Pathophysiology of Diabetes Flashcards
Are GLUT-2 transporters insulin-dependent? How do they allow the entrance of glucose and where?
They are not insulin dependent
Entrance of glucose into hepatocytes via facilitated diffusion
Which GLUT transporter uses translocation? Explain how it works
GLUT-4 is insulin dependent and uses translocation
When insulin attaches to GLUT-4, the GLUT-4 transporters move to the cellular membrane to uptake glucose
What is SGLT?
Sodium-glucose cotransport
Mechanism of glucose uptake from the GI tract and renal tubules
Secondary active transport mechanism
What role does SGLT have in presenting a clinical manifestation of DM?
Hyperglycemia in DM may overwhelm the number of transporter (limited amount!)
Results in glucosuria because glucose is not being reabsorbed
Glycogen
Stored form of glucose in the liver
Glycogenesis
Synthesis of glycogen
Glycogenolysis
Breakdown of glycogen
Glycolysis
Breakdown (metabolism) of glucose
Gluconeogenesis
Synthesis of new glucose, mainly by the liver
From non-carb sources
How does glucose become an energy source for cells?
Glucose
Glucose-6-phosphate (G6P)
Glycolysis –> Pyruvate
Pyruvate enters mitochondria
oxygen available Pyruvate converted to acetyl CoA, which enters the Krebs cycle
ETC produces ATP
In a fed state what form of metabolism is occuring?
Anabolism
In a fed state, where is glucose going in relation to the bloodstream? (GI tract, neural tissue, pancreas, muscle, liver, adipose)
GI –> Glucose is entering the bloodstream from the GI tract
Liver –> glycogenesis and glycolysis is occuring, glucose is entering the liver from the bloodstream
Adipose tissue –> glucose is entering adipose tissue
Pancreas –> is releasing insulin to promote the uptake of glucose
Neural tissue –> uptaking glucose
How does physical activity affect insulin?
Physical activity enhances insulin sensitivity
Muscle contraction enhances GLUT-4 translocation to the cell surface
Important teaching point for patients
What does lipoprotein lipase do?
Breaks down triglycerides from VLDLs and chylomicrons into fatty acids that can diffuse into the adipocyte with glycerol
How does insulin affect the activity of lipoprotein lipase?
Insulin promotes lipoprotein lipase activity
Insulin promotes fat storage
Where is lipoprotein lipase found?
Vascular endothelial cells throughout the body
What does hormone-sensitive lipase do?
Promotes the breakdown of stored triglycerides
Adipocyte then can release free fatty acids and glycerol
In a fasting state, what form of metabolism is occuring?
Catabolism
What two pathways produce glucose in the liver during a fasting state?
Glycogenolysis
Gluconeogenesis
Describe the effects of phosphorylation and dephosphorylation on glucose
Phosphorylation “traps” glucose into cells following its entry. This is a reversible action due to glucose-6-phosphate enzyme.
In a fasting state, the G6P enzyme dephosphorylates the glucose, making it into free glucose that can be transported out of the cell
All cells can carry out this reaction
What are gluconeogenic precursors? What precursors CANNOT be used in gluconeogenesis?
Lactate, amino acids, and glycerol
Fatty acids CANNOT be used
What hormone predominates during a fasting state?
Glucagon
What hormone predominates during a fed state?
Insulin
What two pathways in muscle create the precursors for gluconeogenesis?
Glycogenolysis: breakdown muscle glycogen to G6P. G6P undergoes glycolysis and is converted into lactate
Proteolysis: protein breakdown releases amino acids
What pathway in adipose tissue creates a precursor for gluconeogenesis?
Lipolysis: fat breakdown via hormone-sensitive lipase
Triglyceride broken down to 3 fatty acids + glycerol
How are the products of lipolysis used for energy uptake?
Glycerol is used for gluconeogenesis
Fatty acids travel the circulation to muscle to be used as fuel and to the liver (causing the production of ketone bodies)
In a fasting state, where is glucose going in relation to the bloodstream? (GI tract, neural tissue, pancreas, muscle, liver, adipose)
GI Tract: no glucose movement
Neural Tissue: continued glucose uptake from the bloodstream
Pancreas: releases glucagon into the bloodstream to increase BG levels
Adipose: FFA moving into the bloodstream
Muscle: FFA and glucose uptake from the bloodstream
Liver: Glucose enters the bloodstream via glycogenolysis and gluconeogenesis
Where does ketogenesis occur?
The liver
Describe the pathway of ketogenesis?
Fatty acids released by adipose lipolysis
Oxidized by the liver at a high rate
Acetyl CoA and ketone body production
What states of the body promote ketogenesis?
Prolonged fasting
Absence of insulin
Very low carb diet
High levels of glucagon and stress hormones
Which pancreatic cells synthesize insulin?
Beta cells of the islets of Langerhans
Which pancreatic cells synthesize glucagon?
Alpha cells
What is the significance of the structure of an insulin molecule?
Proinsulin: contains insulin and a connecting peptide (c-peptide)
The c-peptide is used to measure endogenous insulin production (no insulin means no c-peptide)
Can also help differentiate causes of hypoglycemia
What are incretins?
Peptides that stimulate the secretion of insulin
Examples: GLP-1 and GIP
What breaks down incretins?
DPP-4 enzyme
Which incretin can inhibit glucagon?
GLP-1
Insulin secretion: oral glucose vs. IV glucose response
There is more insulin secreted in response to oral glucose vs. IV glucose
Describe the feedforward mechanism of glucose in the GI tract
Glucose in the GI tract increases insulin secretion, anticipating a rise in blood glucose
When is glucagon production the highest?
In the early morning
What is a counter-regulatory or counter insulin hormone?
A hormone that tends to increase blood glucose
Opposite effects of insulin
What is glucagon’s role in the liver?
Increases glycogenolysis
Increases gluconeogenesis
Increases ketone body formation
Decreases triglyceride synthesis
Minor role in lipolysis
What tissue lacks receptors for glucagon?
Skeletal muscle
What are examples of counter-insulin hormones?
Glucagon
Cortisol
Epinephrine
Placental hormones
Growth hormone
Stress hormones _____ blood glucose levels
INCREASE
What effect does increased BG have on healing?
If not attended to, increased blood glucose can delay healing time significantly
Growth Hormone
Released during hypoglycemia
Acts as counter insulin
Excess –> acromegaly –> diabetes
What doubles a child’s risk of developing T1DM?
The risk is doubled
if a parent developed Type 1 DM before age 11
If both parents have T2DM, what is their children’s risk of developing it?
If both parents have Type 2 DM, their
children have about a 50% risk of developing Type 2 DM
Type 2 DM is an example of what kind of disease?
Polygenic and multifactorial
What is monogenic diabetes?
AKA “neonatal diabetes”, typically diagnosed before 6 months of age
Result from mutations in genes that regulate pancreatic beta cell function // do not involve autoantibodies
Different from T1DM
Type 1 DM is what kind of disease? What does this mean/what happens?
Autoimmune disease
Results in the destruction of pancreatic beta cells, meaning no insulin production
Pancreatic alpha cells remain –> continue producing glucagon
What is insulitis?
Infiltration of pancreatic beta cells by pro-inflammatory leukocytes
What are classic DM presentations?
Polyuria
Polydipsia
Polyphagia
Weight loss
Hyperglycemia and hyperlipidemia
What causes the three “polys”? (polyuria, polydipsia, polyphagia)
Hyperglycemia overwhelms the kidneys’ ability to reabsorb glucose
Osmotic diuresis and excessive urination occurs (polyuria)
Dehydration occurs leading to thirst reaction (polydipsia)
Loss of satiety signals (insulin) lead to polyphagia // perception of starving due to no glucose uptake by certain tissues (bc no insulin)
What is usually a patient’s state when they are diagnosed with T1DM?
Often extremely ill at diagnosis
May be in DKA
40%-60% of children under 15 years old in DKA at dx
How does unopposed glucagon action in T1DM affect ketogenesis?
Ketone formation occurs which contributes to metabolic acidosis, as well as osmotic diuresis
Diabetic Ketoacidosis (DKA) is an example of a ____ of T1DM
Sequela
What precipitating events can lead to DKA?
Illness, stress, not injecting insulin, kinked insulin pump catheter, etc.
Describe how DKA occurs in patients with T1DM (eh used the diagram)
Severe hyperglycemia is occuring, but the body perceives that it is starving for glucose (since it is not being taken up by muscle of fat cells)
The liver continues to make glucose (via continued glucagon stimulation)
Adipose tissue also stimulated by glucagon, epinephrine, and cortisol –> activation of hormone-sensitive lipase –> metabolism of triglycerides, generation of free FA and glycerol
FFA used for the formation of ketone bodies
What are the effects of recurrent hypoglycemia on the brain?
Reduced counterregulatory responses
- Decreased or no glucagon response
- Decreased epinephrine and cortisol responses
What is hypoglycemia unawareness?
Lack of autonomic symptoms reduces conscious perception of hypoglycemia
VERY DANGEROUS
Who is at risk to be screened for T2DM?
All patients age 35 or older
Overweight or obese children and adolescents who have at least one risk factor
What is acanthosis nigricans?
Skin condition potentially indicating diabetes
Areas of dark, velvety discoloration in body folds and creases
Affected skin can become thickened (axillae, groin, neck)
Why might people with T2DM go 10 years without a diagnosis?
Changes are gradual
Pancreas initially compensates for insulin resistance by increasing insulin production
Patients are often asymptomatic
The key combinations in T2DM:
Insulin resistance
Beta cell dysfunction
Precipitates by genetic predisposition and/or lifestyle, habits, environment
What is insulin resistance?
Insulin does not have the usual effectiveness at reducing glucose production by the liver and promoting glucose uptake into muscle and fat
More and more insulin may be required to obtain the same effect
GLUT-4 transporters may be reduced in number and/or have less activity
Glucagon in T2DM
Secreted at abnormally high levels
Working against insulin action
Increases hepatic glucose production
Insulin paracrine effect in the pancreas:
Secretion of insulin in the Islets of Langerhans keeps glucagon levels low
How does the body try to compensate for insulin resistance?
Pancreatic cell hyperplasia and hypersecretion of insulin
Pancreatic cells then begin to fail and die
What is prediabetes?
T2DM is usually preceded by prediabetes. Indicated by:
- Impaired glucose tolerance
- Impaired fasting glucose
- Hemoglobin A1c 5.7%-6.4%
Hyperosmolar Hyperglycemic State
Similar to DKA
- Greater fluid loss
- Low level of insulin often prevents ketosis from developing
- Higher hyperglycemic
- Hyperosmolar state with severe intracellular dehydration
HHS Initiating Events
Acute illness (infection)
Decreased fluid intake
Increased stress hormone loss due to fever
Leads to increased stress hormone reaction
Hyperglycemia
How can hypoglycemia occur in patients with T2DM?
Insulin
Oral medications that stimulate insulin release
Older Adults
Criteria for diagnosing diabetes
Hemoglobin A1c > 6.5%
FPG > 126 mg/dL
2-hr plasma glucose > 200 mg/dL
Patient with classic symptoms of hyperglycemia or hyperglycemic crisis = random plasma glucose of > 200 mg/dL
What is Hemoglobin A1c?
Hemoglobin A1c is
formed when the N-
terminal valine of the
beta chains of
hemoglobin A is modified by the addition of glucose.
The resulting molecule is stable and can be measured. An algorithm converts the
percentage of A1c in the serum to an average blood glucose over approximately the last 3 months.
American Diabetes Association recommends that most people with diabetes maintain an A1c of:
vs.
AACE recommends:
Less than 7.0%
6.5% or less
Goals of Glycemic Control
Preprandial glucose: 80-130 mg/dL
1 to 2 hours postprandial glucose: < 180 mg/dL
HgbA1c: < 7.0%
Microvascular DM Sequelae
Retinopathy – major cause of blindness
Nephropathy – major cause of CKD
Macrovascular DM Sequelae
Dyslipidemia
Describe neuopathy
Sequelae of chronic DM
Polyneuropathy (distal, stocking then glove)
Very painful or can cause loss of sensation
Autonomic neuropathy – orthostatic hypotension, tachycardia, silent MI, gastroparesis, sexual dysfunction
Describe how foot ulcers can develop in patients with chronic DM
Neuropathy + vessel disease + poor wound healing
Patients may not feel pain/trauma on their foot, leading to ulcer (and poor wound healing contributes)
Can lead to amputation
Describe how infections occur in patients with chronic DM
Decreased blood flow
Abnormal leukocyte function
Increased sepsis risk
What are the two types of diabetic retinopathy?
Proliferative: new blood vessels, fragile, disorganized
Non-proliferative: blood vessels leaky, can lead to macular edema
Important teaching point for diabetic retinopathy:
Dilated retinal exams are the standard of care
What is gastroparesis?
Syndrome of objectively delayed gastric emptying in the absence of mechanical obstruction and cardinal symptoms:
Nausea, vomiting, early satiety, bloating, and/or upper abdominal pain
Important Patient Teaching Point: Foot Ulcers
Regular self foot checks and regular podiatrist visits can minimize the risk of wounds and amputation
General Patient Teaching for T1 and T2 DM
Keep diabetes under control, self-care is key!
Keep BP well-controlled
Regular monitoring of A1c, fasting BG, kidney function, and lipids
Regular PCP visits, regular dilated retinal exams, frequent foot checks, referral to podiatrist as needed
What is gestational diabetes?
Disorder of glucose intolerance of variable severity with onset during pregnancy
Increases risk of both mother and child developing T2DM
Risk factors for gestational diabetes
Severe obesity
Prior history of gestational diabetes
Previous large babies (macrosomia)
Presence of glycosuria
Strong family history of T2DM
What test is done to test for gestational diabetes?
Oral glucose tolerance testing (OGTT) at 24-28 weeks gestation
Gestational Diabetes Pathophysiology
Increased counter insulin hormones (human placental lactogen, estrogen, progesterone, cortisol, human placental growth hormone)
As the placenta grows larger, more and more of these hormones are produced
Leads to maternal insulin resistance and higher levels of circulating glucose
If the pregnant person experiences hyperglycemia, what happens to the fetus?
Fetus will increase production of insulin, but then risk HYPOglycemia at birth
Sequelae of gestational diabetes
Infant: metabolic abnormalities, stillbirth, macrosomia, neonatal hypoglycemia. Increased risk of T2DM later
Pregnant Person: Dev. of T2DM or impairment in glucose tolerance later in life
Management of Gestational Diabetes
Dietary counseling, exercise, and
blood glucose/ketone monitoring; medications, including insulin may be needed
Non-pharmacologic Management of Prediabetes and T2DM
Education and self-management
Diet and weight loss
Increased physical activity
Decreased sedentary time
Qualifications for metabolic surgery
Recommended if BMI > 40
OR
BMI 35.0-39.9 + hyperglycemia not adequately controlled with lifestyle interventions and optimal medical therapy
Types of Metabolic/Bariatric Surgery
Gastric Band
Gastric Sleeve
Gastric pouch
