Endocrine

stimulate B-cells to release insulin

• includes metformin
• inhibit gluconeogenesis, increase GLUT4 translocation

• decrease degradation of incretins (hormones that stimulate insulin secretion), doesn't cause weight gain
• SE: pancreatitis

• Occurs @ rate dependent on intracellular [glucose]
• Liver, B-cells: glucokinase (high Km, can serve as glucose sensor-important in B-cells!!; sequestered in nucleus by glucose regulatory protein - glucose stimulates release, F6P stimulates sequestering)
• Muscle: hexokinase (low Km)

• lactate, aa's, glycerol
• pyruvate -pyruvate carboxylase-> OAA -PEPCK-> -Fructose1,6bisphosphatase-> -G6Phosphatase-> glucose

Glycogen -glycogen phosphorylase-> G1P -> G6P

Glucose -> G6P -> G1P -glycogen synthase-> glycogen

• glucagon inhibited -> no hepatic glucose release
• insulin release stimulated -> no hepatic glucose release, uptake of glucose by cells

• liver - glycogen, 24hr supply
• muscle
• - glycogen - not available for brain
• -protein - second largest store, not good
• adipose - fate, largest store

• GLUT2 - liver, B-cells uptake porportional to plasma [glucose], high Km
• GLUT1
• GLUT3 - low Km, allows brain to take up same amt of glucose regardless of plasma concentration

insulin causes glucose transporters to go to the membrane

• Phosphofructokinase (PFK-1): F6P->F1,6P
• Pyruvate kinase (PEP->pyruvate)

• Positive: F2,6P, AMP
• Negative: ATP, citrate, H+
• Side rxn for regulation only: F6P -PFK-2-> F2,6P
• PFK-2 is a bifunctional enzyme!!!

• Positive: F1,6P
• Negative: ATP, alanine
• Glucagon phosphorylates and inactivates

• F6P -> F2,6P
• glucagon increases cAMP, phosphorylation of PFK-2, inhibits glycolysis
• Insulin dephosphorylates PFK-2, stimulates glycolysis

• Heart: EPI increases cAMP, PKA activity, but the PFK-2 isoform is activated by phosphorylation. Stimulates glycolysis.
• Skeletal muscle: bifunctional enz not phosphorylated by PKA. Regulation by intracellular concentration.

• Pyruvate dehydrogenase (PDH)
• inhibited by NADH, ATP, acetylCoA
• Inactivated by phosphorylation
• Ca2+ activates the phosphatase, which activates the enzyme

• controls gluconeogenesis
• controlled by transcription
• decreased by insulin
• increased by fasting, glucagon, gluco/thyro-corticoids

• opposite of PFK-1
• positive: citrate
• negative: AMP, F2,6P

• glycogen storage disease
• G6Phosphatase deficiency

• insulin: dephosphorylation, activates glycogen synthase
• glucagon: phosphorylation, activates glycogen phosphorylase

• glucagon acts thru cAMP, PKA to phosphorylate
• insulin acts thru protein phosphatase, desphosphorylates

• Depend on the liver to release glucose in fasting state
• need G6Phosphatase

• Inhibits it
• May have low blood sugar the next day

• illness
• obesity
• inflammation/cytokines
• sedentary lifestyle
• pregnancy
• cirrhosis
• genetic factors
• Remember: 80% will adapt, not become DM2

• portion cleaved off pro-enzyme to get the active form
• measured because it has a longer half life than insulin
• other tests: - anti-GAD, insulin Abs

• glycogenlysis and gluconeogenesis
• glycogen synthesis is taking place, but not fast enough

• cannot uptake glucose
• ion pumps fail
• K+ loss (whole body)

• Triglycerides are broken down into free FAs, glycerol -> DKA
• Normally restrained by insulin

• Thiazolidinediones
• activation of PPARs
• - insulin resistance decreased
• - leptin levels increase

• 30mil DM2
• 1.5 mil DM1 in the USA, clusters w/atuoimmune disorders

• hyperglycemia
• nephropathy
• retinopathy
• neuropathy - amputations, impotence, hypoglycemia

• coronary artery disease
• cerebrovascular disease
• peripheral vascular disease (amputations)