Biochemistry Final - Diabetes

General differences between Type I and Type II diabetes

Type I: insulin-dependent, deficient production of insulin, usually starts in childhood, prone to ketoacidosis, not associated with obesity

Type II: onset in adulthood, impaired responses to insulin (insulin-insensitive), not prone to ketoacidosis, associated with obesity, more common type

Basis of insulin deficiency in type I diabetes

autoimmune destruction of pancreatic beta cells by antibodies (insulitis)

causes deficiency in insulin

Metabolic consequences of type I diabetes for glucose

1. decreased glucose metabolism

2. increase glucose output via mobilization of glycogen and gluconeogenesis

3. high plasma glucose levels

4. glucosuria (glucose in urine)

5. polyuria (excessive urination- water follows solute)

6. polydipsia (excessive thirst)

7. polyphagia (increased appetite and food intake)

basis of ketoacidosis in type 1 diabetes

Increased ketogenesis decreases blood pH (more acidic) faster than the bicarbonate buffer system can keep up with

why are type I diabetics at risk of hypoglycemia

treating type I diabetes with insulin leads to increased uptake and utilization of glucose

insulin inhibits glucagon and energy-producing processes

takes glucose out of blood → hypoglycemia

What is prediabetes and its characteristics

Mild hyperglycemic state that indicates risk of type II diabetes

1. Insulin resistance (cells are not responding to insulin)

2. impaired fasting glucose (increase in glucose caused by increased gluconeogenesis)

3. Increased A1C (shows long term BG levels)

what is the lipid burden hypothesis

excessive lipids stored in adipocytes causes lipid accumulation in other tissues (liver and muscles)

this affects regular cellular metabolism and insulin signaling

how is PPAR-gamma expressed differently in type II diabetes

low expression in adipocytes

high expression in liver and muscles

how does adipose dysfunction lead to insulin resistance in skeletal muscles

Subcutaneous fat releases FAs into systemic circulation, causing buildup of lipid droplets in muscle

Droplets impair GLUT4 transporter function, muscles cannot uptake glucose

role of MCP-1 in insulin resistance

Produced by enlarged adipocytes → causes an immune response to produce TNF alpha

role of cytokines (TNF alpha) in insulin insensitivity

exports FAs from adipocytes to muscles and liver

how does overnutrition lead to insulin resistance in the liver

Overnutrition leads to increase in malonyl CoA, causing more FA synthesis, TAG synthesis, and FA metabolites

Inhibits insulin signaling

how does FA accumulation in muscles lead to insulin resistance

FA uptake → increased beta oxidation

Beta oxidation outpaces TCA and ETC, creating reactive oxygen species

Reactive oxygen species inhibits insulin signaling

what is glucose-stimulated insulin secretion

increase in BGL after a meal (post-prandial) stimulates insulin secretion

how do functional pancreatic beta cells release insulin

K+ channels in the membrane of beta cells pump K+ out of the cell

High energy state inhibits K+ channels and activates Ca2+ channels

Increase in Ca2+ inside the cell triggers release of insulin granules (triggering pathway, K+ channel dependent)

Insulin granules trigger amplifying signals that eventually lead to insulin release (amplifying pathway, K+ channel independent)

how does increased fatty acid oxidation result in increased pyruvate cycling and insulin hypersecretion

overnutrition → fatty acid oxidation → acetyl coA → increased pyruvate production → increased insulin secretion

role of endoplasmic reticulum in beta cell dysfunction

insulin is made in the ER

hypersecretion of insulin → ER stress → misfolded proteins → beta cell death

normal role of amylin released from beta cells

slows gastric emptying and increases satiety signal

role of amylin in beta cell dysfunction

how does weight loss and exercise work to treat type II diabetes

how do sulfonylureas work to treat type II diabetes

Inhibit K channels on beta cell membrane, activating Ca2+ channels and stimulating insulin production regardless of BGL

how do GLP-1 agonists work to treat type II diabetes

Stimulates insulin release and decreases beta cell apoptosis

how do biguanides like Metformin work to treat type II diabetes

Activates AMPK

how do thiazolidinediones function to treat type II diabetes

Activates PPAR-gammas

how do alpha-glucosidase inhibitors work to treat type II diabetes

inhibit glucose absorption in the intestine by inhibiting digestive enzymes

Metabolic consequences of type I diabetes for lipids

1. decreased storage of lipids in adipocytes

2. decreased synthesis of TAGs in hepatocytes

3. increase in processes needed to mobilize FAs and use them for energy

4. increase in acetyl CoA and ketogenesis because OAA is being used for gluconeogenesis in the liver

Metabolic consequences of type I diabetes for proteins

increased breakdown of proteins and amino acids