ABOUT AUTHORS:
Sachin B. Khetmalas*, Pramod B. Ghanwat, Rushikesh T. Bande
Govt. college of pharmacy, Amravati,
kathora naka, Amravati(Maharashtra) 444604.
*sachin.khetmalas@gmail.com
ABSTRACT:
Diabetes mellitus is a chronic metabolic disorder. It is mainly characterized by hyperglycemia and when the renal threshold for glucose reabsorption is exceeded then glucose splits into the urine (glycosuria), polyuria and thus also leads to polydipsia. Insulin deficiency causes wasting through increased breakdown and reduced synthesis of proteins. In type I diabetes, there is absolute deficiency of insulin, without insulin treatment such patients die due to diabetic ketoacidosis. In type II diabetes patients having insulin resistance in it. Such patients are often obese and usually present in older patients.Various complications develop as a consequence of metabolic disorder, often over many years. Many of these are the result of blood vessels, either large (macrovascular disease) or small (microangiopathy). Microangiopathy is a distinctive feature of diabetes mellitus and particularly affects retina, kidney and peripheral nerves. Diabetes mellitus is common cause of chronic renal failure. It is associated with accumulation of osmotically active metabolites of glucose, produced by the action of aldose reductase.
REFERENCE ID: PHARMATUTOR-ART-1773
INTRODUCTION:-
Diabetes mellitus is group of syndrome characterized by hyperglycemia altered metabolism of lipids, carbohydrates and proteins with an increase risk complications from vascular disease[1]. It was reported that there is a higher incidence of retinopathy, neuropathy, nephropathy etc. together with diabetes. A wide spread pathological change is thickening of capillary membrane, increase in vessel wall matrix and cellular proliferation resulting in vascular complication like lumen narrowing, early atherosclerosis, sclerosis of glomerular capillaries, retinopathy, neuropathy and vascular insufficiency. It may affect the disruption of carbohydrate and fat metabolism[2]. Diabetes is a metabolic disorder where in human body does not produce or properly uses insulin, a hormone that is required to convert sugar, starches, and other food into energy[3]. Human body has to maintain the blood glucose level at a very narrow range, which is done with insulin and glucagon. The function of glucagon is causing the liver to release glucose from its cells into the blood, for the production of energy. The condition may be multifactorial origin in which heredity, age, sex, pregnancy, obesity, autoimmune, infections and emotional disturbances may be important. It may precipitated by pancreatic disorders, hormonal disorders (e.g. acromegely and cushing syndrome), or by administration of drugs (corticosteroids or diuretic, especially thiazides)[4].
Two major types of diabetes mellitus are Type I and Type II.
Type I / Insulin dependent diabetes mellitus (IDDM) / juvenile onset diabetes mellitus:
There is b cell destruction in pancreatic islets; majority of cases are autoimmune (Type IA) antibodies that destroy b cells are detectable in blood, but some are idiopathic (Type IB)-no b cell antibody is found. In all type I cases circulating insulin levels are low or very low, and patience is more prone to ketosis[2].
Type II / Non insulin dependent mellitus (NIDDM) / maturity onset diabetes mellitus:
There is no loss or moderate reduction in b cell mass; insulin in circulation is low, normal pr even high, no anti b cell antibody is demonstrable; generally has a late onset (past middle age). Over 90% cases are type II diabetes mellitus. Causes may be (i) Defects in insulin secretion (ii) Resistance to insulin involving muscle, liver and the adipocytes.
Gestation diabetes mellitus (GDM):
This is glucose intolerance being recognized during pregnancy. It can complicate pregnancy leading to prenatal morbidity and mortality, so clinical detection important.
Other specific type of diabetes:
Maturity onset diabetes youth (MODY) is due to impaired insulin secretion with minimal or no insulin resistance, so hyperglycemia is reported in early stage.
Pathological features of Diabetes Mellitus are due to the following factors:
1) Decrease in utilization of glucose by the body cells. This results in increase in blood glucose concentration to 300 to 1200 mg/dl.
2) Increase in mobilization of fats from the fat storage areas. This results in abnormal fat metabolism and deposition of cholesterol in arterial walls causing atherosclerosis.
3) Tissues get depleted from protein i.e. protein depletion in tissues.
Causes:
Diabetes mellitus is actually a chronic disorder related to defective or deficient insulin secretary response. This results into impaired glucose use, which is a characteristic feature of diabetes mellitus i.e. resultant hyperglycemia. Diabetes mellitus arise from primary disorders of the islets cell-insulin signaling system. In general this disease occurs due to the diminished secretion of insulin by the beta cells of the islets of langerhans. Hereditary is also a cause of diabetes. Hereditary causes susceptibility of the beta cells. This leads to the destruction of the beta cells. Obesity is also one of the factors which cause development of clinical diabetes. Obesity results in decrease in the number of insulin receptors in the insulin target cell throughout the body. This results in decrease in the amount of insulin for its normal metabolic effects[5].
Global prevalence of diabetes:
Type II diabetes is the commonest form of diabetes constituting 90% of the diabetic population. The global prevalence of diabetes is estimated to increase, from 4% in 1995 to 5.4% by the year 2025. The World Health Organization has predicted that the major burden will occur in the developing countries. There will be a 42% increase from 51 to 72 million in the developed countries and 170% increase from 84 to 228 million, in the developing countries. The countries with the largest number of diabetic people are, and will be in the year 2025, India, China and United States.
Diabetes in Indians:
Epidemiological studies among migrant Asian Indians in many countries showed higher prevalence of type 2 diabetes compared with the host populations and other migrant ethnic groups. Studies conducted in India in the last decade have highlighted that not only is the prevalence of type 2 diabetes high, but also that it is increasing rapidly in the urban population. The period between 1989 and 1995 showed a 40% rise in the prevalence and subsequently a further increase of 16.4% was seen in the next 5 years. A national survey of diabetes conducted in six major cities in India in the year 2000 showed that the prevalence of diabetes in urban adults was 12.1%. Prevalence of IGT was also high (14.0%). A younger age at onset of diabetes had been noted in Asian Indians in several studies. In the national study, onset of diabetes occurred before the age of 50 years in 54.1% of cases, implying that these subjects developed diabetes in the most productive years of their life and had a greater chance of developing the chronic complications of diabetes.
Urban–rural difference:
An urban–rural difference in the prevalence rate was found indicating that the environmental factors related to urbanization had a significant role in increasing the prevalence of diabetes. The prevalence of diabetes in urbanizing rural population was found to be midway between the rural and urban populations[6].
Type I and Type II diabetes impede a person’s carefree life. When breakdown of glucose is stopped completely, body uses fat and protein for producing the energy. Due to this mechanism symptoms like polydipsia, polyuria, polyphegia, and excessive weight loss can be observed in a diabetic. Desired blood sugar of human body should be between 70 mg/dl -110 mg/dl at fasting state. If blood sugar is less than 70 mg/dl, it is termed as hypoglycemia and if more than 110 mg /dl, it’s hyperglycemia.
Diabetes is the primary reason for adult blindness, end-stage renal disease, gangrene and amputations. Overweight, lack of exercise, family history and stress increase the likelihood of diabetes. When blood sugar level is constantly high it leads to kidney failure, cardiovascular problems and neuropathy. Patients with diabetes are 4 times more likely to have coronary heart disease and stroke. In addition, Gestational diabetes is more dangerous for pregnant women and their fetus.
Pathophysiology:
Insulin resistance means that body cells do not respond appropriately when insulin is present. Unlike type I diabetes mellitus the insulin resistance is generally "post-receptor", meaning it is a problem with the cells that respond to insulin rather than a problem with production of insulin.
Other important contributing factors:
increased hepatic glucose production (e.g., from glycogen degradation), especially at inappropriate times (typical cause is deranged insulin levels, as insulin controls this function in liver cells) decreased insulin-mediated glucose transport in (primarily) muscle and adipose tissues (receptor and post-receptor defects) impaired beta-cell function—loss of early phase of insulin release in response to hyperglycemic stimuli Cancer survivors who received allergenic Hematopoietic Cell Transplantation (HCT) are 3.65 times more likely to report type 2 diabetes than their siblings. Total body irradiation (TBI) is also associated with a higher risk of developing diabetes.
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This is a more complex problem than type I, but is sometimes easier to treat, especially in the early years when insulin is often still being produced internally. Type II may go unnoticed for years before diagnosis, since symptoms are typically milder and can be sporadic. However, severe complications can result from improperly managed type II diabetes, including renal failure, blindness, slow healing wounds (including surgical incisions), and arterial disease, including coronary artery diseases. The onset of type II has been most common in middle age and later age, although it is being more frequently seen in adolescents and young adults due to an increase in screening programs. A type of diabetes called maturity onset diabetes youth is occasionally also seen in adolescents, but this is classified as diabetes due to a specific cause and not as type II diabetes.
Diabetes mellitus type II is presently[update] of unknown etiology. Diabetes mellitus with a known etiology, such as secondary to other diseases, known gene defect, trauma or surgery, or the effects of drugs, is more appropriately called secondary diabetes mellitus or diabetes due to a specific cause. Examples include diabetes mellitus such as MODY or those caused by hemochromatosis, pancreatic insufficiencies, or certain types of medications (e.g. long-term steroid use).
The total prevalence of diabetes increased 13.5% from 2005-2007. Only 24% of diabetes is undiagnosed, down from 30% in 2005 and from 50% ten years ago. About 90–95% of all North American cases of diabetes are type IIand about 20% of the population over the age of 65 has diabetes mellitus type II. The fraction of type II diabetics in other parts of the world varies substantially, almost certainly for environmental and lifestyle reasons, though these are not known in detail. Diabetes affects over 150 million people worldwide and this number is expected to double by 2025.[7] There is also a strong inheritable genetic connection in type II diabetes having relatives with type II, increases risks of developing type II diabetes very substantially. In addition, there is also a mutation to the Islet amyloid Polypeptide gene that results in an earlier onset, more severe, form of diabetes[8, 9]. About 55 percent of type II are obese —chronic obesity leads to increased insulin resistance that can develop into diabetes, most likely because adipose tissues (especially that in the abdomen around internal organs) is a (recently identified) source of several chemical signals to other tissues (hormones and cytokines). Other research shows that type 2 diabetes causes obesity as an effect of the changes in metabolism and other deranged cell behavior attendant on insulin resistance.[10]
Diabetes mellitus type II is often associated with obesity, hypertension, elevated cholesterol (combined hyperlipidemia), and with the condition often termed metabolic syndrome. It is also associated with acromegly, Cushing syndrome and a number of other endocrinological disorders. Additional factors found to increase risk of type 2 diabetes include aging, high-fat diets [11, 12]
Symptoms of long term Diabetes:
Diabetes retinopathy shows symptoms of pain in the eyes and may even result in loss of vision.
Renal (kidney) disease shows symptoms of swelling (edema) in the feet and legs. It then passes over total body and as the disease progresses, blood pressure also increases.
Tingling, burning, numbness, tightness, shooting or stabbing pain in the hands, feet or other parts of your body, especially at night. Digestive problems also occur if, the nerve controlling internal organs get damaged (autonomic neuropathy).
You may have scanty or profuse sweating, difficulty of sensing when your bladder is full, when there is a low blood sugar, increased sexual problems, weakness, dizziness, and fainting.
Chest pain (angina) or shortness of breath dizziness or light headache, shoulder or stomach pain, fast heartbeat. When alarming symptoms given by the body are ignored and the same status is maintained, it starts damaging body organs, such as heart, kidney, eye, feet, and skin[13].
DIABETIC NEUROPATHY
Diabetic neuropathy is a common cause of morbidity and death among patients with diabetes, generating a huge economic burden. Apart from tight glycemic control, no other evidence-based treatments are known to ameliorate or prevent neuropathy. The duration and level of hyperglycemia are important determinants of microvascular complications of diabetes, including neuropathy. [14] The relative effect of cardiovascular risk factors specifically associated with diabetes (e.g., hypertension, dyslipidemia, and increased weight) or not associated with diabetes (smoking) on the development of neuropathy are incompletely elucidated. The Diabetes Control and Complications Trial reported a 60 percent reduction in neuropathy in the intensively treated groups after five years, but the cumulative incidence of neuropathy (15 to 21 percent) and abnormal nerve conduction (40 to 52 percent) remained substantial. Such findings suggest that neuropathy can develop, despite intensive control of the glucose level. Thus, risk factors besides hyperglycemia are probably involved in the evolution of neuropathy.[15]
Pathophysiology:
The factors leading to the development of peripheral neuropathy in diabetes are not understood completely, and multiple hypotheses have been advanced. It is generally accepted to be a multifactor process. Important contributing biochemical mechanisms in the development of the more common symmetrical forms of diabetic polyneuropathy likely include the following,
Polyol pathway:
Hyperglycemia causes increased levels of intracellular glucose in nerves, leading to saturation of the normal glycolytic pathway. Extra glucose is shunted into the polyol pathway and converted to sorbitol and fructose by the enzymes aldose reductase and sorbitol dehydrogenase. Accumulation of sorbitol and fructose lead to reduced nerve myoinositol, decreased membrane Na+/K+ -ATPase activity, impaired axonal transport, and structural breakdown of nerves, causing abnormal action potential propagation. This is the rationale for the use of aldose reductase inhibitors to improve nerve conduction.
Advanced Glycation End Products (AGE):
The nonenzymatic reaction of excess glucose with proteins, nucleotides, and lipids results in advance glycation end products that may have a role in disrupting neuronal integrity and repair mechanisms through interference with nerve cell metabolism and axonal transport.
Oxidative Stress:
The increased production of free radicals in diabetes may be detrimental via several mechanisms that are not fully understood. These include direct damage to blood vessels leading to nerve ischemia and facilitation of AGE reactions. Despite the incomplete understanding of these processes, use of the antioxidant alpha lipoic acid may hold promise for improving neuropathic symptoms.[16]
Related contributing factors:
Problems that are a consequence of or co-contributors to these disturbed biochemical processes include altered gene expression with altered cellular phenotypes, changes in cell physiology relating to endoskeletal structure or cellular transport, reduction in neurotropins, and nerve ischemia. Clinical trials of the best studied neurotropin, human recombinant nerve growth factor were disappointing. However, with future refinements, one or more of these mechanisms may provide reasonable targets for pharmacological intervention. In the case of focal or asymmetrical diabetic neuropathy syndromes, vascular injury or autoimmunity may play more important roles[17].
Classification of diabetic neuropathy:
It is originally proposed a purely clinical and descriptive classification. Subsequently, research gave a simple classification based on anatomical characteristics, which is now widely accepted[22].
Classification of diabetic neuropathy.
Diffuse:
A .Distal symmetric sensory-motor polyneuropathy
B. Autonomic neuropathy
C. Symmetric proximal motor neuropathy (amyotrophy)
Focal :
A. Cranial neuropathy
B. Radiculopathy/plexopathy
C. Entrapment neuropathy
A. Distal symmetrical sensory-motor polyneuropathy: It is the most common type of diabetic neuropathy. It involves both small and large fibers and has insidious onset. Typically, the most distal parts of the extremities are affected first, resulting in a stocking pattern of sensory loss. As the sensory symptoms advance above the knees, the distal upper limbs and later the anterior aspect of trunk and subsequently the vertex of the head gets involved. It is predominantly sensory neuropathy, with autonomic involvement which is usually subclinical. Clinically apparent motor deficit develops only in rare cases. Its symptoms are extremely variable, ranging from severely painful symptoms at one extreme to the completely painless variety, which may present with an insensitive foot ulcer at the other end. The neuropathic symptoms may be positive or negative. The negative symptoms are - numbness and deadness in the lower limbs while the positive symptoms most commonly include burning pain, altered and uncomfortable temperature perception, paraesthesia, shooting, stabbing and lancinating pain, hyperaesthesia and allodynia. The feet and legs are most commonly affected; rarely less severe similar symptoms are experienced in the upper limbs also. The sensory symptoms and signs are more common than motor symptoms and signs. Common motor signs are absent or reduced ankle reflex, and minimal distal muscle weakness. Motor involvement results in foot deformity. This abnormality redistributes weight bearing and leads to callus and ulcer formation. The proprioceptive loss makes the gait more unsteady and there is a sense of walking on cotton wool. Acute painful neuropathy is a distinct variant of distal sensory neuropathy, presenting acutely with severe sensory symptoms with few sensory or motor signs and often it follows a period of flux in glycaemic control[18].
B. Autonomic neuropathy: Autonomic neuropathy is a serious and often overlooked component of diabetic neuropathy. Any organ of body which is supplied by autonomic nerves can be affected. Studies have confirmed the presence of parasympathetic dysfuction in 65% of the type 2 diabetic patients 10 years after diagnosis and of combined parasympathetic and sympathetic neuropathy in 15.2%. Autonomic neuropathy is not simply an “all or none” phenomenon and its symptoms range from minor to severe. The severe form may affect survival and can cause sudden death.
Symptoms and signs of autonomic neuropathy:
1. Cardiovascular: Postural hypotension,Resting tachycardia,Painless myocardial infarction, Sudden death (with or without association with general anaesthesia), Prolonged QT interval
2. Gastrointestinal: Oesophageal motor incoordination, Gastric dysrhythmia, hypomotility (gastroparesis diabeticorum), Pylorospasm., Uncoordinated intestinal motility (diabetic diarrhoea, spasm), Intestinal hypomotility (constipation), Gallbladder hypocontraction (diabetic cholecystopathy), Anorectal dysfunction (faecal incontinence)
3. Genitourinary: Diabetic cystopathy (impaired bladder sensation, atonic bladder, post micturition dribbling, detrusor hyporeflexia or hyperreflexia), Maleimpotence, Ejaculatory disorders, Reduced vaginal lubrication, dyspareunia
4. Respiratory: Impaired breathing control,Sleep apnoea
5. Thermoregulatory: Sudomotor, Vasomotor
6. Pupillary: Miosis, Disturbances of dilatation
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C. Proximal motor neuropathy: It typically affects the elderly males (> 50 year) suffering from type 2 diabetes mellitus but it can also occur in females and type 1 diabetes mellitus. It may be symmetrical or asymmetrical, and with or without sensory loss. Patient usually presents with difficulty in getting up from squatting position, pain in climbing stairs and marked weight loss (sometimes upto 40% of original weight). It predominantly affects anterior (quadriceps) and adductor compartments of thigh. Wasting and weakness of quadriceps is so severe that the knee often gives way, and patient may fall. This has been labeled as diabetic amyotrophy also. The cause of diabetic amyotrophy is unknown but neurological deficit and anatomical distributions suggest nerve root involvement presumably due to occlusion of the vasa nervosum and infarction. Examination shows wasting and weakness of the anterior and adductor compartments of thigh. The knee jerk is absent, while the ankle jerk may be intact. Sometimes, other muscles, especially the anterior tibial and peroneal muscles may also be involved. [19]
Focal neuropathies or mono-neuropathies: The diabetic patients are also susceptible to a variety of asymmetric and focal neuropathies.
A. Cranial Neuropathy: The third, fourth, and sixth cranial nerves are commonly involved. Elderly patients are the most affected. The third cranial nerve palsy presents with eye pain, diplopia, and ptosis but pupillary response to light is usually spared. The pupillary sparing favours vascular aetiology of IIIrd nerve palsy. Exclusion of other causes of IIIrd nerve palsy is necessary before labelling diabetes as a cause. Spontaneous recovery generally occurs within 6-12 weeks, although recurrent or bilateral lesion may also occur.
B. Truncal Neuropathy: Symptomatic truncal polyneuropathy though less common, tends to occur in the setting of long standing diabetes with other microvascular complications especially peripheral neuropathy. Most of the affected individuals are in the 5th or 6th decade of life, with a variable duration of diabetes.[13] It usually presents with gradual onset of pain and dysaesthesia in the lower anterior chest or upper abdomen with nocturnal intensification. On examination, hypoaesthesia or hyperaesthesia may be present in the appropriate thoracic segment and abdominal muscle weakness leading to abdominal swelling. A careful sensory examination of abdomen and thorax is mandatory in a diabetic person presenting with unexplained thoracoabdominal pain. It resolves spontaneously within 2 to 6 months.
C. Entrapment neuropathy: Also known as pressure palsy, this is relatively uncommon. Median nerve is mostly affected and is secondary to soft tissue changes associated with limited joint mobility. The precise pathogenesis of diabetic peripheral neuropathy despite recent advances remains obscure; however, consensus is that neuropathy in diabetes mellitus is a multifactor disease. The possible etiologic factors suggested include, hyperglycaemia, polyol pathway, non-enzymatic glycation, free radical and oxidative stress. Available evidence suggests that these various pathogenetic factors act synergistically. Many of these hypotheses are based on studies of different animal models of diabetes, but none of these truly reproduce the changes as seen in diabetic neuropathies in humans. [20]
Screening of Diabetic Neuropathy:
Chronic sensorimotor:
All patients with diabetes should be screened for diabetic peripheral neuropathy at diagnosis of type 2 diabetes and 5 years after the diagnosis of type I diabetes and at least annually by examining sensory function in the feet and checking ankle reflexes. One or more of the following can be used to assess sensory function: pinprick, temperature, andvibration perception (using a 128-Hz tuning fork), or pressure sensation (using a 10-g monofilament pressure sensation at the distal halluces). Any history of neuropathic symptoms should be elicited, and a careful clinical examination of the feet and lower limbs should be performed. The feet should be examined for ulcers, calluses, and deformities, and footwear should be inspected at each diabetes care visit. All patients with diabetic peripheral neuropathy, whether symptomatic or not, require foot care education and consideration for podiatric referral.
Monofilament testing:
The monofilaments produce a characteristic force perpendicular to the contacting surface. The force of downward contact increases linearly until the monofilament buckles. Furthermore, repeated use of the devices throughout the day led to a far lower buckling force, thus leading the clinician to over diagnose the loss of protective sensation. Monofilaments can fail for several reasons: they can become damaged, old and uncalibrated. This contributes to lower loading forces and an over diagnosis of peripheral sensory neuropathy. Monofilament units should be replaced frequently and only calibrated instruments should be used. Throwaway or give-away devices are of questionable quality and durability.
Vibration Perception Threshold (VPT):
This testing is the most widely used quantitative sensory testing approach. VPT is associated with large normative and neuropathy databases. VPT evaluation fulfills the key criteria that make it desirable for longitudinal cohort evaluation: The instrument is sensitive, specific and reliable.[21]
CONCLUSION:-
Present project concludes that the need to know diabetic induced complications and regarding other manifestations is very important. As these complications may be fatal if not diagnosed earlier or the prognosis of complications is very bad. The diabetic patient if not treated properly, suffers through other health problems and eventually may lead to multiorgan system failure. Diabetesis under diagnosed in the elderly and is frequently undertreated. The greatest attention should be given to reduction of overall cardiovascular risk. This study aimed to explore the relationship between complicationsand risk factors in the type II diabetes population. Multi-disciplinary approaches to the control of risk factorsand patient self management and education are critical to theprogression and success of diabetes care. In addition, optimized control of glucose level which delays onset and progression of diabetic retinopathy as well as other complications like neuropathy and nephropathy. In simple word, patients who do not follow necessary precaution may have severe damage to various body systems leading to complications i.e. eye causing retinopathy, damaged nerves leading to neuropathy, damage to kidney leading nephropathy.
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