Diabetes and hypoglycaemia

Question 1

Why do we regulate glucose levels?

Answer 1

• Regulated at 3-5mM
• Brain and erythrocytes require a continuous supply - avoid deficiency
• High glucose and metabolites cause pathological changes to tissues - e.g. micro/macrovascular disease, neuropathy - avoid excess

Question 2

what are the metabolic effects of insulin?

Answer 2

• Muscles - decreases protein breakdown and increases AA uptake
• adipose - increases lipogenesis, decreasing lipolysis
• Liver - increases the uptake of AA, glycogenesis and FA production. Reduces ketogenesis, glycogenolysis and gluconeogenesis
• General tissue - increases glucose uptake

Question 3

What are the main counter regulatory hormones?

Answer 3

• Glucagon - secreted by alpha cells of pancreas in response to hypoglycaemia - stimulates glycogenolysis and gluconeogeneis
• Adrenaline - increases glycogenolysis and lipolysis
• GH - increases glycogenolysis and lipolysis
• Cortisol (glucocorticoids) -increases gluconeogenesis

Question 4

What is DM?

Answer 4

• Metabolic disorder
• Chronic hyperglycaemia, glycosuria and associated abnormalities of lipid and protein metabolism
• Increased hepatic glucose production and decreased cellular uptake -> hyperglycaemia
• Blood glucose above 10mM exceeds renal threshold -> glycosuria
• Long term complication if not treated correctly -> micro/macrovascular disease

Question 5

What is the prevalence of diabetes?

Answer 5

• 422 million globally, estimated to increase
• 3.3million diagnosed in UK in 2014
• Doubled since 1996
• Increased due to poor diet, lack of exercise and also that recording of diabetes has increased

Question 6

How do we diagnose diabetes?

Answer 6

• Polyuria (increased urine), polydipsia (increased thirst/drinking) and weight loss (type 1)
• Random plasma glucose >11.1mM
• Fasting plasma glucose >7mM
• OGTT plasma glucose >11.1mM

In the absence of symptoms we test blood samples on two separate days

Question 7

IGT vs IFG?

Answer 7

• Impaired glucose tolerance (pre-diabetes) - fasting plasma 6.1-6.9mM, OGTT 7.8-11.1mM
• Impaired fasting glycaemia - not pre-diabetes, but high risk of developing some CVS diseases - fasting plasma <7mM and OGTT <7.8mM

Question 8

How do you carry out an OGTT?

Answer 8

• Should be done in patients with IFG, unexplained glycosuria, diagnosis of acromegaly (increased GH = increased glucose)
• 75g oral glucose and test after 2 hrs
• Blood samples collected at 0 and 120 mins after glucose
• Subjects tested fasting after 3 days of normal diet
• If glucose decreases, they may have acromegaly. If this doesn’t decrease, then they’re most likely diabetic

Question 9

What is type 1 diabetes?

Answer 9

• Predominantly in children and young adults
• Sudden onset (days/weeks)
• Appearance of symptoms may be preceded by prediabetic period of several months
• Commonest cause is autoimmune destruction of beta-cells
• Interaction between genetic factors and environment - strong link with HLA genes within MHC on Chr6

Question 10

What is the pathogenesis behind type 1 DM?

Answer 10

• HLA class II present as foreign and self-antigens to T-cells, initiating an autoimmune response
• Circulating autoantibody to glutamic acid decarboxylase, tyrosine-phosphate-like molecule and islet auto-antigen
• Most common is islet cell antibody
• Destruction of pancreatic beta cells causes hyperglycaemia due to deficiency of insulin and amylin

Question 11

What does amylin do?

Answer 11

• glucoregulatory peptide hormone co-secreted with insulin

- lowers blood glucose by slowing gastric emptying and suppressing glucagon output from pancreatic cells

Question 12

What metabolic complications do we get from type 1 DM?

Answer 12

• Blood glucose is higher, so there is more water leaving the kidney due to osmosis - excrete lots of urine
• Can get dehydrated from this - leads to mental state changes and confusion -> diabetic coma
• Increased FFA -> increased beta-oxidation -> increased ketone bodies -> ketoacidosis

Question 13

What is type 2 DM?

Answer 13

• Slow onset
• Pts middle aged/elderly - risk increases with age
• Strong familiar incidence
• Insulin resistance/ beta-cell dysfunction - may be due to lifestyle factors like obesity and lack of exercise
• Emergency presentation as HONK

Question 14

What is HONK?

Answer 14

• Metabolic complication of type 2
• Severe hyperglycaemia, severe dehydration from increased urination, increased plasma osmolarity
• No ketosis, minimal acidosis
• Impaired consciousness
• Death if untreated

Question 15

How do we monitor glycaemic control?

Answer 15

• Aim to prevent complications or avoid hypoglycaemia
• Self-monitoring - capillary blood measurement; urine analysis - gives indication of blood glucose conc above renal threshold
• 3-4 months - blood HbA1c (glycated Hb, covalent linkage of glucose to residue in Hb)
• urinary albumin - index risk of progression to nephropathy

Question 16

What is the stepwise treatment for type 2?

Answer 16

• Diet and exercise
• oral monotherapy (metformin)
• Oral combination (Sulphonylureas, Gliptins, GLP-1 analogues)
• Insulin and/or oral agents

Question 17

What are the long term complications from DM?

Answer 17

• Microvascular - retinopathy, nephropathy, neuropathy
• Macrovascular disease - related to atherosclerosis, heart attack and stroke. Affects the endothelial cells -> can lead to hardening of the blood vessels

Question 18

How can they reduce CV risk?

Answer 18

• Attain normal weight and waist circumference
• Eat less fat and salt
• Exercise
• Stop smoking
• HbA1c <7%
• BP target <130/80mmHg
• Total cholesterol <4mM, LDL <2mM

Question 19

What is hypoglycaemia?

Answer 19

• Plasma glucose <2.5mM
• Results in energy failure and neurological damage
• dangerous because glucose is a vital fuel for the brain - only ketones can substitute as last resort

Question 20

What can cause hypoglycaemia?

Answer 20

• Insulinoma
• Inherited metabolic disorders - glycogen storage diseases, galactosaemia, hereditary fructose intolerance
• Drugs - Sulphonylureas, insulin, alcohol abuse
• Endocrine disease - cortisol disorder
• Others - severe liver disease, non-pancreatic tumours, postgastrectomy, renal disease

Question 21

What is an insulinoma?

Answer 21

• Tumour in beta cells of pancreas
• Symptoms - fasting hypoglycaemia, inappropriate high insulin conc when plasma glucose is low.
• C-peptide should be measured - synthesis of insulin will increase, the amount of C-peptide cleaved will also increase. If C-peptide is low, it wont be insulinoma

Question 22

What is glycogen storage disease type 1?

Answer 22

• G-6-phosphatase deficiency
• AR disease
• glucose synthesis from glycogen or gluconeogenesis is blocked
• presents in early infancy; severe fasting hypoglycaemia as only source of glucose is dietary carbohydrate
• accumulation of glycogen causes hepatomegaly; inability to produce glucose from lactate -> acidosis
• Give uncooked cornstarch for slow release of glucose

Question 23

What is galactosaemia?

Answer 23

• Caused by defects on 3 enzymes - most common is galactose-1-phosphate uridyl transferase deficiency
• AR disorder
• Deficiency of Gal-1-PUT impairs conversion of gal-1-p to g-1-p; gal-1-p accumulates in liver (toxic)
• Hypoglycaemia and vomiting/diarrhoea after starting milk feeds
• Galactose excreted in urine
• treat by excluding galactose from diet

Question 24

What is hereditary fructose intolerance?

Answer 24

• AR disorder
• Deficiency of fructose-1-phosphate adolase B
• Ingested fructose accumulates inhibiting glycogenolysis at the phosphorylase step - cant make glyceraldehyde (glycolysis) or dihydroxyacetone-P (gluconeogenesis)
• Severe hypoglycaemia and vomiting after ingesting fruit or sweetened foods
• Fructosuria
• Avoid ingestion of fructose or sucrose

Question 25

What is benign fructose intolerance?

Answer 25

• Absence of fructokinase

- cant convert fructose to f-1-p

Question 26

What is the response to falling glucose levels in fasting?

Answer 26

• Suppression of insulin release, limiting glucose uptake into non-cerebral tissues
• Secretion of glucagon, nor-/adrenaline, cortisol and GH to raise glucose level
• Stimulate hepatic gluconeogenesis, glycogenolysis and FA oxidation

Question 27

What are the symptoms of hypoglycaemia?

Answer 27

• Neurogenic - triggered by falling glucose levels, activated by ANS and mediated by sympathoadrenal release of catecholamies and Ach. Causes mood changes, trembling, paleness, sweating, dizziness, blurred vision, headaches, tiredness, hunger.
• Neuroglycopaenia - glucose deprivation of neurones. Causes confusion, difficulty speaking, ataxia, seizures, coma, death