NROSCI-BIOSC-MSNBIO 1070/2070

November 23, 2015Gastrointestinal 2

Clinical GI Problems Damage to the Enteric Nervous System

Achalasia, or failure of the lower esophageal sphincter to open, is a result of damage to the enteric nervous system in the esophagus. As a result, food becomes trapped in the esophagus, which becomes ulcerated and infected.

A similar condition is Hirschsprung’s disease, where part of the colon loses motility.

These conditions are often treated surgically, or by giving a calcium channel blocker.

Clinical GI Problems

Peptic Ulcer Ulcers are erosions in the lining of the stomach or

duodenum (the first part of the small intestines). An ulcer in the stomach is called a gastric ulcer. An ulcer in the duodenum is called a duodenal ulcer. Together, ulcers of the stomach and duodenum are referred to as peptic ulcers.

Ulcers are most commonly caused by Helicobactor pylori breaking down the mucus layer. Consumption of some substances, including aspirin, excessive alcohol, and toxins associated with smoking, can also weaken the mucus layer.

Ulcers result in pain and discomfort. If a hole goes through the stomach, allowing acid to get into the peritoneal cavity, death will occur.

Clinical GI Problems

Secretory Tumors Zollinger-Ellison Syndrome results

from a gastrin-secreting tumor, which produces excessive stomach acid secretion

Any other type of secretory cell in the GI system can develop into a malignant tumor, resulting in a clinical condition

Clinical GI Problems Gallstones

« Gallstones affect approximately 10% of the population over 30 years old in the United States.

« There are two types of gallstones: cholesterol stones and pigment stones.

Pigment stones are produced when bilirubin precipitates with calcium to form a stone. Typically, bilirubin is conjugated with glucuronic acid to make it soluble. Thus, the presence of beta-glucuronidase de-conjugates the bilirubin and results in its precipitation into stones. Beta-glucuronidase is released from a number of bacteria, and thus infections of the gall bladder can lead to formation of pigment stones.

« Cholesterol stones occur when bile contains too much cholesterol, and results in crystal formation and the growth of crystals into stones.

Clinical GI ProblemsThe treatment for gallstones is

surgical i.e., removal of the gall bladder (cholecystectomy).

After the surgery, bile is no longer stored by the gall bladder, but is continuously released into the duodenum.

Although the total amount of bile released during a meal is lowered, the patient’s digestion does not seem to be impaired, particularly if fat intake is controlled.

Some species of animals (e.g., horse and rat) lack a gall bladder, emphasizing that this organ is not essential if fat consumption is low.

Clinical GI ProblemsGenetic Diseases

A genetic problem can result in the absence of a transporter for a particular nutrient, so it is not absorbed from the GI system.

Because the same transporter is often present in the kidney, the same substance is typically excreted.

Clinical GI Problems Diarrhea

­ There are three main causes of diarrhea:

1. Impaired absorption by the intestine (may result from infection or inflammation)

2. Accumulation of nonabsorbable, osmotically-active agents in the gut lumen

3. Infections of the intestinal wall, that result in excessive stimulation of secretory cells

Clinical GI Problems Ulcerative colitis is a chronic

inflammatory condition of the digestive tract. It is a form of Inflammatory Bowel Disease

that involves inflammation of the inner lining of the colon and rectum.

People with this condition alternate between flare-ups and periods of remission throughout their lives.

The causes of ulcerative colitis are unknown. Current research suggests that possible causes may involve, but are not limited to, heredity, infection, or the immune system.

Clinical GI Problems Crohn’s disease

Crohn's disease is a chronic autoimmune disease that can affect any part of the gastrointestinal tract but most commonly occurs in the ileum (the area where the small and large intestine meet).

Treatments can include immune suppression and surgery to remove the affected part of the intestine.

Clinical GI Problems Diverticulosis and Diverticulitis

Diverticulosis is a condition where small fingerlike pouches form in the wall of the large intestine.

It is one of the most common colon problems in people over 40 years of age.

The inner layers of the large intestine gradually weaken, resulting in the outpocketings.

A complication of diverticulosis results in the fingerlike pouches breaking and spilling the contents of the intestine into the peritoneal cavity. This complication is called diverticulitis.

Control of Food Intake and Glucose Metabolism

Control of Food Intake•Theories about food consumption fall

into two general “camps.” The first group of theories hold that food intake

is triggered by a depletion of energy reserves in one or more tissues. Thus, eating occurs in response to a shortage of appropriate nutrients.

The second group of theories suggest that we are primed to eat unless inhibitory signals associated by meals are released.

Control of Food Intake Two general metabolic states are generally

distinguished:

The pranial state occurs at the time of meal consumption, when there is an abundance of nutrients being absorbed.

Shortly after a meal, however, the postabsorptive state begins, when the body must depend on stored nutrients to support cellular metabolism.

Types of Nutrients Three major types of macronutrients are

used to provide energy for cells: carbohydrates, lipids, and proteins.

Most tissues can use either carbohydrates (in the form of glucose) or lipids (in the form of free fatty acids) to fuel cellular metabolism. > An exception includes the nervous system,

which typically requires glucose for normal metabolism. Unless the brain is provided a constant supply of glucose, consciousness will be lost. Therefore, a critical issue for metabolism is to maintain constant levels of circulating glucose.

Storage of Nutrients During the Pranial Stage

Many tissues store glucose in the form a polymer called glycogen; the largest stores are in the liver and skeletal muscles.

Fat is mainly stored in adipose tissue in the form of triglyceride.

During the pranial phase, many absorbed nutrients are stored as triglyceride or glycogen.

Excess carbohydrate can be converted to lipid for storage (lipogenesis), as glycogen storage capacity is limited and triglyceride is a much more efficient way of storing glucose.

Liberation of Nutrients During the Postabsorptive Stage

During the postabsorptive state, liver glycogen is converted back to glucose in a process called glycogenolysis.

The glucose that is formed enters the blood and is available to all tissues.

In addition, stored triglycerides are mobilized from adipose tissue in a process called lipolysis; as a result, fatty acids and glycerol enter the bloodstream.

The fatty acids are used by the tissues as needed or are converted to ketone bodies (ketogenesis).

Glycerol (the backbone of triglyceride) is converted to glucose in a process called gluconeogenesis.

Ketone Bodies Ketone bodies are products of fatty acid

metabolism; they are produced in the liver and kidney. They include compounds such as acetone.

Ketone bodies can be used for energy by the brain when blood glucose levels are very low (but only as an emergency back-up).

Formation of excess ketone bodies occurs when liver glycogen levels are low. This condition is called Ketosis.

Ketone bodies are acidic, and their formation causes metabolic acidosis.

Overview of Metabolism

Role of the Liver The liver plays a

fundamental role in energy metabolism.

Lipogenesis (also occurs in adipose tissue) and glycogen formation occur in the liver during the pranial period

Glycogenolysis, ketogenesis, and gluconeogenesis occur during the postabsorptive period.

Insulin and Caloric Homeostasis Insulin is secreted from β-cells (endocrine cells) of the

pancreas. Insulin allows most tissues to take up glucose from the

blood for immediate oxidation. Its major targets are the liver, adipose tissue, and skeletal muscle.

The hormone operates by causing GLUT transporters stored in vesicles in the cytoplasm to be translocated to the cell surface

Insulin and Caloric Homeostasis Insulin also stimulates enzymes that produce

glycogen, and inhibits glycogenolysis and gluconeogenesis.

The hormone additionally activates enzymes for protein synthesis and inhibits enzymes that promote protein breakdown.

Some tissues do not require the presence of insulin to transport glucose into cells. These tissues include the nervous system and transporting epithelia of the kidney and intestine.

Insulin and Caloric Homeostasis Many factors govern the secretion of insulin:

A major factor is the level of glucose in the blood to which the β-cells are exposed.

Other substances in the blood such as amino acids and ketone bodies can also induce insulin release.

Some hormones, such as GIP, also trigger insulin release.

The β-cells of the pancreas are additionally innervated by sympathetic and parasympathetic postganglionic fibers. Parasympathetic activity stimulates insulin

secretion. Sympathetic activity inhibits the secretion of

insulin.

Glucagon During the postabsorptive period, insulin

secretion drops and secretion of another pancreatic hormone, glucagon, increases.

Glucagon is secreted by α-cells of the pancreas, and acts to stimulate glycogenolysis, gluconeogenesis, and ketogenesis.

Timing of Insulin

Release

During the cephalic phase of insulin secretion, the parasympathetic nervous system acts to stimulate β-cells to release insulin, so that the body prepares for the storage of glucose.

Insulin secretion is potentiated during the gastrointestinal phase, during which parasympathetic activity and hormones such as GIP influence the β-cells.

The levels of blood insulin grow even higher during the substrate phase, when glucose in the blood begins to directly act on the β-cells.

Adiposity and Insulin Superimposed on the factors that

influence insulin secretion is the amount of body fat (adiposity).

People with little body fat have a large number of insulin receptors on adipose tissue and skeletal muscle.

In contrast, obese individuals have a lower concentration of insulin receptors.

As a result, obese individuals tend to have a higher release of insulin after a meal that corresponds to the lower sensitivity of tissues to the hormone.

Diabetes Mellitus Lack of insulin production results in a collection

of diseases known as diabetes mellitus. The word diabetes refers to flow of water

through a siphon (i.e., indicates copious urination), and the word mellitus comes from the term for honey (i.e., indicates large amounts of sugar in the urine). In ancient times this disease was recognized by voiding of large volumes of sweet urine.

It is important to distinguish between diabetes mellitus and diabetes insipidus, which is characterized by the urination of large amounts of “flavorless” urine. Diabetes insipidus results from a deficit in antidiuretic hormone production or diminished action of this hormone in the kidney.

Juvenile-Onset Diabetes Mellitus The most severe form of diabetes mellitus is insulin

dependent diabetes mellitus (IDDM), which is also known as Type I diabetes.

Typically, this condition is an autoimmune disease in which β-cells of the pancreas are destroyed by the immune system.

This aberrant immune response is sometimes triggered by viral infections. Controversial evidence also has suggested that consumption of cows’ milk before the age of four months can induce IDDM, although the mechanism is unclear.

Usually (but not always), Type I diabetes develops in childhood, providing the condition another name: juvenile-onset diabetes. Because patients with this disease are insulin-deficient, the only treatment is insulin injections. About 10% of all diabetes mellitus patients suffer from the Type I disease.

Adult-Onset Diabetes Mellitus The other variant of diabetes mellitus is

non-insulin dependent diabetes mellitus (NIDDM), which is sometimes called Type II diabetes or adult-onset diabetes.

This label is given to a collection of diseases that have a variety of causes, but are not related to a deficiency in insulin production.

NIDDM patients comprise 90% of the patients with diabetes mellitus, and typically are over 40 and are obese.

Adult-Onset Diabetes Mellitus A common hallmark of NIDDM is a delayed

response to an ingested insulin load. This is demonstrated through a procedure

known as a glucose tolerance test. ☤ First, the patient’s fasting glucose concentration is

determined (time 0). ☤ Then, a specific amount of glucose is ingested. ☤ Plasma glucose levels are then measured

periodically for two or more hours. ☤ Normal subjects show a slight elevation in plasma

glucose concentration in the immediate postprandial period, but the level quickly falls to normal as insulin is secreted.

☤ In Type II diabetes patients, however, fasting blood glucose levels are typically a bit above normal, and rise even higher after glucose is consumed.

Adult-Onset Diabetes Mellitus☮The high blood

glucose concentrations in the presence of normal insulin levels are related to the fact that target tissues do not respond appropriately to the insulin. This can result if the number of insulin receptors is low, or the cellular response to the binding of insulin is inappropriate.

Physiology of Type I Diabetes In individuals with Type I Diabetes, digestion and

absorption of glucose by the small intestine proceeds normally.

However, once the glucose reaches the liver transport into hepatic cells is limited because metabolic pathways have not been stimulated.

Thus, glucose levels in the blood rise tremendously resulting in hyperglycemia.

Tissues where glucose transport is not insulin-dependent, such as neural tissue, carry on glucose metabolism as normal, but other tissues such as adipose tissue and muscle are unable to uptake glucose.

As a result, muscle and adipose cells go into fasting-state metabolism. Muscle proteins are broken down to provide a source of energy, as are fat stores in adipose tissue.

The lack of insulin also results in the nervous system producing the sensation of hunger (as will be discussed later during this lecture), and polyphagia occurs.

Physiology of Type I Diabetes Because the liver cannot sense the elevated

plasma glucose concentrations, it initiates glycogenolysis and gluconeogenesis; these processes further elevate plasma glucose levels.

In addition, the liver begins to synthesize ketone bodies.

The high levels of glucose in the blood produce an osmotic load that affects water balance in the body. The levels of glucose often exceed the reabsorption capacities of the kidney and thus glucose is released in the urine.

As a result, water is “dragged” from the kidney, urine volume is high, and blood volume is reduced.

A decrease in blood volume results in a decrease in blood pressure, and a number of compensatory mechanisms are initiated (i.e., high vasopressin levels, activation of the renin-angiotensin system, etc.).

These compensatory mechanisms induce excessive drinking to occur.

However, because of the high vasopressin and angiotensin II levels, widespread vasoconstriction occurs in the body.

Thus, most of tissues in the body have an inadequate blood flow, and receive inadequate oxygen.

As a result, these tissues must begin anaerobic glycolysis to meet metabolic needs, which results in lactic acid production.

The lactic acid secretion into the blood contributes to metabolic acidosis. However, the primary cause of the metabolic acidosis is the release of ketone bodies from the liver.

The high acidity of the blood triggers increased ventilation, acidification of the urine, and hyperkalemia.

If untreated, the metabolic acidosis and hypoxia from circulatory collapse can lead to coma and death.

Physiology of Type II Diabetes Symptoms in patients with Type II

diabetes are not nearly as severe as those in individuals with Type I diabetes.

Although glucose transport into cells is impeded, it is usually not absent.

However, derangements in glucose and fat metabolism can produce a number of severe medical problems similar to those in patients with Type I diabetes.

Treatment of Type 2 Diabetes

A newly-developed drug, AVANDIA® (rosiglitazone maleate), has shown promise in treating Type II diabetes. Rosiglitazone is a highly selective and potent agonist for peroxisome proliferator-activated receptor-gamma (PPARγ).

In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver.

Activation of PPARγ nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization.

In addition, PPARγ-responsive genes also participate in the regulation of fatty acid metabolism.

Glucagon and its Role in Regulating Blood Glucose Levels

Glucagon is released by α-cells in the pancreas; in general its effects are antagonistic to those of insulin.

When plasma glucose concentrations decline after a meal, insulin secretion slows and effects of glucagon on tissue metabolism take on greater significance. It appears that the ratio between insulin and glucagon determines the direction of metabolism rather than an absolute amount of either hormone.

The primary stimulus for glucagon release is plasma glucose concentration. When plasma glucose concentrations fall below 100 mg/dl, glucagon concentration rises dramatically; at higher blood glucose concentrations (when insulin secretion is high), glucagon secretion diminishes considerably although a low basal release is maintained.

Glucagon and its Role in Regulating Blood Glucose Levels

The liver is the primary target tissue of glucagon. Glucagon stimulates glycogenolysis, conversion of glycogen to glucose.

In addition, glucagon stimulates the pathways of gluconeogenesis. These pathways combine to increase glucose output by the liver.

During the overnight fast, 75% of the glucose produced from the liver comes from glycogen scores and the remaining 25% comes from gluconeogenesis.

Glucagon and its Role in Regulating Blood Glucose Levels

Glucagon secretion is also stimulated by an increase in plasma amino acid levels.

This signal serves to prevent hypoglycemia after a high-protein meal.

Recall that amino acid absorption is a secondary stimulus for insulin release. Thus, even if no carbohydrates are consumed along with the protein, glucose transport into cells will be enhanced. This could result in hypoglycemia that threatens the brain’s glucose supply. However, the co-secretion of glucagon in this situation prevents hypoglycemia.

Satiety All mammals eat periodic meals. It is well-documented that one of the major factors that governs the period between meal consumption is the size of the meals that are ingested. The graph to the left shows data for rats consuming liquid meals, but a similar graph could be constructed for humans.

Factors that Lead to Cessation of Eating at the End of a Meal

Gastric Distension[ The stretch receptors in the stomach that detect

distension send their axons to the brainstem via the vagus nerve, where they terminate in the nucleus of the solitary tract.

[ The activity of these stomach stretch receptors is potentiated when the hormone CCK is released from the duodenum. Apparently, the stretch receptors have CCK receptors located near their terminals so that binding of hormone to those receptors makes them more sensitive.

[ In neonates, gastric distension may be a major factor that regulates satiety. This is practical, as newborns consume a single type of food: milk.

[ As animals mature, and meals become more complex, then gastric distension in itself is not a good indicator of caloric consumption. It thus makes sense that many other factors begin to influence food consumption during development.

Factors that Lead to Cessation of Eating at the End of a Meal

Liver AfferentsThese afferents respond to nutrients

(predominantly glucose) reaching the liver through the portal circulation.

In addition, circulating levels of insulin appear to influence the activity of the hepatic afferents.

The axons of these afferents, like the axons of the gastric stretch receptors, project to nucleus tractus solitarius in the brainstem via the vagus nerve.

Factors that Lead to Cessation of Eating at the End of a Meal Adiposity

Body weight influences the size of meals and the period of time between meals.

After being deprived of food, both animals and humans eat more for a period until adiposity returns to levels before the period of lowered nutrition.

A hormone released by adipose tissue, leptin, may be important in controlling food intake.

Leptin receptors are located in the hypothalamus, and this hormone may be an important link between caloric homeostasis and the central control of food intake.

Low leptin levels have been correlated with increases in food intake. Plasma levels of insulin are also correlated with adiposity, as discussed above. Thus, a combination of insulin and leptin levels may be important in regulating appetite through their actions in the brain.

Factors that Lead to Cessation of Eating at the End of a Meal

Ghrelin Ghrelin is produced by stretch-sensitive

cells, mainly located in the wall of the stomach but to some extent in the small intestine.

When the stomach is empty ghrelin is secreted, and when it is stretched secretion stops.

It acts on hypothalamic brain cells to increase hunger, and to increase gastric acid secretion and gastrointestinal motility to prepare the body for food intake.

Ghrelin The receptor for ghrelin is found on the

same cells in the brain as the receptor for leptin.

Ghrelin has been linked to inducing appetite and feeding behaviors.

Circulating ghrelin levels are the highest right before a meal and the lowest right after.

Injections of ghrelin in both humans and rats have been shown to increase food intake in a dose-dependent manner.

Control of Appetite by the

Brain Lesions of the

ventromedial hypothalamus (VMH) result in hyperphagia and obesity.

Conversely, lesions of the ventrolateral hypothalamus (VLH) result in a loss of appetite and starvation.

The results of lesion experiments gave rise to a “dual center” hypothesis of the control of feeding.

This hypothesis suggests that feeding is determined by the net balance of activity in the VMH and VLH, the VLH serving as a hunger center and the VMH serving to inhibit activity of the hunger center. Not surprisingly, this simplistic hypothesis has not explained the results of subsequent experiments.

Neurochemistry of Appetite Control A number of neuropeptides

have been shown to influence feeding, including the following: oxytocin, insulin, neuropeptide Y, opioids, CCK, galanin, and the orexins.

Although neurons do not require insulin for glucose transport, insulin receptors are present on the luminal surface of brain capillaries.

Bound insulin is then transported through the capillary endothelial cells into the brain interstitial fluid.

From there, insulin is free to bind to specific receptors on neurons.

Neurochemistry of Appetite Control A high density of insulin

receptors exists in the ventral hypothalamus, where this peptide undoubtedly influences neuronal activity.

Infusion of insulin into the brain reduces feeding and body weight. In addition, infusion of insulin antagonist into the ventral hypothalamus increases feeding.

Thus, insulin appears to act as a signal of satiety through its effects on the hypothalamus.

Neurochemistry of Appetite Control Neuropeptide Y has been

shown to act in the paraventricular nucleus of the hypothalamus to increase food intake.

Insulin appears to inhibit the production of NPY, and thus some of the effects of insulin may be related to the secretion of NPY.

The graph to the left shows changes in food intake and body weight produced by the infusion of NPY into the paraventricular nucleus of rats for 6 days.

Neurochemistry of Appetite Control Recently, a new group of peptides has been

identified in neurons in the lateral hypothalamus; these peptides are known as the orexins.

The orexin-containing neurons are located at the anatomical site of the feeding center in the lateral hypothalamus, suggesting a possible role for these neurons in the control of food intake.

These neurons project to other hypothalamic regions, including the paraventricular nucleus, as well as to various forebrain areas.

Intraventricular injections of orexins stimulate feeding, suggesting that this peptide might be involved in control of satiety.

Summary of Appetite Control The control of feeding is not well understood,

but appears to be regulated by neurons in the hypothalamus, neurons in the brainstem that send projections to the hypothalamus, and neurons in the cortex.

Feeding is influenced by afferent signals from the stomach and liver and chemical signals such as CCK, insulin, and leptin (the latter two being linked to adiposity).

The integration of these signals by the hypothalamus involves neurons that contain a number of different neuropeptides, whose complex role in producing satiety is yet to be determined.