Diabetes mellitus is usually thought of as an illness involving sugar metabolism, as implied by its name. "Diabetes" refers to excessive urination and "mellitus" to "honey sweet", together indicating loss of large volumes of urine containing lots of sugar. The basic cause of most cases of diabetes is either a loss of production of the hormone insulin (diabetes mellitus 1 or DM1) or a reduced cellular response to the hormone (diabetes mellitus type 2 or DM2). In fact, diabetes mellitus involves almost all angles of metabolism. Lipid and protein metabolism as well as carbohydrate metabolism are dependent upon "physiologically correct" levels of and responses to insulin. We are accustomed to think of diabetes as a disease involving high blood sugar levels as a result of restricted tissue uptake of blood sugar. However, today we know that the loss of regulation of hepatic gluconeogenesis is an equally important element in deficient control of blood sugar levels. Measurement of blood sugar is simple, easily performed by patients and inexpensive. It remains our key to analysis of diabetes mellitus.
The current norms (2003) for blood glucose levels are shown in the following table. The upper limit for normal levels of blood glucose is currently set at less than 5.6 mmol/l while the reference level 2 hours after a glucose load is less than 7.8 mmol/l. Note that interpretation of the data is "temporary". Glucose levels swing somewhat from day to day and from individual to individual. Therefore, if high glucose levels are found, it is advised that measurement should be repeated over the following three days. Only then should hyperglycemia be noted as an enduring symptom and treatment started.
Fasting glucose levels between 5.6 mmol/l and 7.0 mmol/l indicate impaired glucose tolerance (IGT) while higher levels signify diabetes. IGT can be viewed as "pre-diabetes" as most individuals in this group develop diabetes type 2 with time.
In 2003 an expert group suggested reducing the cut point for impaired glucose tolerance from 6.1 mmoles/l to 5.6 mmoles/l. This was expected to increase the number of individuals diagnosed as prediabetics by about 20%. Many of these people have a high risk for developing diabetes type 2 (DM2) later in life. They should, therefore, be advised to revise their lifestyle and work for reduction of their hyperglycemia.
Fasting blood glucose levels are proposed as the leading indication of the metabolic state. This is a rapid, inexpensive and accurate measure of the individual's metabolic situation. The committee suggested that fasting blood sugar be determined every 3rd year after reaching 45 years of age. A glucose tolerance test was deemed unnecessary as long as fasting glucose does not exceed 5.6 mmoles/liter. However, it has recently been pointed out that many DM2 patients achieve normal fasting blood sugar levels but have an increased level after eating and that this can last throughout the day. That is, glucose levels may well reach "correct" levels while sleeping, but that insulin response may remain inadequate after meals. Since high blood glucose levels are associated with long-term diabetic damage, it may be wise to occasionally control two-hour blood sugar levels in all IGT and DM2 patients.
The suggested blood glucose standards are based upon statistical analysis of the correlation between of blood glucose levels and the development of pathological states. Among these is retinopathy, which can lead to blindness. One might have expected a linear relationship between the level of blood sugar and the development of glucose-related diseases. However, this is not the case, as shown in the next figure. Data from three independent studies are shown in which elderly Americans, Pima Indians and Egyptians were observed. These groups are known to be especially prone to development of diabetes type 2. In all cases, an abrupt increase in the frequency of retinopathy was noted when blood sugar levels exceeded 6.0-6.1 mmol/l. This toxic effect of glucose may result from sorbitol formation or follow glycation of proteins, a non-enzymatic coupling of glucose to proteins.
Two pathological processes seem to follow hyperglycemia.
1. Conversion of glucose to sorbitol with ensuing osmotic disturbance.
This occurs through the "polyol pathway", a normal reaction sequence in testes but not other tissues. In the first step, glucose is converted to sorbitol by aldose reductase. In testes, the sorbitol formed is then oxidized to fructose. A problem arises when sorbitol production occurs in other tissues. High serum glucose levels activate aldose reductase in organs which lack sorbitol dehydrogenase. There is no membrane transport mechanism for sorbitol in most cells. Activation of aldose reductase leads to an accumulation of the sugar in various tissues, increasing osmolarity of cell contents and influx of water and often denaturation of cellular proteins. In the lens of the eye, this is thought to be a factor leading to cataract formation.
2. Spontaneous non-enzymatic glucosylation of proteins.
The carbonyl group in glucose makes it a reactive compound. Glucosylation (glycation) of proteins is a normal process which follows reaction of the carbonyl group in glucose with amino groups in proteins. The process is non-enzymatic and the rate of reaction is proportional to the concentration of glucose in the blood. There seems to be no specificity here; most proteins have been found to become glucosylated to a limited degree. It is believed that coupling of sugar molecules to proteins does affect their various functions. Thus, oxygen transport in the retina is thought to be disturbed by glucosylation, leading to development of fragile capillaries, bleeding and retinopathy.
Hemoglobin is one of many proteins which become increasingly glucosylated as blood sugar levels rise. Glucosylated hemoglobin is known as HbA1c. Normally, about 5,5 % of the circulating hemoglobin is combined with glucose. Hyperglycemia can result in a two to three-fold increase in HbA1c . Since the turnover rate for hemoglobin is approximately 100 days, HbA1c values give a picture of the patient's mean blood glucose levels over this time interval. The therapeutic goal for treatment of diabetes is to reduce HbA1c levels to less than 7.0 %.
In effect, glucosylation amounts to denaturation of proteins, this altering the function of important proteins. This is especially important in the nervous and renal tissues and the microcirculation. Glucosylation is thought to be the cause of many of the "late symptoms" of diabetes.
Marked improvements are seen in patients with small changes in HbA1c. In the following table we can see that a 1% fall in HbA1c resulted in improvement in retinopathy and kidney, nerve and cardiac function in the large studies quoted here.
Classification of diabetes mellitus.
Most diabetic patients fall into one of two classifications, diabetes type 1 and diabetes type 2. In the USA and Europe about 80% of all diabetic patients have the type 2 variant.
Patients with diabetes type 1 are afflicted by an autoimmune illness which results in complete destruction of pancreatic insulin-producing cell, the so-called beta cells of the islets of Langerhans. These chronologically ill persons must receive insulin to survive. Given proper guidance they can experience a relative normal life. However, this requires that they take over the responsibilities of the beta-cell "manually". That is, they must monitor their blood sugar level, plan their physical activities and their meals and calculate the amount and type of insulin that they must administer. No easy situation! Hypoglycemic episodes due to unbalanced insulin dosing does occur in the patients.
Those with glucose intolerance or type 2 diabetes are often initially treated by adjusting lifestyle and diet. However, DM2 and IGT are progressive situations. That is, resistance to insulin action develops over a period of years. While changes in diet and motion can initially hinder development of hyperglycemia, many of these patients become dependent upon administration of insulin with time.
Specific treatment of the detailed cause of diabetes type 2 is seldom possible. It would be of great advantage to have exact knowledge of the origin of glucose intolerance and diabetes type 2 in each patient. More than 40 differing causes have been found in some very few cases. These mainly involve enzyme mutations. This is an active research area and may, with time, lead to advances in treatment.
Gestational diabetes is a passing hyperglycemia in pregnancy. This is a genetically determined condition and is handled without insulin treatment. Women who acquire gestational diabetes often develop diabetes type 2 later in life.
Insulin was first identified in pancreatic extracts by Banting and Best in 1922. The first patient who received insulin was 14 year old Leonard Thompson, also in 1922. Diabetes type 1 was a fatal disease prior to Banting and Best's work. We are accustomed to assuming that diabetes patients can be treated and can live a good life. It is therefore shocking to find that treatment of diabetes type 1 with insulin is not economically possible for many patients in underdeveloped countries.
Diabetes type 1 results from an autoimmune destruction of the ß-cells of the pancreas. It has been most commonly accepted that this is a genetically controlled process associated with HLA alleles. However, current knowledge has shown that development of DM1 is not strongly associated with heredity, while there is a strong genetic component in development of DM2. There is a age-dependent spreading of the disease and this has changed with time. Increasing evidence points to a combination of factors leading to beta cell destruction. The disease most commonly develops before 20 years of age as is shown in the figure to the left. However, incidence (cases/100,000) of the disease has changed in the latter half of the 20th century. Patients develop diabetes at an earlier age and the frequency has increased. This implies that there are other factors than the genetic which lead to development of DM1. The figure and data are from Norway and can be found in "The Rise of Childhood Type 1 Diabetes in the 20th Century", Medscape or in the original publication (Diabetes 51, 3353, 2002).
A further indication that factors other than the genetic are involved in development of diabetes type 1 is shown in the next figure. The data are also from Norway and show a clear decrease in the frequency of diabetes type 1 in adults during World War 2 (cases/100,000). This strongly suggests that social and economic factors are involved in development of the disease. The scanty diet and need for physical activity experienced during the war led to weight reduction in many adults. Overweight has been clearly shown to be involved in development of DM2. Is this also a factor in development of DM1? Note that most children who develop DM1 are thin when symptoms develop due to loss of energy as urinary sugar.
The abrupt initiation of DM1 usually noted often follows a viral infection. It has been assumed that beta-cell destruction is an ongoing process but that it is accelerated by such infections. The mechanism involved remains unknown.
It has been commonly assumed that antibodies and T cells specifically attacked beta cells, leading to insulin deficiency and destruction. However, in a recent publication, Shawn Winer et al have shown that Schwann cells which surround the Langerhans islet are autoimmune targeted and destroyed before the autoimmune attack on beta cells and loss of beta cell activity. It appears that antigen-presenting cells move from islets to the pancreatic lymph mode where cell-specific antigens are produced. These attack Schwann cells surrounding the islets, destroying the Schwann cell capsule which surrounds islets. Beta cell destruction follows. (Nature Medicine 9, 198-205, 2003).
Most DM1 patients are today completely dependent upon injections of insulin to sustain life. Current research is aimed at developing oral agents capable of activating the insulin-signal pathway downstream of the insulin receptor. Recently, inhaled insulin preparations have been developed and shown to be quite effective. Click here for information about these. The need for injected insulin may perhaps be eliminated in the future.
Why don't we replace lost ß-cells?
One might think that we could replace destroyed ß-cells and restore insulin secretion and control of metabolism. After all, blood cells, skin and intestine do not disappear after loss of tissue. This was the question a group of researchers at Harvard put forward in a recent study. They investigated generation of ß-cells in mice and looked for formation of new pancreatic islets in adult animals. Surprisingly, they found that no new islets could be identified. In adult mice, ß-cells are formed only by self-duplication and appeared not to arise from stem cells. The permanent loss of ß-cells seen in diabetes type 1 may, therefore, occur because only pre-existing ß-cells give rise to new insulin-producing cells in the adult. The loss of insulin producing ß-cells seen with time in diabetes type 2 may also develop through this mechanism. Go to the original article for more information. Click here to call up "Adult pancreatic ß-cells are formed by self-duplication rather than stem-cell differentiation", Dor et al, Nature 429, 41 (2004).
Is replacement therapy possible?
A fascinating approach to diabetes type 1 therapy would be to replace pancreatic beta-cells with new cells produced in the laboratory. Is this possible? Can we produce human beta cells in vitro? In a recent publication in Science Express 25, November 2004 1-10, Gershengorn et al (click here) present data showing conversion of human pancreatic fibroblast-like cells to insulin-producing cells. Cell replacement therapy just might be possible, but it remains to be seem whether or not fibroblasts in vivo can give rise to viable insulin-producing cells.
Diabetes mellitus type 2 arises from a reduced response of target tissues to insulin (so-called insulin resistance). Insulin levels are often quite high in early type 2 diabetes and resistance to the hormone is counteracted by increased stimulation of the hormone receptor. The etiology of insulin resistance remains unclear, although many hypotheses have been set forth. You can click here for information about insulin's mechanism of action and possible sites development of resistance to this crucial hormone.
We have a better understanding of the physiological changes that give rise to DM2. There is a very clear association between overweight (BMI 25-30) and obesity (BMI>30), the metabolic syndrome, and development of diabetes type 2. A genetic factor is also clearly involved as many ethnic groups are predisposed for the disease. More detailed information about the causes of and classification of diabetes mellitus can be found here.
Diabetes type 2, earlier called "maturity -onset diabetes", typically develops over a period of many years. It usually begins parallel with weight-gain, goes through a period of reduced response to ingested sugar (glucose intolerance or IGT), and ends with the full-blown diabetic state. In contrast to diabetes type 1, the disease develops slowly and goes through several stages as shown in the following figure. Obesity seems to be the most common initiating factor in development of diabetes type 2. The patient typically goes through a period of increasing weight parallel with a loss of sensitivity to insulin, so-called insulin resistance. The body normalizes the metabolic state by producing higher levels of insulin after meals. Usually, the patient is unaware of his or her situation. Following a period of many years, the pancreatic ß-cells no longer manage to continue their enhanced insulin secretion. Insulin levels fall in the face of continuing insulin resistance, resulting in increased fasting blood glucose levels and markedly increased postprandial levels of serum glucose. Increased postprandial blood glucose is the direct cause of the late-onset symptoms of diabetes. The most common cause of blindness is retinopathy which follows glycation of proteins in the retina. Diabetes patients have a 5-fold increased rate of cardiovascular disease compared to "normal" persons. Kidney failure and amputations due to damage to the microcirculation are common among diabetes patients.
An open question is the cause of the increasing fasting blood glucose levels seem in type 2 diabetes mellitus. Very recently, a report by Mitro et al demonstrated that glucose alone ( without additional hormone signals) controls synthesis of key enzymes of hepatic gluconeogenesis and fat production. A possible fail in this direct glucose signalling might possibly be involved in the rise in fasting glucose levels seen in type 2 diabetes. Click here for more information.
It should be noted that the global wave of obesity we now experience applies also to young children. Social factors (fear of kidnapping, parents who drive kids to school and after-school activities, passive TV and PC use, etc.) contribute to reduced physical activity and obesity in children. Simultaneously, energy intake is often increased through an ever-increasing consumption of fast foods, soda pop, sugar coated breakfast food, snacks and confection. Decreased physical activity coupled to increased food intake must and does lead to pronounced weight gain.
Energy-rich foods appear to function abnormally in control of appetite. That is, they do not dampen appetite quickly enough to control eating. Thus, people who use "quick food" often "over-eat", taking in excess calories which often lead to obesity. One possible explanation for this may be the increased use of sugar (sucrose or glucose-fructose mixes) in the food industry. Increased fructose consumption, either from sucrose or the pure monosaccharide may partially explain this lack of appetite control. The hypothalamus includes the appetite center which takes up and metabolizes glucose. Glucose dampens appetite. The hypothalamus does not have fructokinase activity and, there, does not respond to fructose. That is, only half of the sugar intake influences appetite. Pancreatic beta cell also are without fructokinase and do not secrete insulin in response to increased fructose. Insulin is a major controller of appetite in the hypothalamus. Thus, the calories fructose contributes to the diet are not registered by "Appetite Control" and may play a major role in the current obesity epidemic. Diabetes type 2 in young children (formerly limited to adults) is now a serious and growing problem. Control of the long-term symptoms of diabetes type 2 will be a difficult and very expensive problem in the coming decades.
Energy expenditure, the key to weight gain?
There are very many factors, both known and unknown, involved in normal weight regulation. However, the end result is the consequence of the balance between the amount of energy in the ingested food and the amount of energy used. Hormone levels, altered hormone receptors, mutated metabolic enzymes; all of these do influence appetite and energy use. However, the bottom line is, you are what you eat (and do not burn). That is, ingested food in excess of that oxidized to CO2 will be stored as fat. Look at the next figure (modified after Marks, Marks and Smith, Basic Medical Biochemistry). The activity levels shown here correspond to those that are normal in a modern society. A young male student uses most of the energy in his food to support normal body functions (basal metabolism or BMR). Only about 20% of the consumed energy go to support physical activity.
If one leads a more active life (cycling to work, using stairs instead of the elevator, some sports after studying), the total daily energy use increases to about that level that the average person used for 100-150 years ago. It is estimated that, at that time, both men and women used about 3000 kcal/day for the usual daily chores. Note that at this activity level physical activity still accounts for not more than 25-30% of the total energy used daily.
A heavy activity level, as judged by our modern standards, will increase energy use to around 3500 kcalories/ day. By the way, lumberjacks using axes and hand saws are said to have used about 5000 kcalories per day!
The drawings to the right show the result of balancing (or not balancing) food intake with energy expenditure. Clearly, eating more than one uses is "expansive", a balanced food and energy use results in a stable body mass while under nutrition leads to weight loss.
Previously, one could assume that "appetite control" would automatically adjust our feelings of hunger and satiety so that we ate enough to maintain body weight in tact with energy expenditure. Note that for "moderate activity" physical activity accounted for about one-third of the total energy expenditure. "Appetite control" operated in an area of about 1000 kcal/day balancing BMR + physical activity against ingested food. Today, most people use considerably less energy to drive physical activity. For many, about <500 kcal over BMR is all that used. The result is that "Appetite Control" must operate within a set of small limits to cover required intake without exceeding this and favoring fat accumulation. To bring this to the point, note that a nicely packed commercial chocolate cupcake contains about 500 kcalories! It is quite easy to exceed the daily required food intake. Control of appetite and the regulation of metabolism associated with meals appear to be a function of the hypothalamus. Click here for more information.
Weight gain is seen in many societies where the average food intake has not increased. What then, causes increased weight? Many experts believe that a sedentary or passive life style is the best explanation for the trend to overweight. That is, weight gain is more closely related to energy use than energy intake. What has changed in the past decade?
A recent editorial in Mayo Clinical Proceedings listed some examples of sedentary and active ways of doing things. Many of the recent advances (read labor-saving) in our daily environment reduce energy utilization. Given some assumptions one can calculate the approximate difference in total energy use between the "easy and hard" ways of doing common tasks. This lies somewhere around 10,000-15,000 kcal every month or two. That is the equivalent of 1-1,5 kilograms of body fat. People who change life style from an active to a sedentary pattern can in fact increase weight by 5-10 kilos in a year or so. Few of us take this into account when we plan our meals! Doing things the active way, a partial switch to a plant-based diet with no more than 30-35 calorie-% fat and moderate daily motion for between 30-60 minutes should help keep the fat away for many people.
We all have heard that "our western way of life" leads to the physical downfall that we have experienced during the past 10-20 years. The fact is that obesity is a global phenomenon linked more to physical activity than race and culture.
WHO has stated "At the other end of the malnutrition scale, obesity is one of today’s most blatantly visible – yet most neglected – public health problems. Paradoxically coexisting with malnutrition, an escalating global epidemic of overweight and obesity – “globesity” – is taking over many parts of the world. If immediate action is not taken, millions will suffer from an array of serious health disorders".
Let us look at rates of obesity in a global perspective. We have most data from USA and England, but also some data from South America and the Pacific area . About 25-30% of the populations of USA and England have now a BMI of 30 or more. We see the same trend in a little island in the Indian Ocean (Mauritius) and the trend in Brazil is not much better. The most striking figures come from the Pacific region. Here, around 70% of the adults on some islands are obese. The prospects facing health officials and physicians are grim.
Overweight and diabetes type 2.
As I have previously stated, there is a striking correlation between central obesity (or body weight) and the incidence of DM2. We can look at some examples of this in the following two figures. In the first we see the incidence of obesity among Americans state by state. In the course of a nine-year period, the incidence of obesity (BMI>30) rose from 10-14% to greater that 20% for many Americans.
If we than look at development of diabetes in the same period, we find that the frequency of diabetes (mostly DM2 hade risen from <4% to more than 6% for most of the USA. These figures are a minimum, many individuals have impaired glucose tolerance or "pre-diabetes" for many years before they are diagnosed as having DM2.
Now, correlations are one thing, proof of cause is another. However, the evidence that overweight and obesity are coupled to development of diabetes type 2 is very strong. This is very well presented and discussed in a CME program that you can find at Medscape.com by clicking here.
The situation is well-described in the following quotations from Paul Zimmet's article entitled:
"… Type 2 diabetes is poised to become one of the major challenges to public health in the 21st Century and will result in a huge economic burden, particularly in developing nations, through premature morbidity and mortality.
…there will be more than 230 million people with diabetes by 2010. The majority of the new cases will be those with type 2 diabetes.
... Type 2 diabetes is the tip of the iceberg of a cluster of cardiovascular disease (CVD) risk factors, including obesity, hypertension, and dyslipidemia, otherwise known as the "Metabolic Syndrome," "New World Syndrome," or "Deadly Quartet." The natural consequence will be an epidemic of cardiovascular complications, such as coronary heart disease and stroke as well as microvascular complications.
… An important and alarming feature of the diabetes epidemic is that type 2 diabetes is increasing in these younger age groups. In China, Japan, and in the Pacific Islands, more than 70% of children presenting with diabetes have the type 2 form.
… Obesity and lack of exercise have been implicated in this trend, that has been labeled as "Nintendonization". Children are often driven to and from school and then come home and race to the computer or computer-game station instead of playing games or sports outdoors".
Paul Zimmet MD, PhD
60th Scientific Sessions of the American Diabetes Association
June 10, 2000
Genetic background is a strong component in the development of type 2 diabetes. People of western European origin are less sensitive to the effects of overweight than non-Europeans. In the USA, blacks and Latinos have a higher frequency of diabetes type 2 than whites. Asians, especially Chinese and Japanese, develop metabolic syndrome and diabetes type 2 at lower body weights than whites. Thus, these groups develop diabetes 2 in the BMI range from 25-30.
This "puzzle" of sensitivity to diet and development of type 2 diabetes was taken up in a recent article by Jared Diamond in Nature. A figure from this article is presented below. Prevalence of diabetes is relatively low in Europeans and native people living in their accustomed environment. However, native people who convert to a western diet or urban life present a markedly increased incidence type 2 diabetes. Genetic variation can explain differing frequencies of diabetes development in diverse racial groups. However, development of type 2 diabetes among urbanized groups must be a response to the environment. Genes do not change so quickly!
One explanation for this has been the development of a set of "thrifty genes", a genetic adaptation to a poor milieu with a meager diet. A switch to an urban diet and activity level is suggested to rapidly lead to obesity and associated illnesses in such people. Please go to the original article for discussion of this data.
An excellent review article concerning the development and possible causes of the global diabetes epidemic can be found here.