Pharmacology Lecture 22

Front 1

What is the most important fuel for the brain?

Back 1

glucose

Front 2

What pathways are in place to ensure sufficient glucose to the brain?

Back 2

Complex regulatory pathways

Front 3

Brain glucose uptake occurs at the same rate during what 2 periods?

Back 3

absorptive and post-absorptive periods

Front 4

Glucose is not altered by what type of diabetes?

Back 4

type 2

Front 5

Insulin is among the best studied of ___ hormones

Back 5

polypeptide

Front 6

Insulin was the first protein for which the complete ___ sequence was determined?

Back 6

amino aid sequence

Front 7

What was the first hormone to be molecularly cloned?

Back 7

Insulin

Front 8

Insulin is released from what cells?

Back 8

pancreatic β cells

Front 9

Insulin is released from pancreatic β cells in response to what?

Back 9

response to myriad stimuli including elevated concentrations of blood glucose

Front 10

providing hormone replacement (when deficient) or agents that enhance hormone action (when resistance occurs) is a common strategy for what?

Back 10

hyperglycemia

Front 11

In case of insulin, hormone replacement therapy is fairly sophisticated yet complications still exist. What is an example of this?

Back 11

Islet transplantation (It is an experimental treatment for type 1 diabetes mellitus)

Front 12

Over-production of insulin is usually associated with what?

Back 12

insulin resistance or pre-diabetes, insulin secreting tumors (insulinoma) are rare but do exist

Front 13

Earliest known record of the diabetes disease mentioned when?

Back 13

3rd Dynasty Egyptian papyrus; mentions polyuria as symptom (1552 BC)

Front 14

What was diabetes described as in (Arateus, 1st Century AD)?

Back 14

‘the melting down of flesh and limbs into urine’

Front 15

Insulin, the miracle cure treated Leonard Thompson in what year?

Back 15

1922

Front 16

Who discovered insulin?

Back 16

(Banting and McLeod)

Front 17

How many people world wide have diabetes?

Back 17

285 million people

Front 18

In 2005 how many people died from diabetes?

Back 18

1.1 million

Front 19

Almost 80% of diabetes deaths occur in income based countries?

Back 19

low- and middle-income

Front 20

Almost half of diabetes deaths occur in people under the age of what?

Back 20

70

Front 21

55% of diabetes deaths are in men or women?

Back 21

women

Front 22

WHO projects that diabetes deaths will double between when?

Back 22

2005 and 2030.

Front 23

Number of Americans with Diabetes Projected to double or triple by when?

Back 23

double or triple by 2050

Front 24

What activities can prevent or delay the onset of diabetes.

Back 24

Healthy diet,
regular physical activity,
maintaining a normal body weight and avoiding tobacco use can

Front 25

Insulin resistance/Metabolic syndrome is most often associated with what?

Back 25

obesity

Front 26

Insulin resistance/Metabolic syndrome can also occur in what 2 other cases?

Back 26

high stress, immunosuppression

Front 27

Normal pregnancy physiology is a state of _____ insulin resistance

Back 27

maternal

Front 28

normal amounts of insulin are ineffective in lowering plasma glucose concentrations. What disease is this known as?

Back 28

Hyperinsulinemia

Front 29

Hyperinsulinemia has impacts on what?

Back 29

multiple tissues/organs

Front 30

Metabolic syndrome increases risk of developing what 2 diseases?

Back 30

diabetes and cardiovascular disease

Front 31

Insulin is synthesized and secreted from β cells in where?

Back 31

the islets of Langerhans in the endocrine pancreas

Front 32

The islet of Langerhans has 4 cell types which are what?

Back 32

α (glucagon)
Β (insulin)
Δ (somatostatin)
F (pancreatic polypeptide)

Front 33

Insulin is synthesized as what? How many amino acids is it composed of?

Back 33

as pre-proinsulin (110 amino acids)

Front 34

What kind of peptide is cleaved during transport through rough ER to yield pro-insulin?

Back 34

24 amino acid N-terminal signal peptide

Front 35

What 3 other events yield insulin?

Back 35

Protein folding,
di-sulfide bond formation and
further cleavage events

Front 36

What subunits are in chains of insulin insulin with 1 intra-subunit and 2 inter-subunit disulfide bonds?

Back 36

α (21 amino acids) and β (30 amino acids)

Front 37

Insulin is member of family of related peptides called what?

Back 37

IGFs

Front 38

IGFs (IGF1 and 2) are produced in many cells and mediate effects of what?

Back 38

growth hormone and other factors

Front 39

Insulin and IGF receptors are also related and insulin can bind to IGF receptors with what kind of affinity?

Back 39

LOW affinity

Front 40

Insulin secretion is what kind of phase?

Back 40

bi-phasic

Front 41

Insulin secretion is stimulated when?

Back 41

when β cells sense high glucose [ ]

Front 42

How are B-cells excited? What does this regulate?

Back 42

electrically excitable, and this regulates insulin secretion

Front 43

Β-cells are electrically excitable, and this regulates insulin secretion. Ion channels, pumps and transporters combine to regulate what 2 components?

Back 43

intracellular Ca2+ and membrane potential

Front 44

What channels set the resting membrane potential?

Back 44

KATP channels

Front 45

Besides glucose, what are 5 other stimulatory factors?

Back 45

1)Dietary amino acids (ALA, GLY, ARG)
2)Acetylcholine (vagus nerve)
3)Gastrointestinal hormones released from enteroendocrine cells of intestinal mucosa
4)GIP (glucose-dependent insulinotropic peptide)
5) Fatty acids

Front 46

Glucose-stimulated insulin secretion

Step 1) Glucose is taken up by what cells? Via what?

Back 46

pancreatic β cells via GLUT2 (glucose transporter)

Front 47

Glucose-stimulated insulin secretion

Step 2) Glucose is than ____ by ___

Back 47

phosphorylated by glucokinase → glucose “sensor”

Front 48

Glucose-stimulated insulin secretion

Step 3) Glucose is further ____ via ___ ____? What does this result in?

Back 48

metabolized via mitochondrial respiration → ATP generation

Front 49

Glucose-stimulated insulin secretion

Step 4) ↑ [ATP] results in what 4 factors?

Back 49

→ block of K+ channels
→ membrane depolarization
→ influx of Ca2+
→ pulsatile insulin exocytosis (secretion)

Front 50

Glucose-stimulated insulin secretion

Step 5) ___ ____ > stimulus for insulin secretion vs. IV due to stimulatory effects of ___ hormones

Back 50

Oral glucose >

GI hormones

Front 51

Biphasic insulin secretion in response to high glucose concentrations

Back 51

Front 52

Draw a graph demonstrating release of insulin that occurs in respone to an IV glucose load in normal patients and diabetic patients.

Back 52

Front 53

Insulin in the liver inhibits what kind of production? Stimulates up take of what?

Back 53

hepatic glucose production (decreases gluconeogenesisand glycogenolysis)

Hepatic glucose

Front 54

Insulin in the muscle stimulates uptake of what? It inhibits flow of ____ precursors to the liver?

Back 54

Glucose uptake

Flow of gluconeogenic precursors

Front 55

Insulin in adipose tissue stimulates the uptake of what?
Inhibits the flow of what precursor to liver?
What does it reduce?

Back 55

glucose uptake (amount is small compared to the muscle)

Gluconeogenic precursor to liver (glycerol)

Reduces energy substrate for hepatic glucogenesis (nonesterfied fatty acids)

Front 56

Glucagon:______-____hormone to insulin

Back 56

Counter-regulatory

Front 57

Glucagon is what kind of chain?

Back 57

29 aa single chain polypeptide

Front 58

Glucagon is synthesized from what?

Back 58

pre-pro glucagon (180 aa)

Front 59

What cells in islets of Langerhans are there?

Back 59

alpha

Front 60

Glucagon is an agonist for what?

Back 60

GPCR that signals via Gs

Front 61

Glucagon secretion is regulated by what 4 factors?

Back 61

dietary glucose,
insulin,
amino acids
fatty acids

Front 62

Glucagon in the liver increases what 2 components?

Back 62

gluconeogenesis and glycogenolysis

Front 63

Glucagon in adipose tissue increases what?

Back 63

↑ lipolysis (hydrolysis of lipids)

Front 64

Glucagon in the GI tract results in what?

Back 64

relaxation of smooth muscle

Front 65

Glucagon in the heart increases what?

Back 65

force of contraction

Front 66

Signaling pathways for insulin culminate in regulation of what 4 components?

Back 66

Gene expression
Glucose uptake,
glycogen synthesis
lipogenesis—”metabolic effects”

Front 67

Insulin signaling pathways diverge where?

Back 67

at IRS-1

Front 68

Proteins associate with P-TYR residues via what domains?

Back 68

SH-2 domains

Front 69

What signaling events are involved in “metabolic” signaling by insulin?

Back 69

PI-3Kinase signaling

Front 70

Insulin signaling Part 1: Regulation of gene expression via MAP kinase pathway

Step 1: Insulin receptor binds what? What does it undergo? Where does it undergo this?

Back 70

Insulin receptor binds insulin
Undergoes autophosphorylation
On its carboxyl-terminal Tyr residues

Front 71

Insulin signaling Part 1: Regulation of gene expression via MAP kinase pathway

Step 2) Insulin receptor does what? What does it do this to? Where is that components located?

Back 71

Insulin receptor phorylates IRS-1 on its Tyr residues

Front 72

Insulin signaling Part 1: Regulation of gene expression via MAP kinase pathway

Step 3) What binds to what? SOS binds to ____ then ___? What does this cause release and binding of?

Back 72

SH2 domain of Grb2 binds to )-Tyr of IRS-1.
Sos binds to Grb2, then to Ras causing GDP release and GTP binding to Ras

Front 73

Insulin signaling Part 1: Regulation of gene expression via MAP kinase pathway

Step 4) What binds and whats is activated as a result?

Back 73

Activated Ras binds and activates Raf-1

Front 74

Insulin signaling Part 1: Regulation of gene expression via MAP kinase pathway

Step 5) What phosphorylates on what? What is then activated? What then phosphorylates what? What results in this?

Back 74

Raf-1 phosphorylates MEK on two Ser resides activating it.
MEK phosphorylates ERK on a THR and a TYR residue activating it

Front 75

Insulin signaling Part 1: Regulation of gene expression via MAP kinase pathway

Step 6) What moves into the nucleus? What does it phosphorylate? What results in this?

Back 75

ERK moves into the nucleus
and phosphorylates nuclear transcription factors such as ELK1, activating them

Front 76

Insulin signaling Part 1: Regulation of gene expression via MAP kinase pathway

Step 7) What joins what? To stimulate what? And translation of what? Needed for what?

Back 76

Phosphorylated ELK1 joins SRF
to stimulate the transcription
and translation of a set of genes needed for cell division.

Front 77

Insulin activation of phosphodiesterase causes break-down of what?

Back 77

cAMP

Front 78

Regulation of hepatic glucose production (gluconeogenesis):

Insulin activation of phosphodiesterase causes break-down of cAMP → oppose effects of _____ to activate ___ ___ _

Back 78

PKA to activate phosphorylase kinase B (via phosphorylation)

Front 79

Regulation of hepatic glucose production (gluconeogenesis):

Insulin indirectly activates

Back 79

PP-1

Front 80

PP-1 does what to glycogen phosphorylase?

Back 80

de-phosphorylates

Front 81

Hepatic vs. central effects of insulin on regulation of hepatic glucose production: Direct effects of insulin on HGP have been observed in what 2 models?

Back 81

vitro and with animal models

Front 82

What regulates HGP and is required for direct effect?

Back 82

Hypothalamic insulin signaling via PI3Kinase

Front 83

PI3K inhibitors administered ICV block what?

Back 83

insulin regulation of HGO

Front 84

Insulin receptor is what kind of receptor?

Back 84

receptor tyrosine kinase (RTK

Front 85

IR is a receptor tyrosine kinase (RTK) which regulates what?

Back 85

regulates gene expression and metabolic pathways

Front 86

IR is a receptor tyrosine kinase (RTK) which regulates gene expression and metabolic pathways by what kind of signaling?

Back 86

complex signaling events emanating from phosphorylation of IRS-1

Front 87

IR is a prototype for other RTKs including what 2 receptors?

Back 87

EGF and PDGF receptors

Front 88

The binding of adapter proteins such as GRB2 to P-Tyr residues (via SH2 domains) represents what kind of important mechanism that promotes what?

Back 88

for promoting protein-protein interactions initiated by RTKs

Front 89

Dysregulation of insulin signaling pathways is one of the hallmarks of what kind of diabetes?

Back 89

Type 2

Front 90

What Causes of Hyperglycemia in NIDDM?

Back 90

Increased glucose production in liver

Receptor + post receptor defect in Peripheral tissues

Impaired insulin secretion on Pancreas

Front 91

Activation of glycogen synthase by insulin

Step 1) What happens to IRS-1? What does it activate? How does it activate it? What is than converted?

Back 91

IRS-1, phosphorylated by the insulin receptor
activates PI-3k by binding to its SH2 domain
PI-3K converts PIP2 to PIP3

Front 92

Activation of glycogen synthase by insulin

Step 2) PKB bound to ___ is ____ by ___? This results in in what?

Back 92

PKB bound to PIP3 is phosphorylated by PDK1.
Thus activated , PKB phosphorylates GSK3 on a SER residue,
inactivating it

Front 93

Activation of glycogen synthase by insulin.

Step 3) What can't GSK3 do? What remains active?

Back 93

GSK3 inactivated by phosphorylation cannot convert glycogen synthase (GS) to its inactive form by phosphorylation, so GS remains active

Front 94

Activation of glycogen synthase by insulin.

Step 4) Synthesis ____ from ___ is accelerated?

Back 94

synthesis of glycogen from glucose is accelerated

Front 95

Activation of glycogen synthase by insulin.

Step 5) PKB stimulates what? From where to where? What does this increase?

Back 95

PKb stimulates movement of glucose transporter GLUT4
from internal membrane vesicles to the plasma membrane
increasing the uptake of glucose

Front 96

During Activation of glycogen synthase by insulin, Transmission of the signal is mediated by what 2 Kinases?

Back 96

PI-3 kinase (PI-3K) and protein kinase B (PKB).

Front 97

During the Epinephrine cascade. Epinephrine triggers a series of reactions in what? What does this result in?

Back 97

hepatocytes in which catalysts activate catalysts, resulting in great amplification of the signal.

Front 98

Binding of a small number of molecules of epinephrine to specific β-adrenergic receptors on the cell surface activates what?

Back 98

adenylyl cyclase

Front 99

Cross talk between the insulin receptor and the β2-adrenergic receptor (or other GPCR).

When INS-R is activated by insulin binding, its Tyr kinase directly phosphorylates what 2 components?

Back 99

the β2-adrenergic receptor (right side) on two Tyr residues (Tyr350 and Tyr364) near its carboxyl terminus

and indirectly (through activation of protein kinase B (PKB)) causes phosphorylation of two Ser residues in the same region

Front 100

Cross talk between the insulin receptor and the β2-adrenergic receptor (or other GPCR).

The effect of these phosphorylations is internalization of the ___ receptor? Reducing the respons to the ___ ___?

Back 100

adrenergic receptor,

the adrenergic stimulus

Front 101

Cross talk between the insulin receptor and the β2-adrenergic receptor (or other GPCR).

Alternatively (left side), INS-R–catalyzed phosphorylation of a GPCR (an adrenergic or other receptor) on a carboxylterminal Tyr creates the point of what? What serves as the adapater protein?

Back 101

nucleation for activating the MAPK cascade

with Grb2 serving as the adaptor protein

Front 102

Elevated fasting plasma glucose concentrations are a hallmark of what?

Back 102

T2DM

Front 103

During the night (basal/fasting conditions) the liver produces glucose to support the needs of the brain. In T2DM the ↑ in basal HGO closely correlates with what?

Back 103

fasting hyperglycemia

Front 104

Following glucose ingestion, insulin is secreted into the ___ ____ and carried to the ___? What is suppressed?

Back 104

portal vein and carried to the liver, where it suppresses hepatic glucose output.

Front 105

If the liver is insulin-resistant, it will continue to produce what?

Back 105

glucose →marked hyperglycemia

Front 106

Hyperglycemia is also a potent inhibitor of what?

Back 106

HGO

Front 107

the livers of T2DM patients are also markedly _____-_____

Back 107

glucose-resistant

Front 108

In T2DM, dysregulation of key regulatory enzymes involved ___ and ___ appear to be part of the underlying mechanism

Back 108

gluconeogenesis and glycolysis

Front 109

What may also play a major regulatory role?

Back 109

Central insulin resistance

Front 110

Effect of diabetes on life expectancy vs non diabetics:

Type 1
Type 2

Back 110

Type 1 on average ↓ 20 yrs
Type 2 on average ↓ 30-50% vs. non diabetics

Front 111

What 3 factors can greatly improve outcomes for diabetic patients?

Back 111

Early diagnosis, careful glucose monitoring and control

Front 112

What is a Critical biomarker for glucose control?

Back 112

Glycosylated Hemoglobin (HbA1c):

Front 113

What another factor tat is important in management of diabetes? ( aside from healthy living)

Back 113

A biomarker of average glucose control over long term

Front 114

A non-enzymatic rxn occurs between ___ and _ __ _ in hemoglobin (hb)?

Back 114

glucose and 1° amino groups

Front 115

Concentrations of HbA1c in blood is directly related to what?

Back 115

to blood glucose concentrations over the life cycle of the RBC (120 days)