Insight review articles

insight
review articles
NATURE
|
VOL 414
|
13 DECEMBER 2001
|
www.nature.com
813
A
ll forms of diabetes are characterized by
chronic hyperglycaemia and the development
of diabetes-specific microvascular pathology
in the retina, renal glomerulus and peripheral
nerve. As a consequence of its microvascular
pathology, diabetes is a leading cause of blindness, end-
stage renal disease and a variety of debilitating
neuropathies. Diabetes is also associated with accelerated
atherosclerotic macrovascular disease affecting arteries
that supply the heart, brain and lower extremities. As a
result, patients with diabetes have a much higher risk of
myocardial infarction, stroke and limb amputation. Large
prospective clinical studies show a strong relationship
between glycaemia and diabetic microvascular
complications in both type 1 and type 2 diabetes
1,2
.
Hyperglycaemia and insulin resistance both seem to have
important roles in the pathogenesis of macrovascular
complications
2–5
.
Diabetes-specific microvascular disease in the retina,
glomerulus and vasa nervorum has similar pathophysiolog-
ical features. Early in the course of diabetes, intracellular
hyperglycaemia causes abnormalities in blood flow and
increased vascular permeability. This reflects decreased
activity of vasodilators such as nitric oxide, increased 
activity of vasoconstrictors such as angiotensin II and
endothelin-1, and elaboration of permeability factors such
as vascular endothelial growth factor (VEGF). Quantitative
and qualitative abnormalities of extracellular matrix con-
tribute to an irreversible increase in vascular permeability.
With time, microvascular cell loss occurs, in part as a result
of programmed cell death, and there is progressive capillary
occlusion due both to extracellular matrix overproduction
induced by growth factors such as transforming growth fac-
tor-
b (TGF-b), and to deposition of extravasated periodic
acid–Schiff-positive plasma proteins. Hyperglycaemia may
also decrease production of trophic factors for endothelial
and neuronal cells. Together, these changes lead to oedema,
ischaemia and hypoxia-induced neovascularization in the
retina, proteinuria, mesangial matrix expansion and
glomerulosclerosis in the kidney, and multifocal axonal
degeneration in peripheral nerves.
The pathogenesis of atherosclerosis in non-diabetics has
been extensively described in recent reviews, and begins with
endothelial dysfunction
6
. In diabetic arteries, endothelial
dysfunction seems to involve both insulin resistance 
specific to the phosphatidylinositol-3-OH kinase pathway
7,8
and hyperglycaemia. Pathway-selective insulin resistance
results in decreased endothelial production of the 
anti-atherogenic molecule nitric oxide, and increased poten-
tiation of proliferation of vascular smooth muscle cells and
production of plasminogen activator inhibitor-1 (PAI-1) via
the Ras 
→
Raf 
→
MEK kinase 
→
mitogen-activated protein
(MAP) kinase pathway
7
. Hyperglycaemia itself also inhibits
production of nitric oxide in arterial endothelial cells
9
and
stimulates production of PAI-1 (ref. 10).
Both insulin resistance and hyperglycaemia have also been
implicated in the pathogenesis of diabetic dyslipidaemia. The
role of insulin resistance has been reviewed recently
5
. 
Hyperglycaemia seems to cause raised levels of atherogenic
cholesterol-enriched apolipoprotein B-containing remnant