BMS 200 Week 1: Diabetes Pathogenesis Part 2

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Questions and Answers

Which aspect significantly contributes to the transition from early insulin resistance to the loss of beta cell mass in T2DM?

Excessive protein synthesis in the pancreas

Improved insulin receptor sensitivity in skeletal muscle

Increased water retention in the kidney

Dysregulated lipid and glucose metabolism across multiple organs (correct)

What happens to circulating nutrients, particularly glucose, in the presence of insulin resistance?

They are converted to glycogen at an increased rate

They are rapidly transformed into stored triglycerides

They are efficiently cleared by the liver and skeletal muscle

They accumulate in the bloodstream for extended periods (correct)

What has been observed in diabetic patients regarding energy storage options?

There is unlimited capacity for energy storage in skeletal muscle

Normal energy storage options become saturated at a tipping point (correct)

There is improved energy storage in visceral fat

Energy storage in muscle significantly increases

Which of the following factors exacerbates the transition to T2DM in the context of insulin resistance?

Leptin resistance and biopsychosocial factors Signup and view all the answers

In the first cycle of the twin cycle hypothesis, what occurs in adipose tissue due to insulin resistance?

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

Which statement best describes the role of skeletal muscle in the twin cycle hypothesis?

Skeletal muscle has an impaired ability to clear nutrients during insulin resistance Signup and view all the answers

What is the predominant consequence of prolonged elevated circulating free fatty acids (FFA) in the body?

Increased burden on the liver to manage elevated FFAs Signup and view all the answers

What role does effective insulin receptor sensitivity have in healthy energy storage?

It enables normal energy storage in healthy depots, like muscle and subcutaneous fat Signup and view all the answers

What happens to elevated levels of FFAs in the liver besides beta oxidation?

Hepatic steatosis Signup and view all the answers

What is the primary role of VLDL in the liver?

Carrying liver-synthesized lipids to other cells Signup and view all the answers

Which apoprotein is NOT associated with VLDL production?

ApoE Signup and view all the answers

What is a likely negative outcome of excessive hepatic steatosis?

Potential progression to liver disease Signup and view all the answers

What characteristic largely defines the life cycle of LDL?

Clearance via liver receptors Signup and view all the answers

What distinguishes IDL from VLDL in terms of their lipid content?

IDL has a lower triglyceride content Signup and view all the answers

How does the liver respond to high levels of FFAs aside from burning?

Storage in the form of triglycerides Signup and view all the answers

What role do apoproteins play in lipoprotein metabolism?

They facilitate the transport of lipoproteins in the bloodstream Signup and view all the answers

Which process is linked to pancreatic fibrosis and fat accumulation?

Increased VLDL delivery from the liver Signup and view all the answers

What signifies the dysfunction of beta cells in a fatty pancreas?

Apoptosis due to high glucose levels Signup and view all the answers

What results from excessive fat and glucose in relation to beta cells?

Transformation into cells resembling alpha cells Signup and view all the answers

Which of the following is NOT a consequence of a fatty pancreas?

Enhanced metabolic homeostasis Signup and view all the answers

What approach is linked to the resolution of fat deposition and fibrosis in the pancreas?

Dietary restriction and resolution of T2DM Signup and view all the answers

What was the daily caloric intake assigned to participants during the initial phase of the DiRECT trial?

825 – 853 kcal/day Signup and view all the answers

The accumulation of which fatty acid is specifically linked to islet cell dysfunction?

Palmitic acid Signup and view all the answers

What percentage of participants in the intervention group experienced a weight loss of 15 kg or more at 12 months?

36% Signup and view all the answers

What is indicative of 'beta cell burnout' as a consequence of a fatty pancreas?

Ongoing insulin secretion despite elevated glucose Signup and view all the answers

What was a critical criterion for participants to be included in the DiRECT trial?

They must have been diagnosed with T2DM within the last 5 years. Signup and view all the answers

What is a possible alternative outcome to apoptosis in the context of fatty pancreas?

Beta cell de-differentiation Signup and view all the answers

What immediate action was taken regarding antidiabetic medications at the start of the DiRECT trial?

All antihypertensive and antidiabetic medications were stopped. Signup and view all the answers

What notable outcome was observed among participants in the intervention group as a measure of treatment success?

Improvement in fatty liver Signup and view all the answers

What is the initial lipoprotein synthesized by the liver that predominantly contains triglycerides?

VLDL Signup and view all the answers

Which of the following proteins is crucial for the activity of lipoprotein lipase (LPL) in peripheral tissues?

ApoC-II Signup and view all the answers

In the context of insulin resistance, what happens to adipose tissue's ability to uptake fats from circulation?

It becomes less able to store triglycerides and instead releases free fatty acids. Signup and view all the answers

How does the receptor-mediated clearance of LDL primarily occur?

By binding to both ApoE and ApoB-100. Signup and view all the answers

What is a primary consequence of high levels of VLDL and inflammation associated with T2DM?

Compromised insulin secretion. Signup and view all the answers

What is the role of adiponectin in the context of subcutaneous fat?

To promote insulin sensitivity. Signup and view all the answers

What results from the oxidation of LDL if it is not cleared effectively?

Promotion of atherosclerosis. Signup and view all the answers

Which factor increases in the presence of insulin resistance and T2DM, affecting food intake regulation?

Leptin ratio compared to adiponectin. Signup and view all the answers

Study Notes

Twin Cycle Hypothesis and T2DM

Type 2 Diabetes Mellitus (T2DM) develops over years, primarily due to insulin resistance.
Transition from insulin resistance to reduced beta cell mass involves dysregulated lipid and glucose metabolism across several organs: liver, muscle, pancreas, skeletal muscle, visceral, and subcutaneous adipose tissue.
The twin cycle hypothesis posits that T2DM starts with early insulin resistance, exacerbated by excessive caloric intake and impaired nutrient clearance in skeletal muscle.

The First Cycle – Liver

Diabetic individuals reach a "tipping point" when normal energy storage becomes saturated.
Healthy energy storage occurs primarily in subcutaneous fat, skeletal muscle (glycogen), liver (glycogen), and minimally in visceral fat.
Positive energy balance and prolonged insulin secretion lead to insulin resistance in skeletal muscle and subcutaneous fat.
Elevated circulating glucose and decreased lipid storage capacity in adipose tissue results in increased free fatty acids (FFA) in the bloodstream.
The liver responds to elevated FFA through three main pathways:
- Burn energy via beta oxidation.
- Store energy as hepatic steatosis (fatty liver).
- Export energy as Very Low-Density Lipoprotein (VLDL).

The Second Cycle – Pancreas

Excess triglycerides (TGs) from the liver contribute to fat accumulation and fibrosis in the pancreas.
Fat accumulation in pancreatic beta cells may lead to apoptosis, increased endoplasmic reticulum (ER) stress, production of reactive oxygen species (ROS), and beta cell "burnout" from continuous insulin production.
Beta cell dysfunction can also involve de-differentiation, causing beta cells to behave more like alpha cells, though this is under ongoing investigation.
Weight loss and dietary modifications can reverse fat deposition and fibrosis in the pancreas, restoring function.

Positive Feedback Loop in T2DM

Progression of T2DM involves a cycle of:
- Insulin resistance → increased hepatic steatosis and VLDL production → TG and FFA accumulation in the pancreas → compromised insulin secretion → hyperglycemia → increased circulating FFAs.
This cycle exacerbates T2DM and leads to elevated levels of VLDL and related inflammation impacting atherosclerosis.

Endogenous Pathway in Lipoprotein Metabolism

VLDL, produced by the liver, consists primarily of triglycerides and includes apoproteins crucial for metabolism (ApoC-II, ApoA-V).
As triglycerides are removed from VLDL, it transforms into Intermediate Density Lipoprotein (IDL) and eventually Low-Density Lipoprotein (LDL).
The liver clears IDL and LDL via LDL receptors that bind to ApoE and ApoB-100.
If LDL is not cleared, it can oxidize, significantly increasing atherosclerosis risk.

Adipose Tissue Function and Saturation

Subcutaneous fat has a limit to how much fat (VLDL) it can store, influenced by genetic and demographic factors.
Insulin resistance hinders the ability of adipocytes to store triglycerides, prompting FFA release.
Adiponectin secretion from beneficial subcutaneous fat struggles to keep pace with increased leptin secretion from visceral fat, worsening insulin resistance.

DiRECT Trial in the UK

Study involved 306 T2DM patients undergoing a weight-loss program led by dieticians and nurses.
Participants followed a strict low-calorie diet (825-853 kcal/day) for three months, then transitioned to sustainable caloric intake over 1-2 months.
Significant weight loss observed in the intervention group, with 24% achieving weight loss of at least 15 kg compared to none in the control group after 12 months.

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Description

Explore the twin cycle hypothesis and its relation to Type 2 Diabetes Mellitus (T2DM) in this quiz. Understand the general model and the two cycles involved in the development of insulin resistance and loss of beta cell mass. Delve into the significant role of dysregulated lipid and glucose metabolism in chronic disease progression.