Pathogenesis of Diabetes Part 2

Podcast Beta

Play an AI-generated podcast conversation about this lesson

Questions and Answers

What is the role of insulin resistance in the twin cycle hypothesis related to T2DM?

It contributes to the loss of beta cell mass over time. (correct)

It leads to immediate improvement in glucose metabolism.

It results in increased muscle sensitivity to glucose.

It causes direct damage to pancreatic cells.

What primarily happens in the first cycle of the twin cycle hypothesis?

Insulin sensitivity increases in visceral fat.

Normal energy storage options become saturated. (correct)

Increased fat storage occurs in the liver.

Skeletal muscle effectively stores excess energy.

What effect does prolonged excess caloric intake have on insulin receptors in tissues?

They experience decreased effectiveness in energy storage. (correct)

They lead to increased triglyceride conversion in adipose tissue.

They enhance nutrient clearing by muscle tissue.

They become more sensitive to insulin over time.

What is the consequence of elevated circulating free fatty acids (FFA) due to insulin resistance?

Prolonged presence of glucose in the bloodstream. Signup and view all the answers

Which nutrient is primarily affected by insulin resistance as per the twin cycle hypothesis?

Carbohydrates, leading to increased blood sugar. Signup and view all the answers

In the context of T2DM, where is excess energy primarily stored when normal storage is overwhelmed?

Subcutaneous fat and liver. Signup and view all the answers

What triggers the onset of the first cycle in the twin cycle hypothesis?

Increased insulin secretion. Signup and view all the answers

How does leptin resistance contribute to T2DM according to the twin cycle hypothesis?

It exacerbates excessive caloric intake. Signup and view all the answers

What occurs in the liver during prolonged insulin resistance that exacerbates insulin resistance in hepatocytes?

Accumulation of lipid (steatosis) Signup and view all the answers

How does elevated circulating free fatty acids (FFAs) specifically impacted insulin resistance?

They activate toll-like receptors (TLRs) and exacerbate insulin resistance. Signup and view all the answers

In the context of T2DM, what is the result of inappropriate gluconeogenesis in the liver?

Increased pancreatic insulin secretion Signup and view all the answers

What is the primary reason for the 'ectopic' deposition of fat in individuals with metabolic syndrome/T2DM?

Insulin resistance at fat storage sites Signup and view all the answers

Which statement correctly describes the pancreatic changes associated with T2DM?

The islets are the primary focus of interest despite being less than 5% of the pancreas. Signup and view all the answers

What metabolic consequence arises from fat accumulation (steatosis) in the liver?

Increased production of triglycerides in VLDL Signup and view all the answers

What is a consequence of fatty pancreas that was initially hypothesized?

Apoptosis of beta-cells over time Signup and view all the answers

Which fatty acid is particularly linked to accumulation in pancreatic beta-cells?

Palmitic acid Signup and view all the answers

What is the relationship between insulin resistance in the liver and gluconeogenesis?

Insulin resistance contributes to uncontrolled gluconeogenesis. Signup and view all the answers

What function does palmitic acid have in insulin-resistant cells?

It activates TLRs and exacerbates insulin resistance. Signup and view all the answers

What physiological change may occur in beta-cells due to excess fat and sugar according to studies?

Beta cell de-differentiation Signup and view all the answers

What dietary intervention has been shown to improve fat deposition and fibrosis in the pancreas?

Dietary restriction Signup and view all the answers

What cellular stress is associated with fatty pancreas and beta-cell dysfunction?

Endoplasmic reticulum (ER) stress Signup and view all the answers

Which type of cell's function may beta-cells mimic due to fatty accumulation?

Alpha cells Signup and view all the answers

How is the excess triglyceride delivered to the pancreas linked to tissue response?

Fibrosis and fatty accumulation in pancreatic tissue Signup and view all the answers

What does the resolution of hepatic steatosis correlate with?

Resolution of fat deposition in the pancreas Signup and view all the answers

What is one major option for the liver when faced with elevated levels of free fatty acids (FFAs)?

Store the energy as hepatic steatosis Signup and view all the answers

Which lipoprotein type is primarily produced by the liver to export energy?

Very-Low-Density Lipoprotein (VLDL) Signup and view all the answers

What role do apoproteins play in lipoprotein metabolism?

They facilitate the clearance of lipoproteins from circulation. Signup and view all the answers

What is a key characteristic of LDL (Low-Density Lipoprotein)?

It plays a significant role in carrying liver-synthesized lipids to other cells. Signup and view all the answers

Which of the following apoproteins is not associated with IDL (Intermediate-Density Lipoprotein)?

ApoA-V Signup and view all the answers

What is the main function of VLDL in lipid metabolism?

To transport triglycerides from liver to peripheral tissues Signup and view all the answers

Which step in the lipoprotein metabolism cycle follows after VLDL in the endogenous pathway?

Formation of LDL from IDL Signup and view all the answers

What is the consequence of hepatic steatosis in the liver?

Progression to liver diseases Signup and view all the answers

What is the role of ApoB-100 in lipoproteins?

It serves as a major structural protein for later clearance by the liver. Signup and view all the answers

Which lipoprotein is directly formed from VLDL as triglycerides are removed?

IDL Signup and view all the answers

What is a major risk factor for the development of atherosclerosis related to LDL?

Accumulation of oxidized LDL Signup and view all the answers

How does insulin resistance affect adipose tissue?

It leads to the release of more free fatty acids. Signup and view all the answers

What is likely to occur as a result of the increased ratio of leptin to adiponectin in insulin resistance?

Poorly regulated food intake. Signup and view all the answers

What happens when the liver clears IDL via ApoE?

IDL is transformed into cholesterol-rich LDL. Signup and view all the answers

Which statement best describes the twin cycle hypothesis related to type 2 diabetes mellitus (T2DM)?

It involves a cycle of lipotoxicity in both the liver and pancreas. Signup and view all the answers

Why do elevated levels of VLDL and inflammation correlate with T2DM?

They contribute to the accumulation of triglycerides in tissues. Signup and view all the answers

Study Notes

Twin Cycle Hypothesis and Type 2 Diabetes Mellitus (T2DM)

T2DM develops after years of insulin resistance, linked to dysregulated lipid and glucose metabolism.
Insulin resistance affects multiple organs: liver, muscle, pancreas, skeletal muscle, visceral, and subcutaneous adipose tissue.
The twin cycle begins with early insulin resistance, particularly exacerbated by excess caloric intake and impaired nutrient clearing in skeletal muscle.

First Cycle – The Liver

Diabetic patients exhibit a "tipping point" where normal energy storage is saturated.
Optimal energy storage occurs in subcutaneous fat, muscle, liver, and a small amount in visceral fat with functioning insulin receptors.
Insulin resistance leads to prolonged blood glucose presence and decreases the capacity of adipose tissue to convert calories to triglycerides.
Increased free fatty acids (FFA) in circulation require processing by the liver.

Metabolic Responses of the Liver

The liver has three major responses to elevated FFAs:
- Burn energy (beta-oxidation).
- Store energy (leading to hepatic steatosis, which is detrimental).
- Export energy (through VLDL production).
Insulin resistance creates an imbalance in glucagon and insulin signaling, vital for liver health.
Long-term insulin resistance results in lipid accumulation (steatosis) which exacerbates insulin resistance in liver cells.

Consequences of Elevated FFAs

Circulating FFAs contribute to increased gluconeogenesis, leading to higher blood glucose levels and more insulin secretion.
The metabolic situation results in fat accumulation in liver cells, elevated VLDL export, and impaired gluconeogenesis control.

Second Cycle – The Pancreas

Pancreatic changes in T2DM are increasingly recognized, notably fat accumulation (i.e., "fatty pancreas").
Accumulation of triglycerides from liver VLDL delivery correlates with pancreatic fat deposition, leading to fibrosis.
Fat in islet cells can cause beta-cell apoptosis due to increased endoplasmic reticulum (ER) stress and reactive oxygen species (ROS).

Fatty Pancreas Effects

Beta-cell dysfunction may also include dedifferentiation, causing them to behave more like alpha cells, which secrete glucagon instead of insulin.
Resolution of pancreatic fat and fibrosis improves with dietary changes and management of T2DM.

Positive Feedback Loop in Metabolism

Insulin resistance results in hepatic steatosis and VLDL output, causing further fat accumulation in the pancreas, which impairs insulin secretion and leads to hyperglycemia.
Increased circulating FFAs contribute to inflammatory processes linked with T2DM which may influence atherosclerosis.

Overview of Lipoprotein Metabolism

VLDL synthesized in the liver contains triglycerides, phospholipids, cholesteryl esters, and vitamin E, characterized by apoproteins ApoC-II and ApoA-V for triglyceride transport.
Intermediate forms IDL and LDL are produced as triglycerides are removed. LDL is cleared by the liver, where uncontrolled levels can oxidize, promoting atherosclerosis risk.

Adipose Tissue Limitations

Adipose tissue reaches a saturation point in fat uptake, influenced by genetic and demographic factors.
Abnormal adipocyte function in insulin resistance leads to the release of FFAs rather than triglycerides, increasing the leptin and adiponectin ratio, complicating appetite regulation.

Studying That Suits You

Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

Description

This quiz explores the twin cycle hypothesis related to Type 2 Diabetes Mellitus (T2DM) as covered in BMS 200. It examines the general model and the two cycles involved, emphasizing the transition from insulin resistance to beta cell dysfunction. It draws from recent research in clinical endocrinology and metabolism.

Pathogenesis of Diabetes Part 2 - BMS 200 Week 1