Discuss Pro-insulin to Insulin cleavage and significance?
Pro-insulin secreted and cleavage occurs in 2 places resulting in bridged sulfa bonds and cleaved C-peptide released
*Cleaved C peptide is a bio-marker to see if patients are making their own insulin
Walk through how Insulin is secreted?
Glucose enters beta cell through GLUT-2
GK enzyme phosphorylates it to make G6P - rate limiting step
G6P enters Krebs cycle and transformed into ATP
Increased ATP closes inward rectifying K channel - changes Vm and Ca rushes into cell to release granules/veiscles which are pre-packaged w/ insulin
There are 3 main problems in the pathway for insulin release that can be seen and each leads to its own inherited insulin disorder. What are they?
1) MODY2 - problems w/ GK enzyme gene therefore decreased ability to convert glucose
2) MIDD - maternally inherited mitochondrial diabetes - mitochondrial gene change that leads to inherited diabetes and deafness
3) HHI - hereditary hyperinsulinemia - activating mutation of SUR1 or Kir6/2 transporters on cell surface so responsive regardless of status of energy stores leading to constant Vm depolarization and CA influx and insulin release
What are insulins effects on the liver?
Promotes glycogen synthesis and FA synthesis - building stores for later use
Stops Glycogenolysis, gluconeogenesis and ketogenesis
What are insulin effects on Adipose?
Promotes FA uptake and TG formation and storage
What are insulins effects on muscle?
Promotes protein synthesis and glycogen synthesis
What 2 systems have Insulin - indepennt effects when glucose is present?
Brain and RBCs take up glucose even when no insulin around
What happens in metabolism during overnight fasting state?
Blood sugar levels drop slightly but kept normal bc Liver constantly breaking down glycogen and making new glucose
+ Basal levels of insulin being released
slight lipolysis and breakdown of AA in muscle to be used in liver
What happens to metabolism after prolonged fasting?
Blood sugar levels fall, insulin low, rise of Glucagon
Increased lipolysis, breakdown of muscle into AA (alanine)
All goes to liver for gluconeogenesis and Ketone body production
What are normal levels of fasting glucose, OGTT (2 hours post glucose load) and Hba1c?
Fasting Plasma glucose < 100
OGTT 2 hours < 140
HbA1c < 5.7
What are 2 states of PRediabetes and how would you diagnose them? What is the biggest risk for these?
1) Impaired Fasting Glucose (IFG) - fasting levels are above normal but < 126 (100-125)
2) Impaired Glucose Tolerance Test - blood sugar level elevated 2hours after glucose but not above 200
Each has intermediate HbA1c levels of 5.7-6.4
Impaired risk for developing T2DM
**Increased risk developing CVD!!
How can you diagnose Diabetes?
Random plasma glucose > 200 regardless of time since last meal + Symptoms of DB (polyuria, unexplained weight loss etc)
Fasting plasma > 125, OGTT > 200, HbA1c > 6.5
Compare and contrast T1 vs T2 DM..
T1 DM: Autoimmune destruction of beta cells, Low-absent insulin levels, Ketosis prone, Thin people. less twin concordance, ICA/IAA/GAD antibodies, HLA ASSOCIATION (DR3, DR4, DQ)
RF: Family Hx
T2 DM: Insulin resistance leading to defect in beta cell action and loss, High or low or normal insulin levles, No ketosis, Obese body type, no antibodies, no HLA, no Autoimmune endocrinopathies,
Tx: Diet/Exercise, pills, injectable meds or insulin
RF: FH, obseity, race, GDM
What is HbA1c test and why is it useful?
sugars bind to and glycosylate Hb in RBC and since RBCs lsat for 3 months is an accurate % of blood sugar levels for 3 month period
higher blood sugars then more HB glycosylated
< 5/7% normal
> 6.5% Diabetes
What cell types are found in pancreatic islets?
Beta cellls - insulin
Glucagon secreting cells (alpha?)
Somatostatin secreting cells
Pancreatic Polypeptide producing cells
What are the stages in development of T1DM?
Genetic Susceptibility + Precipitating event (like infection)
IMmunologic abnormalities but normal insulin
Decreased insulin but normal glucose
Diabetes but still have C-peptide
Discuss the process in the development of T2 DM?
Genetic susceptibility + Enviro + Aging (less beta cel lregenration)
Insulin resistance - increased insulin
Impaired glucose tolerance
Name some races very susceptible to T2DM?
AA and Hispanics
What is gestational Diabetes? Why must you treat it?
Diabets that onsets during pregnancy and resolves after
associated with increased maternal/fetal morbitidity - BABIES AND PLACENTAS are larger
Treatment reduces risk of Csection, should dystonia, nerve damage and birth injuryies in genreal
40% women develop T2 DM within 10 years
What is MODY? how is it inherited?
Maturity Onset Diabetes of Youth
Mutations in GK gene result in inability of beta cell to sense increased glucose and so less insulin released and on average higher blood sugar levels
What is MIDD? inheritence?
Maternally inherited Diabetes and Deafness
caused by A to G mutation in mitochondrial DNA
What are some syndromes of extreme insulin resistance?
PCOS w/ severe hyperandrogenism
Hereditary Insulin reistance
What is HEreditaary Hyperinsulininemia?
Mutations in SUR1/KIR6.1 genes
ACtivating mutations cause insulin release no matter what
What are secondary causes of Diabetes?
- Hemochromatosis - infiltration
- Pancratic cancer
- Cystic Fibrosis - ducts clogged
Other Endo disorders that prevent insulin rom working
- Cortisol excess
- Acromegaly - GH excess
- CAtecholamine excess
- Beta blockers
STatins increase risk of development of T2
What are symptoms of Hyperglycemia?
Poluryia and polydispia
confusion, fatigue, blurred vision
poor wound healing
What happens in DKA? Tx?
Life-threatening condition where insulin deficiency leads to ecxessive lipolysis, unrestrained FA oxidation to produce ketones (Beta-Hydroxybutyrate, Acetoacetate, Acetone)
Metabolic Acidosis, Dehydration, Electrolyte disturbances
DKA Treatment: IV Fluids and INsulin
What is a Hyperosmolar Hyperglycemic state? Tx?
occurs in state of relative reduction of insulin secretion in T2DM
- stress or infection --> Insulin deficiency and Osmotic Diuresis - loss of electrolytes and dehydration and protein catabolism
- Decreased renal perfusion and shock!!1
TX IV Fluid an dINsulin
Distinguishing DKA from HHS:
DKA: Glucose > 250 pH < 7.35
- positive serum ketones and increased anion gap
HHS: Glucose > 600 and pH > 7.3
Bicarbonate > 15
Eosm > 320
(Eosm = effective osmolarity = 2(Na+K)+blood glucose/18
What are complications from diabetes?
What are the 2 principle forms of diabetes related retinal disease?
Non-Proliferative: Macular edema (hard exudates and cholesterol leavage from BV), blot hemorrhage, microaneurism, Cotton Wool spots, fluid in layers of retina
Proliferative: Retinal detachment from new vessels pulling it forward
(TX for new vessels - Bevacizumab!)
What kidney changes occur in Diabetic Neprhopathy?
Thickening of Glomerular BM and Hypertrophy
Increased Mesangial ECM and reduced podocytes
What are signs / symptoms of Diabetic neuropathy?
Peripheral - distal symmetric stocking and glove, motor neuropathy, CN 3, 4, 6, 7
Autonomic - orthostatic hypotension, resting tachycardia, GI neuropathy, Urinary bladder atony, ED