Pathophysiology Type 2 Diabetes Exercise Therapeutic Intervention Biology Essay

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The objective of this essay is to look at the pathophysiology of type 2 diabetes and examine the specific role of a exercise as therapeutic intervention. Type 2 diabetes mellitus is a "multifactorial metabolic disorder which is characterized by chronic hyperglycemia, insulin resistance, and a relative insulin secretion defect" (Surampudi et al, 2009). The pathophysiology of Type 2 DM involves impaired insulin secretion, and impaired insulin action in regulating glucose and fatty acid metabolism in the liver, skeletal muscle, and adipose tissue (Kelley & Goodpaster, 2001). The underlying pathophysiology and complications of type 2 diabetes mellitus are still being investigated. Recent advances in diabetes research have helped to gain a better understanding about insulin resistance and insulin secretion defects (Surampudi et al, 2009). Appropriate use of physical exercise can improve insulin sensitivity and glycemic control, decrease the need for oral medications or insulin and therefore be considered a viable therapeutic intervention (Nelson et al, 2002).

Diabetes mellitus has reached epidemic proportions and affects more than 170 million individuals across the globe (figure 1). Global estimates for the year 2010 predict a further growth of almost 50%, with the greatest increases in the developing countries of Africa, Asia, and South America.1 In more developed societies, the prevalence of diabetes mellitus has reached about 6%,2 and, even more alarmingly, among obese white adolescents 4% had diabetes and 25% had abnormal glucose tolerance.3 Some 90% of diabetic individuals have type 2 (non-insulin-dependent) diabetes mellitus, and within this category no more than 10% can be accounted for by monogenic forms such as maturity onset diabetes of the young and mitochondrial diabetes or late-onset autoimmune diabetes of the adult, which is actually a late-onset type 1 diabetes. Thus, "most diabetes in the world is accounted for by type 2 diabetes, which has a multifactorial pathogenesis caused by alterations in several gene products" (Stumvoll et al, 2005).

Figure 1- The Estimated Number (Millions) of people aged 20-79 with diabetes in 2001 (Stumvoll et al, 2005).

Pathophysiology of type 2 diabetes mellitus

Insulin resistance or reduced insulin sensitivity as it is sometimes refered to as , is present in type 2 diabetes, but also in "obese subjects, in smokers, in patients with increased production of insulin antagonistic hormones such as cortisone and growth hormone, in connection with severe and stressful diseases, and induced by certain medications for example thiazide diuretics" (Scheen, 2003). By defnition, insulin resistance entails the need of elevated than normal plasma insulin levels to maintain normoglycaemia. Therefore, hyperinsulinaemia may be regarded as a marker of insulin resistance (Reaven 1995). The presence of insulin resistance in vivo can be evidenced during various dynamic tests such as an oral glucose tolerance test, an intravenous glucose tolerance test and a so-called euglycaemic hyperinsulinaemic clamp which is regarded as the gold standard measurement (Scheen, 2003). It can be seen that various organs play a crucial role in the pathophysiology of type 2 diabetes. Disruption of the cross -talk between endocrine pancreas, liver, skeletal muscle, adipose tissue and, presumably, gut and central nervous system may lead to alteration of glucose homeostasis and type 2 diabetes (Figure 2) (Scheen, 2003).

Figure 2 - Contribution of endocrine pancreas, liver, skeletal muscle and adipose tissue in the pathogenesis of type 2 diabetes : emerging role of ectopic fat storage in liver, muscle and beta-cell and of adipose tissue as an endocrine organ releasing various adipocytokins in addition to non-esterifi ed fatty acids (NEFA) in presence of positive energy balance and obesity (Scheen, 2003).

The major sites of insulin resistance in type 2 diabetes include the liver, skeletal muscle and adipose tissue (Shulman 1999). In the liver, insulin resistance conveys increased glucose production post-absorptively and reduced suppression of the production of glucose post-prandially. Post-absorptively, a big part of the glucose is consumed by non-insulin-dependent tissues and only about 25% of the glucose is taken up in insulin sensitive tissues and under those conditions, insulin resistance in the liver plays a more important role for glucose metabolism than insulin resistance in extrahepatic tissues. Post-prandially, on the other side of things, glucose is taken up in similar amounts by the liver and the skeletal muscles. Thus, the insulin sensitivity in liver and muscle play an equally important role after a meal (Ostensson, 2001).

The increased hepatic glucose production is possibly related to enhanced gluconeogenesis (Shulman 1999), and it is likely that increased plasma levels of FFAs account for this by activation of some key gluconeogenetic enzymes. Type 2 diabetic patients commonly will also exhibit increased activity of hepatic glucose-6-phosphatase, resulting in increased glucose production through the glucose cycle pathway (Efendic et al,1988). In skeletal muscle and adipocytes, abnormalities have been found in the insulin signalling cascade, resulting in impaired activity of the insulin-regulated glucose transporter GLUT-4. As GLUT-4 expression is normal in muscle from type 2 diabetic patients, the impaired glucose transport could possibly be accounted for by defective insulin mediated translocation of GLUT-4 to the muscle cell surface. Among the detected abnormalities include "decreased activity of tyrosine kinase and decreased activation of insulin receptor substrate-1 (IRS-1) associated phosphatidylinositol 3-kinase and protein kinase B, or Akt kinase" (Shulman 1999).

Impairment of the insulin response to glucose in the pancreatic b-cells is not only a hallmark of type 2 diabetes; it is also a requirement for the disease to develop (Efendic & Ostenson, 1993). The regulation of insulin secretion is extremely complex (Efendic et al, 1991). In addition to glucose, other nutrients such as certain amino acids and free fatty acids (FFAs) stimulate insulin secretion. Gastric hormones, such as glucagon-like polypeptide-1 (GLP- 1) released at food intake, and cholinergic and b2-adrenergic agonists may potentiate the glucose Figure 1 Proposed pathogenesis of type 2 diabetes. effect, while a2-adrenergic agonists, somatostatin and some prostaglandins inhibit insulin release. The mechanism behind impaired insulin release in type 2 diabetes is as yet unknown, but is likely to reside in a defective stimulus-secretion coupling for glucose (Efendic et al, 1991). It is generally accepted that b-cell metabolism of glucose generates ATP that closes ATP sensitive K+ channels, leading to depolarization of the b-cell membrane, opening of voltage-dependent Ca2+ channels, which in turn contributes to increased cytosolic calcium concentrations and exocytosis of insulin. In this complex chain of events, as well as in its modulating factors potentiating or suppressing insulin release, there are several possibilities for interference, resulting in impaired insulin release (Ostensson, 2001).

It is generally agreed that the pathogenesis of the disease has certainly got strong genetic and environmental Components (Hamman, 1992). Genome-wide association studies have led to the identification of many genetic loci and over 220 genes (with several demonstrated in the table 1) with associations that may confer an increased risk of developing T2DM (Gaulton, 2008). There appear to be associations between fetal growth patterns, birth weight, paternal IR and/or T2DM, and umbilical cord insulin concentrations and later susceptibility to T2DM (Florez, 2008)

Table 1 - Genes implicated in Diabetes (Surampudi et al, 2009).

The majority, 70-85% of the patients with type 2 diabetes appear to have a polygenic inheritance which acts in tandem with environmental factors in the development of the disease via stage of impaired glucose tolerance. The environmental or acquired, factors often relate to lifestyle, and compromise overweight, low physical activity and tobacco use (Hamman, 1992).

Figure 3 : Contribution of genetic predisposition and environment factors in the pathogenesis of type 2 diabetes and interplay between defective insulin secretion and insulin resistance leading to a vicious circle explaining the progression from impaired glucose tolerance (IGT) to type 2 diabetes and the progressive aggravation of the disease (Scheen, 2003).(

Exercise as a therapeutic intervention

Exercise, in addition to diet modification and medication, has commonly been recommended as the main components to diabetic therapy (Nelson et al 1959). People with type 2 diabetes are encouraged to increase physical activity, because several studies suggest there are several potential areas where exercise does appear to have positive effects, although these data are not established in a highly robust manner and usually are derived from relatively small studies without control groups (Thomas et al, 2007).

Exercise is seen to improve (decrease) the insulin resistance of peripheral tissues, and in particular, to alleviate the defect of insulin stimulated glycogen metabolism in skeletal muscle (Ericsson et al 2008).

Exercise was seen to improve postprandial hyperglycemia, even if the effect on fasting hyperglycemia was minimal. There are some data that suggest there could be improvement of postprandial insulin secretion (Houmard et al 2004).

A relatively small number of studies suggest that exercise acutely lowers hepatic glucose production in Type 2 DM (Kelley & Goodpastor, 2001).

Studies of patterns of substrate utilization during exercise appear to indicate that there is substantial similarity in the metabolism of glucose by peripheral tissues in comparing non-diabetic and Type 2 DM individuals, at least at moderate intensity exercise. This would indicate that despite marked defects in insulin-stimulated glucose metabolism in peripheral tissues (mainly skeletal muscle), contraction-mediated patterns of substrate use are substantially similar in diabetic and non-diabetic individuals (Kelley & Goodpastor, 2001).

With the publication of various clinical studies several of which can be seen in table 2, it is becoming increasingly clear that exercise may be a therapeutic tool in a variety of patients with or at risk for diabetes. There are few contrasting studies (Table 3) which would make one question the therapeutic benefits of exercise although several of these studies involve low participant numbers, lacking power to show significant differences which may appear in larger trials. (Ostenson, 2001).

Today exercise, dietary changes and medications are frequently used in the management of type 2 diabetes. However, it is difficult to determine the independent effect of exercise from papers because exercise has been combined with dietary modifications or medications, or compared with a control which includes another form of intervention (Thomas et al, 2007). Also even though exercise is commonly recommended as part of diabetic therapy, its effects in type 2 diabetes are not well documented as comments there have been no large studies with adequate statistical power to guide practitioners in recommending exercise programmes for the management of type 2 diabetes (Kelley & Goodpastor, 2001). Published exercise intervention trials, using different types of intervention, usually have small sample sizes since they are difficult and expensive to conduct (Thomas et al, 2007). The findings have varied Table 2 & 3.

Table 2




Study duration


Tuomilehto et al. 2001


Moderate Exercise 30mins a day

3.2 years

Reduction in the incidence

of diabetes

Wannamethee et al.


5,159 men

Regular walking or



Sporting (vigorous)

16.8 yr

Decrease in incidence of type 2 diabetes mellitius; Decrease in risk of


Houmard et al. 2004


115 min/wk low-volume/

high-intensity jogging

6 months

Decrease in insulin resistance

Tokmakidis et 2004


2 strength training sessions and 2 aerobic training session per week

4 months

Significant reductions were observed

in both the glucose and insulin

areas under the curve.

Table 3




Study duration


Fenicchia et al.2003


resistance exercise program using weight-lifting machines 3 days per week

6 weeks

no significant

changes in insulin concentrations for control or intervention groups

Eriksson et al.,

1998 (7)


Circuit traing 3 times a week

3 months

No significant change in insulin secretion, insulin resistance or glucose control