What is Insulin

• Main anabolic peptide hormone in the body

• anabolism=metabolic pathways that construct molecules from smaller units

• First peptide hormone and protein to be sequenced

• Produced by beta cells in the pancreas

• Alpha and delta cells

Connection between Insulin and Glucose

• Pancreatic beta cells are very sensitive to changes in blood sugar levels

• Glucose is found in

• Carbohydrates

• Proteins

• Fats

• Our body uses glucose as the main source of energy for cellular processes

• Circulates blood as blood sugar

• Needs to get glucose in muscles, fat cells and liver

• Glucose can’t move directly into our cells

• Glucose gets broken down to extract energy for cellular metabolism

• Absence of oxygen in yeast (alcohol)

• Lack of oxygen in muscles (lactic acid)

• Presence of oxygen in mitochondria (cellular respiration)

• Insulin opens the cell doors for glucose

• GLUT4 transporter facilitates diffusion into the cell

• No Insulin: glucose continues to circulate in the blood

• GLUT4 (plasma membrane)

• Muscle: skeletal and cardiac

• Adipose tissue (fat)

• Liver directly receives carbohydrates from intestine and portal vein

• After entering cells, glucose is converted into… (liver will turn glucose in glycogen and triglycerides)

• Glycogen: long term energy storage in muscles (glycogenesis)

• Fats (triglycerides): stored in adipose tissue (lipogenesis)

Glucose Homeostasis

• Insulin is secreted by beta cells when high levels of glucose are detected

• Glucose uptake, metabolism in cells increase

• Blood glucose (sugar) level decrease

• Glucagon is secreted by alpha cells when low levels of glucose are detected

• Stimulates endogenous glucose production in liver: glycogenolysis and gluconeogenesis

Disruption of homeostasis

• Type 1 diabetes: autoimmune disease

• 1.6 million americans

• Destruction of beta cells in pancreatic islets (killing by t cells)

• Alpha and delta cells not damaged

• Metabolic syndrome

• 35% in US adults

• 50% of adults aged 60+

• Higher prevalence in females, hispanics and african americans

• 18.3% 20-39 year olds

• 46.7% 60+

• Believed to be on the rise due to increase

• Type II diabetes

• 30 million people

• 462 million people

• Over 34 million americans

• Preventable disease

• Risk factors; hypertension, obesity, lack of exercise, low HDL and high triglyceride level, and genetics

Type 1 diabetes

• Once beta cells in the pancreatic islets are destroyed, they don’t regenerate

• Manual testing and management of blood glucose levels for the rest of their life

• Patient require supplemental insulin

Synthetic Insulin

• Originally porcine insulin was used in type 1 diabetic patients

• Immune system eventually mounts an allergic response to pig insulin (foreign proteins)

• Solution: recombinantly generated human insulin (tolerated by immune system)

• Insulin isn’t a cure

Metabolic Syndrome

• Associated with risk factors for type 2 diabetes, heat disease, and stroke

• Elevated fasting glucose levels

• Elevated triglycerides

• Reduced HDL cholesterol

• Hypertension

• Obesity

• Elevated waist circumference

• Insulin resistance

Insulin resistance: normal levels of insulin no longer have impact on glucose transport cells into blood sugar levels

Cycle: Feeling hangry, eating carbs, secreting insulin, resist the insulin, sugar stores as fat (build up of triglycerides in liver, heart, kidneys, and muscle) , cell remain unfed

Which of the risk factors fuels development of other diseases

• Obesity and inactivity

• Medications, age, genetics

Signs of metabolic syndrome

• Type 2 diabetes

• Hypertension

• PCOS

• Atherosclerosis

Non-Alcoholic Fatty Liver Disease is Considered to be the Liver’s manifestation of Metabolic syndrome

• NAFLD

• Most common liver disease worldwide (50-100% in obese and overweight individuals

• Occurs without other causes of liver disease (alcohol)

• Increased activity of lipogenic enzymes

• Constant deposition of lipids as a result of insulin resistance

• ER stress response

• Reduced intracellular antioxidant activity

• Increased oxidative stress

Liver Fibrosis will go into liver failure

Healthy liver to inflammation to fibrosis to cirrhosis to liver failure

Functions:

• Filtering blood

• Regulates clotting

• Vitamins and minerals

• Removes bacteria from bloodstream

• Bile production

Pharmaceuticals to manage metabolic syndrome

• Statins: atorvastatin, simvastatin, rosuvastatin (lowers cholesterol)

• Cholesterol absorption inhibitors: ezetimibe (lowers cholesterol)

• Insulin sensitizing agents: rosiglitazone, metformin (increasing sensitivity to insulin)

• GLP-1 Receptor: exenatide (natural secretion)

• DPP-4 Inhibitors (natural secretion)

Other approaches SGLT-2 inhibitors, blocking glucose prescriptions or bariatric surgery

Lifestyle changes to manage and prevent metabolic syndrome

• Exercise: increases glut 4 transporter activity

• May improve inflammatory state

• Weight management: 10% loss of total body weight can reverse fatty acid infiltration to the liver)

• Nutrition:

• mediterranean diet, low glycemic index foods; lower GI: better, fewer more dramatic spikes; whole grains, starchy vegetables, rice, fruit and breakfast cereals

• Therapeutic foods: blueberries (insulin resistance), apple cider vinegar, cooking techniques (avoid maillard reaction where it’s crunch) and reduces sensitivity

Type II is not only resistance to insulin

• Decrease insulin production and beta cell dysfunction and decrease uptake of glucose in response to insulin

• Increase alpha cell activity in pancreas: glucagon activity and exacerbation of hyperglycemic state

• Increase inflammatory cytokine production

• Circulating white blood cells

• Decrease in adiponectin (cytokine reducing plasma levels)

Diabetic nephropathy

• Kidney complication in T1 and T2 diabetics (25%0

• Thickening and scaring of nephrons in the kidney: reduce kidney’s ability to filter waste and remove fluid, MOA is unknown, hypothesize it is connected to high blood glucose levels, kidneys will fail, can be slowed or stop with treatment

Pharmaceuticals to Manage Type II diabetes

• Reduce glucose production by liver

• Augment glucose removal from blood stream

• Increase insulin production by pancreas

• Slow starch absorption from gut

• Slow absorption of foodL incretin therapies, amylin analogs

• Recombinant insulin

Lifestyle changes to treat T2D

• 2001 Finish Diabetes Study (DPS)1

• 522 middle aged, overweight participants

• Intervention: counseling to reduce weight, reduction of total fat/saturate fat intake, increased intake of fiber, increased physical activity

• Findings: T2D is largely preventable

• 2002 Diabetes Prevention Program (DPP)2

• 3234 overweight, high-risk participants with impaired glucose levels

• Intervention: similar to Finish study

• Findings: lifestyle intervention worked better than metformin for T2D prevention

• Smoking cessation 1,2

• Smokers have 30-40% higher risk of developing T2D vs non-smokers

• Global reduction in inflammation, oxidative stress

• Smoking associated with increased abdominal obesity

• Smoking associated with decreased blood flow to legs and feet

• Reduces risk of also developing cardiovascular disease

• Exercise

• Multiple large cohort, long term studies

• Aerobic and resistance training prevented or reduced development of T2D

• Nutrition is critical

• Improves glycemic control

• Reduce blood sugar spikes after eating

• Reduce insulin spikes

• Healing Food Pyramid: Fiber, Light to moderate alcohol consumption, Associated with ↑ adiponectin levels, Good fats: Fats associated with Mediterranean diet • 4 and 8 year study showed decrease requirement for anti-T2D medications and increase in diabetes remission

• Mindfulness

• Reduction in stress levels, blood pressure

• Cognitive-behavioral therapy

• Make patients aware of habits/patterns that could be changed for better overall health

• In T2D: systematic review of 25 clinical trials • Observed glycemic control in patients receiving therapy vs controls in 522 patients

• Biofeedback • Strengthen mind-body connection • In T2D: increased glycemic control in 39 patients

• Supplements to Manage T2d

• Alpha-lipoic acid

• Chromium

• Omega-3 fatty acids

• Coenzyme Q10

• Vitamin K

• L-Carnitine

Risk of using supplementals in T2d

• Selenium

• Insulin like actions

• Uses supplement for other disease (melanoma study)

• B Vitamins

• Caution when giving to the patients with diabetic nephropathy