According to WHO, diabetes is a
chronic disease that occurs either when the pancreas does not produce enough
insulin or when the body cannot effectively use the insulin it produces 1.
Diabetes is a group of metabolic diseases characterized by increase in blood
glucose level resulting from defects in insulin secretion, insulin action, or
both 2. Diabetes mellitus is a generally and clinically heterogeneous group
of disorders that share glucose intolerance in common 3.
Diabetes Mellitus is one of the four
most prevalent Non Communicable Diseases (NCDs)4. It is estimated to account
for approximately 1.5 million deaths in 2012, with more than 80% of diabetes-related
deaths occurring in low- and middle-income countries 1. Relative to
neighboring countries such as Pakistan, Sri Lanka, and Bangladesh, Nepal has a
higher prevalence of type II diabetes mellitus and impaired glucose tolerance5.
According to WHO , there is no exact data of patients with diabetes in Nepal
but 2016 Diabetes profile has shown that 9.1 % Nepali population are living
with diabetes. It includes 10.5% men and 7.9 % women.himalyan tyms.
Disease diabetes Mellitus ranges from
autoimmune destruction of ?-cells of pancreas with insulin deficiency to
abnormalities like resistance to insulin action2.
Diabetes Mellitus has been
classified by the American Diabetes Association (ADA into four categories. They
1. Type I or insulin-dependent diabetes
2. Type II or non-insulin-dependent
diabetes mellitus (NIDDM)
3. Type III diabetes
4. Gestational diabetes
I or insulin-dependent diabetes
mellitus (IDDM) is also known as
juvenile diabetes as it emerges in juveniles 3. This form of diabetes,
accounts for only 5–10% of those with diabetes, results from a cellular
mediated autoimmune destruction of the ?-cells of the pancreas2. It is
characterized clinically by abrupt onset of symptoms, dependence on injection insulin
to sustain life and proneness to ketosis3. Type I diabetes mellitus patients
are prone to complications such as nephropathy, retinopathy and neuropathy.
IDDM appears to be heterogeneous in terms of genetic and environmental factors;
genetic determinants are important for the association of increasing and
decreasing frequency of histocompatibility antigens (HCA) on chromosome 63.
These patients are also prone to other autoimmune disorders such as Graves’
disease, Hashimoto’s thyroiditis, Addison’s disease, vitiligo, celiac sprue,
autoimmune hepatitis, myasthenia gravis, and pernicious anemia7.
Idiopathic diabetes: Some forms of
type 1 diabetes have no known etiologies. These patients have permanent
insulinopenia and are prone to ketoacidosis, but have no evidence of
autoimmunity 8. Individuals with this form of diabetes suffer from episodic
ketoacidosis and exhibit varying degrees of insulin deficiency between episodes
9. This form of diabetes is strongly inherited, lacks immunological evidence
for ?-cell autoimmunity, and is not Human leukocyte antigen (HLA) associated
II or Non-insulin dependent diabetes
mellitus (NIDDM) . It accounts for approximately 90–95% of those with diabetes.
It results from relative insulin deficiency and/or insulin resistance. It has a
genetic basis; appears to be stronger than in IDDM, as evidenced by a more
frequent familial pattern of occurence 3. It frequently presents with minimal
or no symptoms referable to the metabolic aberrations of diabetes 11.
Environmental factors superimposed on genetic susceptibility are undoubtedly
involved in onset of NIDDM types 3. Intake of excessive calories leads to
weight gaining and obesity which is an important factor in the pathogenesis of
NIDDM types 3. Patients with this type of diabetes are obese (60% to 90% of
all NIDDM population 3), and the obesity itself causes some degree of insulin
resistance 11-12. Ketoacidosis occasionally occurs and it is usually seen in association with the stress of another illness
such as infection. 13-15 This type of diabetes often goes undiagnosed for
many years as hyperglycemia develops gradually and at its earlier stages it is
not severe enough for patients to notice any of the classic symptoms of
diabetes. 15-18 .With this type of diabetes insulin levels may appear normal
or elevated, the higher blood glucose levels in these diabetic patients would
be expected to result in even higher insulin values if their ?-cell function is
normal. 19 .Age, obesity, and lack of physical activity increases the risk of
developing this form of diabetes. 20, 21 It occurs more frequently in women
with prior gestational diabetes mellitus (GDM) and in individuals with hypertension
or dyslipidemia, 22 and frequency varies in different racial ethnic subgroups.
22-25.It is often associated with a strong genetic predisposition, more so
than is the autoimmune form of type 1 diabetes. 25, 26
III diabetes,Alzheimer’s disease and it
results from resistance to insulin in the brain. 27 Some researchers have
shown resistance to insulin and insulin-like growth factor as a key factor of
the progression of Alzheimer’s disease. 28 Alzheimer’s can show progress without
the presence of significant hyperglycemia in the brain. 29
Gestational diabetes mellitus (GDM),another
category of diabetes which is defined as any degree of glucose intolerance that
was first recognized during pregnancy, regardless of whether the condition may
have predated the pregnancy or persisted after the pregnancy. 2
Various symptoms of diabetes
mellitus include polyuria, polydipsia, glycosuria, weight loss, sometimes with
polyphagia, and blurred vision.30 Impairment of growth, susceptibility to
certain infections, numbness or tingling in the extremities, are also seen. 31
Hyperglycemia with ketoacidosis or the non-ketotic hyperosmolar syndrome are
acute, life-threatening consequences of diabetes. 30 Tiredness and slow wound
healing is also experienced by the patient. 32
There are various diagnostic tools
to monitor the glycemic level in type 2 diabetes mellitus (DM2). These tools
include FPG (fasting plasma glucose) ADA and glycosylated hemoglobin A1c
(HbA1c) 33. The reference range of FPG is <120 mg/dl (6.7 mmol/l) and HbA1c <7% 34. IFG is defined as fasting plasma glucose values of 100 to 125 mg per dL (5.6 to 6.9 mmol per L); normal fasting glucose values are below 100 mg per dL. 35 The FPG test checks our fasting blood glucose levels34 An impaired fasting plasma glucose level is considered within the range of 100 to 109 mg per deciliter (5.55 to 6.05 mmol per liter). 35 The percent HbA1c of glycated hemoglobin provides an estimate of blood glucose levels over a 3–4 month period. 36 The HbA1c level is used for patient education and counseling, diabetic control, to improve patient motivation, and to monitor management 37 . The coefficient of variation (CV) for the HPLC is 2.6%. 38.FPG and the prevalence of impaired carbohydrate metabolism increases with age39,40.There are many risk factors associated with diabetes and its symptoms. Diabetes Mellitus include modifiable risk factors and non-modifiable risk factors. The modifiable factors are overweight or obesity, physical inactivity, sedentary behavior, dietary factors, smoking, previously identified glucose tolerance (IGT and/or IFG), hypertension, inflammation and intrauterine environment. 42 Whereas the non-modifiable risk factors comprise are age, sex, ethnicity, family history of DM2, history of gestational diabetes and polycystic ovary syndrome. 42 Along with the signs and symptoms various complications can be seen in this disease. These complications may be acute or chronic. The acute complications include Diabetic ketoacidosis (DKA), Hyperglycemic hyperosmolaris syndrome (HHS), Hypoglycemia, Metformin associated lactic acidosis, Mucosa Associated Lymphoid Tumor (MALT). 43 Whereas the chronic complications includes nephropathy leading to renal failure; peripheral neuropathy with risk of foot ulcers, amputation, and Charcot joints and retinopathy with potential loss of vision, macrovascular diseases like Coronary heart disease (CHD), peripheral vascular disease and stroke, skin problems and infections. 43,44 Hypertension, abnormalities of lipoprotein metabolism and periodontal disease are often found in people with diabetes. 45 Globally, diabetes has killed 422 million people in 2014 alone. 46 More than 77 % of morbidity and 88 % of mortality due to Diabetes Mellitus occur in low and middle income countries. 47 In young adults, the absolute incidence of DM2 is low, but a marked surge in diabetes associated morbidity has recently been reported. 48.In recent years, many researchers have been conducted showing relationship of platelet reactivity with complication of diabetes mellitus. Platelet are small discoid shaped blood cells that circulate and participate in hemostasis. Platelet forms primary plug that seals vascular defects and provides required phospholipid surface for recruited and activated coagulation factors49. Platelet are highly granular . Alpha granules contain a variety of adhesion molecules, chemokines , coagulation and fibrinolysis proteins , growth factors , immunologic molecules and other proteins .Dense granules contain ionic calcium , magnesium ,phosphate and pyrophosphate as well as ATP , GTP , ADP and GDP nucleotides and the transmitter serotonin granules secretion on endothelial cells thus results in adhesion and aggregation of platelets50. Platelet indices : It consists of : 1. Mean platelet volume (MPV) 2. Plateletcrit (Pct) 3. Platelet distribution width (PDW) 4. Platelet count (PC) 5. Platelet volume indices (PVI) 6. Platelet large cell ratio (P-LCR) Age , gender , white blood count and other various genetic and non genetic factors attribute to modification of platelet indices51. Mean platelet volume (MPV) is represented as total volume of platelet by total platelet number51. Platelet volume marker of platelet function and activation is measured as mean platelet volume (MPV)50.MPV is an indicator of average size and activity of platelet52. Larger platelet are younger, more reactive and aggregrable. Denser granules ,secret more serotonin and beta thromboglobulin and produce more thromboxaneA2 in compare to smaller platelets50,52 . Studies have shown a constant association of increased MPV with diabetes mellitus53-55 . Higher MPV is emerging as a new risk factor50indicating presence of many large platelets which are newer denser, and more active. PDW directly measures variability of platelet size51. Jindal et al found that PDW was significantly increased in patient with diabetes and reported that it was higher in patients who developed macrovascular complications. PLCR is another marker related to platelet volume and is an indicator of largest particle fraction56. Babu and Basu showed PLCR is inversely proportional to platelet count and directly related to MPV and PDW. Increase in PLCR may indicate the presence of platelet aggregates , mocroerythrocytes and giant platelets. PCT is defined as number of circulating platelets per volume of blood. It is quantitative test for abnormalities in platelet count and calculated as platelet count× MPV/107 56 Dyslipidemia can be described as elevated total cholesterol or triglycerides , or low level of high density lipoprotein (HDL) 57. Dyslipidemia also represent a variety of quantitative and /or quantitative lipoprotein abnormalities 59 . According to etiology , dyslipidemia have been identified as primitive and secondary diseases60while primitive dyslipidemias initially recognize as a genetic origin , type II diabetes is considered as one of most frequent causes of secondary dyslipidemia60. Diabetes is often considered a sugar related disease, but the disease might well have been named diabetes lipidus if only lipids instead of sugar could have been tasted in urine , as suggested by Shafrir and Raz60. The hallmark for type II diabetes are hyperglycemia, insulin deficiency and insulin resistance that associate to characteristic dyslipidemia with type II diabetes mellitus. Insulin resistance being characteristic of type II diabetes mellitus plays an important role in pathogenesis of dyslipidemia61. Increased levels of serum insulin and depletion of ?-cells are results of insulin resistance62and also at level of adipocytes, activity like lipoplysis increases releasing high free fatty acids (FFA) in circulation 63,64. Increased FFA promotes liver TG synthesis resulting formation of large VLDL and elevated plasma VLDL(hypertriglyceridemia) and postprandial hyperlipidemia that is impaired lipoprotein lipase activity 62. Hypertriglyceridemia can trigger thrombogenic alterations in coagulation system and also increased VLDL-TG reduces level of HDL-C . Reduction in HDL results reduction in antioxidant anti atherogenic activities62.Formation of small relatively poor cholesterol poor HDL and LDL particles are results increased VLDL65.These LDL particles then becomes more dense and small ,more prone to oxidation and more readily invade and adhere to arterial wall leading to atherosclerosis61.Cholesterol ester transfer protein (CETP) also play role in diabetic dyslipidemia by reducing HDL-C level by increasing its catabolism 66 Cardiovascular disease generally refers to condition that involve narrowed or blocked blood vessels that can lead to a heart attack chest pain or stroke. Atherosclerosis ,myocardial infarction etc are leading heart diseases. Cardiovascular diseases are leading cause of morbidity and mortality. Atherosclerosis is defines as a progressive disease by accumulation of lipids and fibrous elements in arteries67.Hyperglycemia increases risk of microvascular complication while dyslipidemia is a major risk factor for macrovascular complication68. The mechanism involved in increased platelet activity and cardiovascular risk is interrelated. Platelets play an important role in pathogenesis of thrombosis and atherosclerosis69. Diabetes is a disease with oxidative stress and inflammatory process. People with diabetes (type II) exhibit increase platelet reactivity70.Insulin functionally antagonizes activitation of platelet by antagonizing effect of platelet agonist such as collagen , ADP, epinephrine , and platelet activating factors. Endothelial dysfunction promotes activation of platelets by decreasing production of nitric oxide (NO) prostaglandin and platelet activation70.Antagonism by insulin is mediated by activation of inhibitory G – protein by insulin receptor substance (IRS)71.Insulin resistance thus reflects impaired insulin signaling resulting increased platelet activation .Hyperglycemia , osmotic effects off glucose, activated protein kinase C are first second and third mechanism which causes increase platelet activation by inducing non enzymatic glycation of protein on surface of platelet.Such glycation causes increased expression on surface glycoprotein IIb and IIb /IIIa resulting decrease membrane fluidity and increase propensity of platelet to activate and adhere 70 . Activated platelet act with endothelium of blood vessels and other inflammatory cells by action of different molecules present on platelet surface/ granules like P – selectin 69. Upon activation they undergo rapid changes to damaged endothelial surface, aggregrate with other platelets and interact with leukocytes72. One of the contribution theories states hyperlipidemia increases cholesterol content in platelet and enhances their activity which directly or indirectly contribute to atherosclerosis73. Normally arterial endothelium resist contact with leukocytes including blood monocytes but when endothelial cells undergo inflammatory activation ,they increases expression of various leukocyte adhesion molecules 67.Activated platelet promotes leukocytes arrest on vascular endothelium which is believed to be a key process in development of atherosclerosis74. Leukocytes diapedeses between intact endothelial cells to penetrate tunica intima of arterial wall , where they express scavenger receptor that binds lipoprotein particles modified by glycation or oxidation.these process give rise a foam cell. 67.Foam cells narrows arterial wall giving characteristic thrombi in the blood vessels. Thrombi occuld blood vessels resulting increased cardiovascular risk. In this way platelet volume thus reflects platelet reactivity and suggest as independent risk factors for ischemic events in cardiovascular diseases.