Diabetes Flashcards
metabolic effect of catecholamines
NET: increased glucose production rate
liver
increase glycogenolysis
increase gluconeogenesis
adipose
increase lipolysis
muscle
increase glygenolysis
What inhibits insulin secretion?
norepineprine
somatostatin
GLP receptor agonists mechanism
i.e. Exenatide
glucose dependent insulin secretion
slowed gastric emptying
satiety
reduced glucagon secretion
components of prandial insulin
- carbohydrate ratio
- correction factor
glycogenolysis
Glycogenolysis is the biochemical breakdown of glycogen to glucose whereas glycogenesis is the opposite, the formation of glycogen from glucose. Glycogenolysis takes place in the cells of muscle and liver tissues in response to hormonal and neural signals.
A1C cut off for pre-diabetes
5.7%
humalog
lispro - rapid acting insulin
Risks of Metformin
GI side effects (nausea, cramping, diarrhea)
lactic acidosis
B12 levels
beta cells
secrete insulin
on inside of islets
autoimmune beta cell destruction
T1D
It’s viewed either as an infectious process, usually triggered by certain viruses, namely mumps, rubella, Coxsackie B4; or some toxic insult.
In an individual that is genetically programmed or predisposed to type 1 diabetes the human leukocyte antigen which is responsible for programming antigen presenting cells like the macrophage—the macrophage presents to the T-cell, the T-cell can then work in concert with the B-cell, and this causes the inflammatory process in the pancreas.
It’s like all other autoimmune conditions: the body does not recognize the pancreas as belonging to that individual so the pancreatic beta cell is completely destroyed. This also explains hashimoto’s thyroiditis, which is an autoimmune condition; adrenalitis, adrenal insufficiency, or addison’s disease. All three of these actually come together in a syndrome called schmidt syndome.
gestational diabetes
placental hormones (HPL) cause insulin resistance, 1/20 can’t make enough insulin to overcome the resistance
beta cell dysfunction AND insulin resistance during pregnancy
hyperglycemia during pregnancy - usually resolves after birth
higher risk of morbiditiy and mortality, high risk of later T2D in mom and baby
requires dietary/glycemic management
DPP-4 inhibitor mechanism
DPP-4 breaks down GLP-1/GIP
if inhibit DPP-4 there is more GLP-1/GIP to increase insulin and satiety and decrease glucagon and fasting glucose
synthesis of ketone bodies
made in the liver
- adipocyte - break down of TG into FFA (by HSL)
- FFA transported to hepatocyte and made into acetyl coA in mitochondria
- made into acetone
ketone bodies can be used by muscle and brain
insulin to protein metabolism
anabolic
stimulates
- AA transport into tissues
- Protein synthesis in muscle/adipose/liver/other tissue
inhibits
- proteind egredation in muscle
- urea formation
risks of SGLT2 inhibitors
genital candidiasis
DKA, UTI
dehydration
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates.
What stimulates insulin secretion?
increased [glucose]
FFA
AA
Acetylcholine
GLP-1/GIP
Risks of GLP-1 receptor agonists
acute pancreatitis
thyroid c-cell tumor
nausea/diarrhea/vomiting
acute renal failure
what is normal post-prandial glucose
120-140
glucose sensors
device that provides continuous readings and data about trends in glucose levels
fingersticks still required BID for calibration
IFG
impaired fasting glucose
126>FPG >100
predicts increased risk of diabetes and micro/macro vascular complications
cellular mechanism of glucagon
- glucagon binds glucagon receptor
- increase G protein(alpha)
- increase adenylyl cyclase
- increase cAMP
- increase PKA
- increase glycogenolysis, gluconeogenesis
decrease glycogen synthesis, glycolysis
rapid insulin release
due to preformed vesicles
prolonged release after synthesis
released in a pulsatile manner
PTEN
involved in insulin signalling - dephosphorylate PIP3 to PIP2 (and turn of insulin signalling) - oppose effects of insulin
in cancer - mutation of PTEN - high PIP3 - continuous insulin signaling
pre-mixed insulin analogs
intermediate + rapid acting insulin combos
i.e. Novolog
to decrease injections and inject amt
Insulin total daily dose higher in T1D or T2D
TD2!! ave .4-1 units/kg
TD1 = .4 units/kg - usually sensitive so require less
diabetic foot
ulceration, infection: cellulitis, gangrene - amputation
interplay of:
neuropathy
atherosclerosis
microvascular disease
susceptibility to infection (WBC can’t get there)
causes of vascular damage in diabetes
oxidative stress and endothelial dysfunciton
advanced glycosylation end products
glycosylated/oxidized LDL and small dense LDL are highly atherogneic!
procoagulant and inflammatory state
sequence of insulin formaton
- Insulin is made as preprohormone, single peptide chain à then successively cleaved
- Cleaved to first give proinsulin, which has lost leader sequence
- C peptide removed and end up with active insulin: 2 separate chains (A+B) joined by disulfide bonds
C peptide is secreted along with active insulin measuring C peptide is a way to measure how much active insulin a person is secreting if that person happens to be treated with exogenous insulin
pathogenesis of T1D
one defect - no insulin secretion!
no hepatic insulin effect (unrestrained glucose production)
no muscle/fat insulin effect (impaired glucose clearance)
Metformin mechanism
inhibits gluconeogenesis by decreasing hepatic glucose output and lowering FFA concentrations
increases insulin sensitivity in peripheral tissues (muscle and liver)
- improves insulin sensitivity, no hypoglycemia, lowers fasting glucose by 20%
maturity onset diabetes of the young
autosomal diminant pattern (mutations in glucokinase, hepatic nuclear factor genes) impair insulin secretion in response to glucose
what is the insulin level in prediabetes?
Individuals who have prediabetes, even with a fasting glucose of 100, they’re already compensating for the insulin resistance by making an incredibly higher amount of fasting insulin levels. So even with a fasting level of 100, which is not that different than 80, you can see that there’s a huge amount of compensation that has to be undertaken in order to even obtain a level of 100.
When you get to levels of 126 fasting, which is already in the diabetic range, you can see that the insulin levels fall.
By the time the individual develops a sugar of 200 the insulin levels have really come down dramatically because the pancreas, like most organs, cannot deal with the constancy of pressure or tension related to insulin resistance.
So the pancreas decompensates, no different than the sterling law of the heart. People go into heart failure over time because the heart can no longer deal with the chronic stress of hypertension, for example.
is T1D or T2D familial?
T2D
The bottom line in what causes diabetes is the inability of the pancreas to generate enough insulin in order to deal with insulin resistance. And insulin resistance basically, again, comes from insulin receptor defects. There are 64 genetic defects that have been described in type 2 diabetes. They affect the ability of the insulin receptor to function properly, or there may be some problems or abnormalities in the transcription factors in the insulin signaling pathway.
Symlin
i.e. Pramlintide
T1D, T2D
helps with weight gain (insulin makes gain wait)
adjunct antihyperglycemic with mealtime insulin, injectable
synthetic analoge of amylin (prolongs gastric emptying, reduces post prandial rise in plasma glucagon, decreases caloric intake through centrally mediated apptitie suppression)
this reduces post prandial glucose levels and A1c - doesn’t reduce glucose enough on it’s own
what diabetes complications are reversible?
related to hyperglycemia - metabolic decompensation
gestational diabetes
refractive errors
WBC function
some neuropathy
IGT
impaired glucose tolerance
2h PG on OGTT
200>IGT >140
predicts increased risk of diabetes and cardiovascular disease
fasting plasma glucose cut off for diabetes
126
genetics of T2D
more heritable than T1 (90%)
no HLA association
lipotoxicity
FFAs, TGs –> impair insulin secretion/increase hepatic glucose production, toxic!
progression of beta cell dysfunction, ROS + ER stress
There are individuals that have very high levels of free fatty acids. They develop what is called lipotoxicity, which also does the same thing: impairs insulin secretion and generates hepatic glucose production. Individuals that have both have a very severe form of insulin resistance. There’s some literature that suggests that if you have someone that has very high free fatty acid levels, even if you just lower the free fatty acid levels then the pancreas will function better, the beta cell can rejuvenate, and that will lead to improvement in carbohydrate metabolism.
what if A1c is better than expected?
does this patient have anemia?
blood transfusion?
hypoglycemia?
what is normal fasting blood glucose?
about 90 mg/dL
65-105
autoanitbodies in T1D
ICA
GAD
Benefits of Metformin
low cost
lower A1c by 1-1.5%
weight loss
low risk of hypoglycemia
biochem diff between insulin analogues?
diff AA modifications to affect absorption and thus half life
Cellular mechanism for stimulation of glucose uptake by insulin?
- Inuslin R
- IRS
- PI3K Phosphorlates PIP2 to PIP3
- PDK and AKT are bound to PIP3, PDK phosphorylates Akt
- Akt turns on AS160
- AS160 phosphorylates Rab GDP
- Rab GDP activates vesicles containing GLUT4 to merge with plasma membrane, more GLUT4 on membrane = more glucose uptake
[muscle contraction also stimulates glucose transoort to help normalize transport
Risks of sulfonylureas
hypoglycemia
weight gain (hunger from const insulin)
Sulfonylureas
There are other factors (ie. not [glucose]) that affect insulin release, which we can take advantage of clinically
Sulfonylureas close K channel à act to increase insulin present in cell à used clinically to DM2 to increase insulin release
insulin
The one hormone that functions to facilitate glucose utilization (ie. movement toward storage forms like glycogen and triglycerides) = insulin
Insulin is secreted when blood [glucose] is increased à stimulates uptake into tissues and conversion to storage forms
blood flow in islet
flows center to periphery, glucose stimulates insulin secretion which inhibts glucagon (outsie)
blood containing high [glucose] is delivered first to the core of the islet via the celiac artery à insulin released by beta cell in response to high [glucose] à insulin first acts locally to suppress glucagon secretion by alpha cell
metabolic effects of GH
- enhance lipolysis and ketonemia
- impairs glucose uptake in cells
- increases hepatic glucose output
4. protein sparing - increases protein synthesis via IGF1
- promotes growth and development
glucagon in adipose
catabolic
break down TG to FA
insulin pump
pumps replace periodic injections by delivering rapid-acting insulin continuously throught the day using a catheter
basal-bolus technique still employed
insulin rates change through the day so you can adjust rates based on the time of day and activity levels (bolus insulin) - exercise, stress, alcohol. illness, steroids
retinopathy
in 80% after 30 yrs of DM1
vessels become leaky and leak blood - exudates, small dot hemorrhages and infarcts
proliferative - neovascularization can lead to vitreous hemorrhage and retinal detachment
fasting plasma glucose cut off for impaired fasting glucose
100
what general factors lead to hyperglycemia
- excessive glucose production
- impaired glucose tolerance
HSL
one enzyme activated by glucagon which mobilizes fatty acids from TG
What is the rate limiting step in insulin release?
glucokinase: phosphorylation of glucose in the cell
honeymood period
and then interestingly enough after the diagnosis and treatment of diabetes insulin levels increase again—called the honeymoon phase. So what is a honeymoon phase? The honeymoon phase is, as you can see, a recrudescence of the ability of the pancreatic cell to function
When you treat someone with insulin, 1) it’s not a black or white or dichotomous process. It’s usually a gradual transition from making a little insulin to making no insulin. If you treat someone that has a high sugar with insulin at the very early stages of the disease, you basically take off the pressure on the beta cell to function. So the beta cell can actually recuperate some of its functionaoli if you reduce the hyperglycemic stress. And this probably accounts for the honeymoon period.
A very common path of treatment is to use a very small amount of insulin, and you have to be very careful so that that they don’t become hypoglycemic, and using very small amounts of insulin over a very long period of time is felt to be able to prolong the survivability of their innate beta cells because you’re basically putting their beta cells at rest. This doesn’t necessarily mean that they will be cured of diabetes, but it makes the likelihood of developing fulminant diabetes less, and instead of going up to 4 or 5 injections with fulminant presentation of diabetes, these individuals may do very well for a prolonged period of time with maybe 1 or 2 injections. So you can’t cure diabetes with this approach, but you can make it much easier to defer the full need for multiple doses of insulin.
What insulin signaling step is inhibited in T2D?
beta subunit phosphorylating (activating) IRS
In DM2, it’s technically serine getting phosphorylated rather than tyrosine
insulin to lipid metabolism
anabolic
stimulates
- FA and TG synthesis in tissues
- uptake of TG from the blood into adipose/muscle
- rate of cholesterol synthesis in the liver
inhibits
- lipolysis in adipose tissue (lowering the FA level)
- FA oxygenation in muscle and liver ketogenesis
NPH
intermediate insulin
i.e. humulin/novolin
inset in 1-3h, lasts 6-12h
usually if need more variable, pregnant, etc.
2 hour plasma glucose cut off for diabetes
200
alpha cells
secrete glucagon (oppose insulin)
in the periphery of islets
glargine
i.e. lantus
long acting (basal) insulin
onset in 1-2h, no peak, lasts 24h
C protein
if you’re treating with insulin and want to measure endogenous insulin - measure C peptide because it’s secreted with insulin!!
C peptide removed end up with active insulin: 2 separate chains (A+B) joined by disulfide bonds
C peptide is secreted along with active insulin à measuring C peptide is a way to measure how much active insulin a person is secreting if that person happens to be treated with exogenous insulin
insulin on carb metabolism
anabolic
stimulates
- glucose transport in adipose/muscle
- rate of glycolysis in adipose/muscle (breakdown of glucose for E)
- glycogen synthesis in adipose/muscle/liver
inhibits
- glycogen breakdown in muscle/liver
- rate of glycogenolysis (breakdown of glycogen to glucose) and gluconeogenesis (generation of glucose from other things) in the liver
Why does T2D worsen over time?
beta cell function worsens
insulin resistance remains relatively constant
delta cells
secrete somatostatin
inhibit insulin and glucagon secretion (vs. in pituitary, where somatostatin is also inhibitory)
less of them
cellular mechanism for insulin secretion in response to glucose
baseline: insulin + C in secretory granules, K is able to easily leave the cell, reg by ATP:ADP - glucose doesn’t do it directly
1. glucose enters beta cell, is phosphorylated and goes through cycle to be made into ATP
2. increase in ATP –> K channels and inhibits (closes) them, no more K can enter
3. Increased intracellular K (because it can’t leave)
4. change in membrane potential (depolarization) –> opens Ca channel, Ca influx
5. Ca sstimulates vesicles to fuse with the membrane and secrete calcium, beta cells begin making more insulin
beta cell mass
Individuals that are obese and normal versus lean and normal have a much higher beta cell volume, again because these individuals tend to be insulin resistant.
So the beta cells tries to compensate to a very large degree. However the ability of the beta cell to compensate is short lived, and over a period of time the volume of the beta cell tends to decrease as the individual progress from normal glycemia to prediabetes to the diabetic state.
SGLT2 inhibitors mechanism
i.e. Invokana
90% of glucose is reabsorpbed early in PT by SGLT2, resorptive capacity of the kidney becomes overwhelmed at 180
if inhibit SGLT2, glucose spills in urine and lose it
major effects of glucagon
catabolic effects
- break down glycgoen (to glucose), protein (to AA), TG (to FFA)
- make glucose and ketone bodies
where is there hormone insensitive glucose utilization
brain
blood cells
[hormone sensitive in liver, muscle, adipose]
pathogenesis of T2D
two defects
impaired insulin secretion
insulin resistance (hepatic/muscle/fat)
glucagon n skeletal muscle
catabolic
- break down protein to AA
- take up ketone bodies and fatty acids to use for E
insulin signalling cascade
- insulin binds R, tyrosine kinase –> conformational change and auto-phosphorylate beta domain
- IRS binds beta subunit
- IRS is phosphorylated by beta domain
- P on IRS activates PI3 kinase
- PI3 kinase phosphorylates PIP2 to PIP3 (on plasma mem)
- PIP3 is a binding site for both PDK1 and PKB/Akt
- PDK1 phosphorylates Akt
- active PKB or Akt complex dissociates, active complex can carry out many actions that result from insulin binding to cell
reversibility of pre-diabetes
If you can identify people at this point earlier on [gold rectangle), before the slope of the curve really gets [accentuated?], you can reverse—this is the importance—you can reverse this without using medication. Once you get to this point [pink oval], where the beta cell function is really severely compromised, many of these individuals may not be able to reverse the disease process at all because the damage has already been done. And many of these individuals here may or will require medication.
glucagon in the liver
breaks down glycogen to glucose and FFA
atherosclerosis in diabetes
What we have on the bottom is kind of important, because we all think of macrovascular disease or mircrovascular disease as a function of having diabetes, and that’s of course true. But what often isn’t recognized is that as prediabtets is a very insidious latent process. It kind of goes on without any symptoms, under the radar screen. So does the atherosclerotic process. So you can see that individuals even before they develop diabetes already get deposition of atherosclerotic plaques. Many of these individuals will have microvascular disease at the time of their diagnosis. It doesn’t occur commonly, probably only about 10% of individuals with prediabetes have complications. But they do have complications, and they may have cardiovascular complications.
So if we talk about the treatment of diabetes and co-risk factors like hypertension and hyperlipidemia, the same adage, the same wisdom, applies to prediabetes. Because these individuals still have a hazard ratio, they have a greater risk of developing heart disease and stroke, even at a relatively minimal elevation of glucose levels above those that don’t have prediabetes. The importance of identifying an individual at risk of diabetes isn’t only for prevention of progression to diabetes, but it’s prevention of the developing more severe cardiovascular disease and mircovascular disease. So prediabetes is not a benign condition.
2 hour plasma glucose cut off for impaired glucose tolerace
140
