L 43-44 Diabetes

Question 1

In the US, diabetes is the leading cause of what morbidities?

Answer 1

End stage renal disease
Adult-onset blindness
Non-traumatic amputation of the leg
Death (top 10 cause)

Question 2

Diabetes is a group of metabolic disorders that all share what feature?

Answer 2

Hyperglycemia

Question 3

How has the definition of diabetes changed recently?

Answer 3

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.

Question 4

How is BMI related to DM?

Answer 4

Having a BMI greater than 30 leads to 8-12x risk of DM

Question 5

Where in the world are the most rapid rises in DM incidence?

Answer 5

Third world countries that are getting more access to food–china, india

Question 6

What are the three lab tests used to diagnose DM and their normal ranges?

Answer 6

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.

Question 7

At what blood glucose level do you start to see glucose in the urine?

Answer 7

160 mg/dl

Question 8

Who is recommended to be screened for DM?

Answer 8

BMI greater than 25 with one or more of:
Hx of HTN
High risk ethnicity
Hx gestational diabetes

Question 9

Who are the high risk groups for DM?

Answer 9

African American
Native American
Hispanics
India
China

Question 10

What is the problem with prediabetes?

Answer 10

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

Question 11

DM classification types

Answer 11

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

Question 12

What are causes of secondary DM?

Answer 12

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

Question 13

What are the genetic diseases associated with increased risk of DM?

Answer 13

Turner Syndrome
Down Syndrome
Kleinfelter Syn
Prader-Willi Syn

Question 14

Physiology of Insulin

Answer 14

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

Question 15

In what form is insulin produced?

Answer 15

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

Question 16

How is insulin release triggered?

Answer 16

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

Question 17

Describe pathway that releases insulin from beta cells

Answer 17

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

Question 18

Physiologic effects of incretins GLP-1, GIP, and the DPP-4 enzyme

Answer 18

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

Question 19

Actions of insulin throughout the body

Answer 19

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

Question 20

What are the metabolic effects of having no insulin (or being insulin resistant)?

Answer 20

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

Question 21

What is the insulin signaling pathway?

Answer 21

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

Question 22

What is the pathogenesis of type I DM?

Answer 22

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

Question 23

What is the genetic component of type I DM onset?

Answer 23

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

Question 24

What are the environmental factors associated with type I DM onset?

Answer 24

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

Question 25

How are the B cells killed in type I DM?

Answer 25

Autoreactive TH1 lymphocytes, cytokines, CD8 CTL directed against B cell antigens: GAD, and islet antigen 512

Question 26

What are the lessons learned from the PIMA indians?

Answer 26

There is a population in AZ and in Mexico that have identical genes and very similar caloric intake. The difference is that the indians in Mexico have a much lower rate of DM II along with a much larger amount of physical activity. Some take this to mean that diabetes is an exercise deficiency disease.
We are meant to be so much more active than we currently are.

Question 27

Genetic influence on DM II

Answer 27

Huge genetic influence
Polymorphisms in beta cell function most commonly implicated (insulin secretion)
No HLA association except with Pima Indians

Question 28

Pathogenesis of DM II

Answer 28

Combination: insulin resistance and impaired insulin secretion

Increased visceral adipose causes increased FFA mobilization, decreased adiponectin, increased cytokines and other proteins which all together lead to insulin resistance

Question 29

Effects of insulin resistance

Answer 29

High fasting glucose levels: failure to inhibit gluconeogenesis in the liver

Postprandial hyperglycemia: from impaired glucose uptake in tissues

Excess FFA: failure to inhibit lipoprotein lipase in adipose tissue increasing insulin resistance