Chapter 21 - Diabetes and Obesity

glucose uptake where the glucose is converted into glucose-6-phosphate

what does insulin stimulate in the muscle and adipose tissue

the conversion of glucose-6-phosphate to glycogen by activating glycogen synthase and inactivating glycogen phosphorylase

what does insulin stimulate in the liver

activates which inactivates ACC by phosphorylating it → allows fatty acid breakdown into acetyl-CoA

what enzyme does high levels of glucagon activate and lead to

activates phosphatase which activates ACC by dephosphorylating it → prevents breakdown of fatty acids into acetyl-CoA

what enzyme does high levels of insulin activate and lead to

lipoprotein lipase

enzyme that breaks down triacylglycerols in the lipoproteins to smaller fatty acids and monoglycerides that are transported into tissues and burned for fuel or reassembled for storage

glucagon

what do α pancreatic cells secrete

insulin

what do pancreatic β-cells secrete

somatostatin delta

what do pancreatic δ-cells secrete

in the islets of Langerhans

where are the alpha, beta, and delta cells found in the pancreas

• glucose enters β-cells via GLUT2

  • enters glycolysis, [ATP] increases

• ATP binds to ATP-gated K+ channels

  • K+ channels close, depolarize the plasma membrane

• triggers opening of voltage-gated Ca2+ channels

  • Ca2+ in cytosol triggers release of insulin by exocytosis

how do β-cells secrete insulin in response to increasing blood glucose levels

the 24 amino acid long signal sequence targets it into the ER where the storage vesicles form and disulfide bonds form

what target proinsulin into the ER and what forms

Ca2+ activates them → they cleave the C-peptide from proinsulin in the storage vesicles

what activates proteases and what do they cleave in regards to insulin

C-peptide

what do tests of insulin levels measure

• immediately after meal, glucose increases

  • insulin stimulates glycolysis and glycogen synthesis

• 2+ hours post-prandial, blood glucose starts droppings

  • glycogen secreted, liver glycogen releases glucose

• 4 hours post-prandial, more glucagon, more TAG hydrolysis, FA become fuel for muscle and liver

fuel use over 4 hours of normal human metabolism

insufficient production of insulin, usually due to autoimmune destruction of β-cells, usually develops early in life, used to be called insulin-dependent or juvenile diabetes

type 1 diabetes

insulin resistance, usually develops in late adulthood, usually associated with obesity, and cells don’t respond appropriately to insulin

type 2 diabetes

blood sugar

in both forms of diabetes what becomes elevated

excessive urination and thirst

when the body tried to dilute the glucose what physiological responses occur

fat breakdown is accelerated leading to high production of ketone bodies

in type 1 diabetes what breakdown is accelerated and what does it lead to high production of

ketoacids which raise blood [H+] leading to ketoacidosis

what are some of the ketones produced from fat breakdown in type 1 diabetes

• bicarbonate buffering system activation which leads to altered breathing

• breakdown of ketone body acetoacetate produces acetone which is breathed out

• untreated diabetes leads to dramatic weight loss

what does ketoacidosis lead to in diabetes 1 patients

bicarbonate buffering system

neutralize gastric acid and stabilize the intracellular pH in epithelial cells through secretion of bicarbonate ion into the gastric mucosa

126 or higher

what blood glucose level is a warning sign for diabetes

below 50 (in men) or 40

what blood glucose level is a warning sign of various hypoglycemic conditions

after several hours of fasting (normally high after meal)

when is blood glucose level determined in regards to eating

they can be glycosylated, especially at free amino groups

what can occur to proteins due to long-term elevated blood sugar

hemoglobin is abundant, has many exposed amino groups during formation, and entry of glucose into erythrocytes is not regulated → compromises O2 delivery especially in extremities

why is hemoglobin easily glycosylated during long-term elevated blood sugar and what does it lead to

increased risk of cardiovascular disease, renal failure, and damage to small blood vessels and nerves

long-term effects of elevated blood sugar

endocrine organ

what type of organ is adipose tissue

peptide hormones called adipokines

what does adipose tissue release

carry information about fuel stores to the brain

what do adipokines do

adipokines

what type of hormone are leptin and adiponectin

it’s an appetite suppressant sent from adipose tissue to brain

what is leptin and where is it sent from and to

obese mice → once injected they lost weight and temperature returned to normal

what was leptin first identified in and what happened when it was injected

OB gene (homozygous)

what gene were the obese mice a result of

obese and diabetic

what were Db/db mice

leptin receptor in mice (expressed mostly in hypothalamus)

what does DB gene encode in mice

just above the brain stem and links endocrine system to neurons

where is hypothalamus located and what does it link

acts in the hypothalamus and suppresses appetite

what does α-MSH do

increases appetite

what does neuropeptide Y (NPY) do

activates → α-MSH

inactivates → NPY

what does leptin activate and inactivate

NPY

what does insulin inactivate

NPY

what does PYY and GLP-1 inactivate

NPY

what doe grehlin activate

anorexigenic (appetite-suppressing) hormones

what type of hormones does leptin stimulate production of

sympathetic NS

what system does leptin stimulate

gene expression

leptin triggers a cascade that regulated what

orexigenic (appetite-stimulating) hormone

what type of hormone is NPY

• sends signals to eat

• levels rise in starvation

• levels rise in ob/ob and db/db mice

NPY cause to rise/signal

it’s an anorexigenic (appetite-suppressing) hormone

what type of hormone is α-MSH

melanin by melanocytes in skin and hair

acting through melanocortin 1, what does α-MSH stimulate production and release of

it dimerizes

what occurs to leptin receptor when leptin binds

JAK (Janus Kinase)

what enzyme phosphorylates 2 Tyr in the receptor dimer

STAT3, STAT5, STAT6 (Signal Transducers and Activators of Transcription)

what does leptin receptor become docking for after dimerization

they dimerize, move to nucleus, and stimulate transcription

what occurs after STATs are phosphorylated

gene for precursor to the α-MSH

what do STATs increase transcription of

orexigenic neurons

what type of neurons have insulin receptors that insulin can bind to

• inhibits release of appetite-stimulating NPY

• stimulated appetite-suppressing α-MSH

what does insulin binding to orexigenic neurons do

liver and muscle

what does leptin make more sensitive to insulin

• insulin receptor has intrinsic Tyr kinase activity

• leptin receptor, when occupied by leptin, is phosphorylated by a soluble Tyr kinase (JAK)

• they phosphorylate IRS-2

• IRS-2 activates PI3K which has downstream consequences that include inhibition of food intake

proposed mechanism for cross talk between receptors for insulin and leptin

makes more insulin

with type 2 diabetes, how does the body initially respond

• insulin resistance

• abdominal obesity

• high TAGs

• low HDL

• high BP

• elevated blood glucose

type 2 diabetes and metabolic syndrome symptoms