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Introduction to Endocrinology and Diabetes: Assessment, Analysis, and Associated Dental Management Guidelines

INTRODUCTION TO ENDOCRINOLOGY

The Endocrine System: Facts and Function

The endocrine system regulates and maintains responses to:

• Stress and injury
• Growth and development
• Absorption of nutrients
• Energy metabolism
• Water and electrolyte balance
• Reproduction, birth, and lactation

The glands associated with the endocrine system include the pituitary gland, the pineal gland, the hypothalamus, the thyroid gland, the parathyroid glands, the thymus, the adrenal glands, the gonads (the ovaries and testes), and the pancreas. The endocrine glands release hormones into the bloodstream that are meant to alter the metabolism of respective target organs by increasing or decreasing their activity.

The neuro-endocrine system is controlled by the hypothalamus. The hypothalamus sends messages to the pituitary gland. In turn, the pituitary gland releases hormones that regulate body functions through affects on the other endocrine glands.

The hypothalamic nuclei control endocrine function through three mechanisms: (1) direct neural connections, as in the case of the adrenal medulla; (2) the release of hypothalamic hormones (ADH and oxytocin are prime examples); and (3) the production of releasing or inhibiting regulatory factors. Releasing or inhibiting factors control secretory activities in the pituitary gland.

Releasing factors promote the release of TSH, ACTH, and the gonadotrophic hormones (LH and FSH). The factors involved are called thyroid hormone-releasing factor (TRF), corticotrophin-releasing factor (CRF), and gonadotrophin-releasing factor (GnRF).

Inhibiting factors control the release of prolactin and MSH. A releasing factor (GH-RF) and an inhibiting factor (GH-IF) regulate growth hormone secretion. A single releasing or inhibiting factor may have secondary effects on other endocrine cells in the pituitary.

Endocrine Hormone Categories

The hormones released fall into three basic categories:

• Amino acid derivatives (such as catecholamines, thyroid hormones, and melatonin)
• Peptides
• Steroids, which are derivatives of cholesterol

Homeostatic Feedback Mechanisms

Many of the endocrine glands are linked to the hypothalamus by positive or negative homeostatic feedback mechanisms. Most endocrine glands are under the control of negative feedback mechanisms, which decrease the deviation from an ideal normal value and are important in maintaining homeostasis. Regulation of the blood calcium level is a good negative feedback example. In positive feedback mechanisms, the original stimulus is promoted rather than negated. Oxytocin released during childbirth promotes uterine contractions and is a good example of a positive feedback mechanism.

Pituitary Gland

The pituitary gland has two lobes, an anterior lobe and a posterior lobe. The anterior lobe produces and secretes seven hormones in response to stimulation from the hypothalamus.

Anterior Pituitary Hormones

The anterior pituitary secretes the following hormones:

• Thyroid-stimulating hormone (TSH): TSH stimulates the release of thyroid hormones.
• Adrenocorticotrophic hormone (ACTH): ACTH stimulates the release of glucocorticoids.
• Follicle-stimulating hormone (FSH): FSH stimulates estrogen secretion and ova/egg development in females and sperm production in males.
• Luteinizing hormone (interstitial cell-stimulating hormone; LH/ICSH): LH/ICSH causes ovulation and progesterone production in women and androgen production in men.
• Prolactin (PRL): PRL stimulates the development of the mammary glands and the production of milk, mitosis, and the growth of body tissues.
• Growth hormone (GH/somatotrophin): GH stimulates cell growth and protein synthesis via the release of somatomedins by the liver. This stimulation occurs almost immediately, at a time when glucose and amino acid concentrations in the blood are elevated. A second effect appears hours later, as glucose and amino acid levels are declining. Under these conditions, GH causes the breakdown of glycogen and lipid reserves and directs peripheral tissues to begin using lipids, instead of glucose, as an energy source. As a result, blood glucose concentrations rise. These effects appear through an interaction between growth hormone and somatomedins.
• Melanocyte-stimulating hormone (MSH): MSH stimulates the production of melanin in the skin.

TSH, ACTH, FSH, and LH hormones are tropic hormones that simulate other endocrine glands, and, in response, the other endocrine glands produce hormones that affect metabolism. For example, TSH from the pituitary gland stimulates the thyroid gland to produce thyroid hormones; in turn, thyroid hormones inhibit the release of calcium in the blood. ACTH acts on the cortex of the adrenal gland to produce steroid hormones. FSH and LH act in women and men by regulating various sexual characteristics. Prolactin acts on the breast tissue glands of nursing mothers, causing milk production.

Growth hormone (GH) stimulates protein synthesis and cell division in cartilage and bone tissue. Gigantism results when excessive amounts of growth hormone are produced during childhood. Pituitary dwarfism occurs when too little growth hormone is produced, and acromegaly occurs when too much GH is produced during adulthood.

Posterior Pituitary Hormones

The supraoptic and paraventricular nuclei of the hypothalamus produce antidiuretic hormone (ADH) and oxytocin. These hormones are released into the vasculature surrounding the posterior pituitary gland. ADH release occurs when the electrolyte concentration in the blood rises and when blood pressure or blood volume declines. ADH reduces the amount of water lost at the kidneys.

During the birthing process, oxytocin stimulates smooth muscle contractions in the uterus and mammary glands. The uterine action helps with labor, and mammary gland stimulation helps with milk production.

Patterns of Hormonal Interactions

The endocrine system functions as an integrated unit and hormones often interact. Two hormones may have antagonistic, synergistic, permissive, or integrative effects.

Hormones and Growth

Normal growth requires GH, TX, insulin, PTH, and gonadal steroids. As the hormonal concentrations change, so do growth patterns.

Hormones and Stress

Stresses of many different kinds can produce a characteristic response involving both the nervous and endocrine systems. This response is known as the general adaptation syndrome (GAS). There are three phases to the GAS: the alarm phase, the resistance phase, and the exhaustion phase.

The Alarm Phase

The alarm phase is predominately neural in origin and results from sympathetic activation. Epinephrine is the dominant hormone of the alarm phase. During the alarm phase, ADH and CRF are also released by the pituitary gland.

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The Resistance Phase

During the resistance phase energy consumption remains elevated due to the production of glucocorticoids, epinephrine, growth hormone, glucagon, and thyroid hormones.

Glucocorticoids are the dominant hormones of the resistance phase. The goals of the resistance phase include mobilization of lipid and protein reserves, elevation and stabilization of blood glucose levels, and conservation of glucose for neural tissues.

The Exhaustion Phase

Exhaustion may result from a depletion of energy reserves, failure to produce the required hormones, or the collapse of one or more vital systems.

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Hormones and Behavior

Many hormones affect the functional state of the nervous system producing alterations in mood, emotional states, and various other behaviors.

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DIABETES OVERVIEW, FACTS, AND TESTS

Diabetes Overview

The pancreas, gut, and kidneys regularly play significant roles in glucose homeostasis. Consequently, dysfunction at all these levels occurs with diabetes. It is important to review the mechanisms involved to better understand the newer therapies that are targeting these specific areas in the management of diabetes.

The Pancreas

The pancreas contains exocrine and endocrine cell populations. The endocrine cells are found within the pancreatic islets, the islets of Langerhans. Alpha cells secrete glucagon, and β cells of the pancreas produce the anabolic storage hormone insulin. These hormones affect glucose metabolism in the body. Insulin lowers blood glucose by increasing the rates of glucose uptake and utilization in peripheral cells. Insulin plays a very important role in the metabolism of carbohydrates, proteins, and fats. Protein synthesis, fat deposition, and glycogen formation increase under insulin stimulation. Insulin enhances the conversion of glucose to glycogen, amino acids to proteins, and fatty acids to triglycerides. Absence of insulin causes elevated glucagon levels, muscle wasting, and high levels of acetoacetic acid and β hydroxybutyricacid in the blood. Excessive glucose (hyperglycemia) in the blood causes it to spill into the urine resulting in glycosuria and frequent urination.

Total lack of insulin leads to ketoacidosis. Insulin is produced and released in response to eating, in order to utilize the sugars and store excess amounts for use during starvation. Thus, in the fed state, insulin levels are high after eating.

Glucagon action is opposite to that of insulin. It elevates blood glucose by increasing the rates of glycogen breakdown and glucose production in the liver. Glucagon stimulates the release of fatty acids from adipose tissues and amino acids from skeletal muscles. It is important to know that the brain always gets glucose at all times, and it does not matter if the individual is in a fed state or is starving. In the extreme fasting state, glucagon levels rise and elevate blood glucose thus making it available to the brain. Therefore, alpha and beta cells monitor the glucose concentrations of the circulating blood.

Gut and Glucose Homeostasis

The gastrointestinal tract has a crucial role in the control of energy homeostasis through its role in the digestion, absorption, and assimilation of ingested nutrients. Enteroendocrine cells have important roles in regulating energy intake and glucose homeostasis through their actions on peripheral target organs, including the endocrine pancreas. After food ingestion, the digestion and absorption of nutrients is associated with increased secretion of multiple gut peptides that act on distant target sites to promote the efficient uptake and storage of energy. These peptide hormones are synthesized by specialized enteroendocrine cells located in the epithelium of the stomach, small bowel, and large bowel, and are secreted at low basal levels in the fasting state.

Plasma levels of most gut hormones rise rapidly within minutes of nutrient intake and fall quickly thereafter, mainly because they are cleared by the kidney and are enzymatically inactivated. Gut hormones activate neural circuits that communicate with peripheral organs, including the liver, muscle tissue, adipose tissue, and islets of Langerhans in the pancreas, to coordinate overall energy intake and assimilation. Gastrointestinal/incretin hormones such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP1), which cause an increase in the amount of insulin released from the β cells of the islets, augment the magnitude of meal-stimulated insulin secretion from islet β cells in a glucose-dependent manner. Incretin action facilitates the uptake of glucose by muscle tissue and the liver while simultaneously suppressing glucagon secretion by the α cells of the islets, leading to reduced endogenous production of glucose from hepatic sources.

Kidneys and Glucose Homeostasis

The kidney also plays a significant role in maintaining glucose homeostasis. This includes functions such as release of glucose into the circulation via gluconeogenesis, uptake of glucose from the circulation for its own energy needs, and reabsorption of glucose at the level of the proximal tubule. Renal release of glucose into the circulation is the result of glycogenolysis and gluconeogenesis, respectively, involving the breaking down and formation of glucose-6-phosphate from precursors (for example, lactate, glycerol, and amino acids). With regard to renal reabsorption of glucose, the kidneys normally retrieve as much glucose as possible, rendering the urine virtually glucose free.

The glomeruli filter approximately 180g of D-glucose per day from plasma, all of which is reabsorbed through glucose transporter proteins that are present in cell membranes within the proximal tubules. If the capacity of these transporters is exceeded, glucose appears in the urine. Transporters that are active (sodium-coupled glucose co-transporters) and passive (glucose transporters) mediate the process of renal glucose reabsorption. In hyperglycemia, the kidneys may play an exacerbating role by reabsorbing excess glucose, ultimately contributing to chronic hyperglycemia, which in turn contributes to chronic glycemic burden and the risk of microvascular consequences.

Type 1 Diabetes

The exact etiology of type 1 diabetes is not known. Autoimmune attack on the β cells of the pancreas is thought to cause destruction of the cells and consequent lack of insulin production. An environmental stimulus, however, is the cause in most cases. The patients are usually younger, thin, and prone to ketosis, weight loss, and blackouts. Adults can get type I diabetes, as well.

Type 2 Diabetes

These patients have a combination of insulin resistance and insulin deficiency. Of diabetics encountered, 90% suffer from type 2 diabetes. Type 2 diabetes has a higher genetic predisposition compared to type 1 diabetes.

The patients are usually obese and older at the time of disease onset. However, this fact has changed with the obesity epidemic affecting populations globally. It is not uncommon now to encounter obese patients in their preteens, teens, or twenties who are suffering from type 2 diabetes.

Diabetes Symptoms and Signs

The following are symptoms and signs of diabetes:

• Polyuria (excessive urination), polydipsia (excessive thirst), and polyphagia (excessive appetite) are the hallmark symptoms associated with diabetes. Patients with type 1 experience these symptoms a lot more frequently compared to patients with type 2.
• It is not uncommon for these patients to experience weight loss, fatigue, and blurred vision due to elevated blood sugar levels.
• A history of weight loss is a lot more common in the type 1 patient than in the type 2 patient. The blurred vision is caused by adherence of sugar to the optic lens and changes in glycosylation of cornea and lens when sugars go rapidly up or down. The blurring of vision improves when sugar levels improve, with treatment.
• Poor wound healing and opportunistic infections occur with chronic elevation of the blood sugar values.

Diabetes Diagnostic Tests

Fasting Blood Sugar (FBS)

A diagnosis of diabetes is made when the fasting blood sugar (FBS) is ≥126 mg/dL. With treatment, the FBS should be maintained between 70–120 mg/dL. The FBS should be maintained >70 mg/dL to avoid severe hypoglycemia.

Impaired FBS

A patient is said to have pre-diabetes or impaired fasting glucose when the FBS is 100–125 mg/dL. The patient can normalize the impaired FBS sugar levels with stringent implementation of proper diet control and exercise.

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Postprandial Blood Sugar (PPBS)

For optimal control, the PPBS, or the two-hour post-meal blood sugar, should be maintained between 120–160 mg/dL.

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Random Blood Sugar

A diagnosis of diabetes is made when a random blood sugar is ≥200 mg/dL.

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Oral Glucose Tolerance Test (OGTT)

The OGTT measures the patient’s ability to utilize glucose in a laboratory setting. The patient’s FBS is checked, and the patient is made to drink 75 g of glucose. The blood sugar levels are then monitored at half-hour intervals for two hours. The patient is said to be pre-diabetic if the blood sugar />