Current Concepts of Chronic Diabetic Complications

Sarwono Waspadji
Div.of Endocrinology & Metabolism,
Dept. of Medicine, FMUI, University of Indonesia, Jakarta.

Diabetes vascular disease consist of Macroangiopathy involving large vessels (brain, heart
and peripheral artery disease), and Microangiopathy related to small vessels (eyes, kidneys,
neuropathy, brain and also heart). Both macroangipathy and microangiopathy started with
cytosolic hyperglycemia, disfunction, through several pathogenesis mechanisms (sorbitolpathway, AGE-pathway, DAG-Protein Kinase C and Hexosamine-pathway, in concert
through oxidative stress), leads to complex pathobiomolecular changes, thereafter the
development of endothelium dysfunction.

The complex pathobiomolecular changes involve abnormal protein and cell function due to
increasing AGEs as well as the impact of circulating AGEs on the renal-vascular connective
tissue impairment and increase cytokines and growth factors production. Increased sorbitol
causing alteration of myoinositol osmolality and redox potensial leading also to altered cell
function. The increase of DAG activation followed by PKC activation, leads to altered
enzimes function (cPLA2, Na K ATPase), altered genes expresions and also growth factors
production. All of these pathobiomolecular abnormalities in concert resulted in both
microvascular and macrovascular complications of diabetes mellitus.
Hyperglycemia as well as increased Free Fatty Acid (FFA) commonly found among
uncontrolled diabetics induced ROS, RNS and oxidative stress which subsequently activate
stress activated protein kinase IKKb- leading to NFKB activation, inos expression and
increase NO production, S Nitrosilation ending in altered IRS-1 /insulin Resistance.
Oxidative stress also activate JNK and p38MAPK, leading to serine activation and ending
also in altered IRS-1/Insulin Resistance. Oxidative stress also affected JAK/STAT, leading to

increase cytokines, angiotensins as well as Endothelin-1 production, leading to futher

increase of oxidative stress.

The increased Reactive Oxygen Spesies will subsequently induce also the increase of
hexoamine flux, sorbitol formation, PKC and AGE production. Other effects of ROS include
increase LDL oxidation and accelerated atherogenesis; decreased NO availability and
impaired vasorelaxation as well as peroxinitrit induction leading to lipid peroxidation, DNA
damage and protein nitration. All of these pathobiomolecular processes will at the and lead to
chronic diabetic vascular complications. These chronic diabetic vascular complications cause
escalating cost and pose economic burden to the patients, medical professions and
government alike. Therefore prevention for the development of vascular disease is
enormously important.
Some well recoqnized cardiovascular risk factors including hypertension, dyslipidemia,
diabetes, smoking etc. (tradisional risk factors), through oxidative stress, are associated with
changes in the vessel wall (endothelial dysfuction) that eventually lead to vascular disease.
Genetic susceptability also play a role in the development of chronic diabetic vascular
complications. Poor dietary habits, and overnutrition will lead to adiposity and various
metabolic abnormalities supporting the new concept that adipocyte is not only energy storage
but adipocyte is the most important endocrine organ producing many adipocytokines as the
basic molecules causing the abnormal pathobiomolecular changes in the development of
chronic vascular complications. Many new risk factors for the development of chronic
vascular complcations (non tradisional risk factors) derived from the new concepts of these
adipocyte dysfunction.
The spectrum of vascular disease care ranges from primary prevention, dealing with
subclinical vascular disease, as well as secondary and tertiary prevention. Primary and
secondary prevention are mostly done in out patient setting, while tertiary prevention needs
management care in patient setting. The newly recoqnized risk factors should be considered
in the management of chronic diabetic vascular complications, especially in the primary
prevention in the development and use of prophilactic drugs to prevent the establishment of
chronic diabetic vascular complications. The beneficial effects of Lifestyle modifications can
be well explained by understanding the basic mechanism and the improvement of abnormal
conditions by dietary modifications as well as exercise and reduction of adiposity.
In the pathogenesis of vascular disease there are traditional and non tradisional risk factors.
Among the risk factors both tradisional as well as the non tradisional, many of them can be
modified although some are unmodiafiable, such as factors related to aging process, gender,
family history of vascular disease and hereditary factors. From Framingham study, we have
the facts that the more the risk factors are, the higher is the the Odds ratio of developing
vascular disease. Further discussion will focus on factors related to metabolic problems,
namely Diabetes Mellitus, Dyslipidemia, Hipertension and Obesity, the most important and
most modifiable factors for the development of vascular disease.
In Type2DM, the basic abnormality is insulin resistance, mostly in muscle, liver and fat.
Body compensation thereafter causing hyperinsulinemia, with normal blood glucose. As beta
cells become exhausted, hyperglycemia ensues, leading to the development of IGT, and then
Diabetes. With time, the beta cells worsen, the insulin production and secretion become less.
Several strategies to prevent the emergence of vascular complications of diabetes might be
done: 1) Prevention of IGT, 2) Prevention of progression of IGT to T2DM, 3) Glycemic

control and 4) Treatment of established cardiovascular risk factors. The Clinical chalenges
for these purposes are recognizing and understanding factors contributing to diabetes and
cardiovascular disease(cardio-metabolic risk) and developing effective strategies to reduce
and treat cardiovascular disease in diabetics.Glycemic control is one of the most important
strategies.To achieve optimal blood glucose control, many algorithms have been put forward
to guide physician treated diabetics rationally, including Perkeni (Indonesian Society of
Endocrinology) guidelines.
As for Dyslipemia, treatment always start with Life-style modification. Only after about 6
weeks the target lipid profile still can not be achieved, additional lipid lowering drug(s) might
be added accordingly. Similar attempts has to be done for hypertensive patients. The
management should start with livestyle changes first. Only whenever there is a compelling
evidence such as the present of DM, hypertensive drug(s) can be given earlyer. For the
management of Obesity, lyfestyle modifocation should also be the first step. Even only
about 5 - 10 % body weight reduction might give beneficial impacts in term of reducing
vascular disease. Only after about 3 6 months of obesity management without results we
can initiate drug therapy or then embark into further treatment modalities such as bariatric
surgery.
Early detection of chronic diabetic vascular complications should be done as part of regular
management of diabetes. This should be part of standard diabetes care done in the primary
level. Early detection will lead to early management of chronic diabetic vascular
complications, which are mostly done in specialized care by specialist in the related field.
Good referral system and coordination therefore are necessary for optimal prevention and
management of these chronic diabetes vascular complications.
In conclusion, prevention strategies are very important for the management of vascular
disease. Life style modification is very useful to prevent vascular disease as well its
metabolic components: diabetes mellitus, dyslipidemia, hypertension and obesity. In the
management of Diabetes Mellitus all efforts should be taken into account including the active
management of other vascular risk factors related to diabetes, namely hypertension,
dyslipidemia and obesity. Active action should be implemented soon to be able to cope with
escalating magnitude of the problems, done together by all health personnel, including the
primary care physicians, goverment, institutions and other related stake holder.

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