06 - Insulin and Glucagon

hormonal regulation of fuel

1800 calories used per day at rest, with normal requirement being 2500 calories per day

• carbohydrates is major dietary source

• fat is secondary source

• protein is important as building material, very expensive as fuel

energy balance

• source of fuels → diet

• broken down into glucose, free fatty acids, ketone bodies

• oxidation of fuels → 60% heat, 40% ATP and energy

  • 60-70% → resting metabolic rate

  • 25-30% → movement

forms of energy storage

• glycogen → small reservoir (<1 day)

  • liver stores and supplies to other tissues by releasing into circulation

  • muscle stores and supplies to itself

• triglyceride → largest reservoir (several weeks)

  • adipose tissue

  • high ATP content due to β-oxidation

• protein → large reservoir (very costly)

  • used only in starvation

digestive phase

glucose is digested in diet and released to skeletal muscle, liver, and adipose tissue

• stored as glycogen and/or triglyceride

• glucose can be released by liver and go back into circulation

• dominant hormone → insulin

fasting phase

energy can be released when needed

• glucose output from liver

• amino acids from skeletal muscle

• free fatty acids from adipose tissue

  • triglyceride from adipose can be released to liver to generate glycerol and then glucose

• dominant hormone → glucagon

essential requirements for glucose

hormones balance flow of glucose into and out of storage

• brain

• red blood cells

• protein (amino acids) → can provide carbohydrate substrate

• kidney → stores glucose in severe stress

hormonal control of nutrients for metabolism

• anabolic → puts into storage

  • increased insulin

• catabolic → take out of storage (counter-regulatory)

  • decreased insulin

  • glucagon

  • epinephrine

  • growth hormone

  • cortisol (permissive)

  • thyroid hormone (permissive)

insulin

dominant regulator of glucose, where increased insulin lowers blood glucose levels

• responds to increases and decreases in substrate availability

• promotes storage of glucose

• loss of insulin promotes release of glucose from storage

glucagon

counter-regulator of insulin, where increased glucagon increases blood glucose levels

• protects against hypoglycemia

• acts almost exclusively on liver

  • acts to break down glycogen in liver

• increases plasma glucose

epinephrine

important in exercise and stress, where increased epinephrine is utilized for energy mobilization

• stimulates metabolic processes to break down glycogen and deliver

  • increases heart rate and cardiac output

• muscle and adipose tissue

• stimulates glycogenolysis

• stimulates lipolysis

growth hormone

increases lean body mass, where it is glucose-sparing

• small effect on regulation

• anabolic protein in muscle → IGF-1

• catabolic → carbohydrates and lipids

• decreases insulin sensitivity in peripheral tissues in prolonged exposure

  • provides alternative fuels during stress

• renal metabolic effects to become glucose producer

  • important during regulation of acidosis and NH₃ production

cortisol 

glucocorticoid essential for life, only living 24 hours without it

• permissive effects with other hormones

  • required for normal metabolism

• stimulate hepatic gluconeogenesis

• promotes protein catabolism

• required for glucagon and epinephrine synergistic effect

thyroid hormone

main effect is permissive, making metabolic processes “work better”

• generally catabolic

hormone interactions

in an experiment → three hormones administered: cortisol, glucagon, epinephrine

• glucagon + epinephrine → sum of effect on blood glucose

• glucagon + epinephrine + cortisol → synergistic effect on blood glucose, raising levels higher than the sum of all three by themselves

exercise plasma glucose and insulin

• as glucose is consumed by body’s metabolic demand, it is immediately put back into circulation → steady-state of plasma glucose

• during exercise, plasma insulin decreases to keep plasma glucose at steady-state

  • relieves inhibition of free fatty acid release

  • fall in hormones may be important

energy needs

body can regulate expenditure of energy, and adapt to meet those changing needs

• rate of fat oxidation not as great as glycogen and not efficient

• can achieve approximately 50% of maximum effort when relying on fat metabolism

• glucose taken during exercise must be moderated → prevent hormonally mediated problems with FFA availability and inappropriate disposition of glucose into tissues not involved in exercise

• muscle fatigue correlates with depleted muscle glycogen

pancreas endocrine and exocrine function

• acinar → exocrine

  • non-endocrine function involved with regulation of GI function

• islets of Langerhans → endocrine function involved with glucose homeostasis

  • ⍺-cell → glucagon

  • β-cell → insulin

  • δ-cell → somatostatin

  • F-cell → pancreatic polypeptide

  • cells are interdispersed within islets of Langerhans, exhibiting paracine cellular communication

forms of circulating insulin

• monomer → active

• dimer → inactive

• hexamer → 3 dimers connected with two zinc ion bridges

insulin synthesis

• preproinsulin

• proinsulin → folded on itself with disulfide bridges

• insulin + C-peptide → enzymes clip off excess of molecule

  • C-peptide is produced every time insulin is made

  • used for marker of endogenous insulin production

insulin secretion

controlled by nutrients, hormones, and nerves

• glucose-triggered secretion of β-cell

  • glucose enters via GLUT-2 (insulin-independent)

  • glucose metabolism increases ATP

  • ATP closes K⁺_ATP channel → cell depolarizes

  • opens voltage-gated Ca²⁺ channels → exocytosis of insulin and C-peptide

• incretin effect (GLP-1, GIP)

  • enhances insulin release when glucose is high in GI tract

  • prevents hyperglycemia

• neural input

  • parasympathetic (Ach) → increase insulin

  • sympathetic (epi, NE) → decrease insulin

biphasic release

• initial burst → pre-formed insulin present in secretory granules

  • loss of this phase is hallmark for type 2 diabetes

• secondary phase → slowly developing, from synthesis and secretion of insulin

  • sustained as long as stimulus present

  • requires protein synthesis

regulation of insulin

blood glucose is the regulator of insulin release

• threshold for release → 50 mg/dL

• half-maximal → 150 mg/dL

• maximum response → 300 mg/dL

• negative feedback of glucose on insulin release

• glucose increase both synthesis and release of insulin

• oral glucose more effective than IV

• stimulator → glucose, amino acids, free fatty acids, glucagon, GLP-1, ACH, β-adrenergic receptor

• inhibitor → somatostatin, ⍺-adrenergic receptor, stress

actions of insulin

lowers blood glucose, fatty acids, and amino acids

• promotes storage forms → glycogen, triglycerides, proteins

• decreases release from storage

• increases K⁺ and PO₄^3- uptake 

insulin effects on skeletal muscle

stimulates glucose uptake

• stimulates glucose transport (GLUT-4) → insulin-independent glucose transport with muscle activity

• stimulates glucose utilization

  • increased metabolic uptake → increased glycogen synthesis, decreased breakdown, decreased gluconeogenesis

  • keeps intracellular glucose low

• increases FFA storage

• increases protein synthesis → amino acid uptake, decreased protein degradation

insulin effects on liver

stimulates glucose uptake

• stimulates glucose transporter (GLUT-2) → insulin-independent glucose transport

• stimulate glucose utilization → decreased glycogenolysis, increased metabolic uptake, decreased gluconeogenesis

  • increased glycogen synthesis

  • keeps intracellular glucose low

• increases FFA storage → decreased ketogenesis 

• increased protein synthesis → amino acid uptake as substrate for gluconeogenesis, decreased protein degradation

insulin effects on adipose tissue

stimulates glucose uptake 

• stimulates glucose transporter (GLUT-4) → insulin-dependent glucose transport

• stimulates glucose utilization → increased metabolic uptake 

  • increased triglyceride synthesis

  • keeps inracellular glucose low

• increased FFA storage → increased glucose uptake

  • increased activity of lipoprotein lipase (LPL)

  • decreased activity of hormone sensitive lipase (HSL)

    • decreased insulin = increased lypolysis

diabetes

• type I → insulin-dependent

  • autoimmune destruction of β-cells

  • treat with insulin replacement

• type II → insulin-independent

  • normal insulin production, defective secretion or receptor resistance

  • treat with oral hypoglycemics → sulfonylureas

  • linked to obesity, inflammation, and decreased adiponectin

  • desensitization due to excessive FFA

acute effects of diabetes mellitus

• hyperglycemia

  • lack of insulin uptake

  • loss of insulin inhibition of catabolism

  • increased glucagon

  • glucose release from liver

  • FFA release from adipose tissue

• glucosuria → exceed T_max in proximal tubule

• polyurea → osmotic diuresis

• hyperlipidemia

• ketonemia and ketonuria

• aminoacidemia

• hyperkalemia

chronic effects of insulin loss

• weight loss → lipoprotein lipase (LPL) not active, loss of inhibition hormone sensitive lipase (HSL)

• shorter life expectancy

• atherosclerotic changes

• cardiovascular lesions → macrovascular disease, accelerated atherogenesis, MI, stoke, large vessel peripheral vascular disease

• microvascular lesions → thickening of capillary basement membranes, diabetic retinopathy

• renal disease

• neuropathy → deterioration of nerves that results in PNS and ANS dysfunction

glucagon

secreted by ⍺-cells to prevent hyoglycemia by increasing hepatic glucose output

• liver is main physiological target organ

• opposite to insulin

• increases gluconeogenesis and decreases glycolysis

  • glycolysis prevented by cAMP-mediated depletion of F2,6P

• increases plasma glucose

FFA and glucose synthesis

FFA release acts as “glucose sparing” effect

• FFA cannot be directly converted to glucose 

  • provide energy in liver to support gluconeogenesis

  • acetyl CoA cannot be converted to pyruvate needed for gluconeogenesis

• FFA stimulates formation of glucose from other sources

  • activates enzymes in gluconeogenic pathway

glucagon action on lipids and proteins

• lipid metabolism 

  • liver is the main target for increase in ketogenesis and inhibition of lipogenesis

  • increases plasma ketones, requiring presence of increased plasma FFA

  • increases lipolysis

  • increases plasma FFA

• protein metabolism → catabolic

  • inhibits protein synthesis

  • increases protein degradation

glucagon non-metabolic actions

• increases secretion of insulin

  • direct paracrine effect, from glucose levels

  • raises plasma glucose levels

• increases cardiac contractions

• relaxes esophageal smooth muscle

glucagon secretion

balances nutrients in response to excess calories with a meal, acting to restore plasma glucose and nutrients

• stimulator → decreased glucose, increased amino acids (arginine), sympathetic activation (epi, NE), GI hormones (CCK, GIP)

• inhibitor → increased glucose, insulin (paracrine), somatostatin, FFA, GLP-1

glucagon synthesis

• biosynthesis of a typical peptide

  • single chain of 29AA and MW 3500

  • half-life of 3-4 minutes

  • prehormone processed in Golgi to make secretory product

• secreted via exocytosis from strorage granules

  • stimulated by fall in plasma glucose and glucose entry into ⍺-cell

    • insulin-dependent glucose entry

    • begins with increased cAMP for increased Ca²⁺

  • maximally inhibited by plasma levels exceeding 200 mg/dL

  • maximally stimulated by glucose levels below 50 mg/dL

  • circulates free in plasma

somatostatin

autocrine hormone made by δ-cells as paracrine inhibitor within pancreas

• inhibits exocrine function of pancreas regulating GI tract

• decreases nutrient absorption

• inhibits digestion and motility

• inhibits endocrine function of insulin and glucagon

coordinated hormonal response

• short sprints

  • during → minimal hormonal involvement

  • after → insulin and glucagon act to replenish glycogen

    • transfer glucose from liver to muscles

• marathons

  • during → utilization of all metabolic regulatory hormones

    • fall in insulin → increased lypolysis

    • glucagon → glucose transfer from liver to muscle

    • GH → increased lipolysis

    • epinephrine → increased lipolysis, glycogen breakdown, and cardiac output

    • cortisol → slow rise with stress

    • thyroid → little response

  • after → insulin and glucagon act to replenish glycogen

    • transfer glucose from liver to muscles

    • increased dietary nutrients