Diabetes: how to fight an epidemic Matthew Lloyd Oxford Splash 2019 • Lesson goals • Gain a basic understanding of the pathology and treatment of the major types of diabetes • Consider the trends in diabetes and obesity prevalence and the associated costs and discuss what can be done to address them
What is diabetes? Diabetes is defined by its symptoms (high blood glucose). It is actually a group of diseases with different causes and requiring different treatments Characterised by recurrent or persistent hyperglycaemia. Diagnostic criteria include fasting blood glucose ≥ 7 mmol/L or glycated haemoglobin ≥6.5% May be caused by insufficient insulin secretion, insulin sensitivity or both Nearly all cases are type I or type II. There are also rare hereditary forms, and some women experience temporary gestational diabetes during pregnancy Complications of diabetes can be serious, reducing life expectancy by >10 years in type I and up to 10 years in type II
How is blood glucose regulated? Plasma glucose (PG) homeostasis is a balancing act. Levels should be maintained in a safe range of approximately 4-6 mmol/L Stimulus: rising PG Stimulus: falling PG Response: glucagon secretion Response: peripheral glucose uptake Response: insulin secretion Response: liver glycogen breakdown and glucose release Response: liver glucose uptake and glycogen synthesis
How is blood glucose regulated? Endocrine tissue of pancreas Islets constitute only 1-2% of pancreas volume but receive 10–15% of its blood flow
Types of diabetes Type II (T2DM) is most common form, and the only form that is currently preventable
T2DM Pathology and Risk Factors Obesity is the main risk factor • Other risk factors include: • Age >45 • South Asian, East Asian, Pacific Islander, Native American, Latino, or African ethnicity • Family history of T2DM ~30% of UK population is obese ~10% of UK adults have T2DM This is a public health crisis! But why such a strong association with obesity?
T2DM Cause and Progression Absolute deficiency of insulin secretion (loss of beta cell function) Relative deficiency of insulin secretion (decompensation) Compensatory increase in insulin secretion Insulin resistance Result: dramatic swings between hyperglycaemia and hypoglycaemia But how does insulin resistance arise in the first place?
T2DM Cause and Progression Regulation of fat metabolism and carbohydrate metabolism is highly integrated. Defects in fat metabolism probably precede insulin resistance Glycogen storage capacity is limited. Following a carbohydrate-rich meal, excess glucose is converted to fat Inactivity increases fat deposition, whereas exercise increases capacity of muscle to take up and use glucose and improves mitochondrial function When safe storage capacity for fat is exceeded, fat is stored in unsuitable tissues e.g. liver and muscle Fat is metabolised in preference to glucose, leading to reduced glucose uptake Chronic inflammation may contribute to disease development Metabolic syndrome is characterised by abdominal obesity, high blood pressure, high blood sugar, high serum triglycerides (fats), and low serum HDL (“good cholesterol”)
Complications of diabetes If blood glucose levels are not properly controlled by treatment, diabetes can have life-threatening complications Cause of death in 50% type II diabetics In 2012, 79% of NHS diabetes spending was on treating complications
Recap Quiz How many types of diabetes are there? 1 2 4 >4 Which hormones oppose the effects of insulin? Choose as many as you think are correct Cortisol Glucagon Adiponectin Adrenaline Which organs are capable of sensing blood glucose levels? Choose as many as you think are correct Brain Intestine Pancreas Liver
Recap Quiz Can you identify the complications of diabetes and avoid the decoys? Choose as many as you think are correct Nephropathy Osteopathy Psychopathy Neuropathy Which tissues are major glycogen stores? Choose as many as you think are correct Pancreas Liver Cardiac muscle Skeletal muscle
Treatments for T2DM Lifestyle modification: less sugar in diet, more exercise, balancing caloric intake and expenditure First-line pharmaceutical treatment: metformin Regulation of blood cholesterol Drugs that enhance insulin secretion: sulfonylureas, incretin mimetics and DPP-4 inhibitors (gliptins) Insulin therapy (when endogenous production fails) Bariatric surgery Current NICE guidelines are to gradually intensify drug regimen (both in terms of dosage and number of drugs), while advising lifestyle changes Too few people succeed in making their lifestyle healthier. Do we need a more radical approach to incentivise change?
Your Challenge Remember that prevention is better than cure! Treating chronic diseases accounts for ~70% of UK healthcare expenditure, much more than is spent on improving overall public health! You will divide into four teams to complete this challenge Background 10% of NHS spending is on diabetes. In 2012, 79% of NHS diabetes spending was on complications, many of which are preventable. How could this £14 billion/year be spent more efficiently? Your task You have been asked to develop a public health strategy to reduce type II diabetes incidence and improve treatment outcomes in a cost-effective manner. You will have 15 minutes to outline your draft action plan in a poster format; you will then present your ideas as a team. There will be a prize for the best poster/presentation.
Some potential solutions Low cost of sequencing offers potential to identify at-risk individuals for targeted early intervention if can identify suitable markers Additional cardiovascular benefits Increased use of bariatric surgery for obese patients Metformin prescription to pre-diabetics? Genetic screening? Increased funding for school/community sport and health education Prevention (core focus) Media campaigns? NHS diabetes budget Early lifestyle intervention Incentives for positive change Management (maintaining normoglycemia to prevent complications) Improve diagnosis rates More effective use of digital databases e.g. AI to trawl patient records Implement new technologies Regenerative medicine? Note: research spending to develop better treatments (or even a cure!) is also important Treating complications (to be avoided) Closed-loop insulin delivery (applies to type I and late-stage type II) Continuous, prick-free PG monitoring
Useful Links for Further Reading Classification of diabetes https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3006051/ Complications of diabetes http://clinical.diabetesjournals.org/content/26/2/77 Glucose-sensing mechanisms in beta cells (in-depth review) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1569593/ NICE treatment guidelines for T2DM https://bnf.nice.org.uk/treatment-summary/type-2-diabetes.html NHS spending https://www.diabetes.org.uk/about_us/news_landing_page/nhs-spending-on-diabetes-to-reach-169-billion-by-2035