BMS200 diabetes

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Questions and Answers

What are the three major options the liver has when experiencing elevated levels of FFAs?

Export, transform, or reduce

Receive, produce, or excrete

Burn, export, or metabolize

Burn, store, or export (correct)

What is the purpose of VLDL in the liver?

Convert lipids into glucose for energy

Store excess energy as fatty acids

Export synthesized lipids to other cells (correct)

Transport cholesterol to the kidneys

During the life cycle of lipoproteins, what transformation occurs after VLDL?

VLDL transforms directly into HDL

VLDL becomes triglycerides and then cholesterol

VLDL is converted into IDL, then LDL (correct)

VLDL is absorbed by tissues without transformation

Which apoproteins are associated with the initial formation of VLDL?

ApoB-100, ApoA-V, ApoC-II Signup and view all the answers

What is the final clearance mechanism for LDL by the liver?

LDL receptor for ApoB-100 and ApoE Signup and view all the answers

What is the primary storage form of energy found in the liver?

Glycogen Signup and view all the answers

What happens to adipose tissue during the first cycle of insulin resistance?

It loses some ability to convert calories into stored triglycerides. Signup and view all the answers

Which factor contributes to the increased levels of circulating free fatty acids (FFA) during insulin resistance?

Longer retention of glucose in the bloodstream Signup and view all the answers

In a state of positive energy balance, what effect does constant insulin secretion have on skeletal muscle?

It creates insulin resistance in skeletal muscle. Signup and view all the answers

What role do effective insulin receptors play in energy storage?

They aid in normal energy storage within healthy energy depots. Signup and view all the answers

What initiates the twin cycle hypothesis in T2DM?

Early insulin resistance Signup and view all the answers

Which organ is primarily involved in the first cycle of the twin cycle hypothesis?

Liver Signup and view all the answers

What characterizes the transition from early insulin resistance to the loss of beta cell mass?

Dysregulated lipid and glucose metabolism Signup and view all the answers

Which of the following factors contributes to insulin resistance in the twin cycle hypothesis?

Impaired nutrient clearance by skeletal muscle Signup and view all the answers

What effect does leptin resistance have on caloric intake in the context of T2DM?

It exacerbates excess caloric intake Signup and view all the answers

In the context of the twin cycle hypothesis, what is a consequence of saturated energy storage options?

Increased risk of developing T2DM Signup and view all the answers

Which body tissues are primarily disrupted in their metabolic processes in the twin cycle hypothesis?

Skeletal muscle and liver Signup and view all the answers

What is a significant contributor to the development of T2DM as outlined in the twin cycle hypothesis?

Environmental and psychosocial factors Signup and view all the answers

How does the twin cycle hypothesis explain the role of adipose tissue in T2DM?

It indicates unregulated fat storage affecting insulin sensitivity Signup and view all the answers

What is the overall impact of impaired nutrient clearance in T2DM according to the twin cycle hypothesis?

It results in worsening insulin resistance Signup and view all the answers

Study Notes

Energy Storage and Insulin Sensitivity

Subcutaneous fat, glycogen, and energy storage play roles in muscle and liver, with glycogen being the primary energy source.
Energy in the liver is also stored as glycogen, which can be converted to glucose.
Visceral fat contains limited energy reserves, but has a role in energy homeostasis.
Effective insulin receptors are essential for normal energy storage in healthy adipose tissue.

First Cycle of the Liver and Insulin Resistance

Prolonged positive energy balance and insulin secretion lead to insulin resistance in skeletal muscle and subcutaneous fat.
Elevated glucose levels remain in circulation longer, and adipose tissue becomes less effective at converting calories into triglycerides.
Increased circulating free fatty acids (FFAs) result, necessitating liver management.

Liver's Response to Elevated Free Fatty Acids

The liver can manage elevated FFAs through:
- Burning energy via beta-oxidation.
- Storing energy, leading to hepatic steatosis (undesirable).
- Exporting energy as very low-density lipoproteins (VLDL), increasing triglycerides (TGs) and cholesterol.

Characteristics and Lifecycle of VLDL

VLDL synthesized in the liver contains triglycerides, phospholipids, and cholesteryl esters; important apoproteins include ApoC-II, ApoA-V, and ApoB-100.
VLDL transforms to intermediate-density lipoprotein (IDL) which is then further converted to low-density lipoprotein (LDL) after triglyceride removal.
LDL is cleared by liver receptors, particularly targeting ApoB-100 and ApoE.

Twin Cycle Hypothesis and T2DM

Type 2 Diabetes Mellitus (T2DM) develops from long-lasting insulin resistance, leading to disrupted lipid and glucose metabolism across multiple organs.
The cycle starts with insulin resistance, exacerbated by excess caloric intake and impaired nutrient clearance by muscles.

Insulin Resistance Feedback Loop

The feedback loop involves insulin resistance escalating hepatic steatosis and VLDL output, resulting in triglyceride and FFA buildup in the pancreas, which compromises insulin secretion.
Elevated FFAs contribute to inflammation often seen in T2DM, potentially increasing atherosclerosis risk.

Adipose Tissue Saturation

Genetic factors determine the maximum fat storage capacity in adipose tissue, which can become saturated, leading to insulin resistance.
Subcutaneous fat can release adiponectin, enhancing insulin sensitivity, although its secretion may lag behind leptin from visceral fat.
T2DM alters the leptin-to-adiponectin ratio, negatively affecting food intake regulation.

Evidence and Testing of the Twin Cycle Hypothesis

Investigations focus on confirming the hypothesis through observed changes in fatty liver, pancreatic fat, weight loss, and triglyceride levels post-T2DM treatment.
Long-term T2DM may challenge the reversal of these cycles due to significant beta cell mass loss.

DiRECT Trial Overview

In the UK, 306 T2DM patients underwent an intense weight-loss program, stopping all antihypertensive and antidiabetic medications while consuming 825–853 kcal/day initially.
The purpose of the trial was to evaluate the effectiveness of dietary intervention over 12 months.
Results indicated a significant weight loss in 24% of participants in the intervention group compared to none in the control group.

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