L 43-44 Diabetes Flashcards
In the US, diabetes is the leading cause of what morbidities?
End stage renal disease
Adult-onset blindness
Non-traumatic amputation of the leg
Death (top 10 cause)
Diabetes is a group of metabolic disorders that all share what feature?
Hyperglycemia
How has the definition of diabetes changed recently?
Diabetes is now defined by some to be: “Premature CV death that is associated with chronic hyperglycemia, blindness, renal failure”
It can be considered a vascular disease.
How is BMI related to DM?
Having a BMI greater than 30 leads to 8-12x risk of DM
Where in the world are the most rapid rises in DM incidence?
Third world countries that are getting more access to food–china, india
What are the three lab tests used to diagnose DM and their normal ranges?
FPG: fasting glucose, 70-100 normal, greater than or equal to 126 to diagnose
2-Hr postprandial blood sugar: less than 140 normal, greater than 200 after oral glucose tolerance to diagnose
HbA1c: less than 5.6% normal, 6.5 or greater to diagnose
Any one of these alone can diagnose DM.
At what blood glucose level do you start to see glucose in the urine?
160 mg/dl
Who is recommended to be screened for DM?
BMI greater than 25 with one or more of:
Hx of HTN
High risk ethnicity
Hx gestational diabetes
Who are the high risk groups for DM?
African American Native American Hispanics India China
What is the problem with prediabetes?
These people are literally pre-diabetic. This means they are on the road to diabetes and are really a lower version of the disease.
Increased risk of CV disease and others
DM classification types
Type I: absolute deficiency of insulin from beta cell destruction–immune mediated
Type II: insulin resistant with relative insulin deficiency
Secondary
Long term complications same for all
What are causes of secondary DM?
Pancreatic: chronic pancreatitis, cystic fibrosis, pancreatectomy, HEMOCHROMATOSIS–iron accumulates in liver, pancreas, heart, pituitary causing decreased libido, decreased LH, FSH, increased glucose
Endocrine: Cushing, Acromegaly, Glucagonoma, Somatostatinoma
Infections: Coxsackie B, CMV
Drugs: glucocorticoids, thiazides, protease inhibitors, beta adrenergic agonists, statins
What are the genetic diseases associated with increased risk of DM?
Turner Syndrome
Down Syndrome
Kleinfelter Syn
Prader-Willi Syn
Physiology of Insulin
Glucose in gut signals release of insulin and inhibition of glucagon
High insulin and low glucagon cause liver to stop gluconeogenesis and start glycogenesis
Insulin allows peripheral structures to uptake glucose
In what form is insulin produced?
Insulin is produced in islet beta cells as a preprohormone that must then be cleaved for activation. This produces C-peptide which is used to measure endogenous insulin
How is insulin release triggered?
Glucose uptake by pancreas via GLUT2 receptors has two effects: 1) immediate release of insulin, 2) stimulation of active synthesis of insulin
Intestinal hormones such as incretins, AA’s stimulate insulin release but not production
Describe pathway that releases insulin from beta cells
Glucose binds insulin independent GLUT2 receptor and produces ATP in the mitochondria
Increased ATP closes the K+ channels causing depolarization of the cell
Depolarization opens Ca2+ channels and the influx of Ca2+ causes the immediate release of insulin
Sulfonylurea binds to the K+ channel and also releases insulin
Physiologic effects of incretins GLP-1, GIP, and the DPP-4 enzyme
Ingesting food causes release of gut hormones called incretins–GLP-1 and GIP
These are broken down by the enzyme DPP-4 and made inactive
GLP-1 and GIP act to increase insulin release from beta cells
GLP-1 decreases glucagon from alpha cells
Actions of insulin throughout the body
Principle action of insulin is to increase the rate of glucose transport into the cell
In muscle, becomes glycogen and is used for ATP
In fat, stored as lipid
Overall, actions are anabolic!– produce glycogen, lipids, proteins, and signals cell growth and differentiation and DNA synthesis
What are the metabolic effects of having no insulin (or being insulin resistant)?
Adipose: liposlysis, less glucose uptake, less lipogenesis
Muscle: less glucose uptake, less glycogen synth, less protein synth
Liver: more gluconeogenesis, less glycogen synth, less lipogenesis
What is the insulin signaling pathway?
Insulin binds a tyrosine kinase receptor, signals via IRS-1-4 to activate MAP kinase pathway and PI3K–AKT pathway to increase growth and differentiation
AKT signals insertion of GLUT4 transporters in membrane
What is the pathogenesis of type I DM?
Abrupt onset after more than 90% of beta cells are destroyed
Autoimmune process that has been present for several years
It is an interaction between beta cell destruction, genetic susceptibility, and environmental factors
What is the genetic component of type I DM onset?
Genes: 50% concordance with twins–at least 30 loci for the genes, half of the genetic component is due to MHC genes–95% of cases have HLA-DR3/DR4 which allow for autoimmune reactions
T-cells are dysregulated by CTLA 4 and PTPN-22 genes which are polymorphisms that interfere with T-cell selection and regulation
What are the environmental factors associated with type I DM onset?
Viruses: Coxsackie B, measles, mumps, rubella, CMV, EBV
Possible that childhood infections are protective and preventing these diseases in kids may cause dysregulation of their immune system causing autoimmunity later
