Diabetes and Pre-Diabetes Flashcards
What is the role of ghrelin?
Amplifies the want for food. In many people with obesity, even after large meals when ghrelin levels should be suppressed, they are still elevated
Proinsulin is cleaved to produce the mature insulin form and a C-peptide. What is the main use of C-peptide diagnostically?
Because insulin has such a short half-life (minutes), C-peptide is a much better diangostic marker for levels of insulin secretion
How is insulin secreted?
In a biphasic pattern, with the first acute ‘burst’ being a rapid response to rising glucose levels (typically after a meal) due to preformed insulin (up to 10x more than fasting basal state) and then the B cells synthesize more if the glucose levels remain high
In pre-diabetics, pts start to lose the ability to respond rapidly to the initial increase in glucose (lose the first phase and rely more on the second phase)
How is insulin in the B cells stimulated to be released?
glucose enters the cells through GLUT-2 receptors (insulin independent) which it is glycoslyated via glucokinase to form glucose-6-phosphate and then undergoes the Kreb’s cycle to form ATP. When the ATP:ADP ratio rises, it inactivates/closes a membrane K+ channel which depolarizes the cell. This depolarization activates membrane Ca2+ channels causing an influx of Ca2+, which causes insulin to be secreted into the bloodstream. This process is extremely rapid
Describe Type I diabetes
Type I diabetes primarily occurs in young people and is the result of severe insulin. Note that Type I diabetes acocunts for only 5% of all diabetes cases
Describe Type II diabetes
Type II diabetes is usually seen in older adults and is the result of increasing insulin resistance (thus, insulin levels may be normal or even elevated but it is not working as it should but eventually levels will drop)
Which type of diabetes is more prone to ketoacidosis? Why?
Type I diabetes because insulin prevents ketone body formation. Note that even 20% of type II diabetics present with ketoacidosis
Which type of diabetes has more of a genetic association?
Type II has up to 80% twin concordance whiel Type I has less than 50%
What is normal fasting glucose? Normal OGTT? A1c?
FPG less than 100 mg/dl
2-hPG less than 140 mg/dl
A1c- less than 5.7
What is pre-diabetes fasting glucose? OGTT? A1c?
100-125 mg/dl
140-199 mg/dl
A1c-5.7-6.4%
What is diabetes fasting glucose? OGTT? A1c?
126+ mg/dl
OGTT: 200+ mg/dl
A1c- 6.4+%
What things can cause polydipsia and polyuria?
DI, DM,
hypokalemia and hypercalcemia (these inhibit AQP-2 synthesis)
How is A1c made?
Hemoglobin is glycated via non-enzymatic reactions when glucose enters the RBC for energy
NOTE: This is a 3-month average
What is another important thing to know about A1c levels?
Red cells can actually remove/deglycate the hemoglobin using an enzyme called Fn3k
Development of diabetes
Environmental stresses precipitate genetic predispositions to develop diabetes. This is a very polygenic disorder (many many genes!))
Type I diabetes is thought to be the result of a viral infection causing auto-antibodies against B cells and wiping out insulin production (HLA type I)
in Type II diabetes there is B cell dysfunction on top of environmental stresses
Type I development
Individuals start out with a genetic predisposition for type I (not as penetrant as type II) and are then exposed to a virus which causes production of auto-antibodies that destroy B cells (GAD, ICA, IAA, and ZnT8 are some types). Then there is an attempt of regeneration which CAN reverse the effects but eventually subsequent attacks will cause loss of the first phase of insulin secretion. This occurs over YEARS
What HLA types have been shown to predispose to Type I diabetes?
Chromosome 6. DR3 or DR4 expressed in 95% of Europeans with Type I (and co-expressed in 60%). DR2/DR2 is very protective
Role of DQ beta chain (Asp-57) in predispostion to type I diabetes
Neg/Neg- full susceptibility
Pos/Pos- full protection
Neg/Pos- 10% susceptible
NOTE: DR4/DR$ overrides protective DQ alleles
Other HLA connections to type I diabetes?
DQ7 provides priamry protection adn DQ8 provides primary susceptibility
Risk factors for Type II Diabetes?
Fam Hx, Age (due to decreased activity, loss of B cell mass, and insulin resistance), Ethnicity (non-European and especially some Native Indians, not that different from others), Obesity, HTN, Dyslipidemia, major mental illness, women who have heavy birth weight babies, meds)
What are the main effects of insulin besides lowering BG?
It suppresses glucose production by the liver, stimulates lipogenesis and protein synthesis, and inhibits keotgenesis
T or F. Abdominal fat is much more correlated with the likelihood of developing type II diabetes than overall obesity and fat deposition in areas such as the arms, legs, etc.
T.
Development of Type II Diabetes
**CONCURRENT development of insulin resistance (less so) and decreased insulin secretion (more so)**. In addition, there is impaired glucagon suppression after a meal (doesnt really elevated but doesnt decrease like it should) AND increased hepatic glucose output via hepatic insulin resistance preventing glycogen storage breakdown (normal 1mg/kg/min and in type II it goes up to at least 2mg/kg/min)
How is glucagon suppressed after a meal?
via GLP-1 secretion from the intestines that binds to B cells to increase insulin secretion which downregulates glucagon (attenuated in diabetes)
How else is type II diabetes developed?
There is increased SGLT2 (reabsorbs 90% of glucose in the kidneys) and GLUT2 activity (up to 4x)
What is insulin secreted with?
Amylin
What are the roles of amylin?
Decreasing gastric emptying, decreasing glucagon secretion, promoting satiety, and decreasing appetite.
Amylin is decreased in type I AND type II diabetes. Which one is assoicated with more suppression?
Type I because it is also secreted from the B cells
