Diabetes: how to fight an epidemic Matthew Lloyd Lesson goals Gain - - PowerPoint PPT Presentation
Oxford Splash 2019 Diabetes: how to fight an epidemic Matthew Lloyd 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
Lesson goals
and treatment of the major types of diabetes
prevalence and the associated costs and discuss what can be done to address them
Matthew Lloyd Oxford Splash 2019
Diabetes is defined by its symptoms (high blood glucose). It is actually a group
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 Normal fasting blood glucose is 4-6 mmol/L
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: insulin secretion Response: glucagon secretion Response: peripheral glucose uptake Response: liver glucose uptake and glycogen synthesis Response: liver glycogen breakdown and glucose release Organ that takes up most glucose in response to insulin is skeletal muscle – it’s a major energy user and glycogen store
Endocrine tissue of pancreas
Islets constitute only 1-2% of pancreas volume but receive 10–15% of its blood flow
Pancreas is unusual as it is both an endocrine and exocrine organ! Islets of Langerhans contain two cell types that directly sense glucose levels and respond by altering their secretion of hormones. Beta cells secrete insulin and alpha cells glucagon. Note: somatostatin produced by delta cells has regulatory action within islet (inhibits insulin secretion) but you don’t need to know this.
Type Cause Onset Proportion of diabetics Treatment Type I
Autoimmune destruction of pancreatic beta cells Sudden, usually in childhood or adolescence 5-10% Insulin replacement
Type 2
Insulin resistance and insufficient compensatory secretion Gradual, late childhood to old age 90-95% Lifestyle changes, drug and/or insulin therapy
Neonatal
Mutations affecting insulin secretion (but not synthesis) Sudden, aged <6 months <1% Sulfonylurea drugs
Maturity onset diabetes of the young (MODY)
A variety of mutations in metabolic genes Gradual, usually aged <30 1-2% Drug or insulin therapy (depending
Type II (T2DM) is most common form, and the only form that is currently preventable
Note: insulin resistance may be present for 10-20 years before clinical onset of type II diabetes. This period is called pre-diabetes. Main focus will be on type 2 as this is gives us the greatest potential for reducing the global disease burden.
20% 80%
Obesity Other
Other risk factors include:
Native American, Latino, or African ethnicity
But why such a strong association with obesity?
~30% of UK population is obese ~10% of UK adults have T2DM This is a public health crisis! Obesity is the main risk factor
Increasing obesity prevalence is primary driver of increasing T2DM incidence, as reflected by the strong positive correlation between BMI and diabetes risk. Note: caucasians have lowest risk of developing diabetes for a given BMI. Perhaps because have had longest to adapt to high carbohydrate diet?
Insulin resistance Compensatory increase in insulin secretion Relative deficiency
(decompensation) Absolute deficiency of insulin secretion (loss
Result: dramatic swings between hyperglycaemia and hypoglycaemia
But how does insulin resistance arise in the first place?
Beta-cell function is already reduced by half by time of diagnosis – becomes increasingly difficult to reverse diabetes so important to intervene early. Note: hyperglycaemia is exacerbated by increased basal glucagon secretion, leading to inappropriate glucose release by liver after a meal. Conversely, glucagon may be too low overnight, leading to fasting hypoglycaemia
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”)
This diagram summarises the factors that contribute to T2DM development. I’ve highlighted in red the causes that cannot be controlled, and in green those where people have the power to make positive choices.
If blood glucose levels are not properly controlled by treatment, diabetes can have life-threatening complications In 2012, 79% of NHS diabetes spending was on treating complications
Cause of death in 50% type II diabetics
Microvascular and macrovascular disease: high blood glucose damages blood vessels (e.g. through atherosclerosis) and other tissues Note: gestational diabetes increases risk of heart disease in newborn
How many types of diabetes are there?
Which hormones oppose the effects of insulin? Choose as many as you think are correct
Which organs are capable of sensing blood glucose levels? Choose as many as you think are correct
Write down your answers and put your name at the top. I will announce the top scorer(s) at the end of the class. How many types of diabetes are there? >4 Which hormones oppose the effects of insulin? Glucagon, adrenaline, cortisol – these promote the use of energy stores, whereas insulin and adiponectin promote the uptake and storage of glucose from food Which organs are capable of sensing blood glucose levels? Pancreas (beta and alpha cells), intestine (gut L cells secrete GLP-1 and other peptide hormones) and brain (hypothalamus contains specialised neurons that sense glucose and play a role in regulating pancreatic insulin secretion and appetite). Note that liver metabolism is regulated by PG, but it is not a precise sensor (does not involve electrically active cells)
Can you identify the complications of diabetes and avoid the decoys? Choose as many as you think are correct
Which tissues are major glycogen stores? Choose as many as you think are correct
Can you identify the complications of diabetes? Retinopathy (can lead to blindness), neuropathy (nerve damage), nephropathy (kidney damage/failure), stroke, CVD are all complications of diabetes Which tissues are major glycogen stores? Skeletal muscle, liver and cardiac muscle. Pancreas does not store significant amounts of glycogen in healthy people, but it is found in beta cells from diabetic donors and animals
Europe actually has lower diabetes prevalence than most of world, probably due to lower genetic susceptibility as well as lifestyle factors. Note: significant numbers live with undiagnosed diabetes, which increases danger of complications
Current NICE guidelines are to gradually intensify drug regimen (both in terms
Too few people succeed in making their lifestyle healthier. Do we need a more radical approach to incentivise change? 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 Not fully understood how metformin works, but decreases glucose production by the liver and increases insulin sensitivity of body tissues Note undesirable side effects to some drugs e.g. weight gain, increased pancreatic cancer risk Bariatric surgery very effective due to substantial weight loss
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
format; you will then present your ideas as a team. There will be a prize for the best poster/presentation.
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!
NHS diabetes budget Prevention
(core focus)
Management
(maintaining normoglycemia to prevent complications)
Treating complications
(to be avoided) Note: research spending to develop better treatments (or even a cure!) is also important Early lifestyle intervention Metformin prescription to pre-diabetics? Implement new technologies
Continuous, prick-free PG monitoring Closed-loop insulin delivery (applies to type I and late-stage type II) Regenerative medicine? Incentives for positive change
Increased use of bariatric surgery for obese patients Genetic screening?
Low cost of sequencing offers potential to identify at-risk individuals for targeted early intervention if can identify suitable markers Additional cardiovascular benefits Increased funding for school/ community sport and health education Media campaigns?
Improve diagnosis rates
More effective use of digital databases e.g. AI to trawl patient records
How do these ideas compare with the ones you came up with?
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-