Pathogenesis of Diabetes Part 2 - BMS 200 Week 1

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.

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.