Metabolism Pathways Flashcards
1
Q
effect of niacin
A
best HDL increase, but no evidence of use in treatment.
would rather use exercise, sustained weight loss, alcohol,, stop smoking
2
Q
Tendinous Xanthomas
A
Lipid deposits in achilles and extensor tendon of hands
seen with high cholesterol.
3
Q
Glucocerebroside
A
sphingolipid
4
Q
Glycerol P dehydrogenase
A
converts Dihydroxyacetone phosphate into glycerol Phospate in liver and adipose
5
Q
Colestipol
A
bile acid sequestran
6
Q
Steps in Glycogen synthesis
A
G6P -(phosphoglucomutase)-> G1P–> UDP Glucose - (glycogen synthase-> Glycogen
7
Q
Polyolpathway
A
Aldolase reductase enzyme that converts glucose to sortitol and fructose to muck up the cell
found in lens of eye, periocytes, nerves, kidney
Tx: aldose reductase Inhibitor
8
Q
Fatty Acid alpha hydroxylase
A
hydroxylates phytnic acid at alpha C before entering intoo Beta oxidation
9
Q
SREBP
A
Steroid Regulatory element binding protein
sequestered in the ER when cholesterol levels are high to inhibit transcription of HMG CoA Reductase in Cholesterol synthesis.
Released from ER when cholesterol levels are low.
10
Q
Risks of Recombinant insulin
A
variable absoprtion, does not mimics insulins release into portal vein as from pancreas
11
Q
polyols
A
alcohol sugars
sorbitol, mannitol, hydrogenated starches.
don’t get absorbed.
12
Q
Short acting insulin onset, peak, duration
A
onset: 30-60 minutes (0 for IV) peak 2 hours duration: 6-8 hours must take 30 minutes prior to eating Route: SQ or IV
13
Q
Growth hormones
A
released from anterior pituitary and is reelased by hypoglycemia and stress.
increase lipolysis, and favors using lipids over proteins.
14
Q
does lowering TG reduce CV death/events?
A
not yet! still not shown in scientific study
15
Q
Ratio of TG to cholesterol in lipoproteins
A
Chylomicrons 10:1
VLDL 5:1
Remnants 1:1
LDL TG
16
Q
when does glycogenolysis occurs
A
4 hours after meal
17
Q
3- Hydroxybutyrate dehydrogenase
A
form 3-hydrozybutyrate from acetoacetate.
18
Q
FDA approved use of Omega 3 FA
A
TG >500
19
Q
What energy source is used for Cholesterol synthesis
A
NADPH and ATP
20
Q
Detemir (levemir)
A
long acting insulin - extra FA chain so binds to albumin to have slower peripheral distribtuion
12-20 hours duration
21
Q
How does a small H+ gradient play out?
A
Increase respiration due to increased Oxygen consumption
22
Q
HIgh intesnsity statins
A
Atorvostatin, Resuvastatin
23
Q
Mixed Function oxidase
A
adds double bonds to Palmitic acid to make unsaturated
24
Q
what is produced from TCA cycle
A
3 NADH, 1 FADH2, GTP
25
pathogenesis of high TAGs
lipolytic toxic hypothesis: increased LPL action to release lipolysis productions and increase adhesion, inflammation and coagulation.
2) remnant entry into subendothelial space to cause foam cell foramtion
26
Cholesterol Ester transfer protein
CETP
| transfers CE to and from Triglyceride rich VLDL, IDL aand LDL.
27
PCSK -9
protein kinase that binds to LDL receptor that decrease recycling and promotes lysosomal degradation.
GOF mutation causes increase LDL
LOF causes decreases LDL
28
Fructose
does not increase glucose levels, but has affect on liver to cause insulin resistance., increase TG in blood, increase visceral adipose.
Fructose enters glycolysis after phosphofructokinase so it is not subject o regulation.
29
Thiolase
4th step in beta oxidation - cleavage
Releases Acetyl CoA
Transferes short FA chain for more Beta Oxidation
30
SE of bile sequestrants
GI symptoms - N, V, blaoting, constipation
Contraindicated with high TG >300
DDI: binds to warfarin and thyroid hormones, BB thaizides
31
ADRs of GLP1 agonist?
Nausea, pancreatitis? Pnacreatic CA?
32
Fructose 1 phosphate
made via fructokinase
33
Insulin actions - liver
Glygcogen synthesis and fat synthesis, does not increase uptake
34
what decrease risk of diabetes
High carb, low calorie diet
lifestyle changes (weight loss)
Mediterranean diet
35
Statins
Inhibitors of HMG CoA reducase in cholesterol synthesis to increase LDL receptor and catabolism of LDL.
36
Loss of CETP
increased HDL
| protective against atherosclerosis.
37
Adenosine binding casette prtoein A1
ABC A1
| facilitates uptake of cholesterol from plaques into HDL
38
Beta hydroxy-CoA dehydrognase
Rx3 in beta oxidation - dehydrognation
| creates double bond with oxygen (instead of alcohol)
39
Lomitapine
MTP inhibition to decrease liver TG incorporation in VLDL and blocks apoB48 in gut
ADRS: steatorrhea
40
Aldolase
converts Fructose 1 phosphate to glyceraldehyde3 phosphate and dihydroxyacetate.
41
Lipemia Retinalis
chylomicrons in vessesl of eye
| associated with high TG
42
Undiagnosed T2D
28%
43
Secondary prevention of T1D
No difference with parenteral insulin
| Oral insulin delays the progression of autoantibodies to create protective T cells
44
ADRs of Ezetimibe
None!
45
Branching enzyme
works alongside glycogen synthase to increase branching.
| More branching increases solubility and increases sites of synthesis
46
Ganglioside
sphingolipid
47
duration of insulin: Glargine, detemir, degludec
Detemir (12-20) < Glargine 24 hr < Degludec 42 hrs
48
Pathogenesis of T1D
genetic predisposition
environmental trigger that causes autimmune attack (t cell) to Beta islet cells
Develppnent of AutoAntibodies with loss of phase 1 insulin release
progresses to clinical onset of diabetes
49
Short acting Insulin
Humulin R, Novulin R
50
Aldolase
Converts Fructose 1 phosphate into Glyceraldehydate and dihydrozyacetone P
51
Glycemic Index
representative of the amount of glucose excursion in response to the ingestion of starch.
small - small glucose release
large - large glucose release, and more insulin release - potenial for more health affects
determined by area under the cruve of blood glucse vs. time - compared to a standardized sample.
52
Hexokinase vs Glucokinase
Hexokinase is present in all tissues, while glucokinase is only present in liver and beta cell
Hexokinase has a low Km (low affinity), while glucokinase has a high Km (so high affinity
Hexokinase has low VMax and Glucokinase has high VMax
These variations make it so, at high glucose concentrations, glocokinase can be active and liver can take up the most glucose.
53
acquired low HDL
diet - increased carb, obesity
Drugs: BB, diuretics, sex steroids
hyper TG, lifestye, sedentary, smoking
54
Basic outline of TCA cycle
Acetyl coA --> Citrate --> alpha-ketoglutarate --> SuccinylcoA --> Succinate --> Fumarate --> malate --> Oxaloacetate
55
SGLT1 and 2/ Na/Glucose transporter Inhibitors
GLIFLOZIN endings
blocks SCLG1 and 2 in proximal tubule of kidney to lower threshold for glucose reabsorption. causes glucosuria.
loss of 100g or 400 cal of glucose per day.
56
Where does Fatty acid oxidation take place
Mostly in the mitochonrial matrix
| some in the peroxisome (LCFA and Branched FA)
57
Inhibitiors of insulin release
diazoxide, somatostatin,
58
Methylmalonyl CoA Mutase
rearrangment of methylmaonyl CoA L to succinyl coA.
| Requires VB12 as coenzyme.
59
cheap DM meds
Metformin, Sulfonyluria, Insulin
60
Types of phospholipids
Glycerophospholipids and sphingolipids
61
PKC pathway in T2D
due to IRS phosphorylation of Serine, to increase DAG, Advanced glycogenic end products, oxidative stress.
to increase collagen formation, adhesion molecules, clotting factors, VEGF, and decrease NO
62
Pathogenesis of atherosclerosis
LDL gets into subendoethlial space to produces oxidized LDL, macrophage release of cytokines and chemokines, the development of FOAM cells.
63
Fate of OAA in cytoplasm
must be converte back to malate and pyruate to enetery back into the mitochondria.
64
Arachidonic Acid
formed from elongation of Linoleic acid (dietary intakeO to form prostaglandins, thromboxanes, leukotriens.
by COX enxymes
65
what lowers TG?
Fibrates, Omega 3 FAs, Niacin, high dose statins (no low)
66
how much does diabetes increase risk of CV disease
2-4x - increased to equivalent of normal person with one MI
67
what drugs promote weight loss for DM?
GLP1 agonists, SGLT1 Inhibitors
68
Glucagon secretion
regulated with hypoglycemia
69
Peroxisome oxidation
Long chain FA and Branched FA underge same reactions with beta oxidation with unique enzymes until they are medium size and are exported for beta oxidation.
70
Humalog
rapid acting insulin
Lispro
28th lysine switched with 29th amino acid proline
71
LDL purpose
delivers hepatic cholesterol to peripheral tissues.
form from modification of VLDL by lipoprotein lipase
Taken up by LDL R via endocytosis.
contains B100
72
Effects of bile acid sequestrant
decrease LDL by 10-30%, increase HDL by 3-5%, increase TG by 5-30%
73
Ceremide
springosine + FA
74
Ezetimibe mechanism
Selective inhibition of cholesterol absorption by binding to NPC1L1 at brush border to decrease liver cholesterol and increase LDL R
75
Where is ATP or GTP required in gluconeogenesis
```
Pyruvate carboxylate (2 ATP)
Phosphoenolpyruvate carboxykinase (2GTP)
Conversion of PEP to F16BP (2 ATP and 2 NADH)
```
76
Risks of Statins
```
Biggest is myopathy
1) Myalgia muscle pain 10-20%
2) Myositis (increase creatinine kinase 2.5%)
3) rhabdo very high CK, less than .1%
New onset T2D (10%)
elevated AST/ALT small risk
rare cognitive impariment
```
77
Retinopathy
#1 cause of blindness
in 10years 90% will have retinopathy
high glucose decreases pericytes blood flow regulation to cuase thickeneing of BM, leakage of soft and hard exudates, hypoxia, and Growth in middle of eye.
Neovascularzation and proliferative retinopathy.
78
Goals of T1D treatmetn
1) Increase glucose transport
2) decrease glucose production - glycogenolysis or gluconeogensis)
Decrease hormone senstive lipase that promotes FFA metabolism and ketone generation
Done via Insulin!
79
other LDL lowering drugs
Bile acid sequestrant/Resins
Exetimibe
Plant sterol
PCSK9 inhibitors
80
Nephropathy
primary cause of kidney failure
35% of those with DM develop this
associated with long preclinical phase with normal GFR, but proteinuria is marker for serious renal disease.
5-10% require dialysis, 20% on dialysis will be alive within 5 years
81
Pyruvate dehydrogenase
converts pyruvate into acetyl co-A
Produces NADH
Activated by Insulin, Ca, ADP
Inhibited by ATP, NADH, Fatty Acids
82
Use of rapid acting insulin
used for prandial therapy and correctional - when pre meal hyperglycemia occurs
83
Degludec (tresiba)
longa acting insulin
| 42 hours duration
84
LDL source
VLDL metabolism
85
Fenofibrate ADRs
Rash, myopathy, increase liver fxn tests, increase Cr (reversible)
86
Effect of ezetimibe
15-20% reduction in LDL
87
ADRs of DPP4 I?
URI, pharyngitis, allergic rxn
88
ADRS of niacin
```
Severe skin rash
moderate/severe liver disease
Hyperuremia
PUD, or IBD
impaired glucose tolerance
```
89
second step of fat biosyntehsis
Conversion of acetyl coA to malonyl coA by actyl coA carboxylase in cytoplasm
90
NPH Novulin N
Int. Acting insulin
91
diabetic fasting glucose
>125
92
What regulates phosphofructokinase 1?
Activated by: Fructose-2,6, bisphosphate and AMP (insulin)
| Deactivated by: ATP and citrate (from TCA cycle)
93
Glucose lowering ability - highest to lowest
metformin and insulin> Sulfonylura > SGLT1/2I> TZD, GLP1A, DPP4
94
GLP1
an incretin
produced from L cells in the intestine.
Stimulated by contents in the gut lumen to potentiate insulin release
Acts on Membrane associated receptrs on beta cells to decrease glucagon, potentiate insulin, decrease apetite, increase Beta cell proliferation, increase gastric emptying.
95
phosphatidylcholine
glycerophospholipid
| found in surfactant
96
how often should LDL be measured
>20 years fasting lipid panel every 4-6 years
| measure Choelsterol, HDL, TG and calcualte LDL
97
Apo C2
Lipoprotein Lipase Cofactor
| Found on chylomicrons, VLDL and HDL
98
Genetic causes of high TG
familial chylomicronemia -due to mutations in LPL, APoC2, GP1HBP
99
phosphoglucomutase
regulates conversion of Glucose 6 phosphate into glucose 1 phosphate and in reverse in glycogen synthesis and metabolism.
100
Glycogen phosphorylase
enzyme the converts glycogen into G1P
Activated by Ca, AMP, Glucagon and Epinephrine
Inhibited by ATP, Insulin and protein phosphatase 1
101
how do you calculate LDL
LDL = Total cholesterol - (HDL + TG/5)
102
Oligomycin
prevents ATP synthesis so NADH and FADH2 build up
103
Fructokinase
converts Fructose into Fructose 1 phosphate
104
NPH Humulin N
Int. Acting insulin
105
Lipoprotein lipases
on endothelium that degrades TAGs into 2 fatty acids and monoacylglycerol and remnant.
involved in both chylomicron and VLDL pathway.
106
Glucose-6 phosphotase
Enzyme that converts G6P to glucose.
| Only found in liver and kidney ER
107
Glycolipids
also glycosphingolipids
spingosine + FA + Mono or oligosacchardies
found in CNS
108
Hexosamine Pathway
from Fructose 6 Phosphate in glycolysis.
| Leads to O-glycosylated glucose to muck up cell
109
what is average value of LDL
116
110
how is the ETC linked to the TCA cycel
via the Succinate to Fumerate linkage in complex 2
111
Potentiators of insulin release
increase insulin in presence of glucose (GLP1, ACh)
112
Diabetic OGTT
>200
113
Glut 4 vs Glut 2
Glut 4 is the glucose transporter for insulin sensitive tissue like muscles and adipose
Glut 2 is the glucose transporter for insulin insensitive tissue like liver and pancreatic beta cell
114
Zellweger syndrome
defect in peroxisomal biogenesis which leads to accumulation of pytantic acid and ether linked glycerol lipids
115
pathogenesis of T2D
Genes, Obesity, inactivity and age all lead to insulin resistance to decrease tissue response to insulin to decrease glucose uptake and cause hyperglycemia.
Hyerglycemia - signals for more insulin so hyperinsulinemia and decrease glucose transport - both of which potentiate Insulin resistance.
Hyperglycemia also overwhelms Beta cells and impairs their function
hyperinsulinemia and impaired Beta cells leads to post-receptor defects that poteniates insulin resistance.
Impaired beta cells occurs due to genetic predisposition, glucotoxicity, and lipotoxicty that potentiate decreased insulin release and hyperglycemia.
116
who is cholesterol formed
acetyl coA into Acetoacetyl CoA into HMGCoA by HMG CoA Synthase (like ketogenesis). Except HGM CoA is then made into Mevalonic acid by HMG coA Reductase. This goes through Geranyl pyrophosphate and farnesly pyrophosphate to form cholesterol
117
structural changes in insulin (rapid acting)
formation of monomers faster to decrease hexamer formation and promote fast absorption in the blood.
118
DPP4 Inhibitors
GLIPTIN endings
| increase the T1/2 of endogenous GLP1 and GIP
119
ATP citrate lyase
converts Citrate to oxaloaceteate and acetyl coA in the cyto.
Requires ATP and CO-A
120
Thiophorase
converts acetoacetate into acetoactyl-CoA in ketogenesis.
| only found outside liver!
121
Fenofibrate
fibrate, TG lower agent
122
Chylomicron purpose
deliver dietary TG to peripheral tissue
deliver Cholesterol to liver in chylomicron remnants
Secreted by intestinal epithelial cells.
Contains: B48, ApoE, and Apo C2
123
NADH and activation or inhibition of TCA
Inhibits Pyruvate dehydrogenease and downstream (isocitrate dehydrogenase)
124
Guidlines for statin use for T2D
40-75 regardless of lipid levels
125
Insulin Receptor
heterotetramer with 2 extracllular alpha and 2 beta chains.
126
Route of rapid acting insulin
SQ injection prior to meal, or pump
127
Methylmalonyl CoA Racemase
2 step in odd chain FA
| D to L
128
Where is glycogen?
liver and skeletal muscle
In liver - glycogen can be converted into blood glucose and sent elsewhere
In skeletal muscle - glycogen must be used for own muscle metabolsim
129
How are TAG broken down?
TAG -- (Hormone sensitive Lipase) --> Fatty acids + glycerol.
Glycerol is used in liver for Glycerol phosphate production
FAtty acids are transfered to mitochoria for breakdown
130
Eruptive Xanthomata
pimple like painless bumps associated with hyper TG
131
Tangeir's Disease
loss of ABC A1
| no formation of HDL and orange tonsils
132
what is the rate limiting step in FA synthesis
Acetyl CoA Carboxylase (Acetyl CoA into malonyl CoA)
133
Mipomersen
antisense RNA to block transcrption of ApoB
134
Gemfibrozil
fibrate - lowering TG agent
135
Omega 3 FA as TG lowering agent
mechanism to decrease VLDL TG production and secretion by blocking formation with long chains
no evidence for reduction of CV events
136
Pyruvate Kinase
Converts Posphoenolpyruvate into pyruvate in glycolysis.
Produces ATP
Activated by: Insulin and Fructose 1,6 bisphosphate
Inhibited by glucagon, ATP, alanine
137
ADRs of SGLT1/2 I?
risk of GU and GI infection
| Hypokalemia
138
Pancreatic Diabetes
due to chronic pancreatitis and decreased exocrine fxn
139
Sphingomyelin
Sphingolipid
140
Pathogenesis of nephropathy
high glucose leads to osmotic diuresis, intrarenal and peripheral hypertension, BM thickening, mesangial prolifeartion, glomerular obliteration
141
Fish eye disease
LCAT deficiency
| decrease HDL that leads to kidney disease
142
Tertiary prevention of T1D
Intensive glucose control
Ab against T lymphocytes (anti CD3) - delays the slowing of phase 1
Abatacept - blocks T cell activation to delay onset.
143
sucrose
is glucose and galactose
144
Autoantibodies in T1D
ZnT8 - zink transporter used in zinc hexamer foramtion
IA-2 potentiates insulin release
GAD65 - protntiates granule relsease
mIAA - anti insulin Ab.
145
Amylose
starch, non branched that is slow absorption.
| Found in basmati and bananas
146
Long acting insulin
Glargine, Detemir, Degludec
| cant mix with other insulins!
147
Drugs in LDL lower capability?
Statin> Bile Acid sequesterant >Exetimibe >Plant sterol
| ?? PCSK9
148
ADR of metformin?
N, bloating, Diarrhea that decrease with slow titration up.
| Risk of lactic acidosis
149
Phosphadtidylserine
glycerophospholipid
150
Types of diabetic neuropathy
Mononeuritis multiplex
Distal symmetric polyneuropathy*
Autonomic neuropathy
Diabetic amyotrophy
151
Screening for T2D
1) BMI >25 of >23 for asians.
2) inactivity, large for gestation age baby, PCOS
3) older than 45 yo, or kids with risk factors (obestiy, Family or maternal Hx)
152
Xantheiasmus
lipid depoits on eyelids seen with hypercholesterol.
| decrease with treatment of LDL
153
Acetyl Co-A --?--> Citrate
Citrate synthase
154
Cholystyramine
bile acid sequestrant
155
Hygiene hypothesis
decreased immune stimulation that suppresses our natural immune system and leads ot increase autoimmuniety and allergies.
156
Plant sterols ADRs
NOne!, but require 2-3 g per day!
157
Glycerophospholipid vs. Sphingolipids
Glycerophospholipid: phospholipid with glycerol backbone + 2 FA + Phosphate and alcohol
Sphingolipid: phospholipid, with sphingosine + FA + Phosphate + Choline
158
Apo B 100
Structural protein that binds to LDL receptor
| found in VLDL, LDL, and IDL
159
Glycemic Load
Glycemic Index X grams of starch
160
Malate Dehydrogenase
Converts malate to oxaloacetate in cytoplasm.
required because only malate can cross mitochondrial membrane
Produces one NADH
161
Metformin Mechanism
Supresses hepatic glucose production, so no effect on insulin
only used for insulin resistance
162
pathogenesis of CV disease in DM
HTN, Hyperlipidemia, hyperglycemia --> damage endothelial, decreased NO, attractive to WBC, platelets, accumulation of lipids in subendothelial space to lead to procoagulation and proatherogenic.
163
Insulin action Adipose
stimulates GLUT4 uptake, increase fat synthesis
164
What is the rate limiting step of Ketone body formation
HMG CoA Synthase
165
Steps for odd chain FA
1) Propionyl CoA convertion to D methylmalonl coA by Pripionyl CoA Carboxylase
2) conversion to L methylmalonyl CoA by Methylmalonyl coA racemase
3) conversion to succinyl coA by Methylmalonyl CoA mutase.
166
Triolase
enzyme the aids inthe formaiton of acetoacetyl-CoA in ketogenesis
167
Evolocumab
PCSK9 Inhiitor
168
what common med promotes high TGs?
oral contraceptives
169
Plant sterols mechanism
Prevent micelle formation in intestine to decrease cholesterol absorption by preventing micelle formation.
170
Cell types in pancrease islet
60% beta - release isnulin
25% alpha release glucagon
delta - release somatostatin
171
HMG CoA Synthase
Acetoactyle CoA into HMG CoA
| rate limiting step in ketone formation. and also in cholesterol synthesis
172
Impaired OGTT
140-199
173
Guidelines for Aspirin use in T2D
only for high risk patients.
174
how to treat low HDL
manage LDL
intensify weight loss and physical activity
Tx TGs
not indiated to increase HDL
175
MODY
maturity onset diabetes of the young
| glucokinase defect in glycolysis, so you don't get insulin release or production.
176
HDL purpose
mediates reverse cholesterol transport from peripehery to liver
Repository for apolipoproteins C and E (needed for chylomicrons and VLDL).
scretes from both liver and intestine.
Forms from ApoA1 with accumulation of cholesterol from plaques
177
Gemfibrozil ADRs
cholelithiasis, myopathy, GI
178
Insulin Receptor binding
Insulin binds and leads to autophosphorylation.
| Which leads to tyrosine phosphorylation of IRS to activate the PI3Kinase pathway or the MAPK pathway
179
Glycogen phosphorylase vs Glycogen Phosphrylase kinase
GPK potenitates the action of GP
180
why does the body want to increase Acetoacetate or 3- hydroxybutyrate in starvation
Acetoacetate or 3HB can diffuse int he blood and entery peripheral tissues.
3HB is converted to Acetoacetate in the tissues (releases NADH).
Acetoacetate can be converted to Acetoacctyle- COA in mitties (an enzyme not found in liver) by Thiophorase which can be made into acetyl coA.
181
Fructose metabolism
Enters below the Posphofructose kinase - so it is less regulated!
182
Corticosteroids
counterregulatory hormones.
Promote protein breakdown for gluconeogenesis and decrease insulin ation.
Potentiates the action of glucagon and catecholamines.
183
what is the change in insulin resistance
most due to signaling problems downstream - change from tyrosine to serine or threonine phosphorylation.
184
autonomic neuropathy
increased HR, or MI risk,
| can affect colon and stomacha s well
185
GLP1 agonists
TIDE endings
stimulates glucose dependent insulin secretion to decrease hepatic glucose output, glucagon output.
also decreases gastric emptying and intake.
used for insulin resistance and decreased production
186
What do you do for high LDL?
Mipomersen
omitapine
LDL aphoresis
187
what are the outside actions of insulin
Decrease food intake, regulate blood flow, regulate salt/water balance, growth stimulation
188
alpha cell role in T2D
increased alpha stimulation to cause increased glucagon levels. Glucagon promotes hepatic glucose output.
189
Alirocumab
PCSK9 inhibitor to decrease LDL
190
what drug to give in Renal Dz for DM?
insulin
191
what happens with odd chain FA oxidation?
last round of beta oxidation you are left with a FA acteyl coA with 3 Carbonds - Propionyl -CoA
192
Carnitine Palmitoyl Transferase 1
converts fatty acid CoA into Acetyl CoA for diffusion of LCFA through mito membrane (inner).
the rate limiting step in Beta oxidation.
Inhibited by large amounts of malonyl coA.
193
what drug is only avaliable SQ for DM?
GLP1 agonists
194
two major emergencies of diabets
DKA - too little insulin and too much glucagon and epinerphine to promote lipolysis and ketone formation.
unknown hypoglycemia - due to mismatched insulin and food intake. overtime you get sensitized, so when you get hypoglycemia, you don't feel any changes and are seizure risk.
195
how does a large H+ gradient play out?
decreased respiration due to lower oxygen consuption
196
apidra
glulisine
| rapid acting insulin
197
Novolog
Asprat
rapid acting insulin
29th AA change to asparate
198
how do we prevent macrovascular complications of T2D?
Statin, lower HTN, aspiring?
199
HBA1C imparied
5.7-6.4%
200
Fatty acid synthase
converts malonyl coA into Palmitic acid in cytoplasm of FA synthesis
Multifunctional enzyme with 7 activiites
Completes 4 step process in formation of Palmitic acid.
201
when is insulin used for T2D?
when lifestyle modification and drugs fail to meet target A1C
contraindications to meds
Signs of insulin deficiency (WL, fasting >250, random >300, A1C > 10%)
DKA, or HHS
202
Wipples triad
BG <50, symptoms of hypoglycemia, symptoms improve with glucose administration
203
VLDL purpose
delivers hepatic TG to peripheral tisses. Gets degraded into LDL
Secreted by liver
contains Apo B100, Apo C2 and Apo E
204
LADA
latent autoimmune diabetes of adulthood.
30-70 YO
>6 months of non insulin requiring Diabetes
+ AutoAb
205
PI3Kinase pathway
activation of AKT to elad to GLUT4 translocation, and glycogen synthesis
THis is the metabolic pathway
206
PCSK9 inhbitors mechanism
mAB that binds to PCSK9 to allow LDLR to recycle
207
low intensity statin
pravastatin, lovastatin
208
Prevalence of T2D
9.3%
209
Effect of Omega 3 FA
lower TG by 15-35% increase HDL, and no effect on LDL
210
what are the steps of beta oxidation in the mitochondria
1) dehydrogenation/oxidation by acyl co dehydrogenases
2) Hydration by enoyl CoA Hydratase
3) Oxidation (dehydrogenationase) by Beta hydrozy-CoA dehydrogenase
4) cleavage by Thiolase
211
How do glucagon and epinephrine signal?
they both increase cAMP to activate PKA to phosphorylate enzymes
212
Phosphoenolpyruvate carboxylase
Converts oxaloacetate in cytoplasm to Phosphenolpyruvate
| Requires 2 GTP
213
Novulin R
Short acting insulin
214
Pripionyl CoA Carboxylase
converts propionyl CoA into Methylmalonyl CoA D - by adding carboxyl group to FA.
Requires CO2 and ATP
215
what is required for the ETC
O2, NADH, FADH2, ADP
216
What are the steps in Triglyceride synthesis
1) Acteyl transferase - adding on FA to 3-Glycerol phosphate backbone.
2) Acteyl transferase - adding 2nd FA to 3-Glycerol phosphate backbone.
3) Phosphatase - removal of phospate to create an alcohol.
4) Acteyl transferase - adding 3rd FA to 3-Glycerol phosphate backbone.
217
Actyl CoA carboxylase
Acetyl CoA --> Malonyl CoA (synthesis of FA)
Cytoplasm
Requires ATP, CO2, Biotin.
Activated by high citrate concentrations and insulin (to increase Vmax)
Inhibited by Long chain Fattay acids and glucagon
218
what is the marker for decreased GFR in nephropathy?
proteinuria
219
Uses of Short acting insulin
DKA, HHG, perioperative, critical hyperglycemia.
220
Niacin
no major benefit in decrease CV events
Decreases synthesis of VLDL by decreasing catabolism of Apo A1
Liver: binds to AMP kinase to increase FA oxidation, and decrease TG synthesis
Adipose : activation Gi to decrease lipolysis
221
Bile Acid sequesterant
high molecular weight qauternary amines that bind to bile acid to prevent reabsoprtion to decrease entrahepatic circulation and promote synthesis of bile.
Ultiamtely decreases liver cholesterol and increase LDL Receptor
222
Clinical features of severe hypertriglyceridemia
```
Eruptive xanthomata
Lipemia retinalis
hepatosplenomegaly
ab pain and acute pancreatitis
lipemic serum
```
223
How do Fatty acids get into the mitochonria
Short and medium <12 C diffuse
LCFA can diffuse through outer membrane, but use Carnitine Palmitoyl Transferse 1 to bind with carnitine to make CoA + Acteyl Carnitine.
This can diffuse through the inner membrane.
CPT2 converts acteyl carnitine back to FA-CoA and carnitine.
224
Accelerator hypothesis
obesity causes increased beta cell stress to lead to increased beta cell antigens in T1D
225
ADRS of PCSK1 I
injection rejection 5%
Drug antibodies <5%
Allergy
Neurocognitive?
226
Apo E
Ligand for Remnant Receptor
Mediates remnant reuptake
found on chylomicron, chylomicron remnant, VLDL, IDL, HDL (NOT LDL)
227
Hormone sensitive lipase
in cytosol - breakdown of TAG into FAT
Activated by Epinephrine
Inhibited by insulin and glucose
228
Apo B48
Mediates chylomicron secretion, structural protein
| Found on Chylomicron and chylomicron remnants
229
Incretin
a signal that increases insulin release in the presence of glucose.
230
what DM drug can cause lactic acidosis
metformin
231
DPP4
degrades GLP1
232
what is produced for each beta oxidation round
1 acetyl coA
1 NADH
1 FADH2
233
Glucose --?--> Glucose-6-phosphate
Hexokinase, glucokinase
234
Advanced Glycolytic End products
producs that get stuck on protein, DNA, cholesterol to disrupt basement membrane, sequester NO, activated deleterious pathways (collagen), cross link DNA to decrease repair.
235
risks of early insulin (animal)
allergy, resistance, lipoatrophy of SQ fat.
236
guidlines for HTN treatment in T2D
<140/90 (lower for those in renal dz)
237
What converts Glucose to Glucose-6 phosphate
Hexokinase and Glucokinase
| Requires ATP
238
alpha oxidation
occurs in the perisoxisome.
Phytanic acid - branched FA is hydroxylated at alpha C by Fatty Acid alpha hydroxylase.
2) Decarboxylated
3) activation for beta oxidation
239
Long acting insulin - onset, peak, duration
onset: 1-1.5 hours
Peak - not pronounced
duration: 12-42 hours depending on type
240
PAI-1
increased in DM to promote coagulation
241
ADRs of Sulfonyluria?
weight gain, hypoglycemia, resistance with long term use
242
what drugs promote weight gain for DM?
Sulonylurea
243
Acyl Co A Dehydrogenase
first step in beta oxidation that creates a TRANS double bond (enoyl CoA)
there are 4 forms of these
short, medium, long, and very long. producess FADH2
244
Rapid acting insulins
Humalog, Novolog, Glulisine, Afrezza
245
when does ketogenesis occur
2 days after meal
246
Gestation Diabetes
```
weight gain during pregnancy to cause insulin resistance
Increased risk of T2D in the future
Fasting >95
1 Hr >180
2 Hr >155
3 Hr >140
more at risk for baby than mother
```
247
Glulisine
apidra
rapid acting insulin
33 Lysine switched with 29th glutamate
248
Pathogenesis of insulin release
Glucose travels through GLUT2 into beta cell
Glucose undergoes Gycolysis and TCA to generate ATP
ATP acts on close K Channel (dependent on ATP) to cause cell depolarization
Depolarization opens Ca (VSCC)
TO cause exocytosis
249
how do we slow the progression of nephropathy
ACEI, glucose control, protein restriction, Bp control
250
Adrenoluekodystrophy
defect in peroxisomal biogenesis.
251
Amylopectin
starch, branched for faster absorption
| found in white bread, potato, pasta
252
effectivness of fibrates
lower TG by 20-40%
| increase HDL by 5-15%
253
How does exercise improve diabetes
depletion of glycogen to increase muscle Insulin sensitivity.
254
Arcus Cornealis
Hypercholesterolesmia
lipid deposits in cornea (gray band around cornea) that starts at 12 and 6, but becomes circumferential.
Can be seen in African americans without high cholesterol.
255
Refsum
back of alpha hydroxylase that leads to accumulation of phyantic acid in liver and kidney.
pigmented retina, poly neuropathy.
256
HDL roles
cholesterol transport, antioxidant, antiinflammatory
257
Sulonylurea
IDE endings
closes ATP sensitive K channels in Beta cells to increase Insulin release.
used for insulin production problems.
258
Phosphofructokinase 1
Enzyme that converts Fructose-6-phosphate into fructose 1-6, bisphosphate
Requires ATP
rate limiting step of glycolysis
259
Fructose biphosphatase -2
enzyme that converts Fructose 2,6 biphosphate back to fructose-6-phosphate.
Activated in fasting state by glucagon
Inhibited in fed state by insulin
260
Fibrates mechanism
induction of PPAR alpha expression to increase intrahepatic oxidation and decreases VLDL TG synthesis
also, decrease APoC3
261
Steps in Glycogen metabolsim
Glycogen -- (glycogen phosphorylase) --> Glucose 1 phosphate -- (phosphoglucomutase)--> Glucose - 6 Phosphate that goes either into glycolysis or Gluccose via Glucose 6 phosphatase.
262
What genes promotes high TG?
Increase in LPL and ApoA5 and a number of others
| each is additive and leads to increasing TG accumulation
263
HMG CoA Lyase
HMG coA into Acetoacetetate
264
Citrate
part of TCA cycle
Activates Fructose 1,6 bisphosphatase in gluconeogenesis
Inhibits Glycolysis by inhibiting Phosphofructokinase 1
265
Mononeuritis multiplex
tiny n. infarctions in nerve root - looks like ptosis, but has good prognosis
266
tests to run when evaluating cause of CAD
Glucose, A1C, TSh, Liver Fx, Creatinine, Urine Protein
267
when does glycogen metabolism occurs
In tissues lacking mitocondria (sperm, RBCs), Brain, in vigorous exercise
268
Colesevelam
bile acid sequestrant used clinically
269
Phosphatidylethanolamine
glycerophospholipid
270
What drugs are weight neutral for DM?
Metformin, DPP4 inhibitors
271
Structure of Triglycerides
GLycerol backbone with 3FA
C1 = saturation
C2 - unsaturated
c3 - either
272
undiagnosed Prediabetes
90%
273
Fructose 1,6 biphosphatase
Converts F1,6 BiP to F6P
Activated by ATP, Acetyl CoA, and Citrate
Inhibited by Fructose 2,6 biphosphatase
274
Basal metabolic rate =
due to the generation of head due to the Hydrogen leak without ATP being made
275
Stages of retinopathy
early, mild, severe, preprolifeative (severe preproliferative is where we try to intervene)
Early proliferative
neovacularization
macular edema
276
Phosphoenolpyruvate -?--> Pyruvate
Pyruvate Kinase
277
When do I use fibrates?
when TG >200 with low HDL
| to decrease TG when not on a statin
278
Impaired fasting glucose
100-125
279
symptoms of hypoglycemia
ANS - increase epinephrine and catecholamines
| Neurologic - head ache, confusion, looks drunk due to not enough glucose in brain
280
Effect of Fatty liver disease
1) ethonol oxidizes acetone into acetate, which is a precursor to Acetyl CoA to increase FA synthesis
2) NADH lows TCA and promotes Glycerol Phosphate production
3) secretion of VLDL is impaired via decreased ApoB100 synthesis in liver --> liver fat accumulation
281
IRS1 normally
is phosphorylated on tyrosine, but when the body is stressed increased TNFalpha, phosphorylation occurs on serine to potentate lipolysis and FFA, so cause insulin resistant and hyperglycemia for healing.
This rxn is normally beneficial, but when you get constant hyperglycemia, it leads to diabetes.
282
Enzymatic differences in Glycolysis and gluconeogenesis-
| Fructose 6 phosphate - Fructose 1,6 Bisphosphate
Glycolysis: phosphofructokinase 1
Gluconeo: Fructose 1,6 bisphosphatase
283
Pyruvate--?-->Oxaloacetate
Pyruvate carboxylase
284
energy expenditure
30 cal/kg
285
Pyruvate carboxylase
converts pyruvate into oxaloacetate
requires Biotin, ATP and CO2
Activated by Acetyl CoA
286
what drugs have CV protective effects?
GLP1 agonist, SGLT1/2 inhibitors
287
Int. Acting Insulin
Neutral protamine hagedorn (NPH)
NPH Humulin N
NPH Novulin N
This one is cloudy!
288
what carries electrons from complex 1 to complex 3 in ETC
Coenzyme Q
289
Galactoscerebroside
sphingolipid
290
lactose
is fructose and glucose
291
what does high TG levels lead to atherosclerosis
with diseases
Metabolic disease (especially in women)
pancreatitis
292
When is FA synthesis promoted
when ATP levels are high and they inhibit isocitrate dehydrogenase to allow citrate to accumulate in to the mito
293
when does gluconeogenesis occur
12 hour after meal
294
Sphingosine
built from palmitoyl Coa and serine
| resembles glycerol but has a nitrogen due to protein component
295
Insulin actions Muscle
Stimualtes GLUT4, increase glycogen synthesis
296
TG levels
```
Normal <150
Borderline 150-199
High 200-499
very high >500
level is qualitative, not an accurate risk assessment
```
297
Targets of insulin therapy
fasting 80-130
2hr post bolus <180
A1C <7% adults, <7.5% kids
298
Glycogen Synthase
enzyme - converts UDP glucose into Glycogen
Adds glucose onto glycogen chain >4 with Glycogenin (starter of chain)
Activated by Glucose 6 phosphate, Insulin, Protein phosphatase 1, and cortisol
Inhibited by: Epinephrine and glucagon
299
Purpose of Glycerophospholipids
Cell membrane component, signaling
300
what DM are expensive
GLP1 agonists, DPP4 I, SGLT1/2, Insulin analogs
301
Int. Acting insulin onset, duration, peak
onset: 1-3 hours
peak 6-8 hours
duration: 12-16 hours
Route SQ only, 2x per day
302
Phosphoenolpyruvate (PEP)
produced through a series of steps from fructose 1.6 bisphosphate in glycolysis
303
Propionyl-CoA
end product of regular Beta oxidation with odd chain FA
304
Rule of 6?
for each 2x dose of statin, expect to decrease LDL by 6%
305
Lispro
Humagloc Rapid acting insulin
306
Phase 1 vs phase 2 insulin release
phase 1 lasts 5 minutes and is quick release of insulin (predocked)
phase 2 starts 8-10 minutes after food ingestions to increase insulin synthesis.
307
Glucose-6-phosphate --?--> Glucose 1 phosphate
Phosphoglucomutase
308
what generates the H+ gradient in ETC
I, III, IV into intermembrane spane
309
MAPKinase pathway
leads to ERK activation ot cause vasoconstriction and growth and mitogenesis. The mitogenic pathway.
310
Glycerol Kinase
converts glycerol into Glycerol Phsophate in liver only
311
Hypertriglyceridemia
Promotes thrombosis, endothelial dysfunction, and less commonly cholesterol in vessel wall
312
Genetic causes of higher LDL
Familial Hypercholesterolemia
AD disease with defect in LDL receptor
Heterozygotes 1:500 have 200-300 LDL levels
Homozygoates (rare) have cholsterol >500
Causes accelerated atheroscelerosis (before 20 yo), Arcus Cornealis, Zantheiasmus, tendinous xanthomas**
313
Fructose 2,6 bisphosphate
produced from fructose6 phosphate in glycolysis by phosphofructokinase -2.
Promoted by insulin in fed state and inhibited by glucagon in fasting state
314
how do we slow the progression of retinopathy
survelliance
Panphotocoagulation
antiVEGF
315
who do we treat with statins
1) those with CVD (high intensity)
2) LDL >190 (high intensity)
3) primary prevention: DM, 40-75 yo, LDL 70-189 (high/mod)
4) primary prevention: no DM, 40-75, LDL 70-189 + >7.5% risk/10 years
316
Malonyl coA --?--> Palmitic Acid
Fatty acid synthase
317
UDP Glucose --?--> Glycogen
Glycogen Synthase
318
First step in Biosynthesis of FA
Citrate from TCA cycle diffuses out of mitochondria and is converted to OAA or Acteyl Co-A by ATP Citrate Lyase.
319
initiators of insulin release
direct stimulation - glucose, AA, drugs
320
Formation of Palmitic acid process
1) condensation to form 3 Ketoacyl ACP
2) Reduction - converts keto to alcohol using NADPH
3) Dehydration - induces double bond
4) reduction - removes double done (NADPH)
Firs 2 Cs are made from actyle coA, the rest are from malonyl Co-A
Palmitic acid is released from FAS by palmitoyl tioesterase
321
Affrezza Onset, peak, duration
onset: 5 min
Peak 1 hour
Duation: 2 hr
dosage cartridges only
322
Enzymatic differences in Glycolysis and gluconeogenesis-
| Glucose Glucose 6 phosphate
Glycolysis: hexokinase and glucokinase
Gluconeogenesis: glucose 6 phosphatase
323
How does Insulin signal?
activates protein phosphatase 1
324
Lecitin Cholesterol Aminotransferase
LCAT makes it so Cholesterol turns into CE of HDL to promote it staying in the lipoprotein center
325
naming glycerophospholipids
Phosph....
326
Debranching enzyme
works alongside glycogen phosphorylase to decrease branching and convert to linear structure
327
Where does Glycerol phosphate come from for Triglyceride synthesis?
Glycolysis in the liver or adipose: produeces Dihydroxyacetone phosphate -- (Glycerol P dehydrogenase) --> Glycerol P - this is the indirect method.
This requires NADH
Direct: in liver only: Glycerol -- (glycerol kinase) --> Glycerol P.
This requires ATP
328
how much insulin does pancreas usually release
30 U/day
329
What is the fate of palmitic acid?
1) elongation in ER or Mito into LCFA
2) remains as is as a FA
3) desaturation (adding double bonds) in ER by Mixed Function Oxidase
330
Phosphatidylinostiol
glycerophospholipid
| signaling molecle
331
what drugs can be combined with metformin in one pill?
DDP4 I, SGLT1/2, Sulfyuria
332
Rapid acting Insulin Onset, peak, and duraiton
onset: 5-15 minutes
Peak: 1-1.5 hours
Duration: 3-5 hours
333
when does FA breakdown occur?
18 hours after meal
334
Treatment goals of lowering TG
prevent pancreatitis, lower below 500 for severe cases
| Lifestyle/statin recommendations`
335
Distal symmetric polyneuropathy
more common in tall epoeple
nerves bathe in high glucose to cause tingling, numb, hyperalgesia that progresses to complete numbness, abnormal structures, hammer toe and ulcers.
336
HbA1C Diabetic
>6.4
337
Enoyl CoA Hydratase
Rxn2 in beta oxidation - hydration
| adds H20 to the double bond
338
Risk factors of Atheroscelrosis
```
Male, AA, Current smoker (risk decreases within 6-12 months of quiting), HTN >140 systolic, High Total cholesterol, decreased HDL, DM
Family Hx (male <55 and female <65)
```
339
protocol for treatment if diabetes in hosptial
stop non insulin meds and use IV insulin with monitoring.
| or scheduled insulin SQ
340
HMG CoA Reductase
converts HMG CoA into mevalonic acid
Rate limiting step for Cholesterol syntehsis
Activated by insulin, and SREBP release from ER
Inhibited by, AMP, Glucagon, and SREBO being sequestered in the ER by high levels of cholesterol.
341
How are ketone bodies formed
Acetyl coA and Fatty Acyl COA combine via triolase to form acetoacetyl-CoA.
HMG CoA Synthase (RL) adds acetyl COA to form HMG CoA.
HMG CoA Lysase cleaves into acetoacetate, which is unsable and usually forms acetone or 3-hydroxybutyrate.
342
Catecholamines
counterregulatory hormones NE and Epi to increase blood glucose
Act on Beta receptor on liver to increase cAMP
343
Glargine (lantus)
long acting insulin - extra arginines added so it forms preciptiate at body's pH for slow release
24 hours duration
344
Glucagon Actiosn
acts with GPCR to increase cAMP and lead to phosphorylation.
345
Fructokinase
converts fructose to Fructose 1 phosphate
| uses ATP
346
How do we prevent microvascular complications of T2D?
lower A1C
347
Afrezza
rapid acting inhaled insulin
348
Humulin R
Short acting insulin
349
Plant sterols effectivity
lowers LDL by 5-10%
350
Uncoupling protein
dissipation of H+ gradient without generation of ATP - as seen in brown fat.
351
Asprat
novolog
| rapid acting insulin
352
Basic pathway of gluconeogenesis
Pyruvate -- (payruvate carboxylase--> Oxaloacetate --> malate -- (malate dehydrogenase) --> oxaloacetate -- (phsophoenolpyruvate carboxykinase) --> Phosphoenolpyruvate --> Fructose 1,6 biphosphate -- (fructose 1.6 biphsophotase) --> F6P --> G6P -- (G6PDehydrogenase) --> glucose
353
when is stimulate insulin released
when >100 serum glucose( Glucose stimulated insulin release)
354
BG for newborns
<12 hours hypoglycemia <30
after 12 hours hypoglycemia <45
after 48 hours hypoglycemia <50
355
Somatostatin
release from hypothalamus and inhibits GH release.
Inhibitor of glucagon and insulin -
Decrease GI motility, splanchnic flow, digestive enxymes and absorption in intestines.
356
what carries electrons form complex 3 to 4 in ETC
Cytochrome C
