Diabetes Mellitus Lecture Notes 2024-2025 PDF

Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي...

Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ Diabetes Mellitus 1 Background The term diabetes is derived from a Greek word meaning “going through,” and mellitus from the Latin word for “honey” or “sweet.” Reports of the disorder can be traced back to the first century AD, when Aretaeus the Cappadocian described the disorder as a chronic affliction characterized by intense thirst and voluminous, honey-sweet urine: “the melting down of flesh into urine.” It was the discovery of insulin by Banting and Best in 1922 that transformed the once-fatal disease into a manageable chronic health. Diabetes is a disorder of carbohydrate, protein, and fat metabolism resulting from a lack of insulin availability or a reduction in the biologic effects of insulin. It can represent an absolute insulin deficiency, impaired release of insulin by the pancreatic beta cells, inadequate or defective insulin receptors or postreceptor regulation, or the production of inactive insulin or insulin that is destroyed before it can carry out its action. 2 Classification and Etiology Although diabetes mellitus clearly is a disorder of insulin availability, it is not a single disease. It divides diabetes into four clinical classes. Included in the classification system are the categories of: 1. Type 1 diabetes (i.e., diabetes resulting from beta cell destruction and an absolute insulin deficiency) ; 2. Type 2 diabetes (i.e., diabetes due to insulin resistance and a relative insulin deficiency) ; 3. Gestational diabetes mellitus (i.e., diabetes that develops during pregnancy) ; 4. Other specific types of diabetes, many of which occur secondary to other conditions (e.g., Cushing syndrome, acromegaly, and pancreatitis). 2.2 Type 1 Diabetes Mellitus Type 1 diabetes mellitus, which is characterized by destruction of the pancreatic beta cells and accounts for 5% to 10% of those with diabetes, is subdivided into: 1. type 1A immune-mediated diabetes and 2. type 1B idiopathic (non–immune-related) diabetes In the United States and Europe, approximately 90% to 95% of people with type 1 diabetes mellitus have type 1A immunemediated diabetes. The rate of beta cell destruction is quite variable, being rapid in some individuals (mainly infants and children) and slow in others (mainly adults). Some individuals, particularly children and adolescents, may present with ketoacidosis as the first manifestation of the disease. Others may have modest elevations in FPG that can rapidly change to severe hyperglycemia and ketoacidosis in the presence of stress and infection. Still others, particularly adults, may retain sufficient beta cell function to prevent ketoacidosis for many years. The destruction of beta cells and absolute lack of insulin in people with type 1 diabetes mellitus means that they are particularly prone to the development of ketoacidosis. One of the actions of insulin is the inhibition of lipolysis (i.e., fat breakdown) and release of free fatty acids (FFAs) from fat cells. In the absence of insulin, ketosis develops when these 1  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ fatty acids are released from fat cells and converted to ketones in the liver. Because of the loss of insulin response, all people with type 1A diabetes require exogenous insulin replacement to reverse the catabolic state, control blood glucose levels, and prevent ketosis. Type 2 Diabetes Mellitus and the Metabolic Syndrome Type 2 diabetes mellitus, previously described as non–insulin-dependent diabetes, describes a condition of hyperglycemia that accompanies a relative rather than an absolute insulin deficiency. It currently accounts for about 90% to 95% of the cases of diabetes. Most people with type 2 diabetes are older and overweight. Recently, however, type 2 diabetes has become a more common occurrence in obese children and adolescents. Although type 1 diabetes remains the main form of diabetes in children worldwide, it seems likely that type 2 diabetes will become the predominant form within 10 years in some ethnic groups. The metabolic abnormalities involved in type 2 diabetes include (figure 1): 1. insulin resistance 2. increased glucose production by the liver, and 3. deranged secretion of insulin by the pancreatic beta cells Figure 1: Pathogenesis of type 2 diabetes mellitus Insulin resistance predates the development of hyperglycemia and is usually accompanied by compensatory beta cell hyperfunction and hyperinsulinemia in the early stages of the evolution of type 2 diabetes. 2  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ Insulin resistance can be defined as the failure of target tissues to respond to insulin, leading to decreased uptake of glucose in skeletal muscle and impaired suppression of glucose production by the liver. Hepatic insulin resistance is manifested by overproduction of glucose despite fasting hyperinsulinemia, with the rate of glucose production being the primary determinant of the elevated FPG in persons with type 2 diabetes. Although muscle glucose uptake is slightly increased after a meal, the efficiency with which it is taken up (glucose clearance) is diminished, resulting in an increase in postprandial (following a meal) blood glucose levels. Specific causes of beta cell dysfunction include an initial decrease in the beta cell mass related to genetic or prenatal factors; increased apoptosis or decreased beta cell regeneration; beta cell exhaustion due to long-standing insulin resistance; glucotoxicity (i.e., glucose- induced beta cell desensitization); lipotoxicity (i.e., toxic effects of lipids on beta cells); and amyloid deposition or other conditions that have the potential to reduce beta cell mass. According to one study, beta cell function was reduced by 50% at the time of diagnosis in type 2 diabetes, and progressively decreased (by approximately 4% per year), resulting in a worsening of hyperglycemia even when the degree of insulin resistance remained stable. The pathogenesis of type 2 diabetes involves both genetic and acquired (environmental) factors. A positive family history confers a twofold to fourfold increased risk for type 2 diabetes, and 15% to 25% of first-degree relatives of persons with type 2 diabetes develop impaired glucose tolerance or diabetes. Despite the strong familial predisposition, the genetics of type 2 diabetes is poorly defined. This is probably because of the heterogeneous nature of the disorder as well as the difficulty in sorting out the contribution of acquired factors affecting insulin action and glycemic control. Among the acquired factors that predispose to type 2 diabetes, obesity and physical inactivity are paramount. Approximately 90% of people with type 2 diabetes are overweight. Obesity has profound effects on sensitivity of tissues to insulin, and as a consequence, on glucose homeostasis. As the body mass index (BMI) increases, the risk of developing diabetes increases. It is not only the absolute amount of fat, but also the distribution of body fat that has an effect on insulin resistance. It has been found that people with upper body (or central) obesity are at greater risk for developing type 2 diabetes and metabolic disturbances than persons with lower body (or peripheral) obesity. The increased insulin resistance has been attributed to the increased visceral (intra-abdominal) fat that can be detected on computed tomography scan and other imaging modalities. Waist circumference and waist–hip ratio, which are both surrogate measures of central obesity, have been shown to correlate well with insulin resistance. Thus, measures such diet and exercise that reduce visceral adiposity are important in the management of persons with metabolic syndrome and obese type 2 diabetics. Although many details of the relationship between adipose tissue and insulin resistance remain to be elucidated, several pathways have been proposed including the role of FFAs, adipose tissue cytokines (adipokines), and the peroxisome proliferator–activated receptor (PPAR- gamma) that is expressed by adipocytes and plays an essential role in adipocyte differentiation. A large number of circulating hormones, cytokines, and metabolic fuels such as FFAs originate in fat cells and modify insulin action. It has been theorized that the insulin resistance and increased glucose production in obese people with type 2 diabetes may stem from an increased 3  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ concentration of FFAs. Visceral obesity is especially important because it is accompanied by an increase in fat storage and postprandial FFA concentrations. This has several consequences: - first, excessive and chronic elevation of FFAs can cause beta cell dysfunction (lipotoxicity); - second, FFAs also act at the level of the peripheral tissues to cause insulin resistance and glucose underutilization by inhibiting glucose uptake and glycogen storage; - and third, the accumulation of FFAs and triglycerides reduces hepatic insulin sensitivity, leading to increased hepatic glucose production and hyperglycemia, especially in the fasting state. A further consequence is the diversion of excess FFAs to nonadipose tissues, including the liver, skeletal muscle, heart, and pancreatic beta cells. In the liver, the uptake of FFAs from the portal blood can lead to hepatic triglyceride accumulation and nonalcoholic fatty liver disease. In addition to the metabolic effects of visceral obesity, adipocytes are the source of a number of important factors (e.g., adiponectin, leptin, FFAs) involved in a wide range of other processes, including glucose and lipid metabolism, inflammation, and thrombosis. In obesity and type 2 diabetes, there is a reduction in the production of some factors that are normally synthesized by adipocytes (i.e., adiponectin), whereas there is an accelerated release of other factors such as angiotensinogen, plasminogen activator inhibitor-1, leptin, and proinflammatory cytokines (e.g., tumor necrosis factor-alpha). Adiponectin, which is secreted by adipocytes and circulates in the blood, is the only known adipocyte-secreted factor that increases tissue sensitivity to insulin. It has been shown that decreased levels of adiponectin coincide with insulin resistance in patients with obesity and type 2 diabetes. In skeletal muscle, adiponectin has been shown to decrease tissue triglyceride content by increasing the use of fatty acids as a fuel source. Adiponectin also appears to have antidiabetes, anti-inflammatory, and antiatherogenic effects. 3 Insulin Resistance and Metabolic Syndrome. There is increasing evidence to suggest that when people with type 2 diabetes present predominantly with insulin resistance, diabetes may represent only one aspect of a syndrome of metabolic disorders. Hyperglycemia in these people is frequently associated with intra- abdominal obesity, high levels of plasma triglycerides and low levels of high-density lipoproteins (HDLs), hypertension, systemic inflammation (as detected by C-reactive protein [CRP] and other mediators), abnormal fibrinolysis, abnormal function of the vascular endothelium, and macrovascular disease (coronary artery, cerebrovascular, and peripheral arterial disease). This constellation of abnormalities often is referred to as the insulin resistance syndrome, syndrome X, or, the preferred term, metabolic syndrome. Insulin resistance and increased risk of developing type 2 diabetes are also seen in women with polycystic ovary syndrome. 4 Clinical Manifestations of Diabetes Diabetes mellitus may have a rapid or an insidious onset. In type 1 diabetes, signs and symptoms often arise suddenly. Type 2 diabetes usually develops more insidiously; its presence 4  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ may be detected during a routine medical examination or when a patient seeks medical care for other reasons. The most commonly identified signs and symptoms of diabetes are often referred to as the three polys (PPP): (1) polyuria (i.e., excessive urination) (2) polydipsia (i.e., excessive thirst), and (3) polyphagia (i.e., excessive hunger). These three symptoms are closely related to the hyperglycemia and glycosuria of diabetes. Glucose is a small, osmotically active molecule. When blood glucose levels are sufficiently elevated, the amount of glucose filtered by the glomeruli of the kidney exceeds the amount that can be reabsorbed by the renal tubules; this results in glycosuria accompanied by large losses of water in the urine. Thirst, results from the intracellular dehydration that occurs as blood glucose levels rise and water is pulled out of body cells, including those in the hypothalamic thirst center. This early symptom may be easily overlooked in people with type 2 diabetes, particularly in those who have had a gradual increase in blood glucose levels. Polyphagia usually is not present in people with type 2 diabetes. In type 1 diabetes, it probably results from cellular starvation and the depletion of cellular stores of carbohydrates, fats, and proteins. Weight loss despite normal or increased appetite is a common occurrence in people with uncontrolled type 1 diabetes. The cause of weight loss is twofold. - First, loss of body fluids results from osmotic diuresis. Vomiting may exaggerate the fluid loss in ketoacidosis. - Second, body tissue is lost because the lack of insulin forces the body to use its fat stores and cellular proteins as sources of energy. In terms of weight loss, there often is a marked difference between type 2 diabetes and type 1 diabetes. Weight loss is a frequent phenomenon in people with uncontrolled type 1 diabetes, whereas many people with uncomplicated type 2 diabetes often have problems with obesity. Other signs and symptoms of hyperglycemia include recurrent blurred vision, fatigue, paresthesias, and skin infections. In type 2 diabetes, these often are the symptoms that prompt a person to seek medical treatment. Blurred vision develops as the lens and retina are exposed to hyperosmolar fluids. Lowered plasma volume produces weakness and fatigue. Paresthesias reflect a temporary dysfunction of the peripheral sensory nerves. Chronic skin infections can occur and are more common in people with type 2 diabetes. Hyperglycemia and glycosuria favor the growth of yeast organisms. Pruritus and vulvovaginitis due to Candida infections are common initial complaints in women with diabetes. Balanitis secondary to Candida infections can occur in men. 5  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ 5 Acute Complications The three major acute complications of impaired blood glucose regulation are diabetic ketoacidosis, hyperosmolar hyperglycemic state, and hypoglycemia. All are life-threatening conditions that demand immediate recognition and treatment. The Somogyi effect and dawn phenomenon, which result from the mobilization of counterregulatory hormones, contribute to difficulties with diabetic control. 5.1 Diabetic Ketoacidosis Diabetic ketoacidosis (DKA), characterized by hyperglycemia, ketosis, and metabolic acidosis, is an acute life-threatening complication of uncontrolled diabetes. DKA primarily affects people with type 1 diabetes but may also occur in persons with type 2 diabetes when severe stress such as sepsis or trauma is present. It may be an initial manifestation of previously undiagnosed type 1 diabetes or may result from increased insulin requirements in type 1 diabetes during stress situations such as infection or trauma that increase the release of stress hormones. For example, a mother may bring a child into the clinic or emergency department with reports of lethargy, vomiting, and abdominal pain, unaware that the child has diabetes. In clinical practice, ketoacidosis also occurs with the omission or inadequate use of insulin. Ketoacidosis reflects the effect of insulin deficiency at multiple sites. Insulin lack results in the rapid breakdown of energy stores from muscle and fat depots, leading to increased movement of amino acids to the liver for conversion to glucose and of fatty acids for conversion to ketones. In the presence of ketosis, the levels of glucagon and counterregulatory hormones (i.e., corticosteroids, epinephrine, and growth hormone) are consistently increased. Furthermore, in the absence of insulin, peripheral utilization of glucose and ketones is reduced. Metabolic acidosis is caused by the excess ketoacids that require buffering by bicarbonate ions; this leads to a marked decrease in serum bicarbonate levels. The definitive diagnosis of DKA consists of hyperglycemia (blood glucose levels 250 mg/dL, low serum bicarbonate, low arterial pH, and positive urine and serum ketones. It can be further subdivided into mild DKA (serum bicarbonate of 15 to 18 mEq/dL [15 to 18 mmol/L], pH 7.25 to 7.30); moderate DKA (serum bicarbonate 10 to 15 mEq/dL [10 to 15 mmol/L], pH 7.00 to 7.24): and severe DKA (serum bicarbonate 10 mEq/dL [10 mmol/L], pH 7.00). Hyperglycemia leads to osmotic diuresis, dehydration, and a critical loss of electrolytes. Hyperosmolality of extracellular fluids from hyperglycemia leads to a shift of water and potassium from the intracellular to the extracellular compartment. Extracellular sodium concentration frequently is low or normal despite enteric water losses because of an intracellular–extracellular fluid shift. This dilutional effect is referred to as pseudohyponatremia. Serum potassium levels may also be normal or elevated, despite total potassium depletion resulting from protracted polyuria and vomiting. The development of DKA is commonly preceded by a day or more of polyuria, polydipsia, nausea, vomiting, and marked fatigue, with eventual stupor that can progress to coma. Abdominal pain and tenderness may be experienced without abdominal disease. The breath has a characteristic fruity smell because of the presence of the volatile ketoacids. 6  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ Hypotension and tachycardia may be present because of a decrease in blood volume. A number of the signs and symptoms that occur in DKA are related to compensatory mechanisms. The heart rate increases as the body compensates for a decrease in blood volume, and the rate and depth of respiration increase (i.e., Kussmaul respiration) as the body attempts to prevent further decreases in pH. The goals in treating DKA are to improve circulatory volume and tissue perfusion, decrease blood glucose, and correct acidosis and electrolyte imbalances. These objectives usually are accomplished through the administration of insulin and intravenous fluid and electrolyte replacement solutions. Because insulin resistance accompanies severe acidosis, low-dose insulin therapy is used. An initial loading dose of regular insulin often is given intravenously, followed by continuous low-dose infusion. Frequent laboratory tests are used to monitor blood glucose and serum electrolyte levels and to guide fluid and electrolyte replacement. It is important to replace fluid and electrolytes and correct pH while bringing the blood glucose concentration to a normal level. Too rapid a drop in blood glucose may cause hypoglycemia. A sudden change in the osmolality of extracellular fluid can also occur when blood glucose levels are lowered too rapidly, and this can cause cerebral edema. Cerebral and other autoregulatory mechanisms may not be as well developed in younger children, placing them at particular risk for development of cerebral edema. Serum potassium levels often fall as acidosis is corrected and potassium moves from the extracellular into the intracellular compartment. Thus, it may be necessary to add potassium to the intravenous infusion. Identification and treatment of the underlying cause, such as infection, also are important. 5.2 Hyperosmolar Hyperglycemic State The hyperosmolar hyperglycemic state (HHS) is characterized by hyperglycemia (blood glucose 600 mg/dL), hyperosmolarity (plasma osmolarity 320 mOsm/L) and dehydration, the absence of ketoacidosis, and depression of the sensorium. HHS may occur in various conditions, including type 2 diabetes, acute pancreatitis, severe infection, myocardial infarction, and treatment with oral or parenteral nutrition solutions. It is seen most frequently in people with type 2 diabetes. A partial or relative insulin deficiency may initiate the syndrome by reducing glucose utilization while inducing hyperglucagonemia and increasing hepatic glucose output. With massive glycosuria, obligatory water loss occurs. If the person is unable to maintain adequate fluid intake because of associated acute or chronic illness or has excessive fluid loss, dehydration develops. As the plasma volume contracts, renal insufficiency develops, and the resultant limitation of renal glucose losses leads to increasingly higher blood glucose levels and severity of the hyperosmolar state. In hyperosmolar states, the increased serum osmolarity has the effect of pulling water out of body cells, including brain cells. The condition may be complicated by thromboembolic events arising because of the high serum osmolality. The most prominent manifestations are weakness, dehydration, polyuria, neurologic signs and symptoms, and excessive thirst. The neurologic signs include hemiparesis, Babinski reflexes, aphasia, muscle fasciculations, hyperthermia, hemianopia, nystagmus, visual hallucinations, seizures, and coma. The onset of 7  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ HHS often is insidious, and because it occurs most frequently in older people, it may be mistaken for a stroke. The treatment of HHS requires judicious medical observation and care as water moves back into brain cells, posing a threat of cerebral edema. Extensive potassium losses that also have occurred during the diuretic phase of the disorder require correction. Because of the problems encountered in the treatment and the serious nature of the disease conditions that cause HHS, the prognosis for this disorder is less favorable than that for ketoacidosis. 5.3 Hypoglycemia Hypoglycemia, or an insulin reaction, occurs from a relative excess of insulin in the blood and is characterized by below-normal blood glucose levels. It occurs most commonly in people treated with insulin injections, but prolonged hypoglycemia also can result from some oral hypoglycemic agents. There are many factors that can precipitate an insulin reaction in a person with type 1 diabetes, including error in insulin dose, failure to eat, increased exercise, decreased insulin need after removal of a stress situation, medication changes, and a change in insulin injection site. Alcohol decreases liver gluconeogenesis, and people with diabetes need to be cautioned about its potential for causing hypoglycemia, especially if it is consumed in large amounts or on an empty stomach. Hypoglycemia usually has a rapid onset and progression of symptoms. The signs and symptoms of hypoglycemia can be divided into two categories: (1) those caused by altered cerebral function and (2) those related to activation of the autonomic nervous system. Because the brain relies on blood glucose as its main energy source, hypoglycemia produces behaviors related to altered cerebral function. Headache, difficulty in problem solving, disturbed or altered behavior, coma, and seizures may occur. At the onset of the hypoglycemic episode, activation of the parasympathetic nervous system often causes hunger. The initial parasympathetic response is followed by activation of the sympathetic nervous system; this causes anxiety, tachycardia, sweating, and constriction of the skin vessels (i.e., the skin is cool and clammy). The signs and symptoms of hypoglycemia are highly variable, and not everyone manifests all or even most of the symptoms. The manifestations are particularly variable in children and in elderly people. Elderly people may not display the typical autonomic responses associated with hypoglycemia but frequently develop signs of impaired function of the central nervous system, including mental confusion. Some people develop hypoglycemic unawareness. Unawareness of hypoglycemia should be suspected in people who do not report symptoms when their blood glucose concentrations are less than 50 to 60 mg/dL. This occurs most commonly in people who have a longer duration of diabetes and A1C levels within the normal range. Some medications, such as beta-adrenergic blocking drugs, interfere with the sympathetic response normally seen in hypoglycemia. If hypoglycemia occurs with alpha- glucosidase inhibitors, it should be treated with glucose (dextrose) and not sucrose (table sugar), whose breakdown may be blocked by the action of the alpha-glucosidase inhibitors. The most effective treatment of an insulin reaction is the immediate administration of 15 to 20 g of glucose in a concentrated carbohydrate source, which can be repeated as 8  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ necessary. Monosaccharides such as glucose, which can be absorbed directly into the bloodstream, work best. Complex carbohydrates can be administered after the acute reaction has been controlled to sustain blood glucose levels. It is important not to overtreat hypoglycemia and cause hyperglycemia. Alternative methods for increasing blood glucose may be required when the person having the reaction is unconscious or unable to swallow. Glucagon may be given intramuscularly or subcutaneously. Glucagon acts by hepatic glycogenolysis to raise blood glucose. Because the liver contains only a limited amount of glycogen (approximately 75 g), glucagon is ineffective in people whose glycogen stores have been depleted. In situations of severe or life-threatening hypoglycemia, it may be necessary to administer glucose (20 to 50 mL of a 50% solution) intravenously. 6 Chronic Complications The chronic complications of diabetes include disorders of the microvasculature (i.e., neuropathies, nephropathies, and retinopathies), macrovascular complications (i.e., coronary artery, cerebral vascular, and peripheral vascular disease), and foot ulcers (Fig. 2). The level of chronic hyperglycemia is the best-established concomitant factor associated with diabetic complications. The Diabetes Control and Complications Trial (DCCT), which was conducted with 1441 patients with type 1 diabetes, demonstrated that the incidence of retinopathy, nephropathy, and neuropathy can be reduced by intensive diabetic treatment. Similar results have been demonstrated by the United Kingdom Prospective Diabetes Study (UKPDS) in 5000 patients with type 2 diabetes. 9  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ Figure 2: Long-term complications of diabetes mellitus. 6.1 Theories of Pathogenesis The interest among researchers in explaining the causes and development of chronic lesions in a person with diabetes has led to a number of theories. At least three distinct metabolic pathways have been implicated in long-term complications of diabetes: 1. intracellular hyperglycemia and disturbance in polyol pathways 2. formation of advanced glycation end products, and 3. activation of protein kinase C. 6.1.1 Polyol Pathway. A polyol is an organic compound that contains three or more hydroxyl (OH) groups. The polyol pathway refers to the intracellular mechanisms responsible for changing the number of hydroxyl units on a glucose molecule. In the sorbitol pathway, glucose is transformed first to sorbitol and then to fructose. This process is activated by the enzyme aldose reductase. Although glucose is converted readily to sorbitol, the rate at which sorbitol can be converted to fructose and then metabolized is limited. Sorbitol is osmotically active, and it has been hypothesized that the presence of excess intracellular amounts may alter cell function in those tissues that use this pathway (e.g., lens, kidneys, nerves, blood vessels). In the lens, for 10  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ example, the osmotic effects of sorbitol cause swelling and opacity. Increased sorbitol also is associated with a decrease in myoinositol and reduced adenosine triphosphatase activity. The reduction of these compounds may contribute to the pathogenesis of neuropathies caused by Schwann cell damage. Aldose reductase inhibitors are in development with the aim of reducing complications resulting from this pathway; however, to date none of them has been successful for a variety of reasons. 6.1.2 Formation of Advanced Glycation End Products. Glycoproteins, or what could be called glucose proteins, are normal components of the basement membrane in smaller blood vessels and capillaries. These glycoproteins are also termed advanced glycation end products (AGEs). It has been suggested that the increased intracellular concentration of glucose associated with uncontrolled blood glucose levels in diabetes favors the formation of AGEs. These abnormal glycoproteins are thought to produce structural defects in the basement membrane of the microcirculation and to contribute to eye, kidney, and vascular complications. Some of the altered cellular functions resulting from AGEs are due to binding to specific receptors for AGEs (RAGEs). 6.1.3 Protein Kinase C. Diacylglycerol (DAG) and protein kinase C (PKC) are critical intracellular signaling molecules that can regulate many vascular functions, including permeability, vasodilator release, endothelial activation, and growth factor signaling. Levels of DAG and PKC are elevated in diabetes. Activation of PKC in blood vessels of the retina, kidney, and nerves can produce vascular damage. A PKC inhibitor is currently in clinical trials for diabetic retinopathy and neuropathy but has shown variable results. 6.2 Neuropathies Although the incidence of neuropathies is high among people with diabetes, it is difficult to document exactly how many people are affected by these disorders because of the diversity in clinical manifestations and because the condition often is far advanced before it is recognized. Results of the DCCT study showed that intensive diabetic therapy can reduce the incidence of clinical neuropathy by 60% compared with conventional therapy. Two types of pathologic changes have been observed in connection with diabetic neuropathies. The first is a thickening of the walls of the nutrient vessels that supply the nerve, leading to the assumption that vessel ischemia plays a major role in the development of these neural changes. The second finding is a segmental demyelinization process that affects the Schwann cell. This demyelinization process is accompanied by a slowing of nerve conduction. Although there are several methods for classifying diabetic peripheral neuropathies, a simplified system divides them into the somatic and autonomic nervous system neuropathies (Chart 33-2). 11  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ 6.2.1 Somatic Neuropathy. Distal symmetric polyneuropathy, in which loss of function occurs in a stocking–glove pattern, is the most common form of peripheral neuropathy. Somatic sensory involvement usually occurs first and usually is bilateral and symmetric, and associated with diminished perception of vibration, pain, and temperature, particularly in the lower extremities.53 In addition to the discomforts associated with the loss of sensory or motor function, lesions in the peripheral nervous system predispose a person with diabetes to other complications. The loss of feeling, touch, and position sense increases the risk of falling. Impairment of temperature and pain sensation increases the risk of serious burns and injuries to the feet. Denervation of the small muscles of the foot results in clawing of the toes and displacement of the submetatarsal fat pad anteriorly. These changes, together with joint and connective tissue changes, alter the biomechanics of the foot, increasing plantar pressure and predisposing to development of foot trauma and ulcers. Painful diabetic neuropathy involves the somatosensory neurons that carry pain impulses. This disorder, which causes hypersensitivity to light touch and occasionally severe “burning pain,” particularly at night, can become physically and emotionally disabling. 12  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ 6.2.2 Autonomic Neuropathy. Autonomic neuropathies involve disorders of sympathetic and parasympathetic nervous system function. There may be disorders of vasomotor function, decreased cardiac responses, inability to empty the bladder, gastrointestinal motility problems, and sexual dysfunction. Defects in vasomotor reflexes can lead to dizziness and syncope due to postural hypotension when the person moves from the supine to the standing position. Incomplete emptying of the bladder predisposes to urinary stasis and bladder infection and increases the risk of renal complications. Gastrointestinal motility disorders are common in persons with long-standing diabetes. The symptoms vary in severity and include gastroparesis, constipation, diarrhea, and fecal incontinence. Gastroparesis (delayed emptying of stomach) is commonly seen in persons with diabetes. The disorder is characterized by complaints of epigastric discomfort, nausea, postprandial vomiting, bloating, and early satiety. Abnormal gastric emptying also jeopardizes the regulation of the blood glucose level. Diarrhea is another common symptom seen mostly in persons with poorly controlled type 1 diabetes and autonomic neuropathy. The pathogenesis is thought to be multifactorial. Diabetic diarrhea is typically intermittent, watery, painless, and nocturnal and may be associated with fecal incontinence. In the male, disruption of sensory and autonomic nervous system function may cause sexual dysfunction. Diabetes is the leading physiologic cause of erectile dysfunction, and it occurs in both type 1 and type 2 diabetes. Of the 7.8 million men with diabetes in the United States, 30% to 60% have erectile dysfunction. 6.3 Nephropathies Diabetic nephropathy, a term used to describe the combination of lesions that occur concurrently in the diabetic kidney, is the leading cause of chronic kidney disease in persons starting renal replacement therapy. Not all people with diabetes develop clinically significant nephropathy; for this reason, attention is focusing on risk factors for the development of this complication. Among the suggested risk factors are genetic and familial predisposition, elevated blood pressure, poor glycemic control, smoking, hyperlipidemia, and microalbumuria. Diabetic nephropathy occurs in family clusters, suggesting a familial predisposition, although this does not exclude the possibility of environmental factors shared by siblings. The risk for development of kidney disease is greater among Native Americans, Hispanic Americans (especially Mexican Americans), and African Americans. The most common kidney lesions in people with diabetes are those that affect the glomeruli. Various glomerular changes may occur in people with diabetic nephropathy, including capillary basement membrane thickening, diffuse glomerular sclerosis, and nodular glomerulosclerosis. Nodular glomerulosclerosis, also called intercapillary glomerulosclerosis or Kimmelstiel- Wilson syndrome, is a form of glomerulosclerosis that involves the development of nodular lesions in the glomerular capillaries of the kidneys, causing impaired blood flow with progressive loss of kidney function and, eventually, renal failure. Nodular glomerulosclerosis 13  Pathophysiology :‫المادة‬ ‫ المصطفى‬:‫أسم الجامعة‬ ‫ االول‬:‫الكورس‬ ‫ الصيدلة‬:‫أسم الكلية‬ ‫ الثانية‬:‫المحاضرة‬ ‫ حيدر عدنان فوزي السلطان‬:‫أسم المحاضر‬ 2025 – 2024 :‫العام الدراسي‬ ‫ مدرس دكتور‬:‫اللقب العلمي‬ Title: Diabetes Mellitus ‫ دكتوراه صيدلة سريرية‬:‫المؤهل العلمي‬ is thought to occur only in people with diabetes. Changes in the basement membrane in diffuse nodular glomerulosclerosis allows plasma proteins to escape in the urine, causing albuminuria, hypoalbuminemia, edema, and other signs of impaired kidney function. Kidney enlargement, nephron hypertrophy, and hyper- filtration are early accompaniments of diabetes, reflecting the increased work performed by the kidneys in reabsorbing excessive amounts of glucose. One of the first manifestations of diabetic nephropathy is an increase in urinary albumin excretion (i.e., microalbuminuria), which is easily assessed by laboratory methods. Microalbuminuria is defined as a urine protein loss between 30 and 300 mg/day or an albumin- to-creatinine ratio (A/C ratio) between 30 and 300 g/mg (normal