Block 3: Diabetes Physiology Flashcards
1
Q
Describe the structure of glucose?
A
- Monosac
- Hexose
- Pyranose ring
- C6H12O6
- Utilized in glycolysis pathway for energy
- Fasting: 70-100 mg/dL
2
Q
How is carb reg affected by diabetes?
A
Type 1: Complete loss of pancreatic insulin
Type 2: High/low insulin, poor tissue utilization
3
Q
What is the “common pathway” for metabolic fuels?
A
Acetyl-Coa
4
Q
What are the types of pancreatic islet cells?
A
- Insulin b-cells (70-80%)
- Glucagon a-cells (5-10%)
- Somatostatin delta-cells (3-5%)
5
Q
What are the characteristics of endocrine hormone signalling?
A
- Chemical regulators of cellular function
- Synthesized by endocrine glands
- Hormones act of target cell initiating a response important for physiology
6
Q
Describe the production of insulin?
A
7
Q
Describe how insulin is structured/processed?
A
Insulin chain folds on itself by disulfide bonds, C-Petide is cleaved from structure while A and B insulin chains remain intact
Both Insulin and the ‘C-Peptide’ are released from the granule
* C-peptide (last longer in the body) is a marker if insulin is being made
8
Q
What is the difference between basal and bolus insulin?
A
Basal: steady, low level of insulin produced throughout the day and night
Bolus: Higher amounts of insulin that are produced when blood glucose is increased, peaks after food intake
9
Q
Describe the control of pancreatic hormones?
A
Glucose: ↑ B-cell insulin (primary)
Catecholamines: ↓ insulin and ↑ a-cell glucagon
A-adrenergic: ↓ insulin (dominant tone)
B-adrenergic: ↑ glucagon (dominant)
10
Q
Describe the insulin feedback system?
A
11
Q
Describe how insulin is released from beta-cells?
A
12
Q
Describe the binding of insulin to receptor? Slide 20
A
Activation of cytoplasmic tyrosine kinase initiates insulin singal transduction at the b-subunit of the insulin receptor
- Insulin bonds to a-subunit of the cell surface receptor
- Insulin binding activates tyrosine kinases on cytoplasmic side, autophosphorylating the receptor
- The activated TK receptor phosphorylates the ‘Insulin Receptor Substrate-1’ (IRS-1)
13
Q
Describe the activation of insulin receptors?
A
Primary action of insulin in muscle and fat for reducing plasma glucose levels
14
Q
What are the the glucose “facilitated” transporters
A
GLUT 1: Most abundant in brain and kidneys
GLUT 2: Glucose sensor, low affinity in b cells and liver
GLUT 3
GLUT 4: Insulin stimulated glucose uptake in the muscle and adipose
15
Q
How does SGLT mediate glucose reabsorption?
A
- Na/K ATPase creates an “energy” gradient with Na+
- Allows glucose to be absorbed against concentration gradient using sodium influx in 2:1 (secondary active transport)
16
Q
Describe the importance of SGLT?
A
SGLT1 is in the straight section of the proximal tubule (S3)
SGLT2 is in the convoluted section of the proximal tubule (S1).
90% of glucose absorption in the kidney is mediated by SGLT2
17
Q
Compare the the differences between SGLT1 and 2?
A
18
Q
What kind of hormone is insulin?
A
Anabolic hormone by increasing energy storage:
Insulin increases fuel storage (↑ anabolism)
Insulin decreases breakdown of fuel (↓ catabolism)
19
Q
What pathway is affected by insulin?
A
- Glucose metabolism
- Glycolytic pathway
20
Q
When does glucocon levels dominate over insulin? How?
A
Fasting state metabolism
1. ↑ Glycogenolysis
2. ↑ Gluconeogenesis
3. ↑ Ketones for lipolysis
All used in ↑ plasma glucose for brain and peripheral tissues
↓ Insulin provides precursors for glucagon activation
21
Q
Where does glucagon primarily act?
A
Liver: glucagon acts to prevent hypoglycemia by increasing plasma glucose and break down fuel stores
22
Q
What kind of hormone is glucagon?
A
Catabolic: increase utilization of fuel storage
Increased lipolysis: B2 and 3
Decreased glycogenesis: a1, B2
Increased glycogenolysis and gluconeogenesis
23
Q
Why are counter-regulatory hormones so important in a diabetic patient?
A
They provide synergistic effects
24
Q
What are the counter-reg hormones?
A
- Glucagon
- Cortisol
- Epinephrine
- Growth hormone
25
What happens during the fed-state?
Increased insulin:
1. Increase glucose uptake in muscle and fat
2. Increase fat storage
3. Increase glycogenesis in liver
4. Blocks and prevents actions of glucagon
26
What is the function of postpranial plasma glucose? How is this affected in diabetics?
1. Rate of carbohydrate digestion
2. Gastrointestinal hormones
3. Plasma insulin levels
4. Muscle uptake and utilization of glucose
**Earliest abnormality seen in diabetes in postprandial hyerglycemia**
* Glucose intolerance or IGT
27
What is IGT?
1. Impaired ability to handle dietary carbs
2. Rise in plasma glucose that occurs after eating carb is greater than normal
Considered an intermediate state between normal glucose and pre-diabetes/diabetes
28
What is a marker for insulin resistance?
Glucose disposal rate decreases as IGT and T2DM progresses even at **identical plasma insulin levels**
29
What are the metabolic markers of impaired fasting glucose?
Blood glucose levels are elevated in the fasting state (>100) but not high enough to be classified as diabetes (>126).
Also an intermediate state
30
Why is pre-diabetes significant?
Cardiovascular risks equivalent to having diabetes
Increases risk of developing diabetes
31
What occurs during the fasting state?
Decreased insulin, increased glucagon:
1. Increase glycogenolysis
2. Increases gluconeogenesis
3. Increases free FA and ketogenesis
4. Increase proteolysis
All effect occur in order to feed the brain
**Diabetic metabolic decompensation is similar to the fasting state**
32
What are the characterisitcs of DM?
1. Metabolic disorder characterized by hyperglycemia
2. Defects in fat, carbs, and proteins
3. Defects in pancreatic insulin production, insulin sensitivity in the tissues or both
4. Progressive disorders resulting in long term chronic complications
33
What the types of DM?
T1, T2, gestational, mature onset diabetes in the young (MODY)
34
What are the characterisitcs of Type 1 DM?
b-cell destruction leading to absolute insulin def
1. Idiopathic
2. Genetic predisposition
3. Autoimmune
4. Ketoacidosis
35
What are the chracterisitcs of T2DM?
Insulin resistance with possible insulin secretory defect (obseity is a main cause)
36
What is gestational diabetes?
Impaired glucose tolerance during pregnancy is a marker of predisposition for type-2 diabetes
37
What is T3CDM?
1. Pancreotogenic DM
2. Loss of b-cell function leading to insulin def
Caused by:
1. Pancreatitis
2. Pancrease removal
3. CF
4. Hemachromatosis
38
What are the presentation of T1DM?
1. Low or diminished C-peptide (severe or complete insulin def)
2. Ketoacidosis
3. Signs of dehydration
4. Onset of sx bay be rapid
**Precipitating or presenting events (three-polys):**
2. Polyuria
3. Polydipsia
4. Polyphagia
39
What is the difference between T1 and T2?
40
What are the causes of T1DM?
1. Genetic predisposition (HLA-linked genes and other genetic loci_
2. Environmental insult (Viral infection and/or damage of beta cells)
41
What are the diabetic HLA polymorphisms?
DR3 and DR4
42
Antigens from extracellular proteins are derived from what peptides?
MHC class II
43
Describe the events of b-cell destruction?
1. Foreign antigens binds with MHC complexes (both 1 and 2) are transported to cell surface of b-cel
2. T-helper cell receptor recognizes this complex (CD4 and 8) which sensitives the T cells and activates macrophages
3. CD8+ T cells are activated by interleukin-2 (IL2) and differentiate into cytotoxic T-cells.
4. Macrophages, activated by interferon (IFN- and IFN-), & tumor necrosis factor
(TNF-) act to destroy the pancreatic b-cells.
5. Beta cells can also be damaged by perforin released from CD8+ cytotoxic T cells
44
Describe the developments of T1DM?
45
What causes hyperglycemia?
1. Under-utilization of glucose
2. Over-production of glucose
46
What are the effects of insulin deficiency?
47
When would you start to see a glucose spill?
Serum glucose of 180-200 mg/dL
Elimination in urine (100g) due to glucose osmotic diuretic properties (5L of water)
48
What are the characteristics of diabetic ketoacidosis?
1. Commonly in T1DM
2. Decrease in insulin and increase in glucagon
3. Maximal gluconeogenesis (increased production) with impaired utilization
4. Activation of the ketogenic process and development of a metabolic acidosis
49
What is ketogenesis?
High glucagon/insulin ratio:
Increased liberation of FFAs due to the loss of the inhibiotry action of insulin on the hormone sensitive lipase
50
Describe how keton bodies form?
1. Increased liberation of free fatty acids (FFAs) due to the loss of the inhibitory action of insulin
2. **(Carnitine Palmitoyltransferase-1 (CPT-1)) activation** that allows long chain FFAs to reach beta-oxidative enzymes in mitochondria where ketone production occurs
3. This results in ketogenesis and high circulating levels of b-hydroxybutyrate, acetoacetate (both weak organic acids) and acetone (fruity breath
Transport to Mitochondria and Activation of CPT-1
51
What are the clinical presentations of ketosis?
1. Anorexia
2. Polydipsia
3. Polyuria
4. Stupor, coma
5. Abdominal pain
6. **Kussmaul breathing (acetone/fruity breath)**
7. Dehrydration/volume depletion
8. Hyperglycemia (>300 and pH <7.3)
9. **Potassium may be normal or elevated, but is misleading due to large total body potassium deficit (diuresis and increased ADH)**
* Hypokalemia: cardiac arrhythmias and arrest
* Hyperkalemia: cardiac arrest
52
What are the RF of T2DM?
1. Age
2. Obesity
3. PA
4. Family hx
5. Pace
6. Pre-diabetes (impared fasting glucose and glucose tolerance)
7. Gestational diabetes
8. Metabolic Syndrome
53
What is the age of T2DM risk groups?
Greater than 40 YO
However, fastest growing age group is teens and YA
54
What are the genetic components of T2DM?
Increased incidence in first degree relatives with Type 2 diabetes
High risk groups include: Aboriginal, Maltese, Native Americans, Polynesian, African Americans.
55
What are the characterisitcs of T2DM risk groups?
**Obesity:** common risk factor
* Adiposity: BMI
* Overwieght: 25-30, Obese >30
**Waist circumference:** men >102, women >88
**Past hx of gestational diabetes**
56
What is the number one risk factor for T2DM?
Obesity
57
Diabetes is the leading cause of:
1. Renal failure
2. New cases of blindness
3. Nontraumatic amputations
58
How many people have Prediabetes in the US?
96 million
59
What are the presentations of T2DM?
1. Gradual and insidious
2. Triple poly
3. Hyperglycemia
4. Hyperosmotic Hyperglycemic nonketotic State (HHS)
Long-term
1. Retinopathy
2. Renal dysfunction
3. Nephropathy
4. Neuropathy
60
Describe the MOA of T2DM?
61
Describe IGT and IFG in relation to T2?
**IGT** is an impaired ability to appropriately manage dietary carbohydrates:
* The rise in plasma glucose after eating carbohydrates is greater than normal.
**IFG** is a consistently elevated fasting blood glucose level
Both are indicators of resistance and intermediate state
Early diagnosis leads to beter CV outcomes
62
What are the presentation of insulin resistance in T2?
Greater than normal amounts of insulin are required to produce a normal biological response:
* Muscle/fat: impaired glucose uptake
* Liver: Impaired glycogenesis, increased glucose production
* Pancreas: compensated with hyperinsulemia and elevated C-peptide
63
What is secondary b-cell failur?
Hyperinsulemia -> b-cell failure -> Worsening hyperglycemia and secondary failure of oral secretagogues, such as sulfonylureas.
Exhaustion of cells
64
What are the secondary events of long term T2?
1. Delay in secretion
2. Loss of B-cell response to glucose
3. Glucagon excess
4. Amylin
5. Reduced circulating levels of incretin (GIP/GLP1)
6. Absolute decrease in amount of insulin secreted
* Loss or burn out of insulin secreting b-cells (exhaustion)
65
What is gestational DM?
Any degree of glucose intolerance with onset or first recognition during pregnancy
66
What are the risk factors of GDM?
1. Family with T2DM
2. African American, Native American, Asian, Hispanic, or Pacific Islander
3. 25 YO or older
4. Overweight
67
What are the consequences of gestational diabetes?
**Offspring:**
1. Macrosomic baby (difficult delivery)
2. Neonatal hypoglycemia
**Long term on offspring:**
1. Increased risk of obestiy
2. Increased risk of diabetes as an adult
68
What are the acute metabolic complications of diabetes?
1. Hypoglycemia coma (iatrogenic)
2. Diabetic ketoacidosis (DKA, primarily type 1)
3. Hyperosmolar non-ketotic coma (HHS, primary type 2)
69
What do you do if your unsure if patient is hyperglycemic or hypoglycemia?
When in doubt treat as if **hypoglycemic**
**Never give an unconscious patient insulin**
70
Why is hypoglycemia dangerous?
An acute, life threatenign problem for diabetic practicing **tight** glucose control
<50mg/dL: Cognitive dysfunction
<30mg/dL: induce coma
**Severe:** 15 mg/dL
**Death if not treated**
71
What are sx of hypoglycemia?
1. Confusion
2. Coma
3. Weakness/HA
4. Lassitude
5. Morning HA
6. Tremor
7. Shakiness
72
What are the acute conditions of hyperglycemia?
1. Diabetic Ketoacidosis (DKA) (T1)
2. Hyperosmolar Hyperglycemic State (HHS) (T2)
3. Morning hyperglycemia (fasting): dawn phenomenon, somogyi effect
73
What are the presentation of Diabetic ketoacidosis?
Can be observed in type-2 diabetics under stress and patients taking SGLT-2 inhibitors
74
What are the presentation of Hyperosmolar Hyperglycemic Nonketotic State?
1. Hyperosmolar Hyperglycemic State (HHS)
2. Hyperosmolar Hyperglycemic Nonketotic State
Extreme hyperglycemia over time
75
What are the complications of DKA, HHS Tx?
1. Cerebral edema
2. Hyperkalemia
3. Hypokalemia
4. Infection
5. Hypoglycemia
76
What are the morning hyperglycemia types?
**Dawn phenomenon**
**Somogyi Effect**
77
What is dawn phenomenon?
Bedtime glucose levels are normal -> see normal or elevated glucose levels during the middle of the night (around 3 AM) -> but then see hyperglycemia in the morning
**Increase basal insulin dose**
78
What is Somogyi effect?
**rebound hyperglycemia**
Bedtime glucose levels are normal -> see low glucose levels during the middle of the night (around 3 AM) -> but then see hyperglycemia in the morning
Too much “basal” insulin at night
Rebound hyperglycemia due to ↑ in counter regulatory hormones and ↑ hepatic glucose production
79
Poor glycemic control and hyperglycemia leads to?
Primary cause of many long term complications related to diabetes
80
Factors that increase risk of diabetic complications?
1. Inactive
2. Overweight
3. Poor blood sugar control
4. Uncontrolled bp
5. High cholesterol
6. Smoking
81
What are the outcomes of glycosylation of proteins?
Dysfunctional and reactive proteins
82
What are the examples of glycosylated proteins?
1. Glycosylated Hb (HbA1C)
2. Basement membrane collagen (glomerulus, capillaries)
3. Glycosylated myeline and neuronal proteins
83
How is a glycosylated protein formed?
**Advance glycosylated end-products (AGEs)** are slow irreversible chemical rearrangements of glycosylated protein that can cross-link proteins, altering the function permanently
84
Describe the polyol pathway?
1. Activated by excessive glucose
2. Aldose reductase converts glucose to D-sorbitol
3. Sorbitol is converted to D-fructose
4. D-sorbitol and D-fructose are non-diffusable sugars
85
86
What are the microvascular complications of diabetes?
1. Retinopathy
2. Nephropathy
3. Autonomic and sensory neuropathy
87
Diabetic retinopathy is the leading cause of what?
Blindness
88
What underlies microvascular complications of diabetes?
Vascular microangiopathy
89
What are the stages of retinopathy?
1. Non-proliferative/background
2. Pre-proliferative
3. Proliferative
90
What is non-proliferative retinopathy?
1. Opthalmoscope is used
2. Retinal microaneurysms (2 yr onset)
3. Blot hemorrages and macular edema
4. Hard exudates
91
What is pre-proliferative retinopathy?
Lesions related to ischemia
1. Cotton wool spots
2. Intraretinal microvascular abnormalities are the earliest signs of neovascularivation
92
What is proliferative retinopathy?
Photocoagulation may reduce the level of Vascular Endothelial Growth Factor (VEGF) elaborated by the peripheral, poorly perfused retina
Leads to vitreous hemorrhage and retinal detachment
93
What is the treatment for proliferative retinopathy?
Laser phocoagulation reduces the risk of severe visual loss by 50%
94
95
How is the polyol pathway affect the diabetic retinopathy?
1. Prolonged activation leads to pericyte death from osmotic damages
2. New blood vessels bud in areas of pericyte deterioration -> neovascularization and proliferative retinopathy
96
What is the difference between autonomic and peripheral sx of diabetic neuropathy?
Autonomic: urinary incontinence, gastric stasis, othrostatic hypotension
Peripheral: Development of foot ulcers and lower extremity amputations
97
What causes foot ulcers and amputations in diabetic patients?
Microvascular disease (poor perfusion) and secondary neuropathy (poor sensation)
98
99
How is the stomach affected by autonomic neuropathy?
Gastroparesis: delayed emptying of the stomach
100
Mortality from all causes in ESRD patients ____ higher than in those without renal dysfunction
20X to 40X
101
Hyperglycemia in diabetic nephropathy is caused by?
Glomerular and tubule basement membrane glycosylation and thickening
102
What are the lab presentations of diabetic nephropathy?
1. Proteinuria
2. Microalbuminuria (excretion of 30–300 mg/day)
20X higher risk of developing nephropathy than in normoalbuminuric patients
103
Describe the overall complications of diabetes?
Eye damage
Kidney disease
Nerve damage
Foot damage
**Leads to**
Infections
Slow wound healing
Gum disease
Erectile dysfunction
104
What are the macrovascular diseases of diabetes?
1. Hypertension
2. DLD
3. Vascular inflammation
4. Thrombolic risk
5. Atherosclerosis
**Heart disease is the main determinant of life expectancy in diabetic patients**
105
What disease state is the leading cause of premature death in diabetics?
Coronary heart disease
106
What are the characteristics of atherogenic DLD?
1. Elevated TG
2. Reduced HDL
3. Normal to elevated LDL
* Increased oxidation of LDL
* Oxidized LDL
107
What is metabolic syndrome?
A complex interrelationship of metabolic abnormalities related to insulin resistance associated withan increased risk of coronary artery disease
108
How do you minimize cardiovascular risk factors?
1. Control HTN
2. Statins for at risk patients
3. Aspirin 81 mg daily
109
What is the best way to reduce long term diabetic complications?
Glycemic control
110
What is the clinical trial that studied T1D?
The Diabetes Control and Complications Trial (DCCT)
111
What is the clinical trial that studied T2D?
UK Prospective Diabetes Study (UKPDS)
