METABOLISM Diabetes mellitus, a common metabolic disorder resulting from defects in insulin secretion or action or both and is characterized by an increase in insulin resistance in conjunction with the inability of pancreatic beta cells to secrete sufficient insulin to compensate (American Diabetes Association, 2005; Centre for Disease Control and Prevention 2005). Mortality and morbidity in T2DM are due to occurrence of microvascular complications such as diabetic nephropathy, neuropathy and retinopathy along with macrovascular complications such as accelerated atherosclerosis causing ischemic heart and cerebrovascular disease ( Morrish NJ, et al. 2001). Types of Diabetes mellitus Two major forms of diabetes occur—Type 1 diabetes mellitus (T1DM) and Type-2 diabetes mellitus (T2DM). T1DM occurs when the insulin-producing β-cells in the pancreas are destroyed, typically by an autoimmune, T 13
80
Embed
METABOLISMshodhganga.inflibnet.ac.in/bitstream/10603/32535/8/4... · Web viewThe polyol pathway, shown schematically in Fig: 3, focuses on the enzyme aldose reductase. Aldose reductase
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
METABOLISM
Diabetes mellitus, a common metabolic disorder resulting from defects in
insulin secretion or action or both and is characterized by an increase in
insulin resistance in conjunction with the inability of pancreatic beta cells
to secrete sufficient insulin to compensate (American Diabetes
Association, 2005; Centre for Disease Control and Prevention 2005).
Mortality and morbidity in T2DM are due to occurrence of microvascular
complications such as diabetic nephropathy, neuropathy and retinopathy
along with macrovascular complications such as accelerated
atherosclerosis causing ischemic heart and cerebrovascular disease
( Morrish NJ, et al. 2001).
Types of Diabetes mellitus
Two major forms of diabetes occur—Type 1 diabetes mellitus (T1DM) and
Type-2 diabetes mellitus (T2DM). T1DM occurs when the insulin-
producing -cells in the pancreas are destroyed, typically by anβ
autoimmune, T cell-mediated mechanism, resulting in the production of
insufficient amounts of insulin (Wang TT, et al. 1998). T2DM is caused by a
resistance to insulin combined with a failure to produce sufficient insulin.
T2DM is commonly linked to obesity, which can cause insulin resistance
(Henegar JR, et al. 2001; Chagnac A, et al. 2003). Despite the different
pathogenic mechanisms of T1DM and T2DM, they share common
symptoms including glucose intolerance, hyperglycemia, hyperlipidemia
and similar complications. A pivotal role for reactive oxygen species (ROS)
13
METABOLISM
has been proposed in both the development of insulin resistance and in
the pathogenesis of both micro- and macro-vasculature complications
(Sharma K, et al. 1999; Zanatta CM, et al. 2008; Brosius FC, et al. 2008).
Etiology and Pathophysiology of Type-2 Diabetes
Etiology
Diabetes mellitus has reached epidemic proportions and affects more than
170 million individuals worldwide. 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 (Zimmet P, et al.
2001). In more developed societies, the prevalence of diabetes mellitus has
reached about 6% (King H, et al. 1995) and, even more alarmingly, among
obese white adolescents 4% had diabetes and 25% had abnormal glucose
tolerance (Sinha R, et al. 2002) 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 (Fajans SS, et al.
2001) and mitochondrial diabetes (Maassen JA, et al. 2004) or late onset a
utoim-mune diabetes of the adult, which is actually a late-onset type-1
diabetes (Pozzilli P, et al. 2001). Thus, most diabetes in the world is
accounted for by “common” type-2 diabetes, which has a multifactorial
pathogenesis caused by alterations in several gene products.
14
METABOLISM
The medical and socioeconomic burden of the disease is caused by
the associated complications, (Wei M, et al. 1998; UK Prospective Diabetes
Study (UKPDS), Lancet 1998) which impose enormous strains on health-
care systems. The incremental costs of patients with type-2 diabetes arise
not only when the diagnosis is established but at least 8 years earlier
(Nichols GA, et al. 2000). The devastating complications of diabetes
mellitus are mostly macro vascular and micro vascular diseases as a
consequence of accelerated atherogenesis. Cardiovascular morbidity in
patients with type-2 diabetes is two to four times greater than that of non-
diabetic people (Zimmet P, et al. Nature 2001).
Pathophysiology of Type-2 Diabetes
To understand the cellular and molecular mechanisms responsible for
type-2 diabetes it is necessary to conceptualise the framework within
which glycemia is controlled. Insulin is the key hormone for regulation of
blood glucose and, generally, normoglycemia is maintained by the
balanced interplay between insulin action and insulin secretion.
Importantly, the normal pancreatic β-cell can adapt to changes in insulin
action i.e. a decrease in insulin action is accompanied by upregulation of
insulin secretion (and vice versa). Figure: 1 illustrates the curve linear
relation between normal β-cell function and insulin sensitivity (Bergman
RN, 1989). Deviation from this hyperbola, such as in the patients with
impaired glucose tolerance and type-2 diabetes in fig: 1, occurs when β-
15
METABOLISM
cell function is inadequately low for a specific degree of insulin sensitivity.
Thus, β-cell dysfunction is a critical component in the pathogenesis of
type-2 diabetes (Weyer C, et al. 1999).
However,not only deviation from but also progression along the hyp
erbola affects glycemia. When insulin action decreases (as with increasing
obesity) the system usually compensates by increasing β-cell function.
However, at the same time, concentrations of blood glucose at fasting and
2 hrs, after glucose load will increase mildly (Stumvoll M, et al. 2003). This
increase may well be small, but over time becomes damaging because of
glucose toxicity and in it a cause for β-cell dysfunction. Thus, even with
(theoretically) unlimited β-cell reserve, insulin resistance paves the way
for hyperglycemia and type-2 diabetes (Michael S, et al. 2005).
Insulin resistance
Insulin resistance is said to be present when the biological effects of
insulin are less than expected for both glucose disposal in skeletal muscle
and suppression of endogenous glucose production primarily in the liver
(Dinneen S, et al. 1992). In the fasting state, however, muscle accounts for
only a small proportion of glucose disposal (less than 20%) whereas
endogenous glucose production is responsible for all the glucose entering
the plasma. Endogenous glucose production is accelerated in patients with
type-2 diabetes or impaired fasting glucose (Weyer C, et al. 1999; Meyer
C, et al. 1998). Because this increase occurs in the presence of
hyperinsulinaemia, at least in the early and intermediate disease stages,
16
METABOLISM
hepatic insulin resistance is the driving force of hyperglycemia of type-2
diabetes (Stumvoll M, et al. 2005).
Figure 1: Hyperbolic relation between cell function and insulin sensitivity
In people with normal glucose tolerance (NGT) a quasi-hyperbolic relation exists between cell
function and insulin sensitivity. With deviation from his hyperbola, deterioration of glucose
tolerance (impaired glucose tolerance [IGT] and type2 diabetes [T2DM]) occurs.
Insulin resistance is strongly associated with obesity and physical
inactivity, and several mechanisms mediating this interaction have been
identified. A number of circulating hormones, cytokines, and metabolic
fuels, such as non-esterified (free) fatty acids (NEFA) originate in the
adipocytes and modulate insulin action. An increased mass of stored
triglyceride, especially in visceral or deep subcutaneous adipose depots,
leads to large adipocytes that are themselves resistant to the ability of
17
METABOLISM
insulin to suppress lipolysis. This results in increased release and
circulating levels of NEFA and glycerol, both of which aggravate insulin
resistance in skeletal muscle and liver (Boden G. 1997). Excessive fat
storage not only in adipocytes but “ectopically” in non-adipose cells also
has an important role (Danforth E Jr. 2000). For example, increased
intramyocellular lipids are associated with skeletal muscle insulin
resistance under some circumstances. The coupling between intrahepatic
lipids and hepatic insulin resistance seems to be even tighter (Seppala-
Lindroos A, et al. 2002; Bajaj M, et al. 2003).
The current understanding of the Pathophysiology of Type-2
diabetes suggests that complex interactions exist between multiple
pathways. These include abnormalities in glucose transport mechanisms,
increased activity of specific intracellular metabolic pathways, activation
of protein kinase C isoforms, formation of reactive oxygen species (ROS),
increased production of advanced glycation end products (AGEs) and,
altered activity of a variety of growth factors and cytokines (Liu Y, et al.
2005).
ROLE OF INSULIN RESISTANCE IN TYPE-2 DIABETES
Even if insulin exerts numerous different effects, so far insulin sensitivity
has been considered mainly in the context of glucose metabolism,
especially at the liver and muscle sites (Scheen AJ, et al. 1992). The
presence of insulin resistance in vivo can be evidenced during various
18
METABOLISM
dynamic tests such as an oral glucose tolerance test, an intravenous
glucose tolerance test and a so-called euglycaemic hyperinsulinaemic
clamp (Scheen AJ, et al. 1995). Using the latter approach, it has been
extensively demonstrated that insulin-mediated glucose disposal
(essentially in the skeletal muscle) is largely reduced in patients with type-
2 diabetes. Furthermore, the concomitant use of isotopes showed that
hepatic glucose production is insufficiently inhibited by insulin, thus
demonstrating the presence of both muscular and hepatic insulin
resistance. Despite tremendous advances in molecular biology and the
continued identification of increasingly more molecules involved in the
insulin signaling cascade, the molecular mechanism (or mechanisms) that
underlines the development of insulin resistance in subjects prone to
develop type-2 diabetes still remains elusive (Gerich J. 1998). Genetic
mutations associated with insulin resistance are rare and it seems unlikely
that a single genetic alteration explains a large number of cases of insulin
resistance among type-2 diabetic patients. Rather, it is more likely that a
number of different genes may contribute, some of which may be obesity
genes. Three commonly encountered factors that influence insulin
sensitivity and are apparently not genetically determined are aging,
exercise and dietary constituents. However, even if the effects of age,
exercise and diet are considered, there is still a large between-subject
variation in insulin sensitivity that has to be related to other factors. A
major component of this residual variation may be related to obesity, but
19
METABOLISM
more importantly to differences in body fat distribution (Montague CT, et
al. 2000). A vast majority of type-2 diabetic patients are overweight, and
obesity undoubtedly plays a major role in the development of the disease
(Kahn SE. Diabetologia. 2003). While it is recognized that obesity is an
important determinant of insulin sensitivity (Scheen AJ, et al. 1995), body-
fat distribution seems to be a critical aspect (Montague CT, et al. 2000).
Several groups have made a strong case that the intra-abdominally fat
depot is the primary correlate of insulin sensitivity; while others have
proposed that the central subcutaneous fat depot is the major factor
determining a reduction in insulin sensitivity. Obese individuals with most
of their fat stored in visceral adipose depots generally suffer greater
adverse metabolic consequences than similarly overweight subjects with
fat stored predominantly in subcutaneous sites. Excess abdominal fat mass
is associated with an increased release of NEFA that may trigger a
reduction in insulin sensitivity at both the hepatic and the muscular levels.
In the liver, this results in an increased glucose output (essentially due to
enhanced gluconeogenesis), a decreased insulin extraction and an
increased VLDL production while in the skeletal muscle this results in a
reduction in glucose oxidation and glucose storage as glycogen (so-called
Randle’s effect) (Reaven GM, et al. 1995 ). Numerous insulin-resistant
obese patients have also a so-called metabolic syndrome associating
impaired glucose tolerance (or type-2 diabetes), dyslipidaemia and
arterial hypertension, all factors aggravating the risk of cardiovascular
20
METABOLISM
diseases (Scheen AJ. 1996). A fuller understanding of the biology of central
obesity will require information regarding the genetic and environmental
determinants of human fat topography and of the molecular mechanisms
linking visceral adiposity to degenerative metabolic and vascular disease.
Long-term positive energy balance may lead not only to excess triglyceride
depots in the adipose tissue, but also to ectopic triglyceride storage. The
ability of the adipocytes to function properly when engorged with lipid can
lead to lipid accumulation in other tissues, reducing their ability to
function and response normally. Liver steatosis is a common finding in
obese subjects, especially in those with intra-abdominal fat depot, and
non-alcoholic fatty liver disease is now considered as part of the metabolic
syndrome associated to insulin resistance. In addition, intramuscular
triglyceride levels are increased in obese subjects, and a close relationship
has been repeatedly reported between the degree of ectopic
intramyocellular triglyceride depot and the severity of muscular insulin
resistance (Ravussin E, et al. 2002). Interestingly, ectopic fat accumulation
in insulin sensitive tissues may be associated with insulin resistance
independent of overall obesity. However, the understanding of the causes
and mechanisms underlying fat accumulation in skeletal muscle and the
liver are limited. Identifying why some individuals store fat in insulin-
sensitive tissues, but others do not, may be of great importance for the
development of new insulin sensitizing agents. The role of counter
regulatory hormones in the resistance to insulin in patients with type-2
21
METABOLISM
diabetes remains unclear. Nevertheless, plasma glucagon levels are
regularly increased in type-2 diabetic patients and this hormone could
contribute to enhance gluconeogenesis and hepatic glucose output,
especially in presence of insulin deficiency (Scheen AJ, et al. 1996).
Pharmacological attempts to decrease glucagon secretion led to
substantial reduction in plasma glucose levels, arguing for a significant
role of this hormone in the development of hyperglycemia in type -
2diabetes. Finally, a hemodynamic hypothesis of insulin resistance has
also been put forward (Scheen AJ, et al. 1996). Reduced number of muscle
capillaries and impaired insulin-induced vasodilatation (essentially in the
postprandial state) may contribute to increase the distance and to alter the
insulin diffusion process from the capillary to the muscular cells and there
by insulin action in obese patients with type-2 diabetes (Scheen AJ, et al.
1996).
Fig 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-
22
METABOLISM
cell and of adipose tissue as an endocrine organ releasing various adipocytokins in addition to
non-esterified fatty acids (NEFA) in presence of positive energy balance and obesity.
Role of insulin deficiency in Type-2 diabetes
Beta-cell function in type-2 diabetes has been the subject of intense
investigation for several decades, and considerable progress has been
made during the recent years in the knowledge of the physiology and
Pathophysiology of insulin secretion (Polonsky KS, 1995). Recent data
demonstrated that beta-cell deficit and beta-cell apoptosis are present in
humans with type-2 diabetes (Butler AE, et al. 2003). Once hyperglycemia
exists, beta-cell dysfunction is clearly present in subjects with type-2
diabetes (Polonsky KS. 1995). Individuals with type-2 diabetes also show a
decrease in the potentiation by oral rather than parenteral glucose
loading, a phenomenon known as the “incretion effect” which is associated
to glucose-dependent insulin tropic peptide (GIP) and glucagon-like
peptide (GLP)-1 secreted by enterocytes. In addition, alterations in
pulsatile insulin release and ultradian oscillatory insulin secretion can be
observed. Finally, inefficient proinsulin processing to insulin and a
reduction in the release of islet amyloid polypeptide (IAPP, also known as
amylin) has been observed in established type-2 diabetes (Kahn SE,
Diabetologia. 2003).
Several mechanisms have been proposed to explain the -cellβ
deficiency observed in subjects prone to develop type-2 diabetes (Scheen
23
METABOLISM
AJ, et al. 1996). Unfavorable metabolic environment may also play a
deleterious role, especially increased glucose levels that may induce
glucotoxicity (Yki -Jarvinen H. 1992) and a chronic increase in NEFA levels
that may induce lipotoxicity, both processes contributing to alter insulin
secretion. Interestingly, ectopic deposition triglycerides in pancreatic
islets has also been reported, a condition that may contribute to
dysfunction of the beta cell. Indeed, although the mechanism of lipotoxicity
in the beta cell remains unclear, it has been suggested that accumulation of
triglycerides increases nitric oxide, which causes oxidative damage and
apoptosis in the cells (Unger RH. 2002). Finally, defects in insulin signaling
pathways associated with insulin resistance in peripheral tissues have
recently been found to disrupt insulin secretion by pancreatic beta cells,
suggesting that insulin resistance in the beta cells may be, at least partly,
responsible for the beta-cell dysfunction and the development of type-2
diabetes (Greenberg AS, et al. 2002).
Metabolic changes in Type-2 Diabetes
Hyperglycemia is considered a major factor in the development of T2DM
and the adverse effects are recognizable through induces through four
major pathways: (i) increased polyol pathway flux (ii) increased advanced
glycation end-product formation (iii) activation of protein kinase C and
(iv) increased Hexosamine pathway flux (Setter SM, et al. 2003). An
increase in the entry of glucose into the polyol pathway, the diacylglycerol
24
METABOLISM
(DAG) synthetic pathway, and the Hexosamine pathway was found in
mesangial cells cultured under high glucose conditions (Masakazu H, et al.
2003).
Polyol pathway
The polyol pathway, shown schematically in Fig: 3, focuses on the enzyme
aldose reductase. Aldose reductase normally has the function of reducing
toxic aldehydes in the cell to inactive alcohols, but when the glucose
concentration in the cell becomes too high, aldose reductase also reduces
that glucose to sorbitol, which is later oxidized to fructose. In the process
of reducing high intracellular glucose to sorbitol, the aldose reductase
consumes the cofactor NADPH (Lee AY, et al. 1999). But as shown in Fig: 3,
NADPH is also the essential cofactor for regenerating a critical intracellular
antioxidant, reduced glutathione (Engerman RL, et al. 1994).
Subsequently, sorbitol is oxidized to fructose via sorbitol dehydrogenase,
with NAD+ reduced to NADH, providing increased substrate to complex-I
of the mitochondrial respiratory chain. Since the mitochondrial
respiratory chain is thought to be a major source of excess ROS in diabetes,
provision of additional electrons for transfer to oxygen-forming
superoxide would augment mitochondrial ROS production. In addition,
since sorbitol does not cross cell membranes, its intracellular
accumulation results in osmotic stress. Osmotic stress perse increases
cellular cytosolic generation of H2O2 (Pingle SC, et al. 2004). The polyol
25
METABOLISM
pathway increases susceptibility to intracellular oxidative stress
(Brownlee M, 2005).
Fig 3: Hyperglycemia increases flux through the polyol pathway. From Brownlee M: Biochemistry
and molecular cell biology of diabetic complications. (Nature 414:813–820, 2001.)
Formation of AGE’s
Binding of advanced-glycation end products (AGE) to receptor for AGE
(RAGE) produces a cascade of cellular signaling, such as Protein kinase C