Hodgkin, Rosalyn Yalow and others – have played an essential role.9 Diabetes has changed a great deal since the endeavours of Banting and his colleagues. They recognized diabetes as a rare disease that develops primarily in thin children and adolescents; a phenotype commonly referred to as type 1 diabetes. This form of the disease is the result of an autoimmune destruction of the insulin-producing pancreatic beta cells (Figure 1A). Nowadays, type 1 diabetes is fairly common in children and adolescents. But the great majority of individuals with diabetes have developed the disease during or after adulthood; this form is called type 2 diabetes and it coincides with overweight, a sedentary lifestyle and high calorie diets. The ensuing metabolic disturbances in diabetes damage the circulatory system.10,11 Diabetes doubles or triples the risk of macrovascular complications (coronary heart disease, stroke and peripheral artery disease). The risk of microvascular complications (neuropathy, nephropathy and retinopathy) is 5 to 10 times as high.12-17
Type 1 diabetes and the enigma
Type 1 diabetes represents an epidemiological conundrum. Although early health statistics are scarce, available data suggest that the disease was very rare at the beginning of the twentieth century. Its incidence appears to have been stable until the 1950s, when an increase was documented in several countries.18 This trend prompted researchers to launch international multicentre studies. These efforts took off in 1980 and included subjects aged 14 and younger.19 The Diabetes Epidemiology Research International (DERI) study group,20 the World Health Organization’s Diabetes Mondiale (DIAMOND) project,21 and the EURODIAB are among the studies.22 These sources have reported an annual 3% increase in the incidence of type 1 diabetes since the 1980s.21,23,24 The steepest increase has been noted in the 0-4 age group, and the mean age at onset has decreased. The incidence in Europe is predicted to rise by 70% between 2005 and 2020 (Figure 1B).25 The explanation for the increase remains elusive. One hypothesis is that improved survival has increased the pool of susceptible genes. However, the rapid increase in the incidence and the striking spatiotemporal variations cannot be explained by genetic changes alone.26-29 It follows that environmental factors are making a major contribution. Something has changed in the environment, causing more children and adolescents to develop type 1 diabetes, at a younger age and with less genetic predisposition.26,30 The trigger that elicits the autoimmune process is totally unknown.31 It is believed that the increase in individuals aged 14 and younger represents a left shift in the age of onset as mirrored by a corresponding decrease in the remaining population. It implies that the cumulative incidence has not changed; individuals simply develop the disease earlier in life, which is why some refer to it as the spring harvest theory.18,19,32 Epidemiological studies have been contradictory in this regard. Two out of three noteworthy studies that support the spring harvest theory originate from Sweden.33-35 Reports from Finland,36 Italy,37 and the UK,38 however, have showed stable or increasing incidence up to the age of 39. It is imperative to resolve the conflicting findings, as they have implications for both research and clinical practice. Figure 1 | (A) Pathogenesis of type 1 diabetes, as proposed by Eisenbarth et al.39 (B) The Incidence of type 1 diabetes has increased 3% annually in the last few decades. Finland and Sweden exhibit the highest incidence rates in the world. Adapted from Atkinson.31
Advances AND CHALLENGES
Management of type 1 diabetes has progressed in the last few decades. The cornerstone of management is intensive insulin therapy to maintain low blood glucose without provoking hypoglycaemia.40 This task has been facilitated by improved insulin preparations and methods for insulin delivery,41 as well as self-monitoring and real-time continuous monitoring of glucose levels.42 The future holds additional promising solutions.43 It is likely that the risk of diabetes-related complications and mortality has decreased in the last decades. Yet individuals with type 1 diabetes still have 2 to 3 times as great a risk of death and their life expectancy is reduced by more than a decade.13,44 In summary, what was once a rare and rapidly fatal condition is now the second most common chronic childhood disease. Despite great strides in knowledge and management, people with type 1 diabetes still face a markedly elevated risk of cardiovascular disease and death. It has been suggested that the cumulative incidence is stable and that the spring harvest theory explains the increase among children. Continued epidemiological surveillance, along with basic science research, will be crucial to discovering the trigger of this autoimmune response.
Type 2 diabetes and the worldwide explosion of obesity
Type 2 diabetes is a different story altogether. In 2013, the International Diabetes Federation called diabetes a worldwide health crisis and one of the most serious diseases humankind has had to face. Approximately 400 million individuals are living with diabetes and another 300 million have impaired glucose tolerance, a precursor to diabetes. The pandemic is engulfing the world. Diabetes caused 5 million deaths in 2013, a figure that is predicted to increase by 50% over the next few decades. The crisis is escalating even though most cases of type 2 diabetes are preventable.45 Developing countries are experiencing the greatest increase in the burden of the disease. It is important to understand just how the pandemic emerged. Gaziano et al discuss the process of epidemiological transition.46 The concept suggests that all societies pass through different epidemiological stages that imprint health and disease. These epidemiological stages are denoted in Figure 2. All societies go through these stages, although at different times and at varying progression rates. The main causes of morbidity and mortality varies between these stages. High-income countries (HICs) started the transition in the early twentieth century and have arrived in stage V. Low- and middle-income countries (LMICs) emerged from stages I and II decades after HICs and progressed rapidly; roughly 80% of people with diabetes today live in LMICs. Figure 2 | Stages of the epidemiological transition.
Most of human history has been characterised by pestilence and famine. Infections and malnutrition were the principal causes of disease and death throughout the world until 1900. Improved nutrition, cleaner water, increased food production and distribution, rising income and public health measures led to declining rates of infections and malnutrition. Life expectancy increased and agrarian societies industrialised. The age of receding pandemics had ended around 1950. Urbanization and industrialization led to radical lifestyle changes. Diets high in saturated fats and carbohydrates, increased smoking and reduced physical activity led to the advent of hypertension and atherosclerosis. Life expectancy increased further due to medical progress and cardiovascular risk factors manifested in coronary heart disease and stroke (collectively referred to as cardiovascular disease). These conditions accounted for 35% to 65% of all deaths during the period of degenerative and manmade disease, which culminated between the 1960s and 1970s.47 As life expectancy continued to increase, the age of delayed degenerative diseases emerged. Cardiovascular disease and cancer were the predominant causes of disease and death, but age-adjusted cardiovascular death rates declined by almost 50%. The reduction was due to aggressive treatment of hypertension, as well as public health campaigns that targeted smoking and consumption of atherogenic diets. The encouraging decline in cardiovascular disease is now up against an unabated increase in overweight, which marks the age of inactivity and obesity. The explosion of overweight and obesity has caused a pandemic in both HICs and LMICs that affects all age groups. It is plausible that the increasing obesity explains the fact that age-adjusted cardiovascular mortality rates have levelled out for young women in the United States.48 One in three Americans are obese,49 and one in five Chinese are overweight or obese.50 Almost 1.5 billion adults were overweight in 2008. The increase is particularly pronounced in LMICs.51-54 Low-income groups in LMICs are experiencing the greatest increase in overweight and obesity.55 It appears that poor people in LMICs are most susceptibility to developing obesity and diabetes.55,56 It should also be mentioned that beta cell function declines with age and the increased longevity has certainly reflected this on the diabetes prevalence.57
Our way of life has changed much in the last century. Urbanization and automation have evolved in tandem since the beginning of the twentieth century. Mass-production of automobiles began in 1910. Cars enabled long distance travel, reduced the need to walk or ride a bicycle and, along with automation, made work and daily life increasingly sedentary. Energy expenditure has declined steadily ever since Henry Ford introduced Model T. Diet in the twenty-first century is characterized by large portions, processed foods, beverages high in sugar, an abundance of saturated animal fats, hydrogenated vegetable fats (containing atherogenic trans fatty acids) and simple carbohydrates. Consumption of plant-based foods is decreasing. Increased dietary fats – particularly saturated fats and trans fats – are promoting obesity, insulin resistance, beta cell dysfunction and glucose intolerance.58 Soft drinks and other beverages high in sugar cause weight gain while increasing the risk of type 2 diabetes and coronary heart disease.59 Maternal overweight during pregnancy can induce epigenetic and gene expression changes in utero that increases the risk of developing type 2 diabetes.60 Industrial production of tobacco started in the 1920s, when cigarette machines were invented. Evidence of the harmful effects of tobacco emerged in the 1960s.61,62 Despite growing evidence, the consumption of tobacco continued to increase for several decades. Only in recent years has the increase plateaued out in HICs, whereas LMICs are experiencing increasing tobacco use.63-65 Tobacco attracts unhealthy habits such as excess consumption of alcohol, soft drinks and processed foods. Smoking per se is associated with insulin resistance and increased risk of type 2 diabetes; a recent study showed that nicotine increases lipolysis, which results in body weight reduction, but this increase also elevates the levels of circulating free fatty acids and thus causes insulin resistance in insulin-sensitive tissues.66-68 Thus, urbanization, automation, automobiles, calorie dense foods, soft drinks, processed foods, tobacco – and habits associated with these phenomena – are the underlying causes of the cardiovascular and diabetes pandemic. These factors can be controlled primarily through legislation.
The irony OF Cuba
Advances in the understanding and treatment of type 2 diabetes over the last two centuries have been extraordinary. In terms of disease, however, no progress has been made since Dobson’s discovery in 1812. The situation is worse than ever and the most worrisome trend is in LMICs, from where migration to HICs is increasing. Given the experience of the tobacco epidemic, it is unlikely that the obesity trend can be reversed in the near future. However, there is evidence that the pandemic can be halted. Shortly after the fall of the Soviet Union in 1989, Cuba suffered an economic crisis due to the loss of its main trading partner. Cubans could no longer enjoy the same level of produce and other amenities. Shortage of food, lack of public transportation and economic hardship reduced food, alcohol and tobacco consumption while people walked or rode their bicycles more. The proportion of physically active Cubans doubled in the first 5 years and average body mass index dropped 1.5 kg/m2, while deaths from diabetes, coronary heart disease and stroke declined by 51%, 35% and 20%, respectively.69 Thus, there is hope but tackling the diabetes pandemic will necessitate legislative actions. In summary, type 2 diabetes has emerged as one of the most common and most serious diseases humanity has faced. The greatest burden of disease and the most adverse trend in risk factors take place in LMICs, from where migration to HICs is accelerating.
Pathogenesis of type 2 diabetes
Blood glucose is regulated by a feedback loop between beta cells and insulin sensitive tissues (hepatic, skeletal muscle and adipose tissue). Insulin sensitivity in these tissues regulates the beta cell response via a feedback signal that is yet to be discovered. What is clear, however, is that the feedback increases as insulin sensitivity diminishes, stimulating beta cells to secrete more insulin in order to maintain glucose metabolism (Figure 3). The longstanding notion that beta cell failure is a late manifestation that is preceded by insulin resistance has been revised. Beta cell function is reduced for years or decades before the onset of diabetes. By the time type 2 diabetes is clinically manifest, more than 80% of beta cell function has been lost.10,70 Genetic predisposition, ethnicity and the environment all govern beta cell function.71-73 Despite scientific advances, the usefulness of genetic markers is very limited once clinical indicators such as obesity, hypertension, dyslipidaemia, blood glucose and family history have been assessed.74,75