T2DM

• Learning objectives

  • Understand the causes of T2DM, the impact of the obesity epidemic on the increase in the prevalence of T2DM, explain our current understanding of the underlying genetic and other aetiopathogenic factors
  • Understand the concept of pre-diabetes: impaired fasting glycaemia and impaired glucose tolerance
  • Explain the clinical presentation of T2DM
  • Describe the metabolic emergencies associated with T2DM: hyper-osmolar non-ketotic coma (HONK) and hypoglycaemia related to specific treatments of T2DM
  • Explain the importance/impact of lifestyle measures in the management of T2DM: weight loss, exercise, dietary changes
  • Briefly review the treatments of T2DM (this will be covered in more detail in a separate pharmacology lecture)
  • Understand the causes of diabetes secondary to pancreatic disease
  • Understand the concept of monogenic diabetes mellitus and the impact of human genetics on the understanding of these rare forms of DM
  • Identify other rare forms of DM
  • Describe the importance of diabetes and pregnancy: importance of antenatal care, gestational diabetes (diagnosis, management, follow-up), and pregnancy in women with known diabetes
  • Explain the challenges of diabetes management/control during childhood and adolescence
• Blood glucose is regulated within very tight limits (4.0 – 7.0mmol /l in health)
• Pancreatic Hormones (from Islets of Langerhans)

  • Insulin (Beta cells)
  • Glucagon (alpha cells)
  • Somatostatin (delta cells)
  • Pancreatic polypeptide (PP cells)
• Incretin Hormones

  • Glucagon-like peptide 1 (GLP-1)
  • Glucose-dependent insulinotropic polypeptide (GIP)
• Counter-regulatory hormones

  • Glucagon (alpha cells)
  • Adrenaline / noradrenaline (adrenals)
  • Cortisol (adrenals)
  • Growth Hormone (pituitary)
• How the β-cell works (simplified version!)

  1. Glucose enters via GLUT2

  2. Glucose is phosphorylated by glucokinase

  3. Glycolysis and ATP generation

  4. Insulin is released via Ca2+ and 'amplifiers'

  5. GLP-1 also stimulates insulin release
• Insulin

  • Increases glucose uptake into fat and muscle
  • Stimulates glycogen synthesis
  • Stimulates storage of triglyceride in adipose tissue
  • Increases protein synthesis
  • Decreases hepatic gluconeogenesis
• Effects of feeding


  1. Rise in nutrients (especially glucose, fat, aa's)

  2. Rise in insulin concentrations; glucagon falls

  3. Glycogen synthesis ↑↑

  4. Gluconeogenesis ↓

  5. Protein synthesis ↑

  6. Switch to carbohydrate oxidation

  7. Lipogenesis ↑

  8. Lipolysis ↓
• Incretins and glucose homeostasis

  1. Ingestion of food releases incretin gut hormones GLP-1 and GIP

  2. GLP-1 stimulates insulin release from beta cells and inhibits glucagon release from alpha cells

  3. GLP-1 and GIP increase peripheral glucose uptake and reduce hepatic glucose output

  4. DPP-4 enzyme rapidly degrades incretins
• Effects of fasting


  1. Fall in nutrients (especially glucose, aa's)

  2. Fall in insulin concentrations (glucagon rises)

  3. Glycogen synthesis ↓

  4. Gluconeogenesis ↑

  5. Protein synthesis ↓

  6. Switch to lipid oxidation (fat burning)

  7. Lipogenesis ↓

  8. Lipolysis ↑

  9. Brain switches to ketone body utilisation
• Diabetes


  • Defined by raised blood glucose
  • Increased blood glucose is due to either deficiency of the hormone insulin (produced in the pancreas), and/or resistance to its action
  • Uncontrolled diabetes (especially in type 1) is a medical emergency and can be fatal
  • Chronically raised blood glucose leads to long term diabetes complications
  • Diabetes treatment can lead to hypoglycaemia
• Diabetes is a chronic medical condition, that frequently leads to disability and death
• 415 million people currently have diabetes worldwide, figure projected to rise to 642 million by 2040

  
• Types of diabetes


  • Type 1 diabetes
  • Type 2 diabetes
  • LADA (late onset autoimmune diabetes)
  • MODY (maturity onset diabetes of the young)
  • Secondary diabetes (eg pancreatitis, Cushing's syndrome, haemochromatosis)
  • Gestational diabetes
• Diabetes Complications

  • Macrovascular disease (3-4 x risk in diabetes, 80% of deaths, MI/ stroke/ PVD)
  • Microvascular disease (leading cause of blindness, renal failure, neuropathy (foot ulceration))
  • Other (cataract, erectile dysfunction, skin (dermopathy), complications of treatment)
  • Psychosocial (employment, insurance, psychological problems, prejudice)
• Screening for complications: Diabetes Annual Review

  1. Review – ask about glucose control, compliance with treatment, hypoglycaemia, erectile dysfunction (men), planning pregnancy? (women of childbearing age), other symptoms, consider employment, driving, social etc.

  2. Foot examination – ask about pain / abnormal sensation, examine: skin, foot structure, pulses, sensation (10g monofilament, vibration perception threshold)

  3. Eye examination – visual acuity, photographic eye screening, fundoscopy

  4. Blood pressure

  5. Urinalysis for albumin (microalbuminuria), proteinuria (dipstick)

  6. Blood tests – HbA1c (glucose control), lipids (CV risk), renal (eGFR)

  
• Obesity and the risk of type 2 diabetes

  As BMI increases, the relative risk of type 2 diabetes increases exponentially

  
• The prevalence of obesity and diabetes in England have been increasing in parallel over recent decades
• Two obesity-related problems in type 2 diabetes

  • Progressive insulin deficiency (pancreas does not make enough insulin, amyloid and fat deposits in pancreas, defective incretin response)
  • Insulin resistance (reduced glucose lowering effect of insulin, genetic component, exacerbated by obesity and physical inactivity)
• Response to feeding (mixed meal) in lean and obese

  Obese subjects have higher postprandial glucose and higher postprandial insulin levels compared to lean subjects, demonstrating insulin resistance
• Excess intra-abdominal (visceral) fat is a strong correlate of metabolic risk and insulin resistance
• Type 2 diabetes is a chronic condition with progressive loss of β-cell function across time
• Weight gain is associated with ectopic fat deposition (liver, muscle, pancreas), insulin resistance and progressive insulin deficiency
• Intra-abdominal fat


  A strong correlate of metabolic risk
• Excess fat


  Causes insulin resistance
• ~50% of β-cell function was already lost at the time of diagnosis in UKPDS
• Weight gain


  Associated with ectopic fat, insulin resistance and progressive insulin deficiency
• Genes for type 2 diabetes

  • FTO & related genes – variant increases risk; associated with 3kg additional weight if two copies of variant (16% of UK population)
  • TCF7L2 gene – increases risk of diabetes; involved in islet cell function

  
• Prediabetes


  State of impaired glucose homeostasis
• Prediabetes definition


  • HbA1c 43-47 mmol/mol (6.0-6.4%)
  • Impaired fasting glucose (IFG)
  • Impaired glucose tolerance (IGT)
• Treatment strategies for prediabetes

  1. Lifestyle (nutrition, physical activity, technology assisted)

  2. Pharmacologic intervention for glycaemic control (metformin)

  3. Prevention of cardiovascular disease (screening and treatment of modifiable risk factors)
• Weight loss can reduce progression to type 2 diabetes
• Metformin


  18% reduction in risk of progression to type 2 diabetes
• Type 2 diabetes clinical presentation

  • Typical symptoms of hyperglycaemia (thirst, polyuria, fatigue, weight loss, blurred vision)
  • Severe hyperglycaemia (non-ketotic hyperglycaemia)
  • Atypical/asymptomatic (identified through screening, present with complications)
  • Often (but not always) overweight
  • More common in some communities (e.g. people of Asian origin)

  
• Energy restriction improves β-cell function and reduces blood glucose, hepatic glucose production and liver triglycerides in type 2 diabetes
• Randomised trial of integrated, structured weight loss or best practice care in people with type 2 diabetes showed diabetes remission as the primary outcome

  
• Lipid-altering therapy including patients with diabetes reduces cardiovascular disease risk
• Risk factor management targets in type 2 diabetes

  • HbA1c <48-53 mmol/mol (6.5-7%)
  • Blood pressure <140/80 mmHg, <130/80 mmHg if CV/renal/eye disease
  • Total cholesterol <4.0 mmol/L, LDL <2.0 mmol/L, HDL >1.1 mmol/L, triglycerides <4.5 mmol/L

  
• SGLT2 inhibitors selectively inhibit SGLT2 in the renal proximal tubule, removing excess glucose
• Glucose-lowering drugs


  • Insulin secretion stimulators (sulphonylureas, insulin secretagogues)
  • Incretin-mimetics / GLP-1 RAs
  • DPP-4 inhibitors
  • α-Glucosidase Inhibitors
  • SGLT-2 Inhibitors
  • Insulin sensitizers (Metformin, Thiazolidinediones)
  • Insulin