Tc
Wed, Dec-14-05, 17:16
http://www.servier.com/pro/diabetologie/diabetographia/ud/06.-
asp
Understanding Diabetes
Blood glucose toxicity and =DF-cell dysfunction
Professor Hideki Ohno Department of Molecular Predictive
Medicine and Sport Science, Kyorin University, School of
Medicine, Tokyo, Japan
Diabetes is associated with many chronic vascular
complications such as retinopathy, nephropathy, and
neuropathy. Although the pathogenesis of these complications
has yet to be fully elucidated, several studies have
indicated a link with the severity and duration of
hyperglycemia.1 Elevated blood glucose levels are thought to
cause such effects via a number of pathways, primarily via
deleterious effects on pancreatic =DF-cell function, which
together with insulin resistance is thought to play a
critical role in the pathogenesis of type 2 diabetes.
Oxidative stress is one of the processes implicated in these
effects on =DF-cell function.
Glucose toxicity and =DF-cell dysfunction
The adverse effects of hyperglycemia on =DF-cell dysfunction
can be divided into three distinct phenomena: glucose
desensitization, =DF-cell exhaustion, and glucose toxicity
(Table 1).2 Glucose desensitization is a physiological
adaptation in which the pancreatic =DF-cell becomes rapidly
yet reversibly refractory to a short exposure of elevated
glucose.3 =DF-Cell exhaustion is the reversible depletion of
the pool of intracellular insulin following long-term exposure
to elevated glucose. It is thought that the =DF-cell defects
associated with these two phenomena are initially reversible
but that they eventually become irreversible following
prolonged exposure to elevated glucose, a process that is
termed glucose toxicity.2,4
TABLE I: Adverse effects of hyperglycemia on =DF-cell
function.
Glucose toxicity and oxidative stress
One mechanism by which the effects of glucose toxicity are
thought to be mediated is oxidative stress,4-6 and
hyperglycemia is known to be one of the main causes of
oxidative stress in patients with type 2 diabetes. Oxidative
stress is a term used to describe an imbalance between levels
of free radicals and antioxidants and has been identified as
an important contributor to many of the vascular complications
of diabetes (Figure 1). A brief summary of the vascular
complications that have been linked to oxidative stress is
given in the text box on page 4. More information about how
oxidative stress causes the vascular complications of type 2
diabetes can be found in issue 3 of Diabetographia.
FIGURE 1: One of the mechanisms by which the effects of
glucose toxicity resulting in prolonged hyperglycemia are
thought to be mediated is oxidative stress. Oxidative stress
is a term used to describe an imbalance between levels of
free radicals and antioxidants and has been identified as an
important contributor to many of the vascular complications
of diabetes. TNF-a, tumour necrosis factor a; TXA2,
thromboxane A2.
During the generation of oxidative stress, prolonged
elevations in blood glucose levels lead to, among other
things, the activation of various intracellular metabolic
pathways, promoting the formation of advanced glycation end
products (AGEs), auto-oxidation, and an increase in the
activity of the sorbitol pathway (Figure 1). A number of
important proteins also undergo glycation, such as the
Cu,Zn-superoxide dismutase (Cu,Zn-SOD), one of the most
important antioxidant enzymes. Erythrocytes in patients with
type 1 diabetes have been found to contain a higher percentage
of glycated Cu,Zn-SOD, which is inactivated under
hyperglycemic conditions compared with controls, thus leading
to oxidative stress.7
These processes have two consequences:
1=2E an increase in the generation of free radicals
(unstable atoms or molecules that in high concentrations
can be extremely harmful to tissues), including reactive
oxygen species
2=2E a decrease in the levels of antioxidants, which usually
act to "mop up" free radicals.
Oxidative stress and =DF-cell dysfunction
For some time there has been a recognized link between the
presence of chronic hyperglycemia and the progressive
deterioration in =DF-cell function seen in patients with type
2 diabetes.8-10 More recently, however, studies in vitro and
in vivo have indicated that this progressive =DF-cell
dysfunction is a result of tissue damage induced by oxidative
stress resulting from this glucose toxicity.4,6,11
=DF-Cells are thought to be particularly vulnerable to
oxidative stress because they contain very low levels of
antioxidant enzymes.12 In support of the hypothesis that
chronic oxidative stress might play a role in the progressive
=DF-cell dysfunction seen in type 2 diabetes are the findings
that the pancreatic =DF-cell undergoes oxidative stress when
exposed to supraphysiologic concentrations of glucose,13,14
and that this process can be prevented by an antioxidant.14
The results of a number of studies in vivo support these
findings. In one study, antioxidant treatment was found to
normalize plasma glucose levels and to restore insulin
secretion in a diabetic rat model (Figure 2).6
FIGURE 2: Glucose-stimulated insulin response in Zucker
diabetic fatty (ZDF) rats was impaired at high glucose
concentrations compared with controls, but was fully
restored by the addition of an antioxidant (aminoguanidine).
Each value represents mean =B1 SEM of triplicate
assessments, each consisting of 10 islets/well and corrected
by subtraction of basal insulin level. (Adapted with
permission from Tanaka et al.6)
Implications for the treatment of type 2 diabetes
Glucose toxicity, as a consequence of prolonged hyperglycemia,
can lead to =DF-cell dysfunction via oxidative stress, which
in itself has been implicated in many of the vascular
complications of type 2 diabetes. This has a number of
implications for the treatment of this disease. The first is
that sustained high levels of blood glucose should be avoided
by the implementation of measures proven to control glycemia.
The United Kingdom Prospective Diabetes Study (UKPDS) found
that strict glycemic control has been shown to have
significant benefit on the incidence of many microvascular
complications, though its effects on macrovascular
complications were less marked.15
Given the link between vascular complications and oxidative
stress, the use of antidiabetic drugs with antioxidant
properties, such as gliclazide, may be another avenue for
investigation. Gliclazide can be distinguished from other
antiglycemic agents by its powerful antioxidant (free-radical
scavenging) properties, which had been demonstrated both in
vitro and in vivo.16 Clinical studies with gliclazide in
patients with type 2 diabetes have demonstrated improvements
in both microvascular and atherosclerotic complications of
type 2 diabetes.17,18 Furthermore, a recently published in
vitro study has been the first to demonstrate that gliclazide,
in contrast to glibenclamide, was able to protect pancreatic
=DF-cells from oxidative damage.19 It can be speculated that
these features are responsible for a lower rate of secondary
failure with gliclazide compared with other second-generation
sulfonylureas such as glibenclamide or glipizide.20
Clinical consequences of oxidative stress
The majority of the complications experienced by patients with
type 2 diabetes that have been linked to oxidative stress (due
mainly to glycated Cu,Zn-SOD21) are mediated through effects
on the vascular system, particularly those of the eye and
kidney, tissues that are insulin dependent. These effects can
have dramatic consequences for patients and include intimal
thickening, increased permeability, increased risk of
atherosclerotic plaques and endothelial dysfunction.22
Diabetic retinopathy
Diabetic retinopathy is the leading cause of blindness in the
working population of the Western world and its prevalence
increases with prolonged duration of diabetes.1 It primarily
affects the retinal blood vessels but can also cause cataract
formation. Regular optical examinations are essential for
diabetic patients. Treatments consist of ablation of the
ischemic retinal vessels by laser treatment (photocoagulation)
to focus blood flow on the healthy retina or surgery.
Diabetic nephropathy
The main changes in the diabetic kidney occur within the
glomerulus where cellular changes lead to a decrease in the
surface area available to filter the blood and, consequently,
a decrease in the glomerular filtration rate (GFR). Diabetic
nephropathy is the leading cause of end-stage renal disease
in most developed countries23 and, currently, no therapy
exists that can halt the progressive loss of GFR. Whereas
hyperglycemia is clearly necessary for the development of
diabetic nephropathy,1 it is not wholly responsible for this
complication. Hypertension and a genetic predisposition may
also play roles in the development of renal disease in
diabetic patients. Therapy for diabetic neuropathy consists
of hemodialysis or kidney transplantation (for patients aged
< 60 years).
Diabetic neuropathy
Diabetic neuropathy is a serious consequence of hyperglycemia
which, once present, cannot be reversed. It can affect
different nerve types (large fiber, small fiber), either
singly or as a group. Neuropathy can lead to a number of
complications, the most important are those associated with
the foot (ulceration, edema, Charcot arthropathy or foot [see
Practical Management article by Jeffcoate and Game, page 5]),
muscle wastage (thigh, calf, trunk, hands), loss of autonomic
function (postural hypotension, foot ulcers, abnormal
sweating), and marked weight loss.1 While conventional
painkillers are of little use in relieving the pain caused by
diabetic neuropathy, strict glycemic control can decrease the
risk of developing this serious complication.1
Summary
The development of chronic hyperglycemia leading to glucose
toxicity can have serious consequences for diabetic patients.
Increased blood glucose levels significantly increase the
risk of irreversible =DF-cell dysfunction via oxidative
stress, and thus the incidence of vascular complications of
type 2 diabetes. However, the consequences of elevated blood
glucose can to some extent be avoided by achieving strict
glycemic control (eg, using dietary modifications and
exercise), and the use of an antiglycemic agent with
additional antioxidant properties (such as gliclazide) may be
a promising therapeutic strategy.
References
1=2E Williams G, Pickup JC (eds). Handbook of diabetes, 2nd
edition. Oxford: Blackwell Science, 1999.
2=2E Poitout V, Robertson RP. Endocrinology. 2002;144:339-342.
3=2E Kilpatrick ED, Robertson RP. Diabetes. 1998;47:606-611.
4=2E Robertson RP, Harmon J, Tran PO, et al. Diabetes.
2003;52:581-587.
5=2E Tanaka Y, Gleason CE, Tran POT, et al. Proc Natl Acad Sci
USA. 1999;96:10857-10862.
6=2E Tanaka Y, Tran PO, Harmon J, et al. Proc Natl Acad Sci
USA. 2002;99:12363-12368.
7=2E Kawamura N, Ookawara T, Suzuki K, et al. J Clin
Endocrinol Metab. 1992;74:1352-1354.
8=2E Robertson RP, Zhang HJ, Pyzdrowski KL, et al. J Clin
Invest. 1992;90:320-325.
9=2E Olson LK, Redmon JB, Towle HC, et al. J Clin Invest.
1993;92:519-524.
10. Poitout V, Olson LK, Robertson RP. J Clin Invest.
1996;97:1041-1046.
11. Piro S, Anello M, Di Pietro C, et al. Metabolism.
2002;51:1340-1347.
12. Lenzen S, Drinkgern J, Tiedge M. Free Radic Biol Med.
1996;20:463-466.
13. Kaneto H, Fujii J, Myint T, et al. Biochem J.
1996;320:855-863.
14. Tajiri Y, Moller C, Grill V. Endocrinology.
1997;138:273-280.
15. UK Prospective Diabetes Study Group. Lancet.
1998;352:837-853.
16. Jennings PE, Scott NA, Saniabadi AR, et al. Metabolism.
1992;41(5 Suppl. 1):36-39.
17. G=E6de P, Vedel P, Parving HH, et al. Lancet.
1999;353:617-622.
18. G=E6de P, Vedel P, Larsen N, et al. N Engl J Med.
2003;348:383-393.
19. Kimoto K, Suzuki K, Kizaki T, et al. Biochem Biophys Res
Commun. 2003;303:112-119.
20. Harrower AD, Wong C. Diabetes Res. 1990;13:19-21.
21. Sen CK, Packer L, Hanninen O (eds). Handbook of oxidants
and antioxidants in exercise. Amsterdam: Elsevier, 2000.
22. King GL, Wakasaki H. Diabetes Care. 1999;22(Suppl.
3):C31-C37.
23. Lappin DW, Doran P, Godson C, et al. Exp Nephrol.
2002;10:120-129.
=20 20
*************
TC
asp
Understanding Diabetes
Blood glucose toxicity and =DF-cell dysfunction
Professor Hideki Ohno Department of Molecular Predictive
Medicine and Sport Science, Kyorin University, School of
Medicine, Tokyo, Japan
Diabetes is associated with many chronic vascular
complications such as retinopathy, nephropathy, and
neuropathy. Although the pathogenesis of these complications
has yet to be fully elucidated, several studies have
indicated a link with the severity and duration of
hyperglycemia.1 Elevated blood glucose levels are thought to
cause such effects via a number of pathways, primarily via
deleterious effects on pancreatic =DF-cell function, which
together with insulin resistance is thought to play a
critical role in the pathogenesis of type 2 diabetes.
Oxidative stress is one of the processes implicated in these
effects on =DF-cell function.
Glucose toxicity and =DF-cell dysfunction
The adverse effects of hyperglycemia on =DF-cell dysfunction
can be divided into three distinct phenomena: glucose
desensitization, =DF-cell exhaustion, and glucose toxicity
(Table 1).2 Glucose desensitization is a physiological
adaptation in which the pancreatic =DF-cell becomes rapidly
yet reversibly refractory to a short exposure of elevated
glucose.3 =DF-Cell exhaustion is the reversible depletion of
the pool of intracellular insulin following long-term exposure
to elevated glucose. It is thought that the =DF-cell defects
associated with these two phenomena are initially reversible
but that they eventually become irreversible following
prolonged exposure to elevated glucose, a process that is
termed glucose toxicity.2,4
TABLE I: Adverse effects of hyperglycemia on =DF-cell
function.
Glucose toxicity and oxidative stress
One mechanism by which the effects of glucose toxicity are
thought to be mediated is oxidative stress,4-6 and
hyperglycemia is known to be one of the main causes of
oxidative stress in patients with type 2 diabetes. Oxidative
stress is a term used to describe an imbalance between levels
of free radicals and antioxidants and has been identified as
an important contributor to many of the vascular complications
of diabetes (Figure 1). A brief summary of the vascular
complications that have been linked to oxidative stress is
given in the text box on page 4. More information about how
oxidative stress causes the vascular complications of type 2
diabetes can be found in issue 3 of Diabetographia.
FIGURE 1: One of the mechanisms by which the effects of
glucose toxicity resulting in prolonged hyperglycemia are
thought to be mediated is oxidative stress. Oxidative stress
is a term used to describe an imbalance between levels of
free radicals and antioxidants and has been identified as an
important contributor to many of the vascular complications
of diabetes. TNF-a, tumour necrosis factor a; TXA2,
thromboxane A2.
During the generation of oxidative stress, prolonged
elevations in blood glucose levels lead to, among other
things, the activation of various intracellular metabolic
pathways, promoting the formation of advanced glycation end
products (AGEs), auto-oxidation, and an increase in the
activity of the sorbitol pathway (Figure 1). A number of
important proteins also undergo glycation, such as the
Cu,Zn-superoxide dismutase (Cu,Zn-SOD), one of the most
important antioxidant enzymes. Erythrocytes in patients with
type 1 diabetes have been found to contain a higher percentage
of glycated Cu,Zn-SOD, which is inactivated under
hyperglycemic conditions compared with controls, thus leading
to oxidative stress.7
These processes have two consequences:
1=2E an increase in the generation of free radicals
(unstable atoms or molecules that in high concentrations
can be extremely harmful to tissues), including reactive
oxygen species
2=2E a decrease in the levels of antioxidants, which usually
act to "mop up" free radicals.
Oxidative stress and =DF-cell dysfunction
For some time there has been a recognized link between the
presence of chronic hyperglycemia and the progressive
deterioration in =DF-cell function seen in patients with type
2 diabetes.8-10 More recently, however, studies in vitro and
in vivo have indicated that this progressive =DF-cell
dysfunction is a result of tissue damage induced by oxidative
stress resulting from this glucose toxicity.4,6,11
=DF-Cells are thought to be particularly vulnerable to
oxidative stress because they contain very low levels of
antioxidant enzymes.12 In support of the hypothesis that
chronic oxidative stress might play a role in the progressive
=DF-cell dysfunction seen in type 2 diabetes are the findings
that the pancreatic =DF-cell undergoes oxidative stress when
exposed to supraphysiologic concentrations of glucose,13,14
and that this process can be prevented by an antioxidant.14
The results of a number of studies in vivo support these
findings. In one study, antioxidant treatment was found to
normalize plasma glucose levels and to restore insulin
secretion in a diabetic rat model (Figure 2).6
FIGURE 2: Glucose-stimulated insulin response in Zucker
diabetic fatty (ZDF) rats was impaired at high glucose
concentrations compared with controls, but was fully
restored by the addition of an antioxidant (aminoguanidine).
Each value represents mean =B1 SEM of triplicate
assessments, each consisting of 10 islets/well and corrected
by subtraction of basal insulin level. (Adapted with
permission from Tanaka et al.6)
Implications for the treatment of type 2 diabetes
Glucose toxicity, as a consequence of prolonged hyperglycemia,
can lead to =DF-cell dysfunction via oxidative stress, which
in itself has been implicated in many of the vascular
complications of type 2 diabetes. This has a number of
implications for the treatment of this disease. The first is
that sustained high levels of blood glucose should be avoided
by the implementation of measures proven to control glycemia.
The United Kingdom Prospective Diabetes Study (UKPDS) found
that strict glycemic control has been shown to have
significant benefit on the incidence of many microvascular
complications, though its effects on macrovascular
complications were less marked.15
Given the link between vascular complications and oxidative
stress, the use of antidiabetic drugs with antioxidant
properties, such as gliclazide, may be another avenue for
investigation. Gliclazide can be distinguished from other
antiglycemic agents by its powerful antioxidant (free-radical
scavenging) properties, which had been demonstrated both in
vitro and in vivo.16 Clinical studies with gliclazide in
patients with type 2 diabetes have demonstrated improvements
in both microvascular and atherosclerotic complications of
type 2 diabetes.17,18 Furthermore, a recently published in
vitro study has been the first to demonstrate that gliclazide,
in contrast to glibenclamide, was able to protect pancreatic
=DF-cells from oxidative damage.19 It can be speculated that
these features are responsible for a lower rate of secondary
failure with gliclazide compared with other second-generation
sulfonylureas such as glibenclamide or glipizide.20
Clinical consequences of oxidative stress
The majority of the complications experienced by patients with
type 2 diabetes that have been linked to oxidative stress (due
mainly to glycated Cu,Zn-SOD21) are mediated through effects
on the vascular system, particularly those of the eye and
kidney, tissues that are insulin dependent. These effects can
have dramatic consequences for patients and include intimal
thickening, increased permeability, increased risk of
atherosclerotic plaques and endothelial dysfunction.22
Diabetic retinopathy
Diabetic retinopathy is the leading cause of blindness in the
working population of the Western world and its prevalence
increases with prolonged duration of diabetes.1 It primarily
affects the retinal blood vessels but can also cause cataract
formation. Regular optical examinations are essential for
diabetic patients. Treatments consist of ablation of the
ischemic retinal vessels by laser treatment (photocoagulation)
to focus blood flow on the healthy retina or surgery.
Diabetic nephropathy
The main changes in the diabetic kidney occur within the
glomerulus where cellular changes lead to a decrease in the
surface area available to filter the blood and, consequently,
a decrease in the glomerular filtration rate (GFR). Diabetic
nephropathy is the leading cause of end-stage renal disease
in most developed countries23 and, currently, no therapy
exists that can halt the progressive loss of GFR. Whereas
hyperglycemia is clearly necessary for the development of
diabetic nephropathy,1 it is not wholly responsible for this
complication. Hypertension and a genetic predisposition may
also play roles in the development of renal disease in
diabetic patients. Therapy for diabetic neuropathy consists
of hemodialysis or kidney transplantation (for patients aged
< 60 years).
Diabetic neuropathy
Diabetic neuropathy is a serious consequence of hyperglycemia
which, once present, cannot be reversed. It can affect
different nerve types (large fiber, small fiber), either
singly or as a group. Neuropathy can lead to a number of
complications, the most important are those associated with
the foot (ulceration, edema, Charcot arthropathy or foot [see
Practical Management article by Jeffcoate and Game, page 5]),
muscle wastage (thigh, calf, trunk, hands), loss of autonomic
function (postural hypotension, foot ulcers, abnormal
sweating), and marked weight loss.1 While conventional
painkillers are of little use in relieving the pain caused by
diabetic neuropathy, strict glycemic control can decrease the
risk of developing this serious complication.1
Summary
The development of chronic hyperglycemia leading to glucose
toxicity can have serious consequences for diabetic patients.
Increased blood glucose levels significantly increase the
risk of irreversible =DF-cell dysfunction via oxidative
stress, and thus the incidence of vascular complications of
type 2 diabetes. However, the consequences of elevated blood
glucose can to some extent be avoided by achieving strict
glycemic control (eg, using dietary modifications and
exercise), and the use of an antiglycemic agent with
additional antioxidant properties (such as gliclazide) may be
a promising therapeutic strategy.
References
1=2E Williams G, Pickup JC (eds). Handbook of diabetes, 2nd
edition. Oxford: Blackwell Science, 1999.
2=2E Poitout V, Robertson RP. Endocrinology. 2002;144:339-342.
3=2E Kilpatrick ED, Robertson RP. Diabetes. 1998;47:606-611.
4=2E Robertson RP, Harmon J, Tran PO, et al. Diabetes.
2003;52:581-587.
5=2E Tanaka Y, Gleason CE, Tran POT, et al. Proc Natl Acad Sci
USA. 1999;96:10857-10862.
6=2E Tanaka Y, Tran PO, Harmon J, et al. Proc Natl Acad Sci
USA. 2002;99:12363-12368.
7=2E Kawamura N, Ookawara T, Suzuki K, et al. J Clin
Endocrinol Metab. 1992;74:1352-1354.
8=2E Robertson RP, Zhang HJ, Pyzdrowski KL, et al. J Clin
Invest. 1992;90:320-325.
9=2E Olson LK, Redmon JB, Towle HC, et al. J Clin Invest.
1993;92:519-524.
10. Poitout V, Olson LK, Robertson RP. J Clin Invest.
1996;97:1041-1046.
11. Piro S, Anello M, Di Pietro C, et al. Metabolism.
2002;51:1340-1347.
12. Lenzen S, Drinkgern J, Tiedge M. Free Radic Biol Med.
1996;20:463-466.
13. Kaneto H, Fujii J, Myint T, et al. Biochem J.
1996;320:855-863.
14. Tajiri Y, Moller C, Grill V. Endocrinology.
1997;138:273-280.
15. UK Prospective Diabetes Study Group. Lancet.
1998;352:837-853.
16. Jennings PE, Scott NA, Saniabadi AR, et al. Metabolism.
1992;41(5 Suppl. 1):36-39.
17. G=E6de P, Vedel P, Parving HH, et al. Lancet.
1999;353:617-622.
18. G=E6de P, Vedel P, Larsen N, et al. N Engl J Med.
2003;348:383-393.
19. Kimoto K, Suzuki K, Kizaki T, et al. Biochem Biophys Res
Commun. 2003;303:112-119.
20. Harrower AD, Wong C. Diabetes Res. 1990;13:19-21.
21. Sen CK, Packer L, Hanninen O (eds). Handbook of oxidants
and antioxidants in exercise. Amsterdam: Elsevier, 2000.
22. King GL, Wakasaki H. Diabetes Care. 1999;22(Suppl.
3):C31-C37.
23. Lappin DW, Doran P, Godson C, et al. Exp Nephrol.
2002;10:120-129.
=20 20
*************
TC