Diabetes Flashcards
Cells of Islet of Langerhans
Beta Cells: Insulin
Alpha Cells: Glucagon
Delta Cells: Somatostatin
PP cells: VIP
Beta Cells
Sole source of insulin in the body
- The body’s primary anabolic hormone
Alpha Cells
Produce glucagon which induces glycogenolysis in the liver
- Antagonizes B cells
Delta cells
Produce Somatostatin
- Suppresses both insulin and glucagon release
PP (Pancreatic Polypeptide) Cells
Produce VIP
- Stimulates GI enzymes and slow GI motility
Insulin Functions
- Transport Glucose and AAs
- Glycogen formation in liver and skeletal muscles
- Glucose transformation to TG (trigliceride-better E)
- Nucleic acid synthesis
- Protein synthesis
- Decreases degradation of glycogen, lipid and protein
- Body’s major anabolic hormones
How is insulin derived?
Derived from pre-proinsulin and proinsulin by sequential peptidase cleavage
- Gene located on Chromosome 11
- Cleavage and storage occurse in the Golgi
Insulin Released in
In 3 phases: Basal, Induced by glucose, prolonged
- T1/2 is about 5 min in blood
- Action opposed by glucagon (released by a-cells in islet)
Tissues depenedent on Insuling for glucose intake
- Striated mucles (including heart)
- Adipose tissue
- Liver
- Fibroblasts
Approximately 70% of body mass
Tissues NOT dependent on insulin for glucose uptake
- Eyes
- Brain
- Nerve
- Kidney
- Blood vessels
Relay on facilitated transporters
Insulin Action on Target Cells
Important screen shot
Insuin => insulin receptor => ATP binding => Tyrosine kinase => Protein kinase => Phosphorylation Dephosphorylation => target enzyme => glucose => Glycogen or Pyruvate
Hyperglycemia
Glucose too high
B-cell release Insulin =>
- Increased absorption of glucose into cells
- Increased rate of respiration
- Increased rate of glycogenesis
This lead to Glucose levels to fall to normal
Hypoglycemia
Glucose too low
a-cells release glucagon =>
- Increased rate of glycogenolysis and release of glucose from liver
- Increased rate of gluconeogensis
- Increased use of fatty acid in respiration instead of glucose (lead to break down of fatty acids)
This result in Glucose increasing to normal levels
Diabetes Mellitus
Flowing through of suger
Genetic/epigenetic disorder characterized by an absolute or relative lack of insulin
- Characterized by hyperglycemia
- Result in an impaired use of carbohydrates => body uses stored or dietary lipids instead
- Altered lipid and protein metabolism
- Accumulation of of acetyl-CoA, acetoacetic acid, β-
hydroxybutyric acid, acetone (ketones)
- Result in acidosis, ketosis, hypercholesterolemia and hyperglycemia
- First recognized metabolic disease: Ancient egyption
- Got a diagnostic biomarker (urine test)
- First successful treatment of a metabolic disease
Acetoacetate
Screen Shot
Diabetes Facts
- Incidence Increased in Blacks, Native Indians
- 80% are Type 2, 10-15% Type 1
- 6-7th leading cause of death in US
A leading cause of
– cardiovascular disease (MI, stroke, accelerated
atherosclerosis in all diabetics )
– adult onset blindness
– non-traumatic lower-limb amputations
– stocking-and glove’ sensory neuropathy
– end-stage renal disease
– markedly increased susceptibility to infections
Types of Diabetes
Non-Reversible:
- Type 1: Insulin dependent
– Type 1A: autoimmune
– Type 1B: no autoimmune
- Type 2(non insulin dependent)
- Monogenetic Forms: MODY, Syndrome-related
Reversible
- Drug Induced: Vacor, Pentamidine, Phenytoin, Steriods
- Gestational: 5% of pregnancies, Major maternal-fetal complecation, malformation, post-maturity
- Insult related: Trauma, buns, pancreatitis, cancer
Diabetes Diagnostic Criteria
Insurance companies made these #
Fasting glucose > 126 mg/dL OR symptoms of DM pluse random plasma of >200 AND/OR plasma glucose >200 after oral loading (OGTT)
- Glycated hemoglobin (HbA1C)>6.5%
Rate of onset is clinically useful:
- Type 1 is rapid
- Type 2 is gradual
Prediabetes Diagnostic Criteria
- Fasting glucose >110<126
- OGTT >140<200 is pre-diabetes
- Glycated hemoglobin 5.7%-6.4%
Blood glucose can be elevated transiently by trauma, burns, infections
- This is why the Dx of diabetes require PERSISTENT elevation of blood glucose
Type 1 DM
Result from a failure of self-tolerance in T cells specific for B-cell antigens (eg. preproinsulin, cleavage products): Autoimmune disease
- Account for 5-10% of all cases; usually young
- Clinical signs may be abrupt but death of B-cells begin years earlier
- Must lose 90% of all B-cells for onset of ype 1 DM
- Absolute deficiency of insulin
- Patient ketosis-prone due to activity of glucagon (keto-acidosis is life-threatening)
- Patient in catabolic state-tine/emaciated
- Frequently associated with other autoimmuneities; Partericularly of thyroid
The first patient treated with insulin
Leonard Thompson
- Survived until 27
Type 2 DM
Lack of insulin availability or effectiveness
- Failure of target tissue to response (insulin resistance)
- Some insulin present; not ketosis-prone
- Strongly associated with obesity; not being seen in children (centeral obesity is worse)
- Dysregulation of adipokines
- Premissive inflammatory milieu
Can be a result of
- Inadequate production
- Premature destruction
- Release out of phase with food intake
- Decrease insulin receptors or their responsiveness
Compare 1 & 2
Screen shot
Screen shot
Acute Clinical Complications of Diabetes
- Hypoglycemia
- Hyperglycemia
- Diabetic ketoacidosis (DKA)
- Hyperosmolar coma
Hypohlycemia
Info
Most common in Type; treatment complication of Type 1 and 2
- May occure when counter-regulatory hormones are stimulated (fasting, exercise, stress) or uncoordinated administration of insulin
- Blood glucose <50 mg/dL
- May be difficult to detect in children and elderly
- Rapidly reversible with glucose/sucrose
Symptoms of Hypoglycemia
Secondary to catecholamine release (adrenergic):
- Sweating, Shakiness, Anxiety, Hunger, Faintness, Tachycardia,….
Secondary to CNS dysfunction (neuroglucopenic):
- Confusion, headaches, weakness, coma, Diplopia,…
Nocturnal Hypoglycemia (usually due to excessive insulin therapy)
- Morning headaches, Night sweats, Loud respiration, Difficulty in awakening, Psychologic changes
Hyperglycemia
Blood glucose of 126+mg/dL usually 160
- 3 polys: Polyuria (frequent urination), Polydipsia (drink a lot), Polyphagia (eats a lot)
– Osmotic dehydration (driving thirst)
– Lower activity of hypothalamic satiety center (huner)
– Increase of plasma osmolality (osmotic diuresis; a lot of hypotonic urine)
- Sever weight loss (type 1)
Important; insufficient insulin diagram
Check Screen Shot
Diabetic Ketoacidosis (DKA)
Increased ketogenesis with loss of insulin activity
- Most common in Type I but occures (uncommonly) in elderly Type 2 patients following stress (trauma, infection,..)
- Ketone bodies are strong acids => lower pH
- pH<7.2 associated with kussmaul breathing; loss of bicarbonate buffering
- Sever dehydration, electrolyte loss, arrhythmias
- Increased FFA and ketones due to lipase activation
- Blood glucose >250mg/dL, usually 500-700 range
- Can be life-threatening
- Fruity smell of breath
Hyperosmolar Coma
Mostly in Type 2 DM patients
- Precipitated by low fluid intake (illness, eg. flu)
- Sufficient insulin present to prevent ketogenesis => Hyperosmolar, hyperglycemic, nonketotic coma
- Late presentation, high glucose level >600+, may reach 3000-4000 mg/dL
- Significant mortality, difficult to treat during
rehydration
Chronic Metabolic Impairments
Formation of advanced glycation end product (AGEs)
- Non enzymatic reaction between glucose-derived cellular elements and amino groups on protein
- Proliferation of smooth muscle and matrix; increased ROS, release of cytokines, and growth factors
Disturbance of polyol pathways in non-insulin dependent tissues:
- Osmotic effects, increases extracellular matrix
Activation of protein kinase C
- Increased ROS, Osmotic injury, pro-angiogenic molecules, activation of multiple signal transduction pathway
Formation of Advanced Glycation End Products (AGE) and Receptor Specific Glycation (RAGE) End Products
Non-enzymatic reactions of glucose-derived precursors with protein amino groups or receptors
1) Cross-link extracellular matrix protein (eg., collagen). trapping protein and lipid within cell
2) Bind to membrane receptors
3) Enchances proliferation of smooth muscle cell and extracellular matrix
4) Release pro-inflammatory cytokines from intima and induces ROS
5) Induces state of pro-coagulant activity
Disturbance of Polyol Pathways
Occurs in tissues not dependent on insulin
- lens, nerve, kidney, blood vessels, with consequent sorbitol increases
In case of elevated intracellular glycose: Overhydration
- Glucose go into cell => Soribitol act on it => fructose
– (Aldose reductase), (sorbitol dehydration)
- These enzymes reaction depete NADPH required for GSH => compromising ROS protection
- Increased osmolarity, => influx of water (underlying pathology in diabetic cataracts)
- Inhibitation of aldose reductase => protect against cataracts and diabetic neuropathy
- Sorbitol inhibit ion pump
Complications of Chronic Diabetes Mellitus
Microvascular disease
- Retinopathy
- Nephropathy
Macrovascular disease
- Coronary artery disease (major cause of death)
- Cerebrovascular disease
- Peripheral vascular disease
Neuropathic disease
- Peripheral symmetric polyneuropathy
- Autonomic neuropathies
- Mononeuropathies
Foot ulcers
Infections
Macrovascular Complications
Atherosclerosis (with increased acetyl-CoA)
- 75% of DM patients <40 years have sever atherosclerosis; - M=F
Setting clinicaly
- Hypertriglyceridemia
- Hyperglycemia
- Alteration of lipoprotein composition
- Procoagulant state
- Hyperinsulinemia in Type 2
Microvascular Disease
- Basement membrane thickening in small blood vessel
- Advanced glycation end products (AGE-RAGE)
- Protein kinase C activation
- Polyol pathway
- Retinopathy >60% of Type I, 20% of Type 2
- Nephropathy: 75% end stage disease after 20 years
Kimmelstiel-Wilson Nodules
In kidney (glymerulor)
- Cannon balls
- Diagnostic for diabeties
Proliferative Retinopathy
Proliferation of blood vessels
- Refract light
- Hazy image
Proliferative Retinopathy
Proliferation of blood vessels
- Refract light
- Hazy image
Nonproliferative Retinopathy
Blood vessel weak
- aneurythm and blled in aqueous part of eye
- Cause blindness
Glaucoma
Too much fluid in eyes
Cataracts
Lense is crystal
- hydrated
- Light can’t pass through
Infection
- Defective neutrophil chemotaxis and phagocytosis
- CMI abnormalities
- Complicated by hyperglycemia, glycosuria, Ketoacidosis, vascular disease
Bacteria and fungal infection is common:
- skin, UTIs, pyelonephritis, vulvo-vaginitis, opportunists (Tb)
- Responsible for ~5% diabetes-related deaths
- Superimposed on trauma and other deficits
Diabetic Foot Ulcers
Symmetric polyneuropathy
- A leading cause of (periphral) ischemia and amputation
- 3 year mortality following amputation 50%
- Microvascular disease + neuropathy + impaired
immunity + trauma + infections + defective repair
+ etc. (all these cause damage in the foot)
- Not reversible; amputation only slow it doen
FOOT CARE IS ABSOLUTELY ESSENTIAL
Diabetic Neuropathy
- Distal, symmetrical sensory polyneuropathy
- ‘Stocking and Glove’ distribution
- Fixed, resting tachycardia and orthostatic hypertension (lose BP when standing)
- Impotence
- Incontinence
- Anhidrosis (no sweating) in lower limbs
- Gustatory sweating
- Mononeuropathy
- Abrupt, painful loss of nerve function
- ‘Foot slap’
Can’t feel it at all; sometimes keep looking at feet to know where feet at
Early Signs/Symptoms of DM
- Skin rashes (non responsive to cream)
- Poor skin healing
- Skin ulcers/abscesses
- Fungal infections
- Tingling of foot (sensory nerves die)
- Numbness
- UTIs
- Blurred vision
- Weight change
- Absent periods
- Erectile dysfunction
- Drowsiness
- Elevated HbA1C
Signs/Symptoms of Severe DM
- Three P’s
- Bed wetting in children
- Severe vision change
- Myalgia (pain in muscles)
- Weakness
- Acne (30% of cases)
- Irritability
- Cardiovascular issues
- Sexual dysfunction
- Absent menstrual periods
- Persistent fungal infections, particularly Candida and Mucor
- Fatigue, often severe
- Headaches
- Weight loss with polyphagia should point to DM
Prevention and Control of DM
- Control weight and diet!!!
- Exercise!!
- Rigorous control of blood glucose!!
- These control factors can delay the onset of major morbidity and mortality. However, even with control, the complications of DM will occur with variable severity in ALL patients
- Most common cause of death is MI; 2nd is renal failure
Metabolic Syndrome
Clustering of 3 of the following conditions:
- Abdominal obesity
- High blood pressure and elevated heart rate
- High blood sugar
- High serum triglycerides
- Low serum HDL
- Unclear etiology-insulin resistance Vs obesity
- Increased TNF from adipocytes
- Diagnosis associated with increased risk of MI, stroke, clinical diabetes Type 2, atherosclerosis
