The Endocrine Pancreas and Glucose Regulation

Endocrine Pancreatic Secretions

*Pancreatic hormones* Endocrine cells, which account for LESS than 2% of the total pancreatic mass, are organized into discrete clusters called *islets of Langerhans* that are scattered throughout the exocrine portion of the pancreas. -Islet cells are highly vascularized and have a MUCH GREATER rate of blood flow than the exocrine portion of the pancreas. -The principal endocrine cells that make up the islets of Langerhans: -β cells: secrete INSULIN -α cells: secrete GLUCAGON -Islets also contain smaller quantities of other endocrine cells that secrete hormones such as somatostatin and pancreatic polypeptide. >Delta cells: Secrete Somatostatin

Sulfonylurea Closes K+ Channels and Increases Insulin Secretion

*Sulfonylureas* are oral hypoglycemic drugs that are used to treat type 2 diabetes in patients that have functioning β cells. -Sulfonylureas bind to the SUR subunit of the ATP-gated K+ channels causing the channel to CLOSE= INCREASING insulin secretion.

Specific Roles of Pancreatic Hormones

-*Insulin*: stimulates uptake and storage of energy substrates (Beta cells) -*Amylin*: SLOWS gastric emptying, inhibits digestive enzyme secretion, promotes satiety, inhibits glucagon secretion >Helps to prevent post-prandial glucose spikes (Beta cells) -*Glucagon*: Stimulates production of glucose by liver (Alpha cells) -*Somatostatin*: General inhibition of exocrine and endocrine pancreatic secretion >Acts in paracrine fashion (Delta cells)

Insulin Abuse by Athletes

-Attempt to increase glycogen storage -Inject insulin and then eat HIGH sugar foods -Risk of hypoglycemia and coma -Often used with steroids

Summary of Factors Influencing Insulin Secretion

-Basic amino acids such as arginine and lysine are more potent stimulators of insulin release than other amino acids. -Incretins: GIP and GLP-1 -Neural control of insulin release

90% of People Who Develop Type 2 Diabetes are Overweight

-Chronic overeating INCREASES blood glucose -> INCREASES insulin secretion -Chronic hyperinsulinemia *DOWN-regulates insulin receptors* >DECREASED sensitivity of target cells to insulin (*"insulin resistance"*) -Often associated with hypertension and hyperlipidemia= "metabolic disease"

Type 2 Diabetes (Treatment)

-Dietary restriction -Weight loss -Exercise -Medications: >*Sulfonylureas*:Stimulate beta cells >*Metformin (Glucophage)* that INHIBITS hepatic gluconeogenesis

Morbidity and Mortality of Diabetes

-Every 10 seconds one person dies of a diabetes-related condition. -Every 10 seconds two people develop diabetes. -Diabetes shortens ones expected lifespan by 15 years - a 40-yr-old with diabetes has the same level of risk as a 55-yr-old without diabetes.

Effects of Glucagon on Fat and Carbohydrate Metabolism are Opposite those of Insulin

-Glucagon increases blood glucose by increasing *liver gluconeogenesis and glycogenolysis* -Increased blood fatty acids and ketone bodies by increasing production in liver and adipocytes >Increased lipolysis and metabolism of fatty acids to KETONES -Under normal physiological conditions, the concentration of glucose in the blood is TIGHTLY regulated and hypoglycemia is PREVENTED OR CORRECTED by an increase in glucagon secretion and a decrease in insulin secretion. >Glucagon protects against falling blood glucose levels by stimulating hepatic glycogenolysis and gluconeogenesis.

Mechanism of β Cell Insulin Secretion

-Glucose transporter *GLUT 2* allows rapid diffusion into β cells via facilitated diffusion at the plasma membrane. -Glucose level determines rate of glucose METABOLISM in β cell -glucokinase initiates 1st step in glycolysis -> generates ATP -ATP closes K+ channel -> cell depolarizes -> voltage-gated Ca2+ channel opens, Ca2+ influx and level rises, and insulin granules release via exocytosis

Effects of Feeding and Fasting on Insulin and Glucagon Release

-In a normal healthy person, the daily pattern of insulin production is characterized by *episodic peaks in plasma insulin levels* that are associated with the ingestion of food and a sustained LOW basal level of release that occurs in the absence of exogenous stimuli. -Glucagon 1/2 life is 8-18 min -Glucagon should read ng/mL

Neural Control of Insulin release

-Islets cells are innervated by both sympathetic and parasympathetic (VAGAL) fibers. -Exercise and stress inhibit insulin release. >This effect is mediated by sympathetic stimulation via alpha2 adrenergic receptors (these receptors are coupled to a Gi protein). -Vagal stimulation of β cells in the presence of glucose can promote insulin release. >This mechanism is thought to promote the release of insulin associated with the cephalic phase of GI activity.

Blood glucose concentration

-Most significant regulated variable: blood glucose concentration -Insulin and glucagon secretion controlled primarily by blood glucose concentration -Insulin and glucagon have mostly opposite effects -The principal physiological stimulus that evokes insulin release is an INCREASE in circulating levels of glucose. >Blood glucose levels are tightly regulated and a rise in glucose concentration above a threshold elicits a rapid secretory response by the β cells.

Control of Glucagon Secretion

-Primary control: NEGATIVE feedback between alpha cells and blood glucose concentration >LOW blood glucose -> INCREASES glucagon secretion >Hypoglycemia is the most important physiological stimulus for the release of glucagon. >The response of α cells to hypoglycemia is mediated, in part, by sympathetic stimulation and by the rise in circulating catecholamines which act through *β2 adrenergic receptors.* -Other factors also increase secretion: -Increased sympathetic activity and epinephrine -Elevated amino acids >Counteracts insulin effect and prevents hypoglycemia after high-protein, low-carb meal >The α cell responds to amino acids, particularly arginine. -Prolonged vigorous exercise and certain types of stress (major surgery, burns, toxemia and tissue infarction) also promote glucagon release.

Down-Regulation of Insulin Receptors Alters Target Cell Responses

-Receptors are down-regulated (decreased number of receptors) by chronically HIGH insulin level >Resulting from *chronic hyperglycemia of obesity or acromegaly* >Also from periods of high carbohydrate intake. -Affinity of receptors is DECREASED by excess glucocorticoids (such as CORTISOL) - High levels of insulin increase the rate of receptor-mediated endocytosis. >The receptor content of the cell is DECREASED by increasing the rate of receptor degradation or decreasing the rate of receptor synthesis. *Result is "insulin resistance"*

Up-Regulation of Insulin Receptors Alters Target Cell Responses

-Receptors are up-regulated by STARVATION -Affinity of receptors is increased by *chronically low insulin level or adrenal insufficiency*

Hypoglycemia (signs/symptoms/causes)

-The signs and symptoms of hypoglycemia are the result of *sympathetic activation and neuroglycopenia (a deficient supply of glucose in the central nervous system)*. -Signs and symptoms associated with *sympathetic activation* include (<60gm/dL): >anxiety >trembling palpitations >tachycardia >sweating -Signs and symptoms associated with *neuroglycopenia* include (<50 gm/dL): >headache >an inability to concentrate >confusion >belligerent behavior and moodiness >a lack of coordination >slurred speech >seizures and coma Causes of hypoglycemia include: >administration of drugs that potentiate the effects of *insulin* (ex: sulfonyl-ureas) >substances that *interfere with gluconeogenesis* (ex: alcohol), insulinomas, rapid gastric emptying in patients with gastrectomies which leads rapid glucose absorption and EXCESSIVE insulin production >Adrenal and pituitary insufficiency >Liver disease >Inborn errors of carbohydrate metabolism

Dieting & Exercise Lowers Risk of Developing Type 2 Diabetes in Overweight Subjects

-U.S. study: 3,000 subjects, 3 years >Diet and exercise group (for 7% weight loss + 30 min. exercise x5/wk) >Metformin (Glucophage) group >Placebo group -Diet/exercise reduced risk by 58% -Metformin reduced risk by 33%

Type II Diabetes and Obesity

-Usually in older patients BUT now also being seen in overweight children -Characterized by IMPAIRED insulin secretion and RESISTANCE of target cells to its effects -T2DM is a heterogeneous group of diseases that are characterized by varying degrees of *insulin resistance with relative insulin deficiency.* -90 to 95% of patients with diabetes mellitus have T2DM. -Insulin deficiency is due to compromised β cell function. -Initially: T2DM patients do NOT REQUIRE insulin treatment (only insulin resistant) but as their disease progresses, some patients may become dependent on exogenous insulin for survival (become insulin deficient). -Spontaneous ketoacidosis seldom develops in T2DM (more often in T1DM).

Following the ingestion of a meal, there is only a brief rise in blood glucose levels because:

1.) A substantial fraction of glucose is shunted into the liver: much of this glucose is converted to glycogen and triacylglycerol 2.) Glucagon levels are suppressed by the increase in blood glucose: this leads to a *suppression* of glucose production by the liver 3.) Insulin stimulates glucose uptake and utilization by skeletal muscle and fat -Although insulin affects nutrient utilization by numerous different tissues, its principal targets with respect to the overall distribution and storage of nutrients are: (1) the liver (2) skeletal muscle (3) adipose tissue

Functional Anatomy of the Pancreas

98% exocrine -Digestive enzymes and bicarbonate -Secreted through pancreatic duct 2% endocrine -Peptide hormones regulating glucose and other intermediary metabolism -Secreted by EXOCYTOSIS >Drains into *Hepatic Portal Vein*

Diabetes I

DEAD SLIDE Type 1 diabetes mellitus (T1DM) -Beta cells show histological evidence of *damage and autoantibodies* are typically present at the time when the initial diagnosis of hyperglycemia is made (LOW INSULIN) -Patients with T1DM are prone to develop *ketoacidosis in the absence of insulin treatment* and they require exogenous insulin for survival (INSULIN RESPONSIVE) -T1DM is an autoimmune response that is triggered in *genetically predisposed individuals* by an infection or environmental stimulus. -Β cell mass declines over time and insulin secretion becomes impaired. -The rate of decline varies from individual to individual. -Overt diabetes results when about 80% of the β cells are destroyed. -About 5 to 10% of patients with diabetes mellitus have T1DM.

Diabetes Mellitus

Diabetes mellitus is a group of diseases characterized by POORLY controlled glucose and lipid metabolism resulting from the *diminished production of insulin (Type I) and/or decreased tissue responsiveness to insulin (Type II). * -AIC > 6.5%: a measure of the quantity of glycated (glycosylated) hemoglobin in the blood -A fasting plasma glucose level > 126 mg/dl -*Impaired fasting glucose* >A fasting plasma glucose level between 110 and 126 mg/dl >2 hour plasma glucose > 200 mg/dl during an oral glucose tolerance test -Symptoms of hyperglycemia: Polyuria, polydipsia (excessive thirst), polyphagia (excessive hunger), etc

Diagnosis of Diabetes by Glucose Tolerance Test

Diagnosis of diabetes if repeated fasting glucose > 126 mg/dL and glucose > 200 mg/dL two hours after oral glucose challenge

Hepatic insulin resistance

Hepatic resistance is characterized by: -Inappropriately high hepatic glucose production in the fasting state and impaired glycogen production and storage following glucose ingestion. -*Decreased uptake of glucose* by skeletal muscle and fat contributes to DECREASED clearance of plasma glucose during the fasting state -Insulin resistance in fat cells also REDUCES lipid clearance and increases circulating levels of free fatty acid levels. >Elevated levels of fatty acids may contribute to insulin resistance.

Problems of Hyper- and Hypo-Secretion of Pancreatic Hormones

Hyper-secretion of glucagon= *Hyperglycemia* >Alpha cell tumor= glucagonoma Hyper-secretion of insulin-> *Hypoglycemia* >Beta cell tumor - insulinoma -Note: Overdosage of insulin in diabetics can cause hypoglycemia -CNS effects of hypoglycemia (sympathetic activation and neuroglycopenia): >sweating >pallor >Increased heart rate >anxiety >confusion >convulsions >coma

Effects of Arginine Infusion on Insulin and Glucagon Release

In a normal healthy person, the daily pattern of insulin production is characterized by episodic peaks in plasma insulin levels that are associated with the ingestion of food and a sustained low basal level of release that occurs in the absence of exogenous stimuli. COUNTERACTION!

Amino Acids Stimulates...

Insulin AND Glucagon -ARGININE -Leucine and Lysine

When is insulin/glucagon dominant?

Insulin dominant in FED state: -Cellular uptake of nutrients carbohydrate and fat storage protein anabolism Glucagon dominant in FASTED state: -CATABOLISM breakdown of carbohydrate, fat, and protein stores -Because insulin and glucagon have opposing effects on the flow of metabolites through metabolic pathways in the liver, the insulin-to-glucagon ratio is an important determinant of hepatic function. -When a person ingests a balanced meal or a meal that is high in carbohydrate content, the* insulin-to-glucagon ratio increases* because the absorbed nutrients have a net stimulatory effect on insulin release and an inhibitory effect on glucagon release.

Insulin Resistance Results in Hyperinsulinemia in Obesity

Obesity is a major risk factor for T2DM. -More than 85% of patients are obese at the time of diagnosis. -Many obese individuals who are not diabetic are *insulin resistant.* -In the above graph: note that an *exaggerated increase in plasma insulin* is required for the OBESE subjects to keep their blood glucose levels within the normal range after they ingest an oral glucose load. -Overall: More insulin release needed to keep circulating glucose levels controlled for T2DM patients. *Insulin receptor down-regulation occurs in obese subjects or during periods of high carbohydrate intake*

Effects of Insulin on Protein Metabolism

Overall: DECREASE blood amino acids and INCREASE protein synthesis -Increase transport of blood amino acids into muscle and other cells -Increase protein synthesis -INHIBITS protein degradation

Effects of Insulin on Fat Metabolism

Overall: DECREASES blood fatty acids and INCREASES triglyceride storage -Increases transport of fatty acids into fat cells -Increases triglyceride synthesis by increasing glucose transport into fat cells -Activates enzymes that catalyze synthesis of fatty acids from glucose -INHIBITS lipolysis

Major Effects of Insulin on Carbohydrate Metabolism

Overall: decreases blood glucose and increases carbohydrate storage -INCREASE glycogenesis in skeletal muscle and liver -DECREASE hepatic gluconeogenesis -INCREASE glucose uptake by fat cells and resting skeletal muscle (GLUT4)

Roles of Pancreatic Hormones

Respond to "feasting and fasting" -The fed state: during eating and first hours after eating >The absorptive state is the 2 to 4 hour period following the ingestion of a meal. >During this period there is a transient rise in absorbed dietary nutrients. >When one ingests a mixed meal, the concentration of insulin in the blood increases and the concentration of glucagon in the blood DECLINES. -The fasted state: between meals

Responses to the Progressive Reduction in Plasma Glucose Concentrations in Healthy Young Volunteers

The brain is metabolically very active and requires a CONSTANT supply of energy. -In the fed state: the brain relies almost *exclusively on glucose* obtained from the blood to meet its energy needs. >Ketones are not utilized to any extent during the fed state because their concentrations in the blood are very LOW. -*Hypoglycemia (low blood glucose levels)* occurs when blood sugar falls below the concentration necessary to maintain the brain's energy needs. >Hypoglycemia elicits characteristic symptoms that are rapidly resolved by the administration of glucose. >When blood glucose levels fall below a certain threshold value, the *hypothalamus activates the sympathetic nervous system.* >The sympathetic nervous system acts on pancreatic islets to stimulate *glucagon release and inhibit insulin release.* >As a result of sympathetic activation, there is a rapid rise in circulating *epinephrine levels*. -Epinephrine protects *AGAINST falling blood glucose levels* by inhibiting glucose utilization by muscle, stimulating hepatic glycogenolysis and gluconeogenesis, inhibiting insulin secretion, and stimulating glucagon secretion and also a profound stimulatory effect on lipolysis.

Blood Glucose Levels and Pancreatic Hormone Secretion

The effects of increases or decreases in blood glucose levels on glucagon and insulin release are exactly opposite. -Faced with increased blood glucose levels beta-cell insulin secretion increases and alpha-cell glucagon secretion decreases. >The opposite pattern occurs when blood glucose levels decrease.

Biphasic Response of the Pancreas to Glucose Perfusion

When the pancreas is perfused with glucose, insulin release exhibits a characteristic *biphasic response*. -The initial phase involves a RAPID increase in insulin secretion that PEAKS within a few minutes after the start of infusion and then DECLINES. -This is followed a *delayed phase* that is characterized by a GRADUAL increase in insulin release to a level that is maintained for the DURATION of the stimulus.

Action of Insulin on Resting Skeletal Muscle and Adipocytes

A large portion of the glucose entering systemic circulation following the ingestion of a meal enters skeletal muscle. -Glucose uptake by skeletal muscle is regulated primarily by insulin and to a lesser extent by the increase in the concentration of blood glucose. -Insulin increases glucose uptake by stimulating the *translocation of the GLUT4 transporters* that are stored in intracellular vesicles to the plasma membrane. -This increases the Vmax for transport. -Exercise also increases the translocation of GLUT4 to the plasma membrane of skeletal muscle cells in humans. >GLUT 2 for liver, but GLUT 4 for skeletal muscle and adipocytes -The amount of glucose used for glycogen formation depends upon how much is being used to supply energy for physical activity. -Although there is more glycogen stored in skeletal muscles than liver, glycogen in skeletal muscle cannot be mobilized to maintain blood glucose levels because skeletal muscle cells LACKS glucose 6-phosphatase (no gluconeogenesis in muscle, only in liver). -Insulin promotes glucose uptake into adipocytes by promoting the translocation of *GLUT4 transporters to the plasma membrane.* >There is an increase in glycolysis following insulin-stimulated glucose uptake. >The glycerol 3-phosphate needed for triacylglycerol formation is derived from pyruvate by an abbreviated version of gluconeogenesis. *Insulin dependent!*

Which of the following promotes insulin secretion?

A) sympathetic stimulation B) somatostatin C) glucagon D) cortisol E) growth hormone --- While insulin inhibits glucagon, glucagon actually STIMULATES insulin secretion. All the other answers directly oppose insulin secretion. Important stimulators of insulin are glucose, amino acids, parasympathetics, and GIP/GLP-1. (C)

Patients with type 2 diabetes are strongly encouraged to exercise because

A. Insulin is not required for contracting muscle to take up glucose B. Exercise-induced sympathetic stimulation increases insulin secretion by beta cells C. Exercise reduces insulin resistance in hepatocytes D. Glucose is not needed by contracting muscle cells - INDEPENDENT of taking glucose when exercising (a)

Plasma glucose and insulin are being monitored in an experimental animal. A test substance is administered, after which insulin rises and glucose falls. The substance most likely is:

A. glucagon B. epinephrine C. GIP (glucose-dependent insulinotropic peptide) D. Somatostatin ----- c

Insulin-dependent (type 1) diabetics have to adjust their insulin dose when they exercise because:

A. uptake of glucose is partially blocked in contracting muscle B. large amounts of glucose are needed by contracting muscle C. muscle contraction causes insertion of GLUT 4 transporters D. muscle contraction causes insertion of GLUT 2 transporters -- Want to avoid insulin action plus muscle action which during exercise by AMPK action will cause insertion of GLUT4 in muscle cells and uptake glucose without the help of insulin (c)

Type II DM and insulin resistance

A.) Relationship between insulin sensitivity and the β-cell insulin response is nonlinear. -This hyperbolic relationship means that assessment of β-cell function requires knowledge of both insulin sensitivity and the insulin response. -Hypothetical regions delineating normal glucose tolerance (green), impaired glucose tolerance (IGT; yellow) and type 2 diabetes mellitus (T2DM; red) are shown. -In response to changes in insulin sensitivity, insulin release increases or decreases reciprocally to maintain normal glucose tolerance — 'moving up' or 'moving down' the curve. -In individuals who are at high risk of developing type 2 diabetes, the progression from normal glucose tolerance to type 2 diabetes transitions through impaired glucose tolerance and results in a 'falling off the curve'. -Those individuals who do progress will frequently have deviated away from the curve even when they have normal glucose tolerance, in keeping with β-cell function already being decreased before the development of hyperglycaemia. B.) Insulin sensitivity and insulin responses during puberty, during pregnancy and in obesity relative to that in healthy adults. -On the basis of the hyperbolic relationship defining β-cell function, the product of insulin sensitivity and the insulin response is 1. -In individuals with normal β-cells, glucose tolerance is preserved during puberty, during pregnancy and in obesity as the decrease in insulin sensitivity is matched by a reciprocal, compensatory increase in insulin release, maintaining the product of 1. C.) Insulin sensitivity and insulin responses in groups of people with type 2 diabetes and those at increased risk of developing type 2 diabetes. -In these groups, the *decline in insulin sensitivity is not matched by a reciprocal increase in the insulin response.* -Instead, the insulin response also declines so the product is less than 1, which is compatible with the idea of β-cell dysfunction.

An 8-yr-old child is diagnosed with type 1 diabetes. Before treatment with insulin is begun, his metabolic profile would include:

An 8-yr-old child is diagnosed with type 1 diabetes. Before treatment with insulin is begun, his metabolic profile would include: A. decreased glycogenolysis B. decreased lipolysis C. increased protein synthesis D. ketogenesis ---- D.

Action of Insulin on Liver Cells

Because insulin and glucagon have opposing effects on the flow of metabolites through metabolic pathways in the liver, the insulin-to-glucagon ratio is an important determinant of hepatic function. -When a person ingests a balanced meal or a meal that is high in carbohydrate content, the *insulin-to-glucagon ratio increases* because the absorbed nutrients have a net stimulatory effect on insulin release and an inhibitory effect on glucagon release. -The *GLUT2 transporter* transports glucose across the plasma membrane of liver cells by facilitated diffusion. >The GLUT2 transporter is a *bidirectional transporter* that has a low affinity (high Km) for glucose. >Because glucose levels of hepatic portal blood are elevated during the absorptive state, glucose enters liver cells via the GLUT2 transporter. -When plasma glucose levels are LOW (during interdigestive periods or during a fast), the low affinity (high Km) of the GLUT2 transporter LIMITS the entry of glucose into liver cells. -When hepatic glucose production is stimulated, glucose levels inside hepatocytes are HIGH and glucose exits the cell via the GLUT2 transporter. *Independent of insulin: Allows glucose to enter and leave to maintain homeostasis*

Role of Pancreatic Secretions

Central role in: -Digestion -Metabolism, utilization, and storage of energy substrates >All exocrine -Controlling glucose homeostasis >Provides a constant supply of glucose to CNS >Endocrine

Insulin: Mechanism of Action

Insulin elicits a response in a target cell by binding to and *activating a receptor tyrosine kinase.* -The insulin receptor is a glycoprotein composed of two external α subunits that have insulin-binding sites and two transmembrane β subunits, each of which contains a tyrosine kinase domain in the cytosolic portion of the subunit. -α subunits are bound to each other and to the external portion of a β subunit by disulfide bridges. -The binding of insulin to binding sites in the α subunits induces a conformational change in the receptor that results in phosphorylation of tyrosine residues (autophosphorylation) within its tyrosine kinase domain. -The activated receptor is able to phosphorylate other tyrosine residues within the receptor and specific tyrosine residues of other intracellular proteins. -Intracellular signaling pathways are activated when the tyrosine kinase domains of the activated receptor phosphorylate various intracellular proteins. -A family of proteins called *Insulin Receptor Substrates (IRS)* are the major targets of insulin receptor tyrosine kinase activity. -When an IRS associates with the activated insulin receptor by means of a phosphotyrosine binding domain (PTB), multiple tyrosine residues in the IRS are phosphorylated. -The phosphotyrosine residues of the IRS, in turn, serve as docking sites for other intracellular signaling proteins. Multiple signaling molecules can aggregate on a single IRS. -By activating various signal transduction pathways insulin is able to stimulate the uptake of nutrients by target tissues, modulate the activities of metabolic enzymes, promote nutrient storage, regulate the transcription of proteins, and induce cell growth and differentiation. NOTE: PTEN - tumor-suppressor phosphatase and tensin homologue GRB2 -growth factor receptor-bound protein 2

Glucose Uptake Mechanism During Exercise

Insulin is NOT NEEDED for glucose uptake in exercising muscle: muscle work CAUSES insertion of GLUT 4 into cell membranes. -Increased cellular metabolism increases adenosine monophosphate kinase (AMPK), which increases GLUT 4 insertion -During exercise sympathetic stimulation of *beta cells* inhibits insulin secretion and so prevents hypoglycemia.

Proinsulin

Insulin is a protein molecule composed of two polypeptide chains (the A chain and B chain) that are held together by a pair of disulfide bridges. -Biosynthesis: The insulin gene codes for a SINGLE chain polypeptide called *preproinsulin* >The secretory granules contain prohormone-converting enzymes that cleave proinsulin into insulin + C peptide. ->Free C peptide from insulin ->Insulin= Alpha and beta unit held together by disulfide bonds. >The contents of secretory granules are released into the extracellular fluid by exocytosis when the *β cell is stimulated*. >Mature secretory granules release equimolar amounts of insulin and C-peptide and a small amount of proinsulin. >During periods of rapid insulin release, the proportion of proinsulin that is released increases. ->Proinsulin has about 10% activity as insulin -Degradation: Insulin has a circulatory T1/2 of about 5 - 8 min. >The liver is the principal site of insulin degradation. >About 50% of the insulin released into portal blood is cleared during a single passage through the liver. >The kidneys and other insulin-sensitive tissues also degrade insulin.

Regulation of Beta Cell Insulin Secretion

Insulin release is induced by a mechanism that is activated by the metabolism of glucose in pancreatic Beta cells -Glucose enters the β cell by facilitated diffusion through *GLUT2 glucose transporters* in the plasma membrane. -On entering the cell, glucose is phosphorylated to glucose 6-phosphate by glucokinase. >The metabolism of glucose 6-phosphate results in an increase in the intracellular concentration of ATP and a rise in the ATP/ADP ratio. -Increasing ATP levels within the β cell INHIBITS K+ efflux through ATP-sensitive K+ channels. >This decrease in K+ conductance DEPOLARIZES the plasma membrane thereby activating voltage-gated Ca2+ channels. -The resultant influx of Ca2+ triggers the release of *insulin by exocytosis* -Equal molar amounts of insulin and C-peptide and a SMALL amount of proinsulin are released by exocytosis. >Proinsulin has about 10% of the biological activity of insulin -Amino acid metabolism by pancreatic β cells also increases the intracellular concentration of ATP which promotes insulin release as described above. -GLP-1 and GIP promote insulin release by binding to G protein-coupled receptors on the β cell that activate the adenylyl cyclase signaling pathway. >Glucagon-like peptide-1 (GLP-1) Gastric inhibitory polypeptide (GIP), also known as the glucose-dependent insulinotropic peptide

Insulin secretion increased by:

Insulin secretion increased by: -Increasing blood amino acid level (*arg, leu, lys*) -Increasing blood FFA level (minor effect) -Entry of glucose into small intestine stimulates secretion of GI hormones called *incretins*: >GIP (glucose-dependent insulinotropic peptide) >GLP-1 (glucagon-like peptide-1) -Increase in parasympathetic activity

Insulin Secretion (inhibition)

Insulin secretion is inhibited by: -Somatostatin (paracrine, from delta cells) -Increase sympathetic activity and epinephrine (Alpha2 adrenergic receptors= *Gi protein*) >Appropriate response during exercise or acute stress >Ensures glucose supply to brain and active muscle

Incretins

There are multiple stimuli associated with the ingestion of a meal that PROMOTE insulin secretion including the nutrients absorbed during the digestive process and various peptide hormones called *incretins that are released into the blood by the intestinal mucosa in response to dietary constituents*. -More insulin is released if glucose is ingested than if an equivalent amount of glucose is administered by an IV infusion. -This happens because cells in the intestinal mucosa release hormones called *incretins in response to the presence of nutrients in the intestinal lumen.* -Various gastrointestinal hormones can stimulate insulin secretion; however, only two of these hormones appear to promote insulin release under normal physiological conditions. These are: GIP (glucose-dependent insulinotropic polypeptide) GLP-1 (glucagon-like peptide-1).

Relationship of Insulin and Glucagon Secretion to Blood Glucose Level (Graph)

This graph shows the relationship between plasma glucose levels and secretory rates for insulin and glucagon. -Note that at a plasma glucose *concentration of around 80 mg/dl* there are relatively LOW levels of both hormones. -As plasma glucose concentration increases insulin secretion increases. -As plasma glucose concentration decreases glucagon secretion increases.