Metabolic States/ Endocrine of Pancreas

Metabolic State

• Two basic metabolic states ensure that cells are provided with energy at all times; states differ in terms of their proximity to feeding and metabolic reactions that predominate

  • Absorptive state

  • Postabsorptive state

Absorptive State

• occurs right after feeding, from the time the ingested nutrients enter bloodstream; can last up to four hours; following processes occur as nutrients are absorbed from small intestine

  • Oxidation of nutrient molecules, primarily glucose, provides fuel to cells

  • Glycogenesis stores excess glucose in skeletal muscle and hepatocytes

  • If glycogen stores are filled liver and fat cells can convert glucose to triglycerides. (lipogenesis)

Absorptive state

• Lipogenesis stores triglycerides in adipocytes and hepatocytes

• Protein synthesis provides structural materials for cells

• Pancreatic hormone insulin orchestrates many absorptive state processes; release is triggered by increased blood glucose levels

Postabsorptive State

• begins once nutrient absorption is complete

  • Usually after four-hour absorptive window has ended

  • Although variable, body is usually in this state in late morning, late afternoon, and most of n

Postabsorptive State

• Anabolic processes slow or stop and following processes dominate

  • Breakdown of proteins in muscle cells releases glucogenic amino acids into blood

  • Ketogenesis in hepatocytes converts fatty acids to ketone bodies and releases them into blood. (many cells can use ketones for energy)

  • Gluconeogenesis and glycogenolysis in hepatocytes release glucose into blood

  • Lipolysis in adipocytes releases fatty acids into blood

  • Oxidation of molecules (fatty acids) provides most cells with fuel

• Glucose sparing – cells catabolize newly delivered fatty acids preferentially to conserve glucose for cells of nervous system; non-nervous system cells can also use ketone bodies and amino acids for fuel

• Several hormones help body adapt during postabsorptive state:

  • Pancreatic hormone glucagon, released when blood glucose level drops; triggers glycogenolysis and gluconeogenesis in liver

  • Epinephrine and norepinephrine;stimulate lipolysis in adipose tissue and glycogenolysis in skeletal muscle

  • Cortisol stimulates gluconeogenesis and processes that release glucogenic precursors into blood

Fasting and Protein Wasting

• Fasting – prolonged period during which little to no food is consumed

• May be intentional, or it could be due to limited availability of nutrient-dense foods or to disease process that prevents ingestion or processing of nutrients

• One consequence of fasting is a condition called protein wasting

  • Normally, after few hours in postabsorptive state, proteins are degraded, and their amino acids are used as primary source of carbon for gluconeogenesis

  • Some degree of protein degeneration is normal and does not harm body

  • However, this cannot go on for long before problems begin to arise

Fasting and Protein Wasting

• First noticeable in muscle tissue (have much higher protein content than other cells); degradation of muscle proteins results in weakness and fatigue, along with significant decrease in muscle mass

•Body does not just rob muscles of protein—does not discriminate among sources of protein or cell populations; can lead to loss of critical structural and functional proteins, including heart, liver, and brain; in severe cases may prove fatal

Regulation of Feeding

• Feeding – controlled by variety of hormonal and neural signals; stimulate and/or inhibit feeding-related nuclei in hypothalamus:

  • Hypothalamus houses two nuclei that control homeostatic variables associated with feeding:

  • Satiety center – elicits feeling of fullness; inhibits desire to eat

  • Hunger center (feeding center) – elic

Regulation of Feeding

• Long-term regulation of feeding is primarily hormonal:

• Leptin – hormone produced by adipocytes; stimulates satiety center and inhibits neurons in hunger center

• Ghrelin – hormone produced by stomach mucosal cells; stimulates neurons in hunger center to promote hunger •

• Hunger center is also stimulated by drop in leptin levels; allows hunger center neurons to become activated

• Short-term signals can also inhibit or stimulate feeding:

• Insulin is released in response to feeding; similar actions as leptin; decreases food intake

• Proteins and fats cause the release of the intestinal hormone cholecystokinin which induces satiety

• Stretching of the stomach stimulates vagus nerve to indirectly suppress hunger center and decrease release of hunger-related neurotransmitters (orexins and neuropeptide Y; promote hunger)

• Levels of certain molecules in blood can stimulate or inhibit these hypothalamic centers; for example, low level of glucose in blood (hypoglycemia) stimulates hunger center and release of orexin

Pancreas

• Endocrine (ductless) and exocrine gland (duct)

• Endocrine portion consists of the Islets of Langerhans (pancreatic islets)

• Exocrine portion consists of acini.

Pancreas (3types of hormone-secreting cells)

• 1. Alpha cells - secrete glucagon

• 2. Beta cells - secrete insulin

• 3. Delta cells- secrete somatostatin (GHIH)

Hormones (Glucagon)

• Glucagon and insulin regulate concentration of glucose in blood

• Glucagon—produced and secreted from alpha cells in pancreatic islets; major target tissues are cells of liver, muscle tissue, and adipose; promotes reactions that increase levels of glucose and metabolic fuels in blood:

  • Breakdown of glycogen (glycogenolysis)

  • Formation of new glucose (gluconeogenesis) in liver

• Glucagon (continued):

  • Breakdown of proteins in muscle tissue to release amino acids for gluconeogenesis

  • Release of fats from adipose tissue for gluconeogenesis and for additional cellular fuels

  • Formation of fuel molecules (ketone bodies) in liver

Hormones (ketone bodies)

• Ketone bodies—four-carbon molecules formed during fatty acid metabolism; released into bloodstream; taken up into skeletal and cardiac muscle cells

  • These cell types (among others like brain) are able to oxidize ketone bodies for fuel, unlike liver cells

  • During extreme caloric restriction or starvation, glucagon promotes rapid ketone body formation; overwhelms capability of cells to use them; accumulate in blood; can cause dangerous lowering of blood pH (ketoacidosis)

Hormones

• Glucagon secretion is inhibited by both elevated blood glucose level and somatostatin

• Glucagon secretion is triggered by:

  • Any decrease in blood glucose concentration

  • Sympathetic nervous system stimulation (Glucose for energy)

  • Circulating catecholamines from adrenal medulla

  • Ingested protein; part of integrated hormonal response that maintains stable glucose levels during feeding

Hormone (Insulin)

• Insulin—decreases blood glucose; primary antagonist of glucagon; produced and secreted from beta cells of pancreatic islets.

• Stimulates following responses in these primary target tissues (liver, cardiac muscle, skeletal muscle, and parts of brain):

  • Promotes uptake and storage of ingested nutrients (lipids, amino acids, and glucose); lowers blood glucose levels

  • Synthesis of glycogen in liver

  • Synthesis of fat from lipids and carbohydrates

  • Promotes satiety (feeling of fullness)

Insulin Resistance (Impaired Insulin Sensitivity)

• A condition in which the body does not respond appropriately to insulin.

• Muscle, fat , and liver cells can’t effectively take up glucose from your blood into the cells.

• Since your cells aren’t efficiently taking up blood glucose the pancreas responds by making more insulin. (hyperinsulinemia)

• Can eventually lead to type 2 diabetes.

• Insulin resistance associated with

  • Obesity

  • Cardiovascular disease

  • Nonalcoholic fatty liver disease

  • Metabolic syndrome - defined by having 3 of the following; 1. excess abdominal weight 2. high triglycerides 3. low HDL levels 4. High B.G 5. High Blood Pressure

  • Polycystic ovary Syndrome (PCCOS)

Hypoglycemia

• Hypoglycemia—blood glucose levels are too low; can be caused by elevated insulin levels

  • Symptoms—weakness, dizziness, rapid breathing, nausea, and sweating

  • Severe hypoglycemia can lead to confusion, hallucinations, seizures, coma, and death; ensues as brain is deprived of adequate glucose (primary fuel for its metabolic reactions)

Hyperglycemia

• Hyperglycemia—blood glucose levels are too high; common causes of chronic hyperglycemia:

• Diabetes

  • Inability to produce or use insulin

  • Symptoms – The three P’s (mostly associated with type 1))

    • Polydipsia – excessive thirst

    • Polyphagia – excessive eating

    • Polyuria – excessive urine production

Type 1 Diabetes

• Type 1 Diabetes (insulin-dependent )

  • Usually develops in people under age 20

  • Autoimmune – body’s own immune system attacks the beta cells – possible genetic or viral triggers – exact cause unknown

  • Target cells are unable to take in circulating glucose

  • Glucose is overproduced in liver because of unopposed actions of glucagon

  • Glucagon also elevates level of ketone bodies in blood

  • Leads to glucose and ketones in urine; draws water from ECF by osmosis (Gradients Core Principle)

  • Causes polyuria (frequent urination) and polydipsia (excessive thirst) from dehydration

Type 2 Diabetes

• Type 2 Diabetes ( Non-insulin dependent)

  • insulin’s target tissues become insensitive to insulin; target cells do not initiate proper responses to increases in blood glucose concentration (insulin resistance)

  • unlike individuals with type 1 diabetes, those with type 2 generally produce enough insulin to prevent ketoacidosis

  • The development of type 2 diabetes is strongly associated with heredity and obesity

Effects of diabetes

• Chronic hyperglycemia has wide-ranging effects:

  • Damages blood vessels, particularly those in heart and lower limbs; results in decreased circulation to these tissues; increases risk of heart attack, nonhealing wounds, and amputation

  • Damages peripheral nerves, again particularly in lower limbs; leads to peripheral neuropathy (numbness, tingling, and burning pain in affected areas)

  • Other tissues affected include lens of eye and capillaries of retina and kidneys; possibly results in blindness and kidney failure

Negative Feedback Loop Associated with Insulin and Glucagon

• Insulin and glucagon are antagonists in complicated feedback loop that maintains blood glucose homeostasis

• Following feedback responses are initiated when blood glucose level increases

  • Stimulus—blood glucose level increases above its normal range, in response to feeding or hormones such as cortisol

  • Receptor – Beta cells of the pancreas detect increased blood glucose

  • Control center—Beta cells increase insulin secretion; alpha cells reduce glucagon secretion

  • Effector/response—insulin decreases blood glucose level by increasing glucose uptake by cells and storage of glucose, amino acids, and fats

  • Homeostatic range and negative feedback—as blood glucose level returns to normal range, negative feedback to beta cells decreases insulin secretion

Negative Feedback Loop Associated with Insulin and Glucagon

• Following feedback responses are initiated when blood glucose level decreases

• Stimulus—blood glucose level decreases below normal range

• Receptor—alpha cells of pancreas detect decreased blood glucose

  concentration, as well as the presence of ingested protein

• Control center—alpha cells increase glucagon secretion; beta cells decrease insulin secretion

• Effector/response—glucagon triggers breakdown of glycogen (glycogenolysis) into glucose and formation of new glucose (gluconeogenesis)

• Homeostatic range and negative feedback—as blood glucose level returns to normal range, negative feedback to alpha cells decreases glucagon secretion