case 9: diabetes type 2 mellitus Flashcards
1
Q
The Endocrine Pancreas
A
- Islets of Langerhans
– β cells - 60%, secrete insulin & amylin
– α cells - 25%, secrete glucagon
– δ cells - 10%, somatostatin
– F cells – pancreatic polypeptide - The insulin/IGF/relaxin superfamily
– Insulin – metabolism, growth
– IGF-I & IGF-II – growth, differentiation
– Relaxin – parturition
– Insulin-like protein – reproduction
– Others - Close proximity of islet cells
– Cell-cell communication
– Insulin inhibits glucagon secretion
– Somatostatin inhibits insulin & glucagon secretion
2
Q
About Amylin
A
- Amylin (islet amyloid polypeptide,
IAPP), a 37-residue peptide
hormone - Co-secreted with insulin from the
pancreatic β-cells in the ratio of
~100:1 (insulin:amylin) - Amylin plays a role in glycemic
regulation by
– Slowing gastric emptying
– Promoting satiety
– -> Preventing post-prandial spikes
in blood glucose levels
β cells produce a lot of insulin to control or lower glucose level
3
Q
Insulin – Synthesis
A
- Preproinsulin – insulin mRNA is translated as preproinsulin
- Proinsulin – removal of signal peptide during insertion into ER
- Insulin – in ER, proinsulin exposed endopeptidases to excise the C
peptide -> the mature form of insulin
– Secretion of insulin & C peptide in equi-molar. Important clinical
indication. Why? patients are injected with recombinant insulin clinically is difficult to differentiate from insulin secreted by patient. measure c peptide from blood to know how much insulin that is self producing insulin
A- & B-chains must be
linked by disulfide bonds
to be bioactive
4
Q
Excitable Cells
A
- Excitable cells – electrically
excitable to change Vm from
resting MP (RMP, or Vr) to
action potential
– e.g neurons, muscle cells
(skeletal, cardiac, & smooth),
and pancreatic β cells
– RMP ~ -60 - -80 mV - The fluctuation of Vm is due to
changes in membrane’s
permeability to specific ions
5
Q
Insulin – Control of Secretion
A
- increase Blood glucose -> entry of
glucose into β cells through
GLUT-2 (facilitated diffusion), more ATP/ADP production - Glycolysis (glucose -> G-6-P
-> pyruvate), Kreb’s cycle
(pyruvate -> acetyl CoA),
oxidative phosphorylation -> increase
ATP -> increase ATP/ADP ratio - ATP binds to ATP-sensitive
K+ channel -> close K+
channel -> no efflux of K+ -> increase
membrane potential - Depolarization -> open
voltage-dependent Ca2+
channel -> Ca2+ influx ->
insulin secretion
6
Q
Oral Hypoglycemic Drugs
A
- At rest, ADP binds to ATP-sensitive K+ channel -> K+ channel remains open
- Glucose-stimulated state -> increase ATP -> ATP-sensitive K+ channel closed
- Oral hypoglycemic drugs (sulfonylureas, meglitinides) -> close K+ channels
-> depolarization -> … -> increase insulin secretion -> hypoglycemic effects
7
Q
Insulin – Actions
A
- When blood glucose level is
high -> increase insulin secretion ->
insulin-R’ activation at target
tissues -> signal pathway
– 1. -> increase insertion of glucose
transporters 4 (recruitment
of GLUT4) to cell
membrane of insulin-
sensitive cells (cardiac,
skeletal muscles &
adipocytes)
– GLUT4 – determinant of
glucose homeostasis
– 2. Anabolic effects (growth,
metabolism of
carbohydrates, lipids &
proteins) - T1/2 = 6 min in plasma, mostly
gone in 10-15 min
– Degraded by proteases in
kidneys, liver & muscle
the more GLUT4 inserted onto membrane of cells the easier it is for glucose to enter into target cell, decreasing blood glucose level
8
Q
Insulin Stimulates Insertion of GLUT4
A
- GLUT4 is rapidly translocated to the cell surface in response to insulin, exercise (more GLUT4 inserted onto membrane) or hypoxia
when insulin action disappear, GLUT 4 packed into cytosol
9
Q
Insulin – Effects by Time
A
- Fast effects (seconds to min)
– Glucose uptake (insulin -> increase GLUT-4 insertion onto membrane) - Mainly in muscle (skeletal & cardiac) cells , adipose cells
- Facilitates glucose uptake in 80% of body tissues (exceptions – brain neurons, pancreatic β cells, intestinal mucosa, kidney
tubules, red blood cells) - GLUT-4 separated from cell membrane 3-5 min after insulin degradation
– Insulin -> increase membrane permeability to amino acids, K+ & PO42- into cells - Intermediate effects (10-15 min)
– Changes in cellular enzyme activities by phosphorylation - Slow effects (hrs to days) – formation of new proteins (growth effects)
10
Q
Insulin – Metabolic Functions
A
- Insulin is the hormone of abundance -> purely anabolic functions
- Carbohydrate metabolism
– increase Cellular uptake of glucose -> decrease blood glucose
– increase Glycogenesis – increase entry of glucose into liver & skeletal muscle cells
(15x faster with insulin) -> increase glycogen storage (5% of liver mass) - Lipid metabolism – increase lipogenesis, decrease lipolysis by decrease hormone-sensitive lipase on hydrolysis of triglycerides
- Protein metabolism – increase cellular uptake of amino acids -> increase proteins
synthesis (anabolic), decrease protein degradation - Insulin on liver
– increase Glycogenesis by increase glucokinase & glycogen synthase
– decrease Glycogenolysis by decrease glycogen phosphorylase
– increase Conversion of glucose into fatty acids (after glycogen storage
mechanisms are saturated) -> increase VLDL -> transport to adipose cells
– decrease Gluconeogenesis
11
Q
Insulin – Other Functions
A
- The growth-promoting activities of insulin
– Insulin is a member of a family of structurally and functionally
similar molecules (IGF-1, IGF-2 & relaxin)
– The family members have growth-promoting activities
(modulates transcription, stimulates protein translocation, cell
growth, DNA synthesis and cell replication) - Insulin and endothelial cell functions
– Insulin exerts vasodilator action in the vascular endothelium as
a result of increased nitric oxide (NO) production - Uptake of amino acids and potassium into the cells that
cannot take place in the absence of insulin - Manage excretion of sodium and fluid volume in the urine
- Enhance learning and memory of the brain functions
12
Q
Regulation of Insulin Secretion
A
- increase Blood glucose level -> increase insulin secretion (most potent)
- Amino acids – -> increase insulin secretion (arginine & lysine most potent)
- Effect of autonomic nerves
– Sympathetic – “fight or flight”, stress hyperglycemia -> decrease insulin
secretion
– Parasympathetic– “rest and repair” (anabolic) -> increase insulin secretion - Effect of incretin hormones (hormones -> increase insulin secretion)
– Glucose in gut -> increase GIP (glucose-dep. insulinotropic peptide, or gastric
inhibitory peptide) secretion -> increase insulin secretion, decrease gastric motility
– Cholecystokinin (CCK), gastrin, secretin -> increase insulin secretion
– increase Blood glucose, amino acids, fatty acids -> increase GLP-1 (glucagon-like
protein) -> major increase insulin (potent antihyperglycemic)
13
Q
GLP-1 and Insulin Release
A
- GLP-1 – glucagon-like peptide-1 from proglucagon gene
- Secreted by intestinal L cells as a gut hormone
- Potent antihyperglycemic – increase insulin & decrease glucagon
- Short half-life (2 min), inactivated by DPP-4 enzyme
14
Q
Effects of Glucagon
A
- Effects of glucagon – catabolic
– increase Glycogenolysis
– increase Lipolysis
– increase Protein degradation
– increase Gluconeogenesis – formation of glc from non-carbohydrate
sources
– increase Ketogenesis – formation of ketone bodies
– decrease Storage of triglycerides in the liver
15
Q
Questions
A
- Why store glycogen rather than just glucose?
– Osmotic pressure problem (remember glucose trapping?) so glucose can continue to enter from blood circulation into liver - Why store glycogen rather than just fat?
– Metabolism of fat requires oxygen (could be a problem for muscle)
– Trouble making glucose (for brain) from fat (fat cannot be reconverted to glucose)
– Fat is stored, but it cannot be mobilized as quickly as glycogen (fewer steps to convert to glucose) - Glycogenenesis – requires glycogen synthase (regulatory enzyme, insulin-sensitive)
16
Q
Pathogenesis of Type 2 DM
A
- a.k.a. Non-insulin-dependent diabetes (NIDDM). Why? B cells can still secrete insulin
- 2 Metabolic defects
– Insulin resistance – decrease ability of peripheral tissue’s response
– (Later stage) β-cell dysfunction – impaired insulin secretion - Environmental factors play a large role (lifestyle, diet etc.)
17
Q
Development of Type 2 DM
A
- Insulin secretion rises as insulin sensitivity falls when an individual goes
from a state of exercise training/being physically active (point A) to
inactivity/sedentary (point B). - When insulin secretion fails to compensate for a fall in insulin sensitivity,
the person will progress to IGT (Point C). If no changes are made at this
point, the disease will progress from point C to Point D (type 2DM). - NGT – normal glucose
tolerance - IGT (impaired glucose
tolerance) – a
transition phase
between normal GT
and DM
18
Q
Prediabetes – IFG and IGT
A
- Prediabetes – a term used to distinguish people who are at
increased risk of developing diabetes. - People with prediabetes have impaired fasting glucose (IFG)
or impaired glucose tolerance (IGT), or both.
– IFG – the fasting blood sugar level is elevated (100 to 125
mg/dL)
– IGT is a condition in which the blood sugar level is elevated
(140 to 199 mg/dL after a 2-hour OGTT), but is not high
enough to be classified as diabetes
19
Q
From Prediabetes to Type 2 DM
A
- Progression to diabetes from prediabetes is not inevitable.
Weight loss and increased physical activity may prevent or
delay diabetes and may return blood glucose levels to
normal
– People with insulin-resistant does not necessarily have type 2
DM unless there is some impairment of insulin secretion - The more a person is insulin-resistant, the less impairment is
required to induce. - Over the years 10-20, there is progressive decline of insulin
secretion, but does not decline to 0 level
20
Q
Obesity
A
- Definition – having an excessive amount of body fat
- Obesity has become an epidemic in USA
- Defined by body mass index (BMI)
- Metric system – BMI = w (kg) / h (m2)
- w = weight in kilograms; h = height in meters
- BMI classification
- BMI < 18.5 – underweight
- BMI between 18.5 and 25 – healthy weight
- BMI between 25 and 29.9 – overweight
- Obesity defined as BMI > 30
21
Q
Complications of Diabetes – Acute
A
- Acute complications due to hyperglycemia
- Hyperosmolar hyperglycemic state (HHS)
– Hyperglycemia -> severe dehydration -> increase in osmolality -> higher
risk of complications -> hyperosmolar non-ketotic
– The presence of some insulin in type 2 DM -> inhibit hormone-
sensitive lipase -> no ketone formation, similar to but different
from DKA - Effect of insulin -> increase uptake of K+ by cells
– In the absence of insulin action -> increase K+ exit from cells into plasma
-> increase plasma [K+] -> hyperkalemia
– The consequences hyperkalemia – changes in cell membrane
potential (depolarization) -> cardiac arrhythmia
22
Q
Complications of Diabetes – Chronic
A
- Chronic complications due to vascular damage
- Macrovascular complications
– Large and medium vessel disease due to accelerated
atherosclerosis -> coronary artery disease, peripheral vascular
disease, stroke
– Main cause of mortality - Microvascular complications
– Capillary dysfunction in target organs -> neuropathy,
nephropathy, retinopathy
– Significant source disability and decrease in quality of life
23
Q
Proposed Mechanisms
A
- What makes DM people sick and die?
– DM patients do not die from hyperglycemia directly, but die from heart attack, stroke, atherosclerosis, renal damage, eye damage - Proposed mechanisms of vascular damage from hyperglycemia
– Aldose reductase pathway and reactive oxygen species
– Advanced glycation end products theory
– Protein kinase theory
24
Q
The Polyol Pathway
A
- In euglycemic state,
– Glucose -> ATP production (glycolysis & Krebs cycle)
– Glucose -> hexose monophosphate shunt
(pentose phosphate pathway) to make NADPH & ribose - In hyperglycemic state, ~30%
of glucose -> the polyol pathway
– increase Glucose -> increase aldose
reductase activity -> increase sorbitol
-> increase fructose in cells
– NADPH -> NADP+
25
Q
Reactive Oxygen Species
A
- Free radicals – chemical compounds with odd number of electrons, extremely unstable and reactive
– Tend to acquire an electron from other substance -> “attack” proteins, lipids, carbohydrates or DNA in its vicinity
– The “attacked” molecules become unstable -> chain reaction -> disruption of a living cell -> cell mutation or death -> tissue damage - also kill bacteria
- Reactive oxygen species (ROS) are reactive chemical
species containing oxygen, many of them are free radicals
26
Q
Antioxidants as Defenses against ROS
A
- The ‘glutathione system’ – present in every animal cells, exert antioxidant effects
– Glutathione – a tripeptide (glutamic acid-cysteine-glycine)
– Glutathione reductase and peroxidase - Oxidized glutathione (G-S-S-G) and reduced glutathione (G-SH)
- NADPH indirectly provides electrons for the reduction of H2O2, thus decrease the reactive oxygen species
27
Q
NADPH, ROS and DM
A
- The glucose uptake in cells of retina, kidney and nervous tissues are insulin-independent
- increase Blood glucose -> depletion of NADPH by aldose reductase -> inability to regenerate reduced glutathione (G-SH) -> increase oxidative stress reactions -> cell death
- increase [Sorbitol] -> decrease nitric oxide -> vasoconstriction in neuronal tissue and eventually ischemia
28
Q
Diabetic Cataract
A
- Sorbitol does not diffuse through cell membranes easily
- -> increase accumulation of sorbitol -> increase osmotic pressure
- -> increase water retention -> cell swelling -> damage -> cataract formation
too much glucose
29
Q
NADH, ROS and DM
A
- Glycolysis requires NAD+
– Glycolysis occurs in the
cytoplasm and it generates
NADH (gains 1 e-) from NAD+
– If NAD+ is not regenerated,
glycolysis will halt
– With O2 in mitochondria NADH
-> NAD+
– If production of NADH exceeds
mitochondrial oxidation of NADH
-> cytoplasmic NAD+ will
become depleted
– The cell regenerate NAD+ from
NADH by making lactate from
pyruvate (anaerobic respiration)
– Cori cycle… - In mitochondria electrons (e-) donated from NADH & FADH2 pass through
the electron transport chain and ultimately reduce O2 to form H2O - ROS are produced from e- leakage to form superoxide (O2.-)
- Normally O2.- -> H2O2 by superoxide dismutase (SOD); H2O2 -> H2O by
glutathione peroxidase (GPX) - In DM patients, the polyol pathway -> increase NADH -> NADH/NAD+ redox
imbalance (more e- leakage) -> increase ROS -> oxidative stress
NAD+ needed to continue glycolysis in cell
refer to pic
30
Q
DM and Free Radicals
A
- Question – which cellular organelle is the major source of
reactive oxygen species, why? - Answer – mitochondria, due to its central role in the energetic metabolism to generate ATP through oxidative phosphorylation (oxidation of electron donors NADH &
FADH2) & electron transfer chain (complex proteins I-V)
31
Q
DM and Free Radicals
A
- Question – NADH & FADH2 are generated during glycolysis/TCA cycle. What is the effect of hyperglycemia on the production of NADH & FADH2?
- Answer – hyperglycemia would increase the cellular glycolytic reactions, thus increase the production of NADH & FADH2 (excess of electron donors)
32
Q
DM and Free Radicals
A
- Question – What is the consequence of an electron donor excess?
- Answer – an excess of electron donors would result in
increased electron delivery and subsequently leading to
more electron leaking.
33
Q
DM and Free Radicals
A
- Question – What is the consequence of an increased
electron leaking? - Answer – an increased electron leaking in the mitochondria
would lead to more anion superoxide generation, thus the
oxidative stress
34
Q
DM and Free Radicals
A
- Question – Does hyperglycemia cause increased free
radical production (and oxidative stress) in other intracellular
structures? - Answer – Yes, hyperglycemia causes oxidative stress in
structures such as endoplasmic reticulum (ER stress) or
plasma membrane (lipids peroxidation)
35
Q
The polyol pathway
activation leads to
A
– decrease NADPH/NADP+ ratio
– decrease Nitric oxide production
– increase Sorbitol -> increase osmotic
stress
– increase NADH/NAD+ -> increase ROS
production -> oxidative
stress
– increase Fructose -> increase non‐
alcoholic fatty liver
disease (NAFLD)
– increase Fructose -> increase glycation
– -> diabetic complications
including retinopathy,
nephropathy, and
neuropathy
refer to pic
36
Q
Dietary Fructose and the Metabolic Syndrome
A
- Over-consumption of fructose:
– In small intestine, fructose -> increase production of uric acid, fatty acids & glucose
– In liver, fructose -> increase production of glucose, VLDL & ApoC -> increase lipogenesis -> non alcoholic‐ fatty liver disease
37
Q
Microvascular Complications
A
- Diabetes is the most common cause of blindness in the US
- Retinopathy has the highest correlation with severity and duration of diabetes (due to microvascular complications)
- Hyperglycemia is the primary cause of diabetic retinopathy
– Vascular endothelium growth factor (VEGF) may be involved in the development of proliferative retinopathy
refer to pic
38
Q
DM-Induced Macrovascular Disease
A
- In contrast to diabetic microvascular disease, hyperglycemia is not the
major determinant of diabetic macrovascular disease - Insulin resistance -> increase lipolysis -> increase free fatty acid (FFA) flux from
adipocytes -> plaque deposition in arterial endothelial cells - In macrovascular endothelial cells, but not in microvascular
endothelial cells, increase free fatty acid (FFA) flux -> increase FFA oxidation by the
mitochondria -> increase ROS -> macrovascular inflammation
39
Q
Intramyocellular Lipid Accumulation
A
- Skeletal muscle – accounts for ~ 80% of glucose uptake in absorptive state
- Insulin resistance would increase total intramyocellular lipid content
40
Q
Through which metabolic mechanism does the intramyocellular lipid accumulation occur?
A
insulin resistance increases lipolysis in fat tissue, so ffa circulating in blood from fat tissue and ffa into muscle cells, so muscle becomes weak and can’t function well
41
Q
Diabetes Mellitus & AGE Theory
A
- Intracellular – high [glucose] -> increase formation of advanced glycation end products (AGEs) from nonenzymatic reactions -> defects in the metabolism pathways
- Extracellular – high [glucose] -> increase AGE’s effect on extracellular matrix -> crosslinking between polypeptides -> abnormal matrix -> interrupts normal cell interactions
refer to pic
42
Q
Protein Kinase Theory
A
- Ca2+ activation of protein kinase C (PKC) & diacylglycerol (DAG) pathways is an important intracellular signaling pathway
- Hyperglycemia -> increase de novo synthesis of DAG -> unregulated activation of PKC
originally pkc stimulated by activation of hormones or cytokines, but without it the cells automatically produce DAG
refer to pic
43
Q
Management of DM – Life Style
A
- Research studies have found that
lifestyle changes can prevent or
delay the onset of type 2 DM among
high-risk adults - Lifestyle interventions included diet
and moderate-intensity physical activity - Diet – nutritional requirements with
weight control - Exercise
– Physical activity -> decrease body weight
and increase insulin sensitivity -> decrease blood glucose levels
vegetables have vitamin c that is an antioxidant and fiber which increases motility of gi tract
insulin binding to receptors cause entry of glucose through GLUT, without insulin stimulation and high exercise it doesnt need insulin there will be increase of GLUT in absence of insulin by exercise
44
Q
Aerobic Exercise & Insulin Sensitivity
A
- Aerobic exercise
– Physical activity that increases the heart rate and the body’s use of O2
– The use of O2 to adequately meet energy demands during exercise via aerobic metabolism - Aerobic exercise leads to:
– increase Use of FFA -> decrease adipokine production, decrease inflammation -> increase insulin sensitivity
– Improvement of the redox state & reducing oxidative stress induced insulin‐ resistance
– Up regulation of GLUT 4‐ in cell membrane of insulin dependent cells‐
– Reduction of plasma levels of ceramide -> prevention of ceramide induced‐ insulin resistance
– increase Phosphorylation of insulin receptor substrate-1 (IRS 1)‐ -> improvement of insulin signal transduction
– Improving β cell function & prevention of β cell apoptosis
– Induction of angiogenesis in skeletal muscle -> increase glucose uptake by myocytes
45
Q
Medication of DM
A
- Oral hypoglycemic therapy
– Glucophage (metformin) – decrease glycogenolysis, decrease
gluconeogenesis, increase insulin sensitivity, decrease glucose release into
the blood
– Sulfonylureas – target to close K+ channels -> depolarization
of β cells -> increase insulin release
– GLP-1 agonists – increase insulin release
– DPP-4 inhibitors – DPP metabolizes GLP-1, extend glp1 half life
– Thiazolidindiones (TZD) – PPARγ agonists - Insulin therapy – in severe cases when insulin major decrease
46
Q
Major Targeted Sites of Drug Classes
A
refer to picture
47
Q
Oral Hypoglycaemic Medications
A
refer to picture
48
Q
Insulin Therapy
A
refer to picture
49
Q
Issues Remain
A
- Can insulin treatment or stimulation of insulin secretion by sulfonylureas, GLP-1 agonists or DPP-4 inhibitors solve the problem of insulin resistance? they are used to stimulate more insulin, but if B cells already depleted, then
- What would be your suggestions as a clinician?
– Diet
– Physical activities
