General medicine parte 1

Diabetes mellitus

Insulin and glucagon

Each time we eat, glucose is absorbed by the gastrointestinal system. Blood glucose homeostasis is regulated by insulin and glucagon. Both are produced by the pancreas, which is an important endocrine and exocrine organ (is both). Insulin acts when the blood glucose level rises and it promotes the uptake of glucose. Therefore, as a consequence of the beta cells in the pancreas releasing insulin into the blood, the liver takes up glucose and stores it as glycogen, and body cells take up glucose. At this point, blood glucose level declines. The set point is when the glucose level is 90 mg/100 mL. Alpha cells release glucagon that acts in the opposite way. It promotes the breakdown of glycogen by the liver; in this way, glucose is released and its level in the blood rises.

Beta cells → insulin
Alpha cells → glucagon

Insulin

Insulin is a peptide hormone composed of 51 amino acids that is synthesized, packaged, and secreted in pancreatic beta cells. It is synthesized as preproinsulin in the ribosomes of the rough endoplasmic reticulum. Then preproinsulin is cleaved to proinsulin, which is transported to the Golgi apparatus where it is packaged into secretory granules located close to the cell membrane. Then proinsulin is cleaved into insulin and C-peptide by the granules. Pancreatic beta cells are found in the islets of Langerhans, which are of various sizes and contain a few hundred to a few thousand endocrine cells. Beta cells are located in the center close to the systemic blood supply from pancreatic arterioles, and they are surrounded by alpha cells. Islets are anatomically and functionally separate from pancreatic exocrine tissue, which secretes pancreatic enzymes and fluid directly into ducts that drain into the duodenum. We have several of these islets. Normal subjects have approximately one million islets that, in total, weigh 1 to 2 grams and constitute 1 to 2 percent of the mass of the pancreas.

Type 1 diabetes mellitus

Type 1 diabetes is a chronic illness characterized by the body’s inability to produce insulin due to the autoimmune destruction of the beta cells in the pancreas. It’s a progressive process of destruction of beta cells by lymphocytes. Even though it frequently occurs in childhood, the disease can also develop in adults. Unlike people with type 2 DM, those with type 1 DM usually are not obese and usually present initially with diabetic ketoacidosis (DKA).

Pathophysiology

The consequence of the beta cells' destruction is the fact that insulin secretion decreases. There is a critical point: a person can be completely asymptomatic until 80-90% of the beta cells are destroyed. Therefore, at 80-90% of the destruction, hyperglycemia develops, and diabetes can be diagnosed. In this case, patients need exogenous insulin to decrease this condition, prevent ketosis, decrease hyperglucagonemia, and normalize lipid and protein metabolism. Autoimmunity is considered the major factor in the pathophysiology of 1 DM. Therefore, there is a role of genetic factors. The genes involved are related to the immune system that act against beta cells molecules.

Etiology

Type 1 DM results from autoimmune destruction of the beta cells of the pancreas and involves both:

• Genetic predisposition: Although the genetic aspect of type 1 DM is complex, with multiple genes involved, there is a high sibling relative risk. Genome-wide association studies have identified several loci that are associated with type 1 DM, but few causal relations have been established. The genomic region most strongly associated with other autoimmune diseases, the major histocompatibility complex (MHC), is the location of several susceptibility loci for type 1 DM—in particular, class II HLA DR and DQ haplotypes.
• Environmental component: Extragenetic factors also may contribute, like toxic viruses, toxic chemicals, exposure to cow’s milk in infancy, and cytotoxins.

Epidemiology

Type 1 is the most common metabolic disease of childhood, and about 1 in every 400-600 children has it. In adults, it’s not as common as in childhood because it constitutes approximately 5% of all diagnosed cases. Type 1 usually starts at 4 years or older, with the peak incidence at age 11-13 years, and it is more common in males than in females. Internationally, rates of type 1 DM are increasing. In Europe, the Middle East, and Australia, rates of type 1 DM are increasing by 2-5% per year.

Age-related demographics

Previously referred to as juvenile-onset diabetes, type 1 DM is typically diagnosed in childhood, adolescence, or early adulthood. Although the onset of type 1 DM often occurs early in life, 50% of patients with new-onset type 1 DM are older than 20 years of age. Type 1 DM usually starts in children aged 4 years or older, appearing fairly abruptly, with the peak incidence of onset at age 11-13 years (i.e., in early adolescence and puberty). There is also a relatively high incidence in people in their late 30s and early 40s, in whom the disease tends to present less aggressively.

Sex and race-related demographics

Type 1 DM is more common in males than in females. In populations of European origin, the male-to-female ratio is greater than 1.5:1.

Prognosis

Type 1 DM is associated with high morbidity and premature mortality. These are related to the short- and long-term complications like:

• Hypoglycemia from management errors
• Increased risk of infections
• Microvascular complications and macrovascular related to larger vessels
• Neuropathic complications
• Macrovascular disease

These complications result in increased risk for ischemic heart disease, cerebral vascular disease, peripheral vascular disease with gangrene of lower limbs, chronic renal disease, reduced visual acuity and blindness, and autonomic and peripheral neuropathy. Diabetes is the major cause of blindness in adults aged 20-74 years, as well as the leading cause of nontraumatic lower-extremity amputation and ESRD. More than 60% of patients with type 1 DM don’t develop serious complications over the long term, but many of the rest experience blindness, end-stage renal disease, and sometimes early death. Patients with type 1 DM who survive the period 10-20 years after disease onset without fulminant complications have a high probability of maintaining reasonably good health. Other factors affecting long-term outcomes are the patient’s education, awareness, motivation, and intelligence level.

History

The most common symptoms of type 1 diabetes mellitus are polyuria, polydipsia (need to drink a lot), polyphagia (eat a lot), lassitude, blurred vision, all of which result from hyperglycemia itself. Polyuria is caused by osmotic diuresis secondary to hyperglycemia. Fatigue and weakness may be caused by muscle wasting from the catabolic state of insulin deficiency, hypovolemia, and hypokalemia. Muscle cramps are caused by electrolyte imbalance. Blurred vision results from the effect of the hyperosmolar state on the lens and vitreous humor. Glucose and its metabolites cause osmotic swelling of the lens, altering its normal focal length. Symptoms at the time of the first clinical presentation can usually be traced back several days to several weeks. However, beta-cell destruction may have started months or even years before the onset of clinical symptoms. The onset of symptomatic disease may be sudden. It is not unusual for patients with type 1 DM to present with diabetic ketoacidosis (DKA), which may occur de novo or secondary to the stress of illness or surgery (stresses that act in part by increasing the secretion of glucagon, catecholamines, and cortisol). Over time, patients with new-onset type 1 DM will lose weight, despite normal or increased appetite, because of depletion of water and a catabolic state with reduced glycogen, proteins, and triglycerides. Weight loss may not occur if treatment is initiated promptly after the onset of the disease. We have an absolute insulin deficiency: this is parallel to an increase of glucagon. The organism has to rely on other substrates to produce energy such as fat (breakdown of fat). The utilization of fat leads to the production of ketones. As a result of the utilization of fat, the pH is reduced. Catabolic state, breakdown of all substrate except glucose increases in blood glucose levels, acidification of our body. All this together are glycosuria. We promote a state called DKA.

Diabetic ketoacidosis

Clinical manifestations

Children with DKA typically present with:

• Anorexia
• Nausea
• Vomiting (body tries to eliminate acid molecule)
• Abdominal pain

Focal pain may occur and can mimic appendicitis or other intra-abdominal pathology. Polyphagia may be present early in the course of the illness. However, once insulin deficiency becomes more severe and ketoacidosis develops, appetite is suppressed. Hyperventilation and deep (Kussmaul) respirations represent the respiratory compensation for metabolic acidosis. Hyperpnea results from an increase in minute volume (rate × tidal volume) and can be increased by tidal volume alone without an increase in respiratory rate. In infants, hyperpnea may be manifested only by tachypnea. Patients may also have fruity breath odor secondary to exhaled acetone. Neurologic findings ranging from drowsiness, lethargy, and obtundation to coma are mainly related to the degree of acidosis.

Diagnosis

DKA is diagnosed when patients with diabetes mellitus exhibit all of the following:

• Hyperglycemia: blood glucose > 200 mg/dL (11 mmol/L)
• Metabolic acidosis: venous pH < 7.3 or serum bicarbonate < 15 mEq/L (15 mmol/L)
• Ketosis: presence of ketones in the blood or urine

Electrolyte abnormalities related to osmotic (glucose) diuresis are a frequent laboratory finding.

Treatment

Average water losses in children with DKA are approximately 70 mL/Kg (range 30 to 100 mL/Kg). Volume depletion is caused by urinary losses from osmotic diuresis, as well as gastrointestinal losses from vomiting and insensible losses from hyperventilation.

• Intravenous fluids (volume expansion)
• Intravenous insulin
• Correction of electrolyte imbalance (potassium deficit)

Complications

They may occur during the lifetime and are related to infections that cause morbidity and mortality in patients with diabetes. Infection may precipitate metabolic derangements, and conversely, the metabolic derangements of diabetes may facilitate infection. Patients with long-standing diabetes tend to have microvascular and macrovascular disease with resultant poor tissue perfusion and increased risk of infection. The ability of the skin to act as a barrier to infection may be compromised when the diminished sensation of diabetic neuropathy results in unnoticed injury. Diabetes increases susceptibility to various types of infections. The most common sites are the skin and urinary tract. Dermatologic infections that occur with increased frequency in patients with diabetes include staphylococcal follicular skin infections, superficial fungal infections, cellulitis, erysipelas, and oral or genital candidal infections. Both lower urinary tract infections and acute pyelonephritis are seen with greater frequency.

For what concerns the long-term complications, the major complications are related to arteries. Several organs can be compromised:

• Kidney
• Brain
• Heart
• Eye
• Nerves

The eye, kidney rely on the small vessels. Brain and heart rely on larger arteries.

Eye - ophthalmologic

(Blood glucose concentrations can alter the water content of the subtraction of the eye. Vascular changes of the retina may predispose to diabetic retinopathy. People with 20-30 years may develop diabetic retinopathy.) Diabetes can affect the lens, vitreous, and retina, causing visual symptoms that may prompt the patient to seek emergency care. Visual blurring may develop acutely as the lens changes shape with marked changes in blood glucose concentrations. This effect, which is caused by osmotic fluxes of water into and out of the lens, usually occurs as hyperglycemia increases, but it also may be seen when high glucose levels are lowered rapidly. In either case, recovery to baseline visual acuity can take up to a month, and some patients are almost completely unable to read small print or do close work during this period. Patients with diabetes tend to develop senile cataracts at a younger age than persons without diabetes. Diabetic retinopathy is the principal ophthalmologic complication of DM. Diabetic retinopathy is the leading cause of blindness in the United States in people younger than 60 years. Vascular changes account mainly for the development of diabetic retinopathy. Whether patients develop diabetic retinopathy depends on the duration of their diabetes and on the level of glycemic control.

Kidney - diabetic nephropathy

About 20–30% of patients with type 1 DM develop evidence of nephropathy, and all patients with diabetes should be considered to have the potential for renal impairment unless proven otherwise. Chronically elevated blood pressure contributes to the decline in renal function. The use of contrast media can precipitate acute renal failure in patients with underlying diabetic nephropathy. Although most recover from contrast medium–induced renal failure within 10 days, some have irreversible renal failure.

Neuropathy

Neuropathy affects up to 50% of patients with type 1 DM, but symptomatic neuropathy is typically a late development, developing after many years of chronic prolonged hyperglycemia. In the peripheral nerves, diabetes causes peripheral neuropathy. We have several types of neuropathy. The four types of diabetic neuropathy are as follows:

• Peripheral distal symmetrical polyneuropathy, predominantly sensory
• Autonomic neuropathy
• Proximal painful motor neuropathy
• Cranial mononeuropathy (i.e., cranial nerve III, IV, or VI)

Of these four types, distal symmetric sensorimotor polyneuropathy (in a glove-and-stocking distribution) is the most common. Besides causing pain in its early stages, this type of neuropathy eventually results in the loss of peripheral sensation. The combination of decreased sensation and peripheral arterial insufficiency often leads to foot ulceration and eventual amputation. The most common alteration is loss of peripheral functions.

Vascular complications

People with diabetes experience accelerated atherosclerosis, affecting the small arteries of the heart, brain, lower extremity, and kidney. Macrovascular disease is the leading cause of death in patients with diabetes, causing 65-75% of deaths in this group, compared with approximately 35% of deaths in people without diabetes. Coronary atherosclerosis often occurs at a younger age and is more severe and extensive than in those without diabetes, increasing the risk of ischemic heart disease. Atherosclerosis of the internal carotid and vertebrobasilar arteries and their branches predisposes to cerebral ischemia. Severe atherosclerosis of the iliofemoral and smaller arteries of the lower legs predisposes to gangrene. Ischemia of a single toe or ischemic areas on the heel are characteristic of diabetic peripheral vascular disease; these result from the involvement of much smaller and more peripheral arteries. Atherosclerosis of the main renal arteries and their intrarenal branches causes chronic nephron ischemia, which is a significant component of multiple renal lesions in diabetes.

Workup - laboratory studies

Plasma glucose: Patients with type 1 diabetes mellitus (DM) typically present with symptoms of uncontrolled hyperglycemia (e.g., polyuria, polydipsia, polyphagia). In such cases, the diagnosis of DM can be confirmed with a random (nonfasting) plasma glucose concentration of 200 mg/dL or a fasting plasma glucose concentration ≥ 126 mg/dL. A fingerstick glucose test is appropriate in the emergency department (ED) for virtually all patients with diabetes. All fingerstick capillary glucose levels must be confirmed in serum or plasma to make the diagnosis.

Hemoglobin A: HbA1c is the stable product of nonenzymatic irreversible glycation of the beta chain of hemoglobin by plasma glucose and is formed at rates that increase with increasing plasma glucose levels. HbA1c levels provide an estimate of plasma glucose levels during the preceding 1-3 months. The reference range for nondiabetic people is 6% in most laboratories. Glycated hemoglobin levels also predict the progression of diabetic microvascular complications. American Diabetes Association (ADA) guidelines recommend measuring HbA1c at least every 6 months in patients with diabetes who are meeting treatment goals and who have stable glycemic control. For patients whose therapy has changed or who are not meeting glycemic goals, the guidelines recommend HbA1c testing every 3 months.

Treatment

Patients with type 1 diabetes mellitus (DM) are dependent on exogenous insulin and require lifelong insulin therapy. Most require two or more injections of insulin daily, with doses adjusted on the basis of self-monitoring of blood glucose levels. A multidisciplinary approach by the physician, nurse, and dietitian, with regular specialist consultation, is needed to control glycemia, as well as to limit the development of its devastating complications and manage such complications when they do occur. Optimal diabetic control requires frequent self-monitoring of blood glucose levels, which allows rational adjustments in insulin doses. All patients with type 1 DM should learn how to self-monitor and record their blood glucose levels with home analyzers and adjust their insulin doses accordingly.

Types of insulin

• Rapid-, short-, intermediate-, and long-acting insulin preparations are available. Recombinant human insulin is now used almost exclusively.
• Rapid-acting insulins include lispro, glulisine, and aspart insulin. These insulins are absorbed more quickly and have a rapid onset of action (5-10 minutes), a short interval to peak action (45-75 minutes), and a short duration of action (2-4 hours). Therefore, they can be administered shortly before eating.
• Long-acting insulins used in the United States include insulin glargine and insulin detemir. Insulin glargine has no peak and produces a relatively stable level lasting more than 24 hours. In some cases, it can produce a stable basal serum insulin concentration with a single daily dose.