Diabetes Flashcards
First phase insulin release: When does it occur?
During the “cephalic phase” - within first ten minutes of eating
What is normal blood glucose?
What does blood glucose need to be to spill into the urine?
100 = normal
300 = into urine
Four characteristics of Type 1 Diabetes
- 10% of all diabetes patients
- Usually autoimmune disorder
- Affects production of insulin: Absolute insulin deficiency due to Beta-cell destruction
- Idiopathic
2 characteristics of type 2 diabetes
- Insulin resistance with relative insulin deficiency
* Accounts for almost 90% of diabetic patients
Syndromes that can create hyperglycemia: Mimic DM (7)
- Maturity-onset Diabetes of the young: MODY
- Exocrine Pancreatic Defects
- Endocrinopathies
- Infections
- Drugs
- Genetic Syndromes
- Gestational Diabetes
What is MODY? + 3 characteristics
Maturity Onset Diabetes of the Young:
o Group of disorders
o Represent genetic defects in beta cell function: Variety of mutations that produce defects in insulin production
o Manifest like a more mild version of Type 1 DM
4 exocrine pancreatic defects that can mimic Type I Diabetes
o Chronic pancreatitis
o Pancreatectomy
o Neoplasia
o Cystic Fibrosis
3 endocrinopathies that can mimic DM, and the hormone that causes elevated blood glucose
o Acromegaly
o Cushing Syndrome
o Hyperthyroidism
3 Infections implicated in triggering Type 1 diabetes
o Cytomegalovirus
o Coxackie Virus B (Hand, Foot, Mouth)
o Mumps
6 Drugs – when taken, elevate blood glucose, cause temporary hyperglycemia
o Glucocorticoids o Thyroid hormone o Alpha-interferon o Beta-adrenergic agonists o Protease inhibitors o Thiazides
Why do beta adrenergic agonists elevate blood glucose?
Any sympathetic stimulation elevates blood glucose
3 Genetic Syndromes associated with diabetes
o Down’s Syndrome
o Turner Syndrome
o Kleinfelter Syndrome
Gestational Diabetes: 4 characteristics
o Temporary Diabetic State
o 3% of pregnancies in US
o Type 2 Diabetic Disorder
o These patients are more likely to develop Type 2 diabetes later in life
When is the most common clinical manifestation of Type I Diabetes?
Teenage years
Two pre-diabetic conditions of Type II Diabetes
- Impaired glucose tolerance (IGT)
* Impaired fasting glucose (IFG)
3 Diabetic Screening Tools
- Fasting Plasma Glucose (FPG)
- HbA1C
- Oral Glucose Tolerence Test (OGTT)
Fasting Plasma Glucose: Numbers for…
• Normal fasting glucose
• Impaired Fasting Glucose
• Diabetes Mellitus
• Normal fasting glucose 126mg/dL
What is HbA1C? What is the time frame it measures?
Represents the percentage of Glucose attached to Hemoglobin. “Glycocylated Hemoglobin.” Reflects longer time scale, but heavily weighted to the last 2-3 weeks.
HbA1C: Numbers
• Normal
• Impaired Glucose Tolerance
• DM
• Normal: 6.5
Oral Glucose Tolerance Test: What does it do? What are you looking for?
• Challenges your body in terms of how it handles glucose: Looking for a spike followed by a return to fasting state
To what patient should you give the OGTT? To what patient should you NOT give the OGTT?
- Given to pregnant women at 26 weeks
- NOT given to someone with a FBG of > 130. REALLY dangerous!
DM Type 1: When do classic clinical manifestations occur?
At >90% Beta cell destruction
Diabetic Ketoacidosis occurs
What are the two mechanisms for beta cell destruction in Type 1 Diabetes?
- T-cell mediated immune attack against poorly defined beta-cell antigens
- Cytokine-induced beta cell damage
3 mechanisms of cytokine-induced beta cell damage
- IFN-gamma
- TNF-alpha
- Interluken-1 induced apoptosis
Auto-antibodies against islet cells or insulin:
• Detected in ____% of patients
• Usually accompanied by …
70-80%
Usually accompanied by by auto-antibodies against beta-cell antigens
A mutation in what gene causes suseptability to DM1?
MHC II Locus of the Genome
A mutation in the MHC II locus in the genome causes what?
Susceptibility to DM 1
o Presence / mutation of certain MHC II Alleles
o Affects T Cell antigen presentation
What occurs with a non-MHC genetic predisposition to diabetes? (2)
o Tandem repeat polymorphs of insulin gene
o Affects negative selection of insulin-reactive T-cells
What environmental factors predispose a person to DM1?
Infection (mumps, rubella) – doesn’t cause the problem, but triggers the autoimmunity that is already there
What is the most powerful risk factor for Type 2 Diabetes?
OBESITY
What body type is considered a risk factor for diabetes?
Apple shape; waist-to-hip ratio of >1
Concordance rates of DM2:
• Between identical twins:
• Between 1st degree relatives:
• General population:
- Between identical twins: 50-90%
- Between 1st degree relatives: 20-40%
- General population: 5-7%
Two metabolic characteristics of DM2:
- 1) PRIMARY EVENT: Decreased sensitivity to insulin by peripheral tissue (insulin resistance)
- Source of injury, beta cells burn out. Result:
• 2) SECONDARY EVENT: Beta-cell dysfunction manifested as inadequate insulin secretion relative to insulin resistance and hyperglycemia
Insulin resistance can clinically precede DM by _____ years
10-20
Abnormalities in individuals with insulin resistance (4)
- Down-regulation of insulin receptors
- Decreased insulin receptor-initiated kinase activity
- Reduced levels of insulin receptor signaling intermediates (PI-33K and MAPK)
- Impaired docking and fusion of GLUT4-containing vesicles with the plasma membrane
3 stages of beta cell dysfunction
- Hyperinsulinemic State
- Early Beta-Cell failure
- Late beta cell failure
When does a hyperinsulenemic state occur?
During early insulin resistance, insulin secretion is higher at every level of plasma glucose.
Can maintain normal levels for years, but beta cells start to burn out.
• Early Beta-Cell failure manifests subtly as: (3)
- Loss of normal pulsatile / oscilating pattern of insulin secretion
- Loss of the “rapid phase” of insulin secretion triggered by elevation of plasma glucose
- Eventually, secretory defects effect all phases of insulin release, even though some basal secretion persists
• Late Beta-cell failure (can) manifest as: (4)
- Decreased beta-cell mass
- Islet cell degeneration
- Amyloid islet deposition
- Absolute insulin deficiency may appear (looking more like Type 1)
Why are obesity and DM2 linked? (3)
1) Elevated circulating Free Fatty Acids (FFAs)
2) Adipocyte hypertrophy stimulates release of cytokines that attract macrophages
3) Chronic inflammation causes increased lipolysis in adipose tissue, which elevates circulating FFAs
Free Fatty Acids cause:
… esp:
Insulin resistance in fat, skeletal muscle and liver cells
.. especially TNF-alpha
Macrophages in adipose: Lean v Obese people
o Adipocytes in lean people contain 5-10% macrophages
o Adipocytes in obese people contain 50% macrophages
Leptin
- Where does it act?
- What does it induce?
- When does it change?
o Acts primarily in the brain at feeding centers in the hypothalamus
o Induces satiety: Helps regulate appetite and feeding relative to energy stores
o Individuals within a normal range of BMI: Lectin levels will increase with higher body fat percentage
What are the two adipokines?
- Adiponectin: Insulin sensitization
* Resistin: Insulin resistance
What is the role of adiponectin?
- What releases it?
- When?
Increases insulin sensitivity
- Released by adipose tissue
- During Times of plenty
What is the role of resistin?
- What releases it?
- When?
Decreases insulin sensitivity / increases insulin resistance
- Released by adipose tissue during lean times of the year
- Tends to decrease insulin sensitivity
Define gestational diabetes
Any degree of gluocse intolerence with onset or first recognition during pregnancy.
Gestational diabetes complicates about ____% of all pregnancies
2.6% of pregnancies
Early pregnancy metabolism (3)
- Body goes into fat storage mode
- Body increases insulin sensitivity
- Mom’s blood insulin is normal
Late pregnancy metabolism
- HPL (Human Placental Lactogen) kicks in and cuases mom to be insulin resistant
- Gives baby an opportunity to siphon mom’s blood glucose
- Mom’s blood insulin rises
What happens physiologically during gestational diabetes?
Mom’s pancreas cannot create enough insulin to compensate for the insulin resistance
Effect of hyperglycemia on a fetus (2). When do most problems occur?
- Congenital heart abnormalities
- Increased growth → Vulnerability to ischemia –> Can lead to still birth ☹
• Most problems during 1st trimester
Typical onset of Gestational Diabetes
24-28 weeks
Classic manifestations of DM (in order)
o Hyperglycemia o Glucosuria (once blood glucose is higher than renal threshold) o Polyuria (due to osmotic diuresis, which traps water) o Polydipsia (because of dehydration due to polyuria)
List four acute complications of DM. When does each occur?
o Hypoglycemia: Complication of DM treatment (insulin, oral diabetic drugs)
o Hyperglycemic (hyperosmolar) coma: DM2 more likely
o Diabetic Ketoacidosis: complication of DM1
o Hyperosmolar hyperglycemic nonketotic syndrome: HHNK, DM2. Wild hyperglycemia, polyuria, polydipsia, but no DKA.
What contributes to hyperglycemia (3)?
o Obvious mechanism: Food consumed. Insulin deficiency or resistance means glucose is trapped in the blood.
o Because the liver is not receiving any glucose, it thinks that it is in a fasting state. (Breaks glycogen stores, performs gluconeogenesis → more gluc into bloodstream, thereby WORSENING hyperglycemia)
o Even though person may be obese and eating, they often have highly stimulated appetites, because metabolic tissue can’t access blood glucose.
What number indicates hypoglycemia in adults v children?
o Adults: Hypoglycemia when < about 70
o Children: Hypoglycemia when < 50 or 60
Define hypglycemia
o Def: A drop in blood glucose below what is normal for age / sex
What is the most common acute complication of Type 1 Diabetes?
Hypoglycemia
Two causes of hypoglycemia
- Metformin or other oral drugs
- Took too much insulin for food consumption (miscalculation(
Two autonomic symptoms of hypoglycemia
- Adrenergic: Tremors / shakiness, anxiety, palpitations / tachycardia
- Cholinergic: Sweating, hunger
Two neurologic symptoms of hypoglycemia
- Weak / fatigued / drowsy, headache, behavior change, confusion
- Diplopia, difficulty speaking – can almost seem drunk. Seizures, coma
Role of SNS in hypoglycemia
Activation of SNS helps make you aware of need for glucose, also enables body to start gluconeogenesis, glucogenelysis, etc.
What happens with hypoglycemic desensitization (3)
o Repeated episodes can cause hypoglycemia unawareness: Loss of autonomic / neurologic cues & loss of SNS stimulation
o The better a person is at controlling glucose, the more likely you are to get to this.
o Counterregulatory mechanisms also become impaired:
Review Glucose Counter Regulation chart on page 10
ok!
What is the cause of diabetic ketoacidosis?
Develops when there is an absolute deficiency of insulin or an increase in a counter-regulatory hormone like catecholamines or glucagon
Risk factors for DKA
ANY KIND OF STRESS: Infection, trauma, surgery, MI, increased psychological stress
Why is it rare to see DKA with Type II DM?
o Because any amount of insulin in the bloodstream helps maintain fat stores.
What does absence of insulin stimulate?
Absence of insulin stimulates elevated fat breakdown → Ketones → Metabolic acidosis
Clinical manifestations of DKA (9)
- Kussmaul respirations
- Postural dizziness
- CNS depression – stuporous state
- Ketonuria
- Nausea
- Abdominal pain
- Dehydration (Thirst / polyuri)
- Hypertensive
- Tachycardic
What are Kussmaul respirations?
(hyperventilation in an attempt to compensate)
3 components you’ll see in the labs of a DKA patient
- Ketones in urine and plasma
- Acidity of 7.3 or less
- High potassium levels
Why would you see a lot of potassium in a DKA patient’s labs? What is happening?
- Potassium shifts out of cells (especially vulnerable to acidosis)
- Insulin brings potassium into cells
- Patient is actually hypokalemic! They are peeing off potassium
When do you see HHNK?
Usually Type 2
Define HHNK
o A constellation of s&s that reflect a hyperglycemic and Non-Ketotic state
o Insulin levels are high enough to suppress lipolysis, but not high enough to facilitate glucose entry into skeletal muscles and fat tissue.
What does HHNK stand for?
Hyperosmolar Hyperglycemic Nonketotic Syndrome
Four clinical manifestations of HHNK
- Hyperglycemia
- Glucosuria
- Polyuria
- Polydipsia
Tissue that is especially vulnerable to uncontrolled diabetes (2). Why?
- Vasculature
- Neural
• Why? These cells cannot regulate the amount of glucose that enters… it simply diffuses in. Therefore, the cellular levels of glucose become really high → Altered cellular metabolism.
Three categories of DM complications
- Macrovascular Disease
- Microvascular Disease (capillaries)
- Neuropathy
3 manifestations of macrovascular disease in DM
- Coronary Artery Disease ATHEROSCLEROSIS
- Cerebrovascular Disease STROKE
- Peripheral Vascular Disease PERIPHERAL ARTERIAL DISEASE (Poor circulation to legs)
2 Manifestations of Microvascular disease
- Diabetic Nephropathy
* Diabetic Retinopathy
What does diabetic nephropathy cause?
o Cause of about 1/3 of all renal failure
Pathophysiology of diabetic nephropathy
o Glomerular basement membrane starts to thicken
→ sclerosis (scarring) of glomerular capillaries
→ Compensatory hypertrophy, hyperfiltration of other nephrons (which have trouble keeping up)
→ Cascades toward renal failure
Two phases of diabetic retinopathy
- Non proliferative phase
* Proliferative phase
Clinical manifestations of diabetic retinopathy: Non-proliferative phase
• Edema, exudate, capillaries start getting damaged – vision is not really impaired unless it’s affecting the macula
Clinical manifestations of diabetic retinopathy: Proliferative phase
• Retina becomes hypoxic
• Angiogenesis (new capillaries form to compensate for ischemia) – can pull on retina, cause it to detach
o Impairs vision
Two types of diabetic neuropathy
- Sensory Neuropathy
* Autonomic Neuropathy
Characteristics of Sensory Neuropathy (5)
o Tends to happen earlier
o Most notable in the extremities – esp lower limbs
o Usually bilateral, very symmetrical
o Characterized as:
• A dulled perception of vibration, temp
• Allodinia: Enhanced sensitivity to light touch (felt as excruciating pain) occurs sometimes
Characteristics of Autonomic Neuropathy (2 characteristics, 3 clinical manifestations)
o Occurs with long-standing diabetes
o Autonomic nerves, reflexes, fucntions are dulled
o Can cause…
• GI issues: N/V, Loss of appetite, bowel / bladder dysfunction
• Erectile dysfunction
• Orthostatic hypotension: Dulling of the barrow reflex, “autonomic dysreflexia”
