Phys Exam 5: Regulation of Metabolism

Nutrients during fasting:

- Glycogen stores depleted - Plasma glucose declines - Major shift to lipolysis allows glucose sparing o Fatty acids o Glycerol o Ketones - Blood glucose is not generated from glycogen, but from glycerol liberated by lipolysis.

Plasma hormones during fasting:

- Increased glucagon/insulin ratio - Growth hormone is elevated - Cortisol remains normal

Insulin

- Insulin is the most important regulator of plasma glucose concentration! - A. Plasma level of insulin - Absorptive state = elevated levels of insulin - Postabsorptive state = lowered levels of insulin

Daignostic tests for Diabetes:

Fasting plasma glucose Oral glucose tolerance test (OGTT) Insulin tolerance test (ITT) *T2DM, not routine Insulin C-fragment (measure insulin secretion) Glycosylated hemoglobin - HbA1C o Red blood cells - lifespan 90 days o HbA1C indicates glucose control over 3-month period - Normal: 4-6% - Diabetics can reach over 9%, therapeutic target 7%

Symptoms of Type 1 Diabetes Mellitus

Glycosurea (sugar in urine) Polyuria - High glucose in urine = high osmolarity - Inhibits reabsorption of water Polydipsia Excessive thirst - Dehydrated, decreased plasma volume Polyphagia (Excessive food consumption) Hyperlipidemia Weight loss (T1DM-specific) - Decreased anabolism and increased catabolism - Cells are starved! Blurred vision (hyperosmotic fluids in lens/retina) Ketoacidosis (T1DM-specific) - Increased ketones decrease plasma pH (ketones from fatty acid metabolism!) - Neural problems - Dizziness, coma, death

Insulin secretion

Peptide hormone - Secreted from Beta cells of pancreatic Iselts of Langerhans - Absorptive State: Increased blood glucose stimulates insulin secretion - Target cells express insulin receptor that responds to increase in plasma insulin concentration to stimulate storage of nutrients

Therapy for Type 1 Diabetes Mellitus

Plasma glucose monitoring Insulin administration (by injection or pump sustained release) Pancreatic Islet transplantation or "artificial pancreas" - Limited success, ongoing research

Symptoms of Type 2 Diabetes Mellitus

Polyuria Polydipsia Hyperlipidemia Fatigue Blurred vision (more severe in T2DM) o Prolonged hyperosmolarity o More severe retinopathy Paresthesia (T2DM-specific) o Neuropathyo Abnormal sensory function Not enough glucose excreted for weight loss in T2DM Ketoacidosis is rare in T2DM (but more likely with trauma/infection)

Pathophysiology of Type 2 Diabetes Mellitus

Reduced insulin sensitivity in target tissues Progressive insulin resistance Related to obesity Hyperinsulinemia compensates early on in prediabetic stages Can lead to loss of insulin secretion o Beta-cells decreased sensitivity to glucose since chronic hyperglycemia *Note that T2DM develops more slowly than T1DM, due to gradual decline in insulin sensitivity in target tissues. More likely to be asymptomatic for prolonged period of time (years), and thus more likely to be undiagnosed.

Hypoglycemia: Symptoms

1st due to SNS reflex: Increased heart rate Trembling Nervousness Sweating Anxiety Later due to lack of glucose for brain: Headache Confusion Dizziness & Incoordination Slurred speech Convulsions Plasma glucose < 40 mg/dL = coma!

Summary of SNS-mediated regulation of metabolism

- Direct innervation of nerves in liver and adipose tissue - Indirect release of epinephrine from adrenal medulla o Epinephrine acts on skeletal muscle, liver, and adipose to mobilize nutrients from storage and increase gluconeogenesis. - Hypoglycemia: increases SNS activity - During prolonged fasting, SNS adapts and decreases activity

Cortisol

- Glucocorticoid hormone produced by adrenal cortex - Under normal resting conditions (non-stressed): o Cortisol has essential, but only permissive role in adjusting to fasting o Effects are opposite of insulin o Cortisol in blood maintains expression of enzymes necessary for lipolysis and gluconeogenesis in adipose tissue and liver - Cortisol deficiency: can lead to hypoglycemia during fasting - High cortisol levels (genetic, stress, drugs): o Decreases insulin sensitivity in muscle and adipose tissue o can lead to insulin resistance

Pathophysiology of Type 1 Diabetes Mellitus

- *Lack of insulin* - Cells are starving despite Hyperglycemia o Plasma glucose above 200 mg/dL o Often 300-400 mg/dL, can reach 1000 mg/dL - Increased lipolysis o Increased ketone production o Hyperlipidemia >Lack of Insulin leads to -Reduced glucose and amino acid uptake and utilization. - No brakes on glycogen and protein catabolism. - No brakes on lipolysis, leads to hyperlipidemia.

Personal Complications and Co-morbidities of Diabetes

- Atherosclerosis (caused by dyslipidemia) - Peripheral vascular disease (see bleeding gums) - Neuropathy (tingling/numbness/pain in extremities) - Infections (severe enough to need amputations) - Retinopathy o Leading cause of vision loss in working age adults o Can progress to complete blindness - Kidney failure

Exercise

- Muscle contraction requires a large amount of energy - Similar to postabsoprtive metabolism o Increases lipolysis o Increases liver glycogenolysis and glucoenogenesis - Exercise decreases plasma glucose, stimulates: o Decreased insulin secretion o Increased glucagon secretion - Increased SNS activity (direct via nerves, indirect via epinephrine)

Blood Glucose Levels

- Normal fasting blood glucose = 70-110 mg/dL - Minimal glucose needed for brain = 40 mg/dL (below this cognitive deficits, even coma) - Saturating glucose concentration for renal proximal tubules = 180 mg/dL (no glucose in urine unless blood glucose is above this level)

Other Controls of Insulin Secretion

- Plasma amino acids o stimulate insulin secretion - Autonomic control o Pancreas is innervated by both parasympathetic and sympathetic nerves o Parasympathetic (rest) increases insulin release o Sympathetic (fight/flight) inhibits insulin release - Epinephrine

Sympathetic Nervous System (SNS) Control of Plasma Glucose

- SNS acts via nerves (direct effect) and epinephrine (indirect effect) - SNS has less effect on plasma glucose than insulin/glucagon ratio - SNS metabolic effects: o Increase glycogenolysis (liver & muscle) o Increase gluconeogenesis (liver) o Increases lipolysis (adipose tissue)

Growth Hormone

- Secreted from pituitary gland - Major effect: stimulates bone growth and protein synthesis - Normally, only minor effect on carbohydrate and lipid metabolism - Effects are similar to cortisol and opposite of insulin o Increases lipolysis and gluconeogenesis responses to other stimuli (glucagon) o Decreases insulin sensitivity in muscle and adipose tissue (less glucose uptake) o Acromegaly (increased GH) can cause insulin resistance

Therapy For Type 2 Diabetes Mellitus

1. Biguanides (metformin, GLUCOPHAGE) - inhibit liver gluconeognesis 2. Sulfonylureas (ORIMIDE, MICRONASE) - promote insulin secretion from pancreas - target ATP-dependent K+ channel 3. GLP-1 agonist (exenatide, BYETTA) - increases glucose-dependent insulin secretion - slows gastric emptying, decreases appetite - resistant to degradation by dpp-4 4. insulin administration in late stages - beta-cells decreased sensitivity to glucose causes decreased insulin secretion

Two incretins

1. Glucose-dependent insulinotropic peptide (GIP) 2. Glucagon-like peptide 1 (GLP-1)

Mechanisms of hypoglycemia

1. Increased blood insulin Insulin-secreting tumors (rare) Drugs increasing insulin secretion Parasympathetic stimulation Overdose of insulin in diabetics (more common) 2. Defect in glucose counter-regulatory systems Inadequate glycogenolysis or gluconeogenesis (Liver disease) Glucagon deficiency Cortisol deficiency *recall that cortisol is permissive to allow anti-insulin effects

Insulin actions (metabolic effects)

1. Increases uptake of nutrients into tissues (mainly skeletal muscle and adipose tissue, NOT LIVER) Glucose, amino acids, fatty acids 2. Stimulates synthesis of storage form of nutrients (Glycogen, protein, triglycerides) 3. Inhibits metabolism of stored nutrients (Glycogenolysis, proteolysis, lipolysis) Insulin does NOT increase liver uptake of glucose. Adipose tissue and muscle express insulin-responsive Glut4, liver does not. Insulin stimulates rate limiting enzyme for glycogen synthesis in muscle and liver.

Exocrine Pancreas

Acinar cells and duct cells.

Incretins

Amplify insulin secretion. - Incretins are gut-derived hormones - Secreted in response to a meal - Amplify glucose-dependent insulin secretion - Work to jump-start insulin secretion in order to prevent a very high rise in blood glucose Incretins prime B-cells to respond to increased concentration of blood glucose. This is a feed forward mechanism. This buffers rise in glucose levels, since incretins are released after ingestion of a meal, but before glucose increases in blood stream. So a smaller increase in blood glucose can increase insulin secretion, this helps maintain blood glucose homeostasis.

Prevalence of Diabetes

As of 2012, 29.1 million Americans (9.3%) have DM o Diagnosed: 21.0 million o Undiagnosed: 8.1 million Prediabetes: 86 million adults (America)

Specific Cellular Mechanisms of Insulin Secretion

As plasma glucose concentration rises, so does beta cell uptake of glucose, which leads to an increase ATP/ADP ratio. The ATP-dependent or ATP-Regulated potassium channel (in pancreatic beta cells) closes in response to increased ATP/ADP ratio. Closing of the channel depolarizes the membrane, prompting the voltage-gated calcium channel to open, which increases intracellular calcium to stimulate insulin secretion. *Potassium channel is target for T2DM therapeutics that mimic ATP to close the channel and increase insulin secretion.

Hormonal Control in the Post Absorptive State

Blood glucose levels are maintained in the postabsorptive state by hormonal and neuronal control systems.

Key difference between postabsorptive state and exercise metabolism:

Despite low plasma insulin levels during exercise, muscles have increased glucose uptake and catabolism for energy...How? >Muscle contraction causes - increase in Glut4 expression - insulin-independent translocation of Glut4 to cell surface (unclear mechanism)

Major Insulin Counter-Regulator in the Postabsorptive State

Glucagon - Secreted by pancreatic alpha-cells - Only target organ is the liver - Main metabolic effect is to increase plasma glucose levels during postabsorptive state to support CNS - In liver: glucagon increases glycogenolysis, gluconeogenesis, and ketone synthesis

GLP-1

Glucagon-like peptide 1: - Glucagon-like peptide is sort of misnomer, it acts to amplify insulin action, whereas glucagon is counter-regulatory to insulin. Don't be confused! - Secreted from duodenum (biphasic) o First: immediately after ingestion of meal, driven by neuronal and hormonal control o Second: 30-60 minutes after meal, driven by direct effect of nutrients in duodenum - Stimulates glucose-dependent insulin secretion - Stimulates synthesis of preproinsulin - Enhances beta-cell proliferation - Decreases glucagon secretion - GLP-1 is only structurally similar to glucagon, but its effects are opposite of glucagon! - Decreases gastric emptying and GI motility - Promotes satiety - GLP-1 secretion often decreased in T2DM *T2DM drugs: analogs of GLP-1

GIP

Glucose-dependent insulinotropic peptide. - Secreted from the duodenum - GIP secretion stimulated by carbohydrates and fats - GIP secreted within minutes of ingesting meal - Stimulates glucose-dependent insulin secretion - Does NOT affect gastric emptying - Inactivated by dipeptidyl peptidase-4 (DPP-4)* - *T2DM drugs target and inhibit DPP-4 to increase GIP levels (will discuss more in Diabetes section)

T2DM

Type 2 Diabetes Mellitus insulin resistance, which means reduced sensitivity to insulin in target tissues, primarily muscle, liver, and adipose tissue. Classic Endocrine Hyposensitivity disorder. 90% of Diabetic patients are type 2. Peak incidence is middle-aged, although recent trend for people to develop T2DM at younger ages, even in teenagers! 80% of T2DM are obese.

Fasting: Protein Catabolism

In early stages of fasting, protein catabolism is also increased. > However, during prolonged fasting of > 3days, ketone levels in the blood rise (from shift to lipolysis providing FFAs for liver to synthesize ketones) and the brain increasingly begins to rely on ketones for energy instead of glucose. * Ketones (fatty acid metabolism product) are different from keto-acids (come from amino acids), so don't get them confused!! However, tends to be confusing since high plasma concentration of KETONES is referred to as Keto-acidosis.

Alpha Cell

Pancreas: secretes glucagon

Insulin Effects on Muscle

Increases glucose and amino acid uptake into muscle. Stimulates glycogen and protein formation Inhibits glycogenolysis and proteolysis

Insulin Effect on Adipose Tissue

Increases glucose uptake and promotes glucose breakdown for triglyceride synthesis. Increases lipoprotein lipase to increase uptake of FFAs for triglyceride synthesis. Also stimulates triglyceride synthesis and inhibits lipolysis.

Since glucagon only acts on the liver, how is lipolysis and proteolysis increased in postabsorptive state?

Insulin usually inhibits both lipolysis and proteolysis, so decreased insulin levels simply removes this inhibitory activity to allow lipolysis and proteolysis to increase!

What stimulates the liver to stop glucose uptake and begin gluconeogenesis and glucose release during the postabsorptive state?

Integrated Endocrine and Neural Control Mechanisms

Beta Cells

Pancreas: secretes insulin

Delta Cell

Pancreas: Secretes somatostatin

Ketones and Proteolysis

Ketones also inhibit proteolysis, thereby preventing serious tissue damage and prolonging survival during fasting. One major ketone is acetone, some of which is exhaled, contributing to the distinctive breath odor associated with prolonged fasting.

Type 2 Diabetes Mellitus: Insulin Tolerance Test

Measure hyposensitivity to insulin stimulation. - No routine procedure. - Danger of hypoglycemia.

OGT

a two-hour test that checks your blood glucose levels before and 2 hours after you drink a special sweet drink (50 gm of glucose).

Primary Regulator of Insulin Secretion

Plasma Glucose Concentration When plasma glucose is elevated it stimulates insulin secretion, and when plasma glucose is lowered to normal or premeal level, it no longer stimulates insulin secretion. > Classic example of homeostasis regulated by negative feedback.

Insulin Production

Preproinsulin: is an amino acid chain with a signaling sequence. Proinsulin: Signal sequence removed, insulin folded with C-chain connecting A-chain and B-chain, which are connected by disulfide bonds. Insulin: A-Chain and B-Chain, C chain has been removed.

Insulin Effects on Protein Metabolisom

Protein is not storage form of energy, but it is important for maintaining cell health and function, so want to produce and conserve protein. Insulin stimulates amino acid uptake into liver and skeletal muscle and promotes protein synthesis (by stimulating ribosomal enzymes). Insulin also inhibits enzymes involved in protein catabolism. *Insulin increases synthesis of lipoprotein lipase (LPL) to increase uptake of FFAs into adipose tissue. It also stimulates triglyceride synthesis and inhibits lipolysis.

Summary of Glucose Counter-Regulatory Hormones:

See Table 16.4 on page 22 of the Regulation of Metabolism Handout.

T1DM

Type 1 Diabetes Mellitus unclear automimmune disease causes destruction of pancreatic Beta cells, so insulin cannot be synthesized and secreted. 9% of DM patients are Type 1. No symptoms until > 80% beta cell loss. Two peak incidences of T1DM, first at puberty, second ~40 yr age.

Regulation of Glucagon Secretion

a. glucagon secretion is increased when plasma glucose levels drop b. Autonomic regulation - Sympathetic (fight/flight) nerves and epinephrine stimulate pancreatic glucagon secretion (to meet increased energy demand) - Parasympathetic (rest) nerves inhibit pancreatic glucagon secretion (to maximize energy storage) c. Transition from absorptive to postabsorptive state driven largely by increase in glucagon:insulin ratio in plasma

Fasting

at least 24 hr since last meal During fasting, fat stores normally last ~60 days. After fat is depleted, protein catabolism increases, leading to death. Usually very painful as diaphragm is degraded and as a result person cannot breathe.

Diabetes Mellitus: Clinical Diagnosis

by fasting glucose measurement or oral glucose tolerance test. To confirm diagnosis, results must be obtained twice more than one week apart. 100 mg/dL is normal 100-125 mg/dL is prediabetes > 125 mg/dL = Diabetes

Hypoglycemia

defined as lower than normal blood glucose (<70 mg/dL) in postabsorptive state (clinically, an overnight fast)

Hyperglycemia

fasting blood glucose above 110 mg/dL (so people can be hyperglycemic without glucose in urine when blood glucose is 111-180 mg/dL)

Diabetes Mellitus

metabolic disorder characterized by inability of insulin to regulate blood glucose levels. Historically, disease was named for its major symptom of high volume of sweet urine. "Diabetes" refers to increased urinary volume "Mellitus" means sweet, because patients often have glucose excretion in urine *please note that a patient with diabetes does not always have glucose in the urine. That is because the glucose transporters in kidney are not saturated until plasma glucose reaches > 180 mg/dL, but a person with diabetes can have fasting plasma glucose in range of 126-180 mg/dL without glucose in urine. Note that a patient can have a small degree of fasting hyperglycemia without being considered diabetic, but they are considered pre-diabetic and at risk for progressing to diabetes

Diabetes: Complications and Co-Morbidity

o Hypertension (71% of DM pts have this) o Dyslipidemia (65% of DM pts have this) o Cardiovascular Disease (1.7X higher death rate in DM pts) o Heart Attack (1.8X higher incidence in DM pts) o Stroke (1.5X higher incidence in DM pts) o Blindness/Vision loss (28.5% of DM pts over age 40) o Kidney disease (44% of kidney failure pts have DM) o Amputations (60% of non-traumatic amputations are DM pts) *As a result of complications and co-morbidities, Diabetes is the 7th leading cause of death, with an annual economic cost of $245 Billion ($176B medical expense, $69B lost productivity)!! ** In Oklahoma: 10.1% of adult Oklahomans have DM, and from 1995 - 2012, Diabetes prevalence tripled in OK!!