Quiz 3 DM Flashcards
1
Q
Define Type 2 DM
A
- Decreased insulin production, and or inability to use normal levels of insulin (insulin resistance) and or increased gluconeogenesis
- Most patients have insulin deficiency
2
Q
What symptoms are related to poorly controlled blood glucose?
A
- Glucosuria anf polyuria (high urine [Glucose] and urine output
- Polydipsia (extreme thirst)
- Dehydration
- Weight loss, fluid depletion and lipid breakdown secondary to insulin deficiency in Type 1 DM
- Hyperphagia (increased appetite)
3
Q
Impaired fasting glucose range?
A
- 5.6-6.9 mmol/L (100-125 mg/dL)
4
Q
HHS Hyperglycemi State
Primarily seen in?
A
Patients with Type 2 DM
5
Q
Explain the insulin signaling mechanism and its effect on muscle and fat tissue.
A
Insulin monomer
-
Receptor
-
Cascade
-
This stimulates the tranlocation of intracellular vesicles containing GLUT-4 transport to allow for the uptake of glucose into those tissues.
Without this muscle and fat tissue have no way of taking in glucose
6
Q
Risks for Hypoglycemia Frequently arise from Exogenous Sources 6 ways
A
- Excess insulin dose, poorly times relative to glucose load or wrong formulation, poor timing of sulfonylurea dose relative to meals
- Poor attention to maintain blood glucose (Infrequent snacks, especially before overnight fast)
- Excessive exercise without attention to insulin dosage, glucose us exceeds rates of glycogenolysis and gluconeogenesis (distance runners)
- Changes in insulin sensitivity
- Alcohol-induced decrease in endogenous glucose production
- Insulin clearance is reduced, renal disease
7
Q
Role of Glucocorticoids (GCs) in Affecting Glucose and Lipid metabolism
GCs increase glucose into the circulation to fuel the brains what 4 ways?
A
- Increase hepatic gluconeogenesis
- Decrease glucose uptake into the muscle and adipose
- Increase the breakdown of fat and muscle to fuel gluconeogenesis
- Inhibit insulin release from B-cells
8
Q
ADA recommends that all people >__ yrs be evaluated every __ yrs and earlier if what risk factors are present?
A
- 45, 3
- Family history, Race/ethnicity
- Onesity or BMI >= 25 kg/m^2
- Habitual inactivity
- History of gestational DM or baby birth weight > 9 lbs
- Cardiovascular issues, high triglycerides (>250) and or low HDL Cholesterol (<35 mg/dl)
9
Q
Mature Onset Diabetes of the Young (MODY)
A
- All of these are relatively rare and they all show dysfunction in the Beta cell.
10
Q
If insulin weighs down the teeter totter and doesnt allow glucagon to play what happens?
What if glucagon weighs it down?
A
- Severe hypoglycemia and death occurs
- Severe diabetic ketoacidosis-death
11
Q
Explain the incretin effect
A
Insulin secretion is stimulated much more when glucose is taken orally rather than when taken intravenously so as to result in similar plasma concentrations
12
Q
DKA diagnostic triad?
A
- Hyperglycemia (250-600 mg/dl)
- High level of plasma ketone bodies (from fatty acid oxidation)
- Metabolis acidosis (pH 6.8-7.3)
13
Q
What are insulins effects on gluconeogenesis, glycogenolysis, glycogenesis, Lipogenesis, lipolysis, Protein synthesis, fatty acid oxidation, Triglycerides, proteolysis
A
- Gluconeogenesis- Inhibition
- Glycogenolysis - Inhibition
- Glycogenesis - Stimulation
- Lipogenesis - Stimulation
- Lipolysis- Inhibition
- Protein synthesis - Increase
- Fatty acid oxidation- Decrease
- Triglycerides- Increase
- Proteolysis- Blocks
14
Q
Hypoglycemia-Associated Autonomic Failure (HAAF)
2nd defense
Defective glucose counter regulation
A
- Glucagon response to falling glucose levels is abnormal- becomes progressively worse as duration of DM
- Mechanism of abnormal glucagon secretion from a-cells is not known, linked to insulin deficiency per se since glucagon levels in pancreas may be normal
15
Q
Go through the insulin signalling mechanism
A
- Insulin binds to tyrosine kinase which phosphorylates it
- The net result is transloation of Glut-4 transporter where then glucose can be taken up by the cell and utilized, GLUT 4 is present in Muscle and Fat and is dependent on GLUT-4 for glucose usage.
16
Q
Glucokinase has a very high ___ for glucose and it rapidly falls as?
A
KM
falls as glucose falls
17
Q
What are the Incretin GLP-1 modes of action?
Theres 6 but really only 5
A
- Stimulates glucose dependent insulin secretion
- Suppression of glucagon
- Slows gastric emptying
- Enhances satiaty and reduces food intake
- Improves insulin sensitivity
- Promotes B-cell neogenesis in animal models
18
Q
Triple Whammy of DKA
3) Metabolic Acidosis
A
- Ketone bodies are relatively strong acids (pKa 3.5) and are buffered by plasma bicarbonate
- As bicarbonate levels decrease metabolic ketoacidosis ensues
- Ketone bodies excreted in urine and via hyperventilation (Kussmaul breathing) to compensate for metabolic acidosis (Fruity breath)
Life threatening Emergency
19
Q
The endocrine pancreas is responsible for?
A
- The production of insulin and glucagon, into pancreatic veins
20
Q
What are the clinical classfications of impaired fasting glucose?
Normal
Impaired
Diabetic
If you have impaired fasting glucose you arent diabetic
A
- FPG < 5.6 mM (100 mg/dl) – Normal
- FPG > 5.6 mM but less than 7.0 mM (126 mg/dl) —- IFG
- FPG > 7.0 (126 mg/dl)
21
Q
Distinction between DKA and HHNKS?
A
22
Q
Interrelationship of Glucose Recovery to Major Symptoms of DM.
A
- Polyuria, glycosuria/glucosuria
- Polydipsia
- Dehydration
- Weight loss
- Hyperphagia (increased appetite)
23
Q
If you have a mutation in the SGLT2 transporter you can have?
In DM individuals, glucose transport is rate limiting and recovery of excess glucose during hyperglycemia is insufficient this produces?
A
- renal glucosuria
- Glucosuria
24
Q
What is the criteria for the diagnosis of diabetes?
There are 4 possible options
A
- A1C >= 6.5%
- FPG>= 126 (7.0 mmol/L) Fasting is defined as no caloric intake for at least 8 hours
- 2 hour plasma glucose >= 200 mg/dl (11.1 mmol/l) during an OGTT. Glucose load should contain 75 g anhydrous glucose dissolved in water
- In patients with classic symptoms of hyperglycemia or hyperglycemic crisis a random plasma glucose >= 200 mg/dl (11.1 mmol/l)
25
In patients with type 2 Diabetes what does the incretin effect do? What does this contribute to in the disease?
* Incretin production is either greatly impaired or absent in Type 2
* This contributes to the inability of pts to adjust their insulin secretion to their needs
* GIP is normal but GLP-1 is reduced and the B-cells tend to become decreasingly responsive to the incretins
26
SGLT2 inhibitors are an attractive target to help manage glucose levels in DMs because?
No long-term problems have been shown in non DM individuals
27
Insulin is produced in a 1:1 molar ration with?
C-peptide
28
Behavioral response to glucose deprivation in CNS?
Neuroglycopenic mildly happens first
29
The physiological action of insulin?
Fatty acid oxidation?
Triglyceride formation?
Inhibits the breakdown of?
Protein synthesis?
Blocks synthesis of glucagon which is the main hormone controlling glycogenolysis and gluconeogenesis. It also increases glycogenesis
* Decreases fatty acid oxidation and free fatty acid levels in blood, we have plenty of glucose sense insulin is being released so there is no reason to oxidize fatty acids for energy
* Increases triglyceride formation in fat cells
* Inhibits the breakdown of muscle protein (Proteolysis)
* Increases protein synthesis
30
There is a readily releasable pool of Insulin to compensate for the sharp increase of glucose intake during eating what does this cause?
Causes a sharp increase of insulin in the initial phase helping to regulate Blood glucose more effectively.
31
Treatment of DKA?
* Short acting insulin should be admin to reduce blood glucose and correct acidosis
* K+ stores are depleted in DKA, K+ repletion to prevent cardiac failure but serum K+ need to be corrected to \>= 3.3 mM prior to insulin infusion
* Fluid replacement- restore circulating volume and maintain renal function to excrete glucose
* Rehydration alone is not sufficient in absence of insulin
32
Amylin is secreted with?
What is the net effect of amylin?
Insulin
Effect is to slow the influx of both endogenous and exogenous glucose into blood and help mathc glucose concentrations with the rate of insulin-induced glucose clearance
33
Hypoglycemic unawareness 3 things
1. Lack of awareness or inattention to symptoms of oncoming hypoglycemia with concomitant failure to ingest sufficient glucose to rectify sympomolgy
2. Results from loss of perception of neurogenics symptoms and chane in glycemic threshold for producing neurogenic symptom. The patient might be used to feeling hypoglycemic and this would cause them to not realize
3. Reduce autonomic responses in type 1 individuals (epinephrine response) may further exacerbate onset
34
Pre-diabetes, Impaired Fasting Glucose (IFG) Impaired Glucose Tolerance (IGT)
* A state of tolerance (utilization) that falls between the normal range and true diabetic state
* Often precedes the development of Type 2 DM
* Not relevant to Type 1
* Is not strictly associated with body mass and can occur in individuals not medically considered over-weight
35
DKA
Diabetic Ketoacidosis
Seen in type 1 mostly but can be seen in type 2 patients often hispanic or AA
36
The exocrine pancreas is responsible for?
Degradation of Carbohydrates and other things
Pancreatic duct ---\> Duedenum
37
WHat can cause neuroglycopenic hypoglycemia?
* Poor rates of gluconeogenesis and limited glycogen stores, its glucose deprivation to the CNS
38
Perception of physiologic changes caused by ANS activation in response to falling blood glucose
Autonomic response- Hunger, sweating, tremor, palpitations
Neurogenic
39
FPG is the general method of screening especially type 2 DM since?
* Many individuals are asymptomatic and Type 2 DM may be present for 10 years prior to diagnosis
* Diabetic complications usually bring patient to physician prior to actual diagnosis of DM
* Early treatment by modification of diet and implementation of appropriate exercise regimens can dramatically alter disease progression.
40
OTC products for treating Low Blood Glucose?
* BD glucose tabs
* Dex4 glucose gel and tab
* Dex4 liquid blast glucose liquid in a 2 oz bottle
* GlucoBurst GLucose gel and tab
* Glutose 15
* 15 g dose for initial treatment to self treat hypoglycemia
* Wait 15 minutes and test blood glucose
* If still below 70 mg/dL take another 15 g
* Get to hospital if it doesn work after 30 g
41
Effect of glucagon on the liver and muscle
* Increases glycogenolysis
* increases gluconeogenesis
* LIVER
* Muscle
* Increases proteolysis
Increases fatty acid oxidation
42
SGLT2 is largely responsible for?
Glucose reabsorption
43
Effect on insulin in muscle
Glucose uptake \_\_\_\_
Glucose oxidation \_\_\_\_
Glycogen Synthesis \_\_\_\_
Net result?
* Increase glucose uptake
* Increase glucose oxidation
* Increase glycogen synthesis
**Net result is increase glucose uptake by muscles**
This process is when blood glucose needs to be lowered in the blood
44
Symptoms of diabetic ketoacidosis?
* N/V, polyuria, abdominal pain, fever, fruit breath, CNS depression, shortness of breath, unexpained hyperglycemia, tachycardia, tachypenia
45
What is the overall effect of insulin being in the liver?
Decrease hepatic glucose production
46
Both insulin deficiency and glucagon excess are required for what to develop?
DKA
Messed up ration promotes glycogenolysis, gluconeogenesis, and formation of ketone bodies
47
Risk of Hypoglycemia assoicated with Endogenous Sources are fairly rare. What are the 3 potential causes?
* Organic hypoglycemia due to insulinoma (tumor in B-cell)
* Other non-pancreatic tumors that may indirectly affect glucose homeostasis, hepatomas, adrenocortical adenomas
* in born errors of metabolism
48
Gestational DM
* Temporary development of impaired glucose tolerance during pregnancy.
49
The main Insulin responsive tissues are? What does insulin do in these tissues?
Skeletal muscle tissue and fat
Insulin stimulates glucose uptake and utilization
50
Hypoglycemia-Associated Autonomic Failure (HAAF)
1st defense?
* Ability of insulin levels to decrease as blood glucose decreases - loss in type 1 DM as insulin levels are a function of pharmacokinetics of insulin formulation administration
51
What are incretins?
Gut hormones which strongly potentiate b-cell insulin secretion induced by rising blood glucose following **oral** intake.
52
Since co-transport occurs with __ Ions, the action of what pump drives glucose transport via SGLT2.
Glucose then exits the S1 segment of the proximal renal tubule through?
* Na ions
* Na+/K+ ATPase pump
* GLUT-2
53
Gluconeogenesis is stimulated by? and Inhibited by?
What is required for this process to happen?
Glucagon and Epinephrine, Insulin
* Requires coordinated supply of precursors from
* Liver (acetyl CoA from fatty acid metabolism)
* Muscle (lactate, pyruvate, alanine and other amino acids from protein breakdown)- Cori Cycle
* Adipose (Glycerol from TG), Free fatty acids released from TG metablism can be used by other tissues (not Brain) for energy production
54
90% of filtered glucose is reclaimed by?
Sodium-glucose transporter 2
SGLT-2
55
When insulin is produced in response to glucose what happends to? LIVER
Glycogen Synthesis \_\_\_\_
Gluconeogenesis \_\_\_\_
Glycogenolysis \_\_\_\_
This process is not dependent on insulin but?
* Increase in glycogen synthesis
* Decrease in gluconeogenesis (production of glucagon)
* Decrease Glycogenolysis (Degradation of glycogen) - Since we are producing glycogen it wouldnt make sense to be degrading it.
Insulin stimulates glucose utilization
56
Hyperglycemic Hyperosmolar State
Most often seen in elderly and?
Often display profound?
Hyperglycemia induces? What else similar to DKA?
Normal to slight ____ in plasma pH?
* Type 2 DM
* Dehydration, hyperglycemia, hyperosmolarity, hypotension, cognitive disorientation
* Osmotic diuresis, resulting in polyuria similar to DKA,
* increased in plasma pH, hypokalemia,
* Concurrent with other illnesses
* Insulin deficiency and inadequate fluid intake are underlying causes
* Absence of ketosis likely due to sufficient insulin secretion to prevent excessice ketone body formation
57
Elevated Glycemic Threshold 3 things
1. Recurring incidence hypoglycemia can lead to further reduction in autonomic responses causing a threshold shift that elicits epinephrine release at increasingly lower blood glucose concentrations
2. Reduced threshold of epinephrine counter-regulation can be reset through tight avoidance of hypoglycemia over 2-4 week period
3. Best treatment is pt education, self monitoring of glucose, flexible insulin regimens, obtainable glycemic goals and strong professional oversight
58
Go through the pathway of Insulin release within Beta cells
59
Pancreatic Beta Cell distruction causes?
net result?
* Lack of Insulin and increase in glucagon
* Decreased glucose utilization
60
Hypoglycemia-Associated Autonomic Failure (HAAF)
3rd defense
* Epinephrine response to hypoglycemia decreases
* Adrenergic blockade usually not a problem unless the patient also has a blunted glucagon response
* May be exacerbated if pt has developed an autonomic neuropathy
* loss of latter two can increase rate of hypoglycemia 25 fold
61
SGLT-1 is mainly responsible for absorption od glucose from the?
Intestines with 10% renal
62
Most important secondary molecule in postprandial insulin release?
Incretin
63
Glucagon-like peptide-1 (GLP-1) released form where in what?
What are the 6 modes of action of GLP-1?
L-cells in the ileum
1. Stimulate glucose-dependent insulin secretion
2. Suppressess glucagon secretion in a glucose-dependent manner
3. Slows gastric emptying
4. Enhances satiety and reduces food intake
5. Improves insulin sensitivty
6. Promotes B-cell neogenesis and proliferation in animal models
64
It is important to note that uptake of glucose in the liver is?
Non-insulin dependent
65
Triple Whammy of DKA
1. Insulin Deficiency causes:
* Increased glucagon and catecholamine secretion
* Increased glucagon and catecholamines stimulate glycogenolysis
* Increased glucagon and catecholamines stimulate hepatic gluconeogenesis
* Reduced ability of glucose utlization via skeletal muscle leading to **hyperglycemia**
66
What is type 1 DM?
* Body does not produce any insulin
* Often first sign of diabetes especially in children is ketoacidosis
67
Triple Whammy of DKA
## Footnote
2) Ketosis
Adipose--\>Free Fatty Acids ---\> Liver ----\> Ketones ----\> Pancreas
No regulation by insulin
68
Proglucagon is differentially processed by L-cells to ____ compared to processing to mature ____ in pancreatic __ cells
* L-cells to GLP-1
* mature glucagon in a-cells
69
Three tiers that occur at certain thresholds of blood glucose?
What is the primary factor?
1. Decrease in insulin as blood glucose decreases (83 mg/dL)
2. Increase in glucagon as blood glucose decreases (68 mg/dL)
3. Increase in epinephrine can complement action of glucagon but is not critical unless glucagon secretion or action is impaired (69 mg/dL)
Glucagon is the primary factor
70
Insulin is processed as?
A single gene
71
Physiology of amylin?
4 points
1. It complements the actions of insulin
2. Suppresses postprandial glucagon secretion
3. Slows gastric emptying
4. The net effect of amylin is to slow the influx of both endogenous (gluconeogenesis) and exogenous (meal driven) glucose into the blood and help match glucose concentration with the rate of insulin induced glucose clearance.
72
What is the main contributing factor for Hypoglycemia?
* Loss of homeostatic counter regulatory mechanisms and autonomic dysfunction contributing to hypoglycemic unawareness
73
In patients with type 2 DM incretin is?
* Either impaired or completely absent
* Beta cells become continuosly unresponsive to incretins
74
What are the Secondary causes of DM?
* Pancreatic Disease, Pancreatitis, and pancreatic cancers
* Endocrine disorders- Cushings disease (Pituitary tumor- adrenocorticotropic hormone and cortisol overproduction leads to insulin resistance)
* Glucagonoma (a cell tumor)
* Genetic-lipoatrophic diabetes
* Drugs, glucocorticoids diuretics, B-blockers
75
Hyperglycemia symptoms?
Gold standard for long term control of blood glucose?
* High blood sugar, levels of glucose in the urine, frequent pee, increased thirst
* measure of glycated hemoglobin (HbA1c) control over the last 3-4 months
76
Both DKA and HHS are associated with?
Absolute or Relative insulin deficiency, changes in plasma osmolarity (volume depletion) and disruption of acid-base balance with (DKA) or without (HHS) ketosis
77
Explaine the Incretin effect
* Incretins are gut hormones that strongly potentiate Beta Cell insulin secretion during **ORAL** glucose intake
* The effect is that when glucose is consumed orally as opposed to IV there is a much more dramatic amount of insulin secreted resulting in a inhibition of glucagon.
78
Clinical Presentations of Impaired Glucose Tolerance?
* Blood glucose between 140-199 mg/dl two hours after oral ingestion of 75 g glucose load
