Apoliprotein B, A1 and Diabetes Type 2

Scientific Essay 2008 38 Pages

Medicine - Internal Medicine



Apoliprotein B, A1 and Diabetes Type

Classification of Diabetes

Feature of IFG/ IGT
Pathophysiology of Prediabetes
Natural history of type 2 diabetes
Clinical significance of prediabetes
Risk for Cardiovascular disease

Apolipoprotein A
Effect of glucose and insulin on ApoA1 gene expression
Effect of insulin resistance on ApoA1 expression
Apolipoprotein B
Insulin and apolipoproteins


Apoliprotein B, A1 and Diabetes Type

Reaz Mohammad Mazumdar

BCSIR, Dhaka, Bangladesh

Diabetes mellitus refers to a group of metabolic disorders of multiple aetiology and characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. The effects of diabetes mellitus include long–term damage, dysfunction and failure of various organs. Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss. In its most severe forms, ketoacidosis or a non–ketotic hyperosmolar state may develop and lead to stupor, coma and in absence of effective treatment, death. Often symptoms are not severe, or may be absent, and consequently hyperglycaemia sufficient to cause pathological and functional changes may be present for a long time before the diagnosis is made (WHO, 1999). It is a major health problem in all nations. Diabetes is the single, most important metabolic disease, widely recognized as one of the leading causes of death and disability worldwide (Zimmet, 1999; Songer, 1995). This devastating disease can affect nearly every system in the body. It can cause blindness, lead to end stage renal disease, lower extremity amputations and increase the risk for stroke, ischemic heart disease, peripheral vascular disease, and neuropathy. Diabetic macro and microvascular complications are resulting in increased disability and enormous health care costs (IDF, 2003).

The Global prevalence of diabetes for all age-groups was estimated to be 2.8% in 2000 and 4.4% in 2030 (Wild et al., 2004). Total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. Overall, diabetes prevalence is higher in men, but there are more women with diabetes than men (Scrichard et al., 2004). The largest proportional and absolute increase will occur in developing countries, where the prevalence will rise from 4.2 to 5.6%, and in Bangladesh, from 3.9 to 4.8%. In developing countries, the majority of people with diabetes are in the 45 to 64 years age range. In the European Region, an average total diabetes prevalence of 7.8 % in the adult population (20 - 79 years) or 48.4 million persons has been estimated in 2003 (IDF, 2003). Without effective prevention programs, diabetes prevalence in Europe is expected to increase to 9.1 % or 58.6 millions in 2025 as estimated by the International Diabetes Federation (IDF, 2003). Number of community based studies conducted in Bangladesh at different time points have revealed an increasing trend of diabetes prevalence ranging from 1.5 to 3.8% in the semi-urban and rural communities (West et al., 1966; Mahtab et al., 1983; Sayeed et al., 1995; Sayeed et al., 1997). In a recent study the prevalence of diabetic patients in Bangladeshi urban population was found to be 7.97% and age adjusted prevalence of diabetes found to be higher in urban than the rural population subjects (Sayeed et al., 1997).

Classification of Diabetes

According to the present classification of diabetes four main classes of the disease are type 1, type 2, Other Specific Types and Gestational Diabetes Mellitus (Table 1) (WHO, 1999 and ADA, 1997). Impaired glucose tolerance (IGT) was an allied category of glucose intolerance in the WHO technical report (1985) but absent in the new classification by WHO (1999). The class “Impaired Glucose Tolerance” is now classified as a stage of impaired glucose regulation, since it can be observed in any hyperglycaemic disorder, and is itself not diabetes. A clinical stage of Impaired Fasting Glycaemia (IFG) has been introduced to classify individuals who have fasting glucose values above the normal range, but below those diagnostic of diabetes (WHO, 1999). Together they are termed as prediabetes.

Table 1: Aetiological Classification of Disorders of Glycaemia (WHO, 1999)

illustration not visible in this excerpt

Gestational diabetes

Type 1 diabetes mellitus

Type 1 diabetes (T1DM) is thought to be caused by autoimmune-mediated destruction of pancreatic β-cell islets, resulting in near absolute insulin deficiency (Harris, 2000). T1DM is characterized by sudden onset of symptoms, proneness to ketoacidosis and need of insulin for survival. The hallmark of the T1DM is pancreatic B cell damage resulting in very low to absolute loss of insulin secretion. T1DM mainly seen in children and young adults and accounts for about 10% of all diabetic patients (ADA, 1997). T1DM is divided on the basis of type of damage of B cells; immune mediated type 1 (Type 1A) and non-immune mediated type 1 (idiopathic type 1, T1B) (ADA, 1997; WHO, 1999). The exact etiological factor(s) are still unknown; multiple genetic and environmental factors are thought to be involved (ADA, 1997; WHO, 1999).

illustration not visible in this excerpt

* In rare instances patients in these categories (eg Vacor Toxicity, Type 1 presenting in pregnancy, etc) may require insulin for survival.

Figure 1: Disorders of Glycemia: aetiological types and clinical stages (WHO, 1999).

Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) accounts for over 90% of cases globally. T2DM is characterized by insulin resistance and/or abnormal insulin secretion, either of which may predominate. People with type 2 diabetes are not dependent on exogenous insulin, but may require it for control of blood glucose levels if this is not achieved with diet alone or with oral hypoglycaemic agents (GCDE) and constitutes 90- 95% of cases (Harris, 2000; Bergenstal et al., 2001).

Gestational Diabetes

Gestational diabetes is carbohydrate intolerance resulting in hyperglycaemia of variable severity with onset or first recognition during pregnancy. Gestational diabetes affects 3-5% of all.

Other specific types

Other specific types are less common forms of diabetes mellitus, but there are those in which the underlying defect or disease processes can be identified in a relatively specific manner. They include, for example, fibrocalculous pancreatopathy, a form of diabetes, which was formerly classified as one type of malnutrition-related diabetes mellitus (ADA, 2005).


Impaired glucose regulation (IGR) or “Prediabetes” is the term used to describe the condition in which blood glucose levels are higher than normal but yet not diabetic. Subjects with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) are referred to as IGR or Prediabetes. The term “Impaired glucose regulation” (IGR) was used by World Health Organization (WHO) and “Prediabetes” by American Diabetic Association (ADA). IGR refers to a metabolic state between normal glucose homeostasis and diabetes. They are not interchangeable and represent different abnormalities of glucose regulation, one in fasting state and one postprandial (WHO, 1999). According to fasting and post load glucose concentration, at present patients with IGR or prediabetes may be stratified into (i) Isolated Impaired glucose tolerance (IGT); (ii) Isolated Impaired fasting glucose (IFG) and; (iII) Combined IFG-IGT (WHO and ADA, 2002).

Impaired glucose tolerance

Impaired glucose tolerance (IGT) is defined as fasting plasma glucose <6.1mmol/l and 2h plasma glucose between 7.8 and 11.0 mmol/l (ADA, 2005). Historically the term IGT was first introduced by the National Diabetes Data Group in 1979 and later, the same word was endorsed by WHO in 1980. In the adult population, age range 20-79 yrs, prevalence of IGT is projected to increase globally from 8.2 in the year 2003 to 9.0% in 2025 and in the same period in Bangladesh from 7.1 to 7.8% (Sicree et al., 2003). IGT is found to be more prevalent than IFG. The prevalence of IGT rises in old age (Unwin et al., 2002). The age standard prevalence of IFG in European population found to be round 11.8 % (Boronat et al., 2002). In a study involving Dutch population the prevalence of IGT was shown to be 13.8 % in men and 14.6% in women (Corpeleijn et al., 2006). IGT patients were followed up for 11 years in Mauritius and of them 46% found to develop diabetes, 28% remained unchanged in category, 4% developed IFG, and glucose levels normalized in 24%. A study by Shaw et al (1999) followed up adult IFG cases and of them 38% developed diabetes, 7% remained unchanged, 17% developed IGT and 38% achieved normal glucose.

Impaired fasting glucose

Impaired fasting glucose (IFG) is defined as fasting plasma glucose between 6.1 and 6.9 mmol/l and 2h plasma glucose <7.8 mmol/l (ADA, 2005). In 1997, the ADA published report mentioned IFG as a new category, which was also adopted in 1999 World Health Organization (WHO) report (Stern and Burke, 2000). Recently American Diabetic Association (ADA) has reduced the lower cut off value of fasting plasma glucose in IFG from 6.1 mmol/l to 5.6 mmol/l (ADA, 2005). IFG found to be more common among men. The prevalence of IFG tends to plateau in middle age (Unwin et al., 2002). The crude prevalence of IFG was found to be 12.4% in rural population of Bangladesh and age-standardized prevalence, however, was 13.0% (Sayeed et al., 2003). Prevalence of IFG among Dutch population found to be 9.7% in men and 6.1% in women (Corpeleijn et al., 2005). However, age standard prevalence of IFG in European population was earlier shown to be 2.8% (Boronat et al., 2002).

Combined IFG-IGT

A reasonable number of subjects, both in abroad and in Bangladesh found to have blood glucose level at the range of IFG and IGT and they are frequently known as IFG-IGT subjects; subjects with fasting plasma glucose between 6.1mmol/l and 6.9 mmol/l and 2h plasma glucose between 7.8mmol/l and 11.0 mmol/l (ADA, 2005). A group of combined IFG-IGT subjects were followed up and progression of this combined IFG-IGT to diabetes was found to be 28% per year (Rasmussen et al., 2007).

Feature of IFG/ IGT

The main feature of IFG and/ or IGT are: 1) a stage in the natural history of disordered glucose metabolism, 2) can lead to any type of diabetes, 3) increased risk of progression to diabetes, 4) increased risk of cardiovascular diseases 5) little or no risk of microvascular diseases, and 6) some patient may revert to normoglycemic (Balkau and Eschwege, 2003). IFG and IGT are asymptomatic and unassociated with any manifested morbidity, but their sole significance lies in the fact that they predict future diabetes or cardiovascular diseases (Stern and Burke 2000). Both IFG and IGT are similarly associated with an increased risk of diabetes mellitus. Risk is higher where IGT and IFG coexists (Unwin et al., 2002). IGT is more prevalent than IFG, less than or equal to 50% of people with IFG has IGT and 20-30% with IGT also has IFG (Unwin et al., 2002). From Diabetes Epidemiology: Collaborative analysis of Diagnostic criteria in Asia study it was found that IGT was more prevalent than IFG in all Asian peoples studied for all age groups (DECODA, 2003).

Pathophysiology of Prediabetes

Consensus Statement regarding IGT/IFG by the International Diabetes Federation (IDF) stated that ‘raised hepatic glucose output and a defect in early insulin secretion are the characteristic of IFG and peripheral insulin resistance is most characteristic of IGT’ (Unwin et al., 2002). This notion was supported by findings of the number of studies which have shown IFG is associated with more B cell failure (Weyer et al., 1999; Davies et al., 2000; Schianca et al., 2003; Li et al., 2003) and IGT with predominantly insulin resistance (Davies et al., 2000; Schianca et al., 2003; Festa et al., 2004). Few have, however, shown that both IFG and IGT have similar impairment of insulin action (Weyer et al., 1999; Li et al., 2003). However in contrast some have claimed that subjects with IFG had more insulin resistance and features of insulin resistance and those with IGT more defective insulin secretion in early and late phase (Tripathy et al., 2000; Hanefeld et al., 2003). The basis for this kind of variation is still unclear. Since genetic factors are involved in both b-cell failure and insulin resistance, racial variation is expected.

A recent study involving Bangladeshi IGR subjects has shown to have different pathophysiological mechanisms in IFG, IGT and IFG-IGT subjects (Rahman et al, 2006). The primary defect in IFG found to be B cell dysfunction with a tendency to insulin resistance and that in IGT insulin resistantce. Combined defects are seen in IFG-IGT subjects. Difference in pathophysiology of IFG, IGT and IFG-IGT in Bangladeshi prediabetes subjects attributed to the genetic background and environmental factor(s).

Natural history of type 2 diabetes

The natural history of type 2 diabetes, starting with normal glucose tolerance, insulin resistance, and compensatory hyperinsulinemia with progression to impaired glucose tolerance (IGT) and overt diabetes mellitus has been studied in different populations; Caucasians, Native-Americans, Mexican Americans, and Pacific Islanders (Saad et al., 1989; Haffner et al., 1995; Weyer et al., 2000; Kahn 2001; Bergman et al., 2002). Type 2 diabetes was invariably associated with the presence of obesity and the close association of diabetes and obesity often termed as diabosity. The progression from normal to impaired glucose tolerance is associated with a marked increase in both fasting and glucose-stimulated plasma insulin levels (DeFronzo, 1988; Saad et al., 1989; Lillioja et al., 1988; Jallut et al., 1990) and a decrease in tissue sensitivity to insulin. The metabolic sequences that eventually lead to T2DM precede the development of hyperglycemia by years or even decades. Insulin resistance, ie., resistance to action of insulin role in promoting glucose uptake by skeletal muscle and fat cells, is the initial metabolic defect. At first, the pancreatic b-cell is able to compensate by increasing insulin levels, leading to hyperinsulinemia. This compensation is able to keep glucose levels normalized for a period of time (up to several years), but IGT develops with mild postprandial hyperglycemia. Clinically, IFG and IGT represent a similar point along the continuum between normal glucose tolerance and frank diabetes: an essentially asymptomatic but still potentially pathological stage characterized by mild hyperglycemia. Both IGT and IFG serve as markers for those who are at greatest risk for developing T2DM. Number of clinical studies have determined the cumulative risk of developing T2DM once IGT is recognized (Rewers and Hamman, 1995). Two additional pathophysiological changes become manifest during the transition from IGT to T2DM. Insulin resistance becomes more severe, a progression that may be due not only to full expression of genetic defects, but also to acquired factors such as obesity, decreased physical activity, and aging. The second change is an increase in basal hepatic glucose production. Some controversy still exists as to whether insulin resistance or inadequate insulin secretion occurs first in the pathogenesis of diabetes. However, a general consensus has emerged that insulin resistance is the primary defect in T2DM (Eriksson et al., 1989).

illustration not visible in this excerpt

Figure 2: Insulin resistance and b -cell dysfunction combine to cause type 2 diabetes

Even though the plasma insulin response is increased two- to threefold above that in normal-glucose-tolerant subjects, overt diabetes does not develop unless a concomitant defect in insulin secretion is present. The defect in insulin secretion can be appreciated when ß-cell function is viewed relative to the prevailing severity of insulin resistance. The progression from IGT to type 2 diabetes with mild fasting hyperglycemia is heralded by an inability of the ß-cell to maintain its previously high rate of insulin secretion in response to a glucose challenge (Saad et al., 1989; Saad et al., 1988) without any further or minimal deterioration in tissue sensitivity to insulin.

Table 2: Natural history of type 2 diabetes

illustration not visible in this excerpt

The earliest detectable abnormality that precedes the onset of diabetes mellitus is an increase in the fasting and glucose-stimulated plasma insulin concentration and a decrease in tissue sensitivity to insulin (Hansen and Bodkin, 1986). With time, this high rate of insulin secretion cannot be maintained and the downward slope of Starling's curve commences. At this point, marked fasting hyperglycemia and glucose intolerance ensue. Studies have demonstrated that hyperinsulinemia precedes the development of type 2 diabetes and hyperinsulinemia is a strong predictor of the development of IGT and type 2 diabetes (Jensen et al., 2002; Dowse et al., 1996; Haffner et al., 1986; Ho et al., 1990). A sensitive and dynamic balance between tissue sensitivity to insulin and the prevailing insulin concentration exists (Warram et al, 1990; Vaag et al, 1992). In general, type 2 diabetes develops when pancreatic β cells fail to secrete sufficient amounts of insulin to meet the metabolic demand. An increased metabolic demand for insulin due to insulin resistance in several tissues usually precedes the development of hyperglycemia. There is thus a period of normal or near-normal glycemia in which pancreatic β cells compensate for insulin resistance by hypersecretion of insulin.

At some point, however, this period of β cell compensation is followed by β cell failure, in which the pancreas fails to secrete sufficient insulin and diabetes ensues (Anderson et al, 2003). The decline in insulin levels, and thus a decrease in insulin's inhibitory effects, allows for increased hepatic glucose production. b-Cell exhaustion may be genetically mediated or result from hypothesized damage to the b-cell from chronic exposure to hyperglycemia, or it may result from adverse effects of increased free fatty acids. Whatever the underlying causes and mechanisms, it is clear that the full phenotypic expression of type 2 diabetes requires both insulin resistance and b-cell dysfunction.



ISBN (eBook)
ISBN (Book)
File size
1.1 MB
Catalog Number
apoliprotein diabetes type




Title: Apoliprotein B, A1 and Diabetes Type 2