Biochemistry Exam Iii - Diabetes

Front 1

Conditions characterized by polyuria (large urine volume)

Back 1

Diabetes (in the most general of terms)

Front 2

Insulin deficiency and/or resistance

Back 2

Diabetes Mellitus

When clinicians and patients use the term diabetes, they’re almost always referring to diabetes mellitus

Mellitus refers to sweet urine.

Front 3

Vasopressin deficiency

Relatively rare

Back 3

Diabetes insipidus

Hypothalamus (central DI) or lack of renal response to it (nephrogenic DI).

Insipidus refers to “tasteless” dilute urine.

Front 4

Most common forms
1. Insullin deficiency from B-cell destruction (5-10%)
2. Insulin resistance and deficiency (90-95%)

Back 4

Forms of Diabetes Mellitus

Other forms
Gestational diabetes
Monogenic forms: MODY, neonatal

DM secondary to other diseases, medications.

Front 5

1. Fasting plasma glucose > 126 mg/dL (7.0 mmol/L)

2. Symptoms of diabetes plus random blood glucose > 200 mg/dL (11.1 mmol/L)

3. Two hour plasma glucose > 200 mg/dL (11.1 mmol/L) during an oral glucose test

4. Hemoglobin A1C > 6.5%

Back 5

Diagnosis for diabetes

HgA1C is not well spread diagnostic, though is on its way

Front 6

100 - 125 mg/dL

Fasting plasma glucose

Back 6

Impared fasting glucose (IFG)

Pre-diabetic state

Note that the diagnosis of diabetes is based on glucose measurements. However, it’s important to keep in mind that diabetes is not simply a disease involving glucose!

Front 7

140-199 mg/dL

Oral glucose tolerance test

Back 7

Impaired glucose tolerance (IGT)

Pre-diabetic state

Note that the diagnosis of diabetes is based on glucose measurements. However, it’s important to keep in mind that diabetes is not simply a disease involving glucose!

Front 8

Lipid and lipoprotein abnormalities


Atherosclerosis:
coronary artery, cerebrovascular, peripheral vascular disease

~70% of diabetics die of CVD!

Back 8

The symptoms, signs, complications of
diabetes are not just related to glucose!

Front 9

1. Diabetes is not just a disorder of glucose

2. Diabetes mellitus is a disorder of insulin

3. Insulin is an anabolic hormone with pervasive effects on metabolism

4. The liver can only store so much glucose.

5. The body attempts to maintain plasma glucose levels between ~70 and 100 mg/dL

6. Diabetes is starvation in the midst of plenty.

7. Tight metabolic control reduces the long-term complications of diabetes mellitus

8. Type 2 diabetes mellitus arises from a continuum of subclinical pre-diabetic metabolic derangements

9. Insulin resistance, metabolic syndrome and type 2 diabetes constitute a global pandemic

10. Yesterday's biochemistry is today's medicine.

Back 9

Dr. Dave's ten concepts.

Front 10

Large urine volume

Glucose gets spilled into the urine

Above 180 mg/dL, kidneys place glucose into urine.

Water follows.

Back 10

Symptoms of polyuria and dehydration

Front 11

Explain the symptom:

Thirsty because of dehydration

Back 11

Polydipsia (thirst)

Front 12

Explain the symptom:

Body is in starvation mode.

Back 12

Polyphagia (hunger)

Front 13

Explain the symptom:

Body is in starvation mode.

Lipids and body proteins are being broken down.

Back 13

Weight loss

Front 14

Explain the symptom:

Body uses amino acids from body protein

Back 14

Weakness

Front 15

Dehydration causes this symptom in the eyes.

Back 15

Blurry vision

Front 16

Retinopathy

Macular edema

Sensory, motor, autonomic neuropathies.

Nephropathy.

Back 16

Microvascular - arteriosclerosis

Primarily caused by chronically elevated blood glucose

Front 17

Coronary artery disease

Cerebrovascular disease

Peripheral artery disease

Back 17

Macrovascular - atherosclerosis

Primarily caused by chronic blood lipid abnormalities

Front 18

High glucose concentration in blood

High ketone body concentration in blood.

Occurs in type I diabetics

Back 18

Diabetic ketoacidosis - Type I Diabetes Mellitus

Hyperglycemia

Front 19

More subtle form of diabetes

Does not develop acidosis because body still produces insulin, enough to stave it off.

Back 19

Hyperglycemic hyperosmolar state - Type II Diabetes Mellitus

Front 20

Decreased insulin

Increased glucagon

HSL is activated

FFA released to blood, which is bound to albumin.

Primarily taken up by fat and muscle

Back 20

Causes elevated plasma FFA

Front 21

Hyperinsulinemia is often found in pre-diabetics

Indicates they are in the resistance phase.

May not be able to detect hyperglycemia

Back 21

Type II diabetes is found to have hyperinsulinemia.

Until the B-cells eventually die.

Front 22

In industrialized nations, there is less habitual physical activity.

Without physical activity, patient is not breaking down fats, but is continuously eating them.

Back 22

Results in obesity, a primary defect that results in Type II diabetes.

Front 23

Hypertriglyceridemia

The liver can only convert 200-300 g of glucose into glycogen

Back 23

Any excess is stored as fat.

Reason why diabetics often have hypertriglyceridemia.

An early sign of metabolic imbalance.
- Fasting > 150 mg/dL

Front 24

1. Central obesity (by waist circumferance)

2. Hypertriglyceridemia: > 150 mg/dL (or specific medication)

3. Low HDL (< 40 mg/dL men, < 50 mg/dL female)

4. Hypertension >130/85 (or specific medication)

5. Fasting plasma glucose > 100 (or specific medication or diagnosis of type II diabetes mellitus)

Back 24

Metabolic syndrome

3 or more of the following.

Front 25

Plasma glucose levels are maintained in the starved state of a normal individual.

Back 25

After two days, the body relies on fatty acids for fuel.

Glucose is still available.

Front 26

Type I diabetics experience ketoacidosis, due to high concentrations of ketone bodies.

Back 26

Type II diabetics do not becasue there's enough insulin to keep everything in the balance.

Changes when B-cells are exhausted and die.

Front 27

Insulin deficiency caused by autoimmune destruction of pancreatic B-cells

Triggered by infections and genetic dispositions

Back 27

Etiology of type I DM

Defect on HLA region, MHC on chromosome 6. (50% of cases)

Front 28

Genetic predisposition and lifestyle factors

Back 28

Type II Diabetes Mellitus

Polygenic, about 60 gene candidates.

Front 29

Muscle:
Decreased:
- GLUT 4 receptors
- Glucose uptake
- AMPK
- PPARy
- FA oxidation

Increased
TAG accumulation
Fatty Acid uptake

Back 29

Occurs when:

Adiponectin decreases
Plasma FFA increases

Front 30

Liver:
Decreased:
- FA oxidation
- AMPK
- PPARy

Increased
- Gluconeogenesis
- TAG
- VLDL
- FA uptake

Back 30

Occurs when:

Adiponectin decreases
Plasma FFA increases

Front 31

Pancreas
- Control insulin secretion

Liver
- Control glucose production and fatty acid oxidation

Muscle
- Glucose uptake pathway (insulin sensitivity)

4. Adipose
- Fat mobilization, adiponectin secretion

Back 31

Pharmaceutical treatment strategies for type II diabetes

Front 32

Increases:
1. Adiponectin

2. AMP kinase

3. Insulin sensitivity

Back 32

Thiazolidinediones

Target: PPARy

Examples:
- Avadnia (rosiglitazone)
- Actos (pioglitazone)

Front 33

Decreases:
- Liver glucose

Increases:
- Insulin sensitivity

Back 33

Biguanides

Target: AMP kinase

Example:
Metformin.

Front 34

Decreases:
1. Intestinal absorption of starch and saccharides

Back 34

alpha-glucosidase inhibitors

Target: a-glucosidase

Examples:
- Precos (acarbose)
- Glyset (miglitol)

Front 35

Increases insulin secretion

Blocks KATP channel.

Back 35

Meglitinides

Target: ATP-sensitive K+ channel/SUR

Examples
- repaglinide
- nateglinide

Front 36

Block KATP channel

Increase insulin secretion

Back 36

Sulfonylureas (1950s)

Target: ATP-sensitive K+ channel/SUR

Examples
- tolbutamide
- glipizide
- glyburide

Front 37

Insulin replacement

Back 37

Insulin

Target: Insulin receptors, many pathways

Examples
- Regular NPH
- Lente

Front 38

KATP channel remains open

Back 38

Diabetes

Can be treated with sulfonylureas/meglitinides (close the channel -> trigger release of insulin)

Front 39

KATP channels remain closed

Back 39

Persistant Hypoglycemia and hyperinsulinemia in infancy.

Cannot be treated with sulfonylureas/meglitinides

Front 40

Normal individual

Increased TAG-VLDL -> CETP -> TAG rich HDL -> Hepatic lipase =

Increased clearance
Decreased HDL levels

Back 40

Diabetic person

Increased TAG-VLDL -> CETP -> TAG rich LDL -> Hepatic lipase =

Small-dense atherogenic LDL
- Increases with higher glucose and FFA's
- Damaged by oxidation

Front 41

What causes the remodeling of HDL and LDL via Cholesterol Ester Transferase Protein (CETP)?

Back 41

Increased levels of triglycerides (TAGs)

Front 42

Back 42

Front 43

Back 43

Front 44

Which enzyme is responsible for remodeling HDL and LDL when TAGs are highly elevated

Back 44

Cholesterol Ester Transferase Protein

Front 45

Therapy sufficient to alleviate acute symptoms

Back 45

Standard control

Front 46

Therapy sufficient to return plasma glucose and HbA1C levels to near normal levels.

Back 46

Tight control.

Problem - if not correctly titrated, may cause problems due to hypoglycemia.

Front 47

Fasting glucose: 90-130 mg/dL

Post-prandial glucose (2hr): <180 mg/dL

HbA1C: <7.0, as close to 6.5 as possible.

Back 47

Treatment goals for insulin replacement

Front 48

Out of these four metabolic derangements, only two classify as 'pre-diabetes'

1. Insulin resistance
2. Glucose intolerance
3. Metabolic syndrome
4. Type 2 diabetes

Back 48

Glucose intolerance
Metabolic syndrome