- Diabetes Type II is caused by a reduction of insulin sensitivity.
- Diabetes ranks in the top 5 for mortality in developed countries.
- Obesity and sedentary life-style are largely to blame for the diabetes epidemic.
- Adipocyte-secreted factors can induce insulin resistance in skeletal muscle.
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PREVALENCE AND PATHOLOGY OF TYPE 2 DIABETES MELLITUS
Type 2 mellitus (T2D or T2DM) has already been described in the medical books of the ancient civilizations of Egypt, Greece, India, Rome and China. It has been claimed that the ancient Chinese have tested for diabetes by observing whether ants were attracted to a person?s urine or not. Medieval European doctors have tested for diabetes, by tasting the urine of diabetic patients, and named it ?sweet urine disease?. The urine contains saccharides because glucose can not be utilized by the organs due to reduced insulin sensitivity.
While Type 2 mellitus occurs throughout the world, it is most common in more developed countries. 2006 246 Million or 6,0 % of the world population were known to be affected. In 2025 that number is expected to rise to 380 Million (7,3 %). Type 2 causes complex and multi-factorial metabolic changes which ultimately lead to damage and function impairment of many organs, most importantly the cardiovascular system, and hence increase the mortality and morbidity significantly.
It has been suggested that in developed countries there are about five times as many deaths indirectly attributable to diabetes than directly attributable. This stems for example from the fact that mortality from diabetes is related to heart disease. This would mean that accounts for about one in twenty of all deaths. (Murray CJL, Lopex A (1996) The Global Burden of Disease. WHO: Geneva). Hence, diabetes type 2 ranks amongst the top five of the most significant diseases in the developed world when it comes to mortality rates.
Additionally, diabetes is the leading cause of new cases of blindness among adults aged 20--74 years and the leading cause of end-stage renal disease, accounting for approximately 40% of new cases. Approximately 60%--70% of persons with diabetes have neuropathy, and >50% of lower limb amputations in the United States occur among persons with diabetes.
REASONS FOR THE ONSET OF T2D
A number of lifestyle factors have long been known to affect the prevalence of Type 2 . Individuals who had high levels of physical activity, a healthy diet (defined as one high in fiber, with a high polyunsaturated to saturated fat ratio, and a lower mean glycemic index), did not smoke, and consumed alcohol in moderation had an 82% lower rate of Diabetes Type 2 as studies have shown. When a normal weight was included the rate was 89% lower. On its own, weight is the largest contributor to Type II occurrence. Obesity contributes approximately to 55% of type 2 diabetes cases. The increased rate of childhood obesity in between the 1960s and 2000s in Diabetes Type 2 is thought to be due to increased average weight and is believed to be the key factor in explaining today?s increase in children and adolescents. Additionally to increased weight a sedentary life-style is a crucial contributor to the onset and progression of the disease.
The risk to develop Type II is about 25% higher for first-degree relatives of diabetic patients. Interestingly, the risk in monozygotic twins the concordance rate for any abnormality of glucose metabolism (either Type II diabetes or impaired glucose tolerance) at 70 years of age exceeded 90% in several studies. Cultural factors are thought to contribute to this effect as well, i.e. obesity that may not only be genetically determined but also passed on by risk behaviours that run in families or are cause by the general social surrounding (even though it is debated as to how much obesity is caused by social influences). Secondly, genetics are thought to be the major contributor to the risk for Mellitus Type II. Genes that are significantly associated with developing Type 2 Diabetes, include a long list. A few of them are: , , , , , , , , and .
Environmental toxins may contribute to recent increases in the rate of Type 2 . Also, rare medical conditions, such as subclinical Cushing's syndrome ( excess) may be associated with Diabetes Mellitus Type 2.
PHYSIOLOGY OF TYPE 2 DIABETES MELLITUS
Since obesity is a key risk factor in the development for T2D the research focus is very much on adipose tissue. Adipose tissue does not only modulate energy balance by regulating both food intake and energy expenditure, but importantly for the onset of Type 2 it also has considerable effect on glucose balance, mediated by endocrine secretion. This is accomplished mainly through the synthesis and release of peptide hormones, the so-called adipokines and non-endocrine mechanisms. Among these factors are: , , and , , , and , and others.
Adipocytokines can induce insulin resistance through several mechanisms, including -mediated serine phosphorylation of , -mediated activation, induction of and production of . Most importantly, adipocytes also release non-esterified fatty acids (NEFAs) into the circulation. They are primarily released when glucose supply is limited and serve as a nutrient source for most organs.
The physiological purpose of circulating NEFAs is to reduce glucose uptake into muscle and adipocytes in order to promote lipid burning as a fuel source in most tissues, in order to spare carbohydrates for neurons and red blood cells, which solely depend on glucose as an energy source. Interestingly, while they serve a purpose under starvation these exact effects match the type 2 diabetic pathology under non-starvation situations.
Several mechanisms have been proposed to account for the effects of NEFAs on muscle, liver and adipose tissue, including activation, oxidative stress, formation, and activation of . A chronic exposure to NEFAs causes a decrease in secretion in various tissues. It has been argued that this effect may involve lipotoxicity which may (amongst other effects) act on mitochondrial membrane potential (reducing oxidative capacity), ATP synthesis and secretion.
Therapies that improve insulin action include ligands which often target adipose tissue. Amongst the most common therapeutics are drugs (i.e. thiazolidinediones like Pioglitazone and Rosiglitazone) that bind and activate the nuclear receptors peroxisome and . PPAR-gamma/RXR form heterodimers that regulate transcription of genes involved in insulin action, adipocyte differentiation, lipid metabolism and inflammation.
The role of skeletal muscle
Also skeletal muscle develops insulin resistance and eventually Type II . It is still debated whether this is merely a secondary effect, as described above, or if muscle is an independent contributor to Type 2 . Accumulation of lipid inside the muscle cell is known to cause insulin resistance, and to reduce insulin stimulated glucose uptake in muscle tissue. A reduced skeletal muscle oxidative capacity can enhance this. Furthermore, type 2 diabetes is associated with an impaired switching from fatty acid to glucose oxidation in response to insulin, the so-called metabolic inflexibility.
The cause of these derangements in skeletal muscle of Type 2 Diabetic patients remains to be elucidated. An impaired mitochondrial function is a likely candidate. Evidence from both in vivo and ex vivo studies supports the idea that an impaired skeletal muscle mitochondrial function, such as oxidative capacity, is related to the development of insulin resistance and type 2 diabetes mellitus.
In muscle , an energy sensing kinase, has been identified as a target for development of pharmaceuticals for prevention and treatment of type 2 diabetes. activation stimulates fat oxidation, glucose uptake into muscle, inhibits lipogenesis and cholesterogenesis, increases hexokinase and content in muscle, and most importantly, enhances insulin sensitivity. Three upstream kinases have been identified: , , and . Specific transcription factors or coactivators such a are phosphorylated by the active , which is crucial for the diverse effects of the .
Other targets of interest in muscle that offer potential in treating insulin resistance are and possibly . Activators of (fibrates, such as Bezafibrate, Ciprofibrate, Gemfibrozil, Clofibrate, and Fenofibrate) offer several wanted side-effects, like improving dyslipidemia, and hypertension and in preventing diabetic nephropathy, inflammation, and cardiovascular disease.
There is now clear evidence that obesity associated with or without
Type 2 is an inflammatory state, consistent with the production of
and other cytokines by adipose tissue. This is probably directly connected to adipose tissue releasing NEFAs, glycerol, and hormones ? including
? and ultimately by release of proinflammatory cytokines. In obesity, the production of many of these adipokines is increased. This causes chronic inflammation of white adipose tissue and is thought to contribute to insulin resistance.
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