Lecture_13_Insulin_Resistance_and_type_2_diabetes_.pdf

🥒 Lecture 13: Insulin Resistance and type 2 diabetes Module 1 - Aetiology Important definitions Glucose intolerance: The body has an inability to metabolise glucose, leading to impaired glucose...

🥒 Lecture 13: Insulin Resistance and type 2 diabetes Module 1 - Aetiology Important definitions Glucose intolerance: The body has an inability to metabolise glucose, leading to impaired glucose uptake and high blood glucose levels. Insulin resistance: The body cannot respond effectively to insulin. As a result, the pancreas produces more insulin to compensate for the reduced response in target tissues. This leads to hyperinsulinemia. Type 2 Diabetes: Diabetes occurs when the beta cells of the pancreas fail to produce sufficient insulin, often following prolonged insulin resistance. Pathophysiological progression of type 2 diabetes Lecture 13: Insulin Resistance and type 2 diabetes 1  Initial stages - glucose intolerance The body becomes unable to metabolize glucose effectively, leading to glucose intolerance. This is typically caused by insulin resistance, which is initially counteracted by high levels of insulin secretion from the pancreas. Pathophysiological progression of type 2 diabetes: Insulin Sensitivity: Initially, there is a decline in insulin sensitivity, which eventually plateaus. As insulin sensitivity decreases, insulin secretion increases as a compensatory response. However, once the beta cells fail to keep up with the excess demand, insulin levels begin to decrease. Plasma Glucose Levels: During the early stages of glucose intolerance and insulin resistance, blood glucose levels are maintained due to the elevated secretion of insulin. Eventually, as insulin secretion declines, blood glucose levels rise, marking the progression to type 2 diabetes and the onset of hyperglycemia. Lecture 13: Insulin Resistance and type 2 diabetes 2  Type 2 diabetes- prevalence Globally, about 1 in 11 adults has diabetes, and 90% of these individuals have type 2 diabetes, making it highly prevalent in today’s society. The major driving factors of the global type 2 diabetes mellitus (T2DM) epidemic: include overweight and obesity, sedentary lifestyle and increased consumption of unhealthy diets Among patients with T2DM, cardiovascular complications are the leading cause of morbidity and mortality Diagnosis of Type 2 Diabetes Estimated that 1/3 of people with diabetes don’t know they have it. Recommended that people over 45 years be tested (every 3 years). Fasting Glucose Test Performed after an 8 to 12-hour fast. Normal Range: Blood glucose is below 5.5 mmol/L. Impaired Fasting Glucose (Pre-diabetes): Blood glucose between 5.5 to 6.9 mmol/L. Diabetes: Blood glucose >7.0 mmol/L on more than one occasion during a fasting state. Oral Glucose Tolerance Test (OGTT): Typically performed if fasting blood glucose is between 5.5 to 7.7 mmol/L or if a random blood glucose measurement is between 7.8 to 11.0 mmol/L. Procedure: The individual consumes a drink containing 75 grams of sugar. Blood glucose is measured 2 hours after consumption. Lecture 13: Insulin Resistance and type 2 diabetes 3  Normal Range: Blood glucose returns to below 7.8 mmol/L within 2 hours. Impaired glucose tolerance: 7.8 -11 mmol Indication of Diabetes: Blood glucose remains around or above 11.0 mmol/L after 2 hours. Prevalence of diabetes increases with age The onset of type 2 diabetes is strongly linked to age. There is a significant increase in the prevalence of type 2 diabetes in individuals aged 45 to 49, and this further increases in the 55 to 59 age group. 92% of individuals with type 2 diabetes are 45 years or older. The proportion of individuals with type 2 diabetes is higher in males than in females. Strong link between overweight/ obesity and the onset of diabetes Graph 1 - Prevalence of Type 2 Diabetes and Weight Categories: As weight increases, the prevalence of type 2 diabetes rises significantly, with a dramatic increase in the overweight and obese categories. Lecture 13: Insulin Resistance and type 2 diabetes 4  Prevalence is particularly high in individuals with morbid obesity. Graph 2 - Odds Ratio of Developing Type 2 Diabetes: Individuals in the lower obese category (BMI 30–39) are four times more likely to develop type 2 diabetes. This likelihood increases to just under 8 times more likely in the morbidly obese category. This is due to an inverse relationship between fat mass and insulin sensitivity. Studies show that with increasing fat mass (adiposity), there is a reduction in insulin sensitivity and an increase in insulin resistance. Lecture 13: Insulin Resistance and type 2 diabetes 5  Regardless of how weight loss occurs, greater fat loss is consistently associated with improved insulin sensitivity. Insulin’s Effects in the Periphery: Insulin is secreted from the beta cells of the pancreas and exerts its effects on three major metabolic sites: the liver, skeletal muscle, and adipose tissue. Liver: Insulin reduces hepatic glucose production by inhibiting gluconeogenesis. Skeletal Muscle: Primary site for glucose uptake in the body. Insulin promotes glucose uptake and its conversion to glycogen. Insulin also promotes the uptake of amino acids and protein synthesis. Adipose Tissue: Insulin promotes glucose uptake, although this effect is much less efficient than in skeletal muscle. Insulin also inhibits lipolysis, promoting triglyceride synthesis. Lecture 13: Insulin Resistance and type 2 diabetes 6  Effects of Insulin Resistance: When insulin can no longer exert its effects, several key changes occur that lead to profound hyperglycemia: Liver: Insulin resistance prevents insulin from inhibiting hepatic glucose production. As a result, gluconeogenesis is unregulated, leading to elevated hepatic glucose production, which contributes to hyperglycemia. Skeletal Muscle: Insulin resistance impairs glucose uptake in skeletal muscle, the body’s primary site for glucose clearance. This is due to the inability of insulin to promote the translocation of the GLUT4 transporter, inhibiting glucose uptake and contributing to hyperglycemia. Adipose Tissue: Insulin resistance increases lipolysis, leading to an increase in circulating free fatty acids. Therefore, insulin resistance and type 2 diabetes not only affect glucose metabolism but also disrupt blood lipid levels. Lecture 13: Insulin Resistance and type 2 diabetes 7  Progression from Glucose Intolerance to Type 2 Diabetes: 1. Insulin Resistance: Initially, insulin resistance at target tissues triggers a compensatory increase in insulin secretion. 2. Beta Cell Failure: When the beta cells of the pancreas can no longer produce sufficient insulin, insulin secretion decreases. This is the hallmark of type 2 diabetes. The combination of unregulated hepatic glucose production, reduced glucose uptake in skeletal muscle, and increased lipolysis in adipose tissue leads to profound hyperglycemia. Lecture 13: Insulin Resistance and type 2 diabetes 8  Treatment strategies for type 2 diabetes The primary goal of treatment for type 2 diabetes is to minimize fluctuations in blood glucose levels, especially episodes of hyperglycemia. Treatment strategies include: Lifestyle Interventions: Calorie restriction Exercise Pharmacotherapies: A key drug used is metformin. Bariatric Surgery: More recently, bariatric surgeries have been used not only for weight loss but also as a treatment for metabolic disease. Complications of type 2 diabetes Metabolic Complications: Ketoacidosis Hyper- and hypoglycemia Hyperosmolarity Systemic Complications: Neuropathies Hypertension Vascular Complications: Microvascular Complications: Increased risk of retinopathy, cataracts, and chronic kidney disease. Macrovascular Complications: Lecture 13: Insulin Resistance and type 2 diabetes 9  Increased risk of stroke, coronary artery disease, and peripheral vascular disease. Combined, these vascular issues can lead to diabetic foot ulcers and non-healing wounds. Module 2- Mechanisms of insulin resistance Insulin resistance: Importance of Skeletal Muscle When we look at the different tissues involved in glucose uptake—gut, adipose tissue, muscle, and brain—it becomes clear that: At rest (basal state), skeletal muscle has relatively low levels of glucose uptake, with the brain being the primary site of glucose uptake. However, in response to insulin stimulation, skeletal muscle responds the most, with a marked increase in glucose uptake. Lecture 13: Insulin Resistance and type 2 diabetes 10  This response is attenuated in individuals who are insulin resistant (IR) or have type 2 diabetes (T2DM) Insulin signalling in muscle cells To explain how insulin signaling works in muscle cells, consider this simplified pathway: 1. Insulin binds to its insulin receptor on the muscle cell membrane. 2. This binding leads to the activation of insulin response substrate 1 (IRS-1) through phosphorylation. 3. The phosphorylation of IRS-1 leads to the activation of protein kinase B (PKB or AKT). 4. The phosphorylation of AKT is crucial because it drives the translocation of GLUT4. 5. GLUT4 is then relocated to the cell membrane, allowing glucose to enter the cell. Lecture 13: Insulin Resistance and type 2 diabetes 11  Primary mechanisms of obesity-associated insulin resistance in skeletal muscle Lipotoxicity Inflammation (low-grade) Altered endocrine signals - adiponectin Mitochondrial dysfunction Decreased capacity to ‘clear’ lipids. Production of reactive oxygen species (ROS) Primary mechanisms of obesity-associated insulin resistance in skeletal muscle ⇒ Lipotoxicity Diabetes is also a disease of defective lipid metabolism With an energy surplus, lipid accumulates in white adipose tissue. Initially, adipose tissue expands to accommodate the energy surplus, but it cannot expand enough + not only is there a limitation in energy storage in white adipose tissue, but with insulin Lecture 13: Insulin Resistance and type 2 diabetes 12  resistance and the inability to suppress lipolysis ⇒ As a result, there is a spillover of free fatty acids. This excess lipid often ends up in other peripheral tissues. Impact of Lipid Accumulation on Various Tissues: Adipose Tissue: ↑ lipolysis, ↑ bad adipokines Muscle: Lipid accumulation ↓ glucose uptake. Liver: ↑ glucose production, ↓ insulin clearance, ↑ cholesterol synthesis (LDL). Pancreas: ↓ insulin secretion and lead to beta cell death. Heart: Ectopic lipid accumulation can lead to increased heart disease or death. Lipids directly inhibit insulin signalling pathways 1. Free fatty acids enter the skeletal muscle myocyte (muscle cell) and are converted into long-chain fatty acids. 2. These fatty acids form triacylglycerides, which can be utilised to produce either: Ceramides (a sphingolipid), or Diacylglycerol (DAG). Lecture 13: Insulin Resistance and type 2 diabetes 13  These two lipid species—ceramides and DAG—inhibit the insulin signaling cascade: DAGs, via protein kinase C, block the phosphorylation of insulin response substrate (IRS). Ceramides prevent the phosphorylation of AKT. ^^ This combined effect prevents the translocation of GLUT4, thus inhibiting glucose uptake by muscle cells. Primary mechanisms of obesity-associated insulin resistance in skeletal muscle ⇒ Mitochondrial dysfunction Mitochondrial structure in mice - lean vs obese In lean animals, mitochondria are abundant and well-organized. In obese animals, there is a defragmentation of the mitochondria, indicating a loss of structural integrity. Mitochondrial changes in human - type 2 diabetes vs control Mitochondria in control individuals exhibit a well-defined structure. In individuals with type 2 diabetes, there is a noticeable defragmentation and a reduction in overall mitochondrial number. Consequences of Mitochondrial Dysfunction: Lecture 13: Insulin Resistance and type 2 diabetes 14  In skeletal muscle of individuals with type 2 diabetes, there is: A reduction in the number of mitochondria. Disorganisation of the mitochondria. Increased production of reactive oxygen species (ROS). Mitochondrial dysfunction and insulin resistance Impaired Insulin Signaling: Decreased mitochondrial functionality impairs lipid oxidation. This impairment contributes to the accumulation of lipids, including DAGs and ceramides. Lecture 13: Insulin Resistance and type 2 diabetes 15  Oxidative Stress: The inability to effectively oxidise lipids leads to oxidative stress and further ROS production. The ROS can feedback and inhibit the phosphorylation of insulin response substrate (IRS). Primary mechanisms of obesity-associated insulin resistance in skeletal muscle ⇒ Inflammation (low-grade) Characteristics of Adipose Tissue in Lean vs. Obese Individuals: Lean Adipose Tissue: Well-vascularized. Predominantly populated by M2 macrophages, which are anti- inflammatory. Obese Adipose Tissue: Expansion of white adipose tissue occurs with a positive energy balance. Lecture 13: Insulin Resistance and type 2 diabetes 16  Impaired angiogenesis results in inadequate remodeling of blood vessels to supply the expanded tissue, leading to hypoxia. Hypoxia can cause necrosis of adipocytes, leading to the infiltration of pro-inflammatory M1 macrophages. Shift in Macrophage Activation: In obese individuals, there is a shift towards a classical M1 activation pathway. M1 Macrophages: Pro-inflammatory and secrete various cytokines, particularly TNF- alpha (tumor necrosis factor alpha). Lecture 13: Insulin Resistance and type 2 diabetes 17  Effects of TNF-alpha on Insulin Action: TNF-alpha is known to alter insulin action in various tissues, including skeletal muscle. Mechanism of Action: When TNF-alpha binds to its receptor, it activates the Janus kinase (JAK) pathway. This action blocks the phosphorylation of insulin response substrate (IRS-1) and AKT. Consequently, it prevents the translocation of GLUT4 to the cell membrane. Lecture 13: Insulin Resistance and type 2 diabetes 18  Primary mechanisms of obesity-associated insulin resistance in skeletal muscle ⇒ Altered endocrine signals - Adopinectin Adipokine (cell-signalling molecules) functions: Adipose tissue secretes a wide range of factors, including: Complement factors Cytokines Chemokines Adipokines By modifying their secretory profile, adipose tissue can influence: Insulin sensitivity Cardiovascular disease risk Arthritis Feedback to the brain to alter food intake and energy expenditure, thereby regulating body weight. Lecture 13: Insulin Resistance and type 2 diabetes 19  Adipokines - factors secreted from adipose tissue that alter metabolic function Adipokines exert wide-ranging effects on various tissues, including: Brain: Regulates satiety. Gut: Modulates incretin secretion. Pancreas: Influences insulin secretion. Peripheral Tissues: Modulates insulin sensitivity in the liver and skeletal muscle. May also affect the browning of white adipose tissue. Lecture 13: Insulin Resistance and type 2 diabetes 20  Adiponectin - a hormone your adipose (fat) tissue releases that helps with insulin sensitivity and inflammation In individuals with obesity, adiponectin levels are lower regardless of sex. Mechanism of Action: Adiponectin binds to its receptor and mimics the effects of insulin by activating AMPK (AMP-activated protein kinase) through phosphorylation. This activation promotes the translocation of GLUT4 to the cell membrane. Adiponectin improves insulin sensitivity through the AMPK pathway, providing a two-fold effect: Enhances insulin action. Promotes GLUT4 translocation. Additional Benefits of AMPK: Associated with increased beta-oxidation, leading to improved mitochondrial function and reduced reactive oxygen species (ROS) Lecture 13: Insulin Resistance and type 2 diabetes 21  production. Involved in cellular protection. Limitations of Adiponectin as a Treatment Despite its beneficial effects in muscle tissue for promoting glucose uptake and increasing fatty acid oxidation, adiponectin is not currently used to treat type 2 diabetes. This is due to potential off-target side effects in other tissues, such as the kidneys, which limit its applicability as a therapeutic agent. Lecture 13: Insulin Resistance and type 2 diabetes 22