Insulin Resistance and T2DM

• T2DM stands for Type 2 Diabetes Mellitus.
• The lecture focuses on the pathophysiology of T2DM.

Learning Objectives

• The study notes cover the relationship between insulin action and secretion in normal metabolic regulation.
• The notes describes the role of beta-cell dysfunction and insulin resistance in T2DM's etiology.
• The notes reviews how obesity contributes to the development of T2DM.
• The study notes explain the metabolic impacts of obesity on the liver, muscle, pancreas, and adipose tissue.
• The study notes explore the molecular mechanisms of insulin resistance within the liver, muscle and adipose tissue in T2DM.
• The notes describe the incretin effect, the incretin hormones and how they help normal glucose homeostasis and in T2DM.
• The study notes describe the function of renal glucose reabsorption in normal glucose homeostasis and T2DM.
• The notes explains the molecular mechanisms of diabetic dyslipidemia and its relevance.

T2DM Definition

• T2DM is diagnosed based on glucose levels.
• Normal fasting glucose is below 100 mg/dL.
• Diabetes is diagnosed with fasting glucose levels greater than 126 mg/dL.
• Pre-diabetes range is 100-126 mg/dL.
• Normal glucose tolerance test (OGTT) is below 140 mg/dL.
• Diabetes is diagnosed by OGTT levels greater than 200 mg/dL.
• Impaired glucose tolerance (IGT) is 140-200 mg/dL.
• Normal HbA1c is about 5%.
• Pre-diabetes presents an HbA1c of 5.7% - 6.4%.
• Diabetes is indicated by HbA1c greater than 6.5%.

Metabolic Dysfunction in T2DM

• T2DM involves dysregulation of lipid, carbohydrate, and protein metabolisms.
• Hyperglycemia leads to microvascular complications.
• Diabetic dyslipidemia contributes to macrovascular complications.
• Myocardial infarction is the primary mortality cause in T2DM.

Core Defects in Diabetes

• Type 1 diabetes is characterized by lack of insulin production due to immune-mediated beta-cell destruction.
• Type 2 diabetes involves insufficient insulin production and reduced tissue response to insulin (insulin resistance).

Obesity and T2DM

• Higher BMI and obesity increase T2DM risk by promoting insulin resistance.
• Most obese people are not diabetic, so insulin resistance alone is not sufficient to cause T2DM.
• The pancreas secretes increasing insulin to compensate and maintain normal glucose levels.
• Pre-diabetes and T2DM develops when pancreas does not secrete enough insulin to compensate for insulin resistance

Pancreatic Beta-Cell Function

• Progression to T2DM is based on pancreatic beta-cell function
• T2DM develops when insulin secretion can no longer compensate for insulin resistance.

Key Concepts in T2DM

• T2DM has a complex etiology that includes abnormal lipid, carbohydrate and protein metabolism.
• Beta-cell dysfunction and insulin resistance appear before T2DM onset.
• Insulin resistance alone is not sufficient to cause T2DM because of hyperinsulinemic compensation.
• Beta-cell dysfunction determines disease progression to hyperglycemia and T2DM.
• Maintaining beta-cell function and improving insulin sensitivity are important prevention and management objectives.

Tissue Dysfunction Leading to Hyperglycemia

• T2DM involves tissue dysfunction in the liver, muscle and pancreas.

Adipose Hypertrophy in Obesity

• Adipose hypertrophy has metabolic and endocrine dysfunction.
• Hyperplasia describes the increasing number of cells in the body.
• Hypertrophy describes the increasing size if cells in the body.
• Obesity causes inflammation from inflammatory cytokine secretion (TNFα, IL-1β, IL-6).
• Obesity causes normal metabolic and endocrine dysfunction.
• Inflammation causes metabolic dysfunction, and insulin resistance.

Insulin Resistance in Adipose Tissue

• Insulin resistance in adipose tissue causes FFA, or free fatty acid increase.
• Increased FFA levels cause lipid accumulation, including insulin resistance in muscle and liver.
• Increased FFA levels cause impaired pancreatic insulin secretion.
• Increased circulating FFA levels in obesity result in lipid accumulation (steatosis) in other tissues.
• Adipose tissue regulates the metabolic functions of other tissues in health and disease.

Elevated Plasma FFA Levels

• Elevated plasma FFA levels cause beta-cell dysfunction and loss.
• Chronic elevation of fatty acids causes impairs glucose-stimulated insulin secretion.
• Elevated fatty acids induces beta-cell death by apoptosis.

Incretin Effect

• The incretin effect is increased insulin secretion by oral vs IV (intravenous) glucose administration.
• The incretin effect is mediated by gut-derived hormones.
• The responsible hormones are glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP).
• Incretins augment glucose-stimulated insulin secretion
• Incretins do not by themselves stimulate insulin release.
• The incretin effect is reduced in T2DM due to low GLP-1 levels.

Intestinal GLP-1 Secretion

• Intestinal GLP-1 secretion is reduced in T2DM due to secretion by endocrine cells (L-cells) of the distal small intestine.
• The mechanisms that cause GLP-1 levels is not well understood.
• The GLP-1 levels is response to nutrient stimulation.

Glucagon Secretion Changes

• Glucagon secretion is elevated in T2DM.
• Low GLP-1 and resistance associated with T2DM contribute to glucagon hypersecretion.
• T2DM patients exhibit hyperglucagonemia from increased glucagon secretion by alpha-cells.
• GLP-1 inhibits glucagon secretion

Lipotoxicity and GLP-1 Deficiency

• Lipotoxicity and GLP-1 deficiency in T2DM causes dysfunction of the endocrine pancreas with hyperglycemia.
• Beta-cell function results in decreased secretion of insulin.
• Alpha secretion, a cell in the pancreas, results in increased glucagon secretion.

Brain Insulin Action

• Brain insulin action regulates whole-body energy and glucose homeostasis.
• Pancreatic insulin secretion is decreased.
• Glucose uptake is increased.
• Appetite is decreased.
• Energy expenditure is increased.
• Gluconeogenesis is descreased.

Insulin Resistance in the Brain

• Insulin resistance in brain contributes to obesity and hyperglycemia in T2DM
• Brain insulin resistance result in increased appetite and decreased energy expenditure.
• Gluconeogenesis in the liver is increased .
• Insulin Secretion of the pancreas is decreased.
• Glucose uptake increase is limited
• Blood Glucose is increased

Renal Glucose Reabsorption

• Glucose is reabsorbed in the proximal tubule of the kidney.
• Filtered glucose is reabsorbed by sodium-glucose cotransporters.
• The function is performed by SGLT2 and SGLT1 by 80-90%, 10-20% respectively.

Glucosuria Threshold

• Maximum reabsorptive capacity determines the threshold for glucosuria.
• The maximum tubular glucose reabsorptive capacity is called Tmg.
• Threshold for glucosuria: plasma glucose concentration at which glucose spills into the urine.
• Normal threshold for glucosuria ~180 mg/dL.

Glucosuria Threshold in T2DM

• Threshold for glucosuria is increased in T2DM.
• Increased Tmg elevates threshold for glucosuria in T2DM.
• Increased glucose reabsorption contributes to hyperglycemia in T2DM.

Hyperglycemia in T2DM

• A number of factors contribute to increased blood sugar.
• Factors such as impaired insulin secretion, increased glucagon secretion, decreased incretin effect, neurotransmitter dysfunction, decreased glucose uptake, increased lipolysis, increased hepatic glucose production, and increased glucose reabsorption.

Diabetic Dyslipidemia

• Diabetic dyslipidemia has a high correlation with T2DM

Metabolic Actions of Insulin In Liver

• Insulin promotes glycogenesis in the liver
• Insulin promotes GLUCONEOGENESIS in the liver

High FFA Levels and Hepatic Insulin Resistance

• Elevated FFA levels in adipose tissue lead to hepatic insulin resistance.
• High FFA causes increased glucose output and VLDL secretion.
• Hepatic insulin resistance causes increased GLUCONEOGENESIS and decreased GLYCOGENESIS
• The result of elevated FFA is an increase in Plasma glucose

Elevated VLDL Secretion

• Elevated VLDL secretion causes decreased HDL-cholesterol
• CETP exchanges VLDL-TG results in lower HDL-cholesterol, but total cholesterol does not change.
• Triglycerides in HDL particles is hydrolyzed, resulting in lipid-poor ApoA-I.
• Lipid-poor ApoA-I is cleared by the kidney.
• A correlation between TG, triglycerides, and HDL-cholesterol is observed.

Elevated VLDL Secretion Effects

• Elevated VLDL secretion causes increased in small/dense LDL-cholesterol.
• CETP also exchanges VLDL-TG for CE in LDL particles.
• TG in LDL is hydrolyzed by HL resulting in smaller and denser LDL particles (SD-LDL).
• SD-LDL particles penetrate vascular wall better and are are highly atherogenic.
• Smaller and denser LDL is high risk for cardiovascular disease.

Insulin Resistance Leads to Diabetic Dyslipidemia

• Hepatic insulin resistance results in increased VLDL secretion.
• The result is increased triglycerides and SD-LDL-cholesterol and decreased HDL-cholesterol.
• The term ‘diabetic dyslipidemia' does not imply the presence of diabetes. Increased triglycerides cause high risk for atherosclerosis, heart attack, coronary disease.
• The cause of diabetic dyslipidemia is insulin resistance, not hyperglycemia.
• The term ‘diabetic dyslipidemia' does not imply the presence of diabetes.

Explore the intricate relationship between insulin resistance and the development of Type 2 Diabetes Mellitus (T2DM). This lesson looks at hyperinsulinemic compensation, pre-diabetes, and the role of relative insulin deficiency. Understand the critical factors determining T2DM development and the importance of maintaining β-cell function.