Diabetes and Hypoglycaemia

Question 1

What is glucose and how is it maintained?

Answer 1

Glucose is the major energy substrate

Its levels are maintained through

• Glycogenolysis
• Gluconeogenesis (lactose, amino acids and fatty acids are used to make glucose)
• Dietary Carbohydrates

Question 2

What is the livers role in terms of glucose levels?

Answer 2

After meals → it will store glucose as glycogen

During fasting → it will make glucose readily available through glycogenolysis and gluconeogenesis

Question 3

List two reasons why glucose levels must be regulated

Answer 3

Avoid Deficiency → brain and erythrocytes require a continous supply

Avoid Excess → High glucose and metabolites cause pathological changes to tissue e.g. micro/macro vascular diseases, neuropathy

Question 4

What are the metabolic effects of insulin?

Answer 4

• Decreases ketogenesis
• Decreases gluconeogenesis
• Decreases glycogenolysis
• Decreases lipolysis, increases lipogenesis
• Increases uptake of glucose into tissues
• Increases amino acid uptake
• Increases glycogen synthesis
• Increased fatty acid synthesis

Question 5

What is the definition of diabetes mellitus?

Answer 5

Metabolic disorder characterised by chronic hyperglycaemia, glycosuria and associated abnormalities of lipid and protein metabolism

Hyperglycaemia is as a result of increased hepatic glucose production and decreased cellular glucose uptake

Question 6

When do you get glycosuria?

Answer 6

When blood glucose > 10mmol/L exceeding renal threshold

Question 7

How do we diagnose for DM?

Answer 7

• In presence of symptoms (polyuria, polydipsia and weight loss for type 1)
  
  • Random plasma glucose >11.1 mmol/l (200mg/dl)
  • Fasting plasma glucose >7.0 mmol/l (126 mg/dl) (fasting is defined as no calorific intake for at least 8 hours)
  • Oral glucose tolerance test (OGTT) – plasma glucose > 11.1 mmol/l
    
    • Given glucose and check levels after a few hours
• In the absence of symptoms
  
  • Test blood samples on 2 separate days

Question 8

What is IGT and IFG?

Answer 8

Impaired glucose tolerance (IGT) → blood glucose is raised above normal levels but not enough to warrant diabetes. However you are at a greater risk of developing diabetes/ cardiovascular disease

• Fasting plasma glucose
• OGTT value of 7.8-11.1 mmol

Impaired Fasting Glycaemia (IFG) → occurs when blood glucose levels in the body are elevated during fasting, but not enough to prompt diagnosis of diabetes

• Fasting plasma glucose and OGTT value <7.8

Question 9

What is an oral glucose tolerance test?

Answer 9

• 75g of oral glucose and test after 2 hours
• Blood samples collected at 0 and 120 mins after glucose
• Subjects tested fasting after 3 days of normal diet containing at least 250g of carbohydrate

Question 10

In what type of patients is the oral glucose tolerance test carried out in?

Answer 10

• IFG (impaired fasting glycaemia)
• Unexplained glycosuria
• Clinical features of diabetes with normal plasma glucose values
• For the diagnosis of acromegaly

Question 11

How can the oral glucose tolerance test be used for diagnosis of acromegaly?

Answer 11

• Higher levels of blood glucose will prevent the release of GH
• In a patient with acromegaly there will still be high levels of GH following the oral glucose tolerance test

Question 12

What are the ways in which diabetes can be classfied?

Answer 12

• TYPE 1 = Insulin secretion is deficient due to autoimmune destruction of beta cells in the pancreas by T-cells
• TYPE 2 = Insulin secretion is retained but there is target organ resistance to its actions
• SECONDARY = Chronic pancreatitis, pancreatic surgery, secretion of antagonists
• GESTATIONAL = Occurs for first time in pregnancy

Question 13

Describe type 1 diabetes?

Answer 13

• Predominantly in children and young adults
• Sudden onset (days/weeks)
• Appearance of symptoms may be preceded by ‘prediabetic’ period of several months

Question 14

What is the pathogenesis of type 1 diabetes?

Answer 14

• Commonest cause is autoimmune destruction of B-cells
• Strong link with human leukocyte antigen genes within the major histocompatabillity complex region on chromosome 16
• HLA class II cell surface will present itself as foreign and self-antigens to T-lymphocytes to initiate an autoimmune response
  • Circulating antibodies to various cells against
• Glutamic acid decarboxylase
• Tyrosine-phosphatase-like molecule
• Islet autoantigen

Question 15

What is the most commonly detected antibody associated with type 1 DM?

Answer 15

Islet cell antibody

Question 16

What occurs as a consequence of type 1 DM?

Answer 16

Destruction of beta cells will cause hyperglycaemia due to deficiency of both insulin and amylin

Question 17

What is amylin?

Answer 17

Amylin is a glucoregulatory peptide hormone that is co-secreted with insulin

It lowers blood glucose by slowing gastric emptying and supressing glucagon output from pancreatic cells

Question 18

What are the metabolic complications of type 1 DM?

Answer 18

Question 19

What is the presentation of type 2 DM?

Answer 19

• Slow onset (months/years)
• Patients middle aged/elderly – prevalence increases with age
• Strong familiar incidence

Question 20

What is the pathogenesis of type 2 DM?

Answer 20

insulin resistance; β-cell dysfunction:

may be due to lifestyle factors - obesity, lack of exercise

Question 21

Describe some metabolic complications of type 2 DM

Answer 21

• Development of severe hyperglycaemia
• Extreme dehydration
• Increased plasma osmolality
• Impaired consciousness
• No ketosis
• Death if untreated
• Hyper-osmolar non-ketotic coma (HONK)

Question 22

What can type 2 DM result in?

Answer 22

Hyper-osmolar non-ketotic coma (HONK) will be ketoacidosis in type 1 DM

Question 23

What is the treatment of type 2 DM?

Answer 23

• Initially you will have foods with a lower glycaemic index and carry out more exercise
• If this does help, then diabetic drugs will be the next option of treatment
  
  • Metformin, sulphonylureas, dipeptidyl peptidase inhibitors (DPP-4)

Question 24

What does metformin do?

Answer 24

Metformin will help increase uptake of glucose from blood and decrease gluconeogenesis

Question 25

What do sulphonylureas do?

Answer 25

Stimulate the cells of the pancreas to make more insulin and help insulin work more effectively

Question 26

What do dipeptidyl peptidase inhibitors do?

Answer 26

DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.

Incretins help the body to produce more insulin only when it is needed and reduce the amount of glucose being produced by the liver when it is not needed

Question 27

How do you monitor glycaemic control?

Answer 27

1. Self Monitoring

• Capillary blood measurement
• Urine Analysis → Glucose in urine gives an indication of blood glucose concentration above the renal threshold

2. 3-4 Months
   * Blood HbA1c
3. Urinary albumin (index of risk progression to neuropathy)

Question 28

What is blood HbA1c?

Answer 28

Glycated Hb; covalent linkage of glucose to residue in Hb

Question 29

What are long term complicatons of T1 and T2 diabetes?

Answer 29

• Micro-vascular disease:
  
  • Retinopathy, nephropathy, neuropathy
    
    • (glucose can damage blood vessels of the eye, nerve endings or nerves)
    • Patients with diabetes will require frequent eye checks
    • Amputations of leg can occur
• Macro-vascular disease:
  
  • related to atherosclerosis heart attack/stroke

Question 30

What are the responses of falling glucose levels in fasting?

Answer 30

• Physiological counter-regulatory response
  
  • Suppression of insulin release, limiting glucose entry into non-cerebral tissues
  • Secretion of glucagon, adrenaline, noradrenaline, cortisol and growth hormone to raise glucose level

Question 31

What are counter regulatory hormones of insulin?

Answer 31

Glucagon = Secreted by alpha cells of pancreas in response to hypoglycaemia, stimulates glycogenolysis and gluconeogenesis

Cortisol = Increased gluconeogenesis

Question 32

What is hypoglycaemia defined as?

Answer 32

Defined as plasma glucose < 2.5 mmol/L

• Hypoglycaemia in diabetic patients
• Hypoglycaemia in patients without diabetes

Question 33

What are the causes of hypoglycaemia in patients with diabetes?

Answer 33

Drugs are usually the most common cause

• Exogenous insulin and insulin secretagogues such as glyburide, glipizide, gimepiride (types of sulfonylureas) will stimulate endogenous insulin
  
  • This supresses hepatic and renal glucose production and increased glucose utilisation

Among drugs used to treat type 2 diabetes earlier in the disease, insulin sensitizers (metformin, Glitazones); glucosidase inhibitors; glucagon-like pepdide-1 (GLP-1) receptor antagonist and DDP-4 inhibitors should not cause hypoglycaemia.

Question 34

What are the causes of hypoglycaemia in patients without diabetes

Answer 34

• Alcohol
• Quinolone, quinine, beta blockers, ACE inhibitors and IGF-1
• Endocrine diseases e.g cortisol disorder
• Inherited metabolic disorders such as hereditary fructose intolerance, glycogen storage diseases, galactosaemia
• Insulinoma (tumour of the pancreas that derives from beta cells and secretes insulin)
• Others = severe liver disease, non-pancreatic tumours (beta cell hyperplasia), renal disease (metab. Acidosis, reduced insulin elimination)
• CKD

Question 35

How can ethanol lead to hypoglycaemia?

Answer 35

inhibits gluconeogenesis but not glycogenolysis

Hypoglycaemia will follow several days alcohol binge with limited food intake = hepatic depletion of glycogen

Question 36

How can sepsis lead to hypoglycaemia?

Answer 36

common cause of hypoglycaemia

Cytokine accelerated glucose utilization and induced inhibition of gluconeogenesis in the setting of glycogen depletion

Question 37

What is reactive hypoglycaemia?

Answer 37

• Also known as postprandial hypoglycaemia - drops in blood sugar recurrent and occur within four hours after eating
• Can occur in both people with and without diabetes,thought to be more common in overweight individuals or those who have had gastric bypass surgery.

Question 38

What are the causes of reactive hypoglycaemia?

Answer 38

• possibly a benign (non-cancerous) tumour in the pancreas may cause an overproduction of insulin,
• too much glucose may be used up by the tumour itself.
• deficiencies in counter-regulatory hormones: e.g. glucagon.

Question 39

What happens in the normal case of hypoglycaemia?

Answer 39

When plasma glucose level decline in fast state pancreatic beta-cells secretion of insulin is decreased (1st defence);

• hepatic glycogenolysis and gluconeogenesis is increased
• There is reduced glucose utilisation of peripheral tissue, inducing lipolysis and proteolysis

Question 40

What counter regulatory hormones in response to hypoglycaemia?

Answer 40

• Pancreatic alpha cells secrete glucagon to stimulate hepatic glycogenolysis (2nd defence)
• Epinephrine release from adrenomedullary to stimulate hepatic glycogenolysis and gluconeogenesis; renal gluconeogenesis
• If hypo is prolonged beyond 4 hours; cortisol and GH will support glucose production and limit utilisation.

Question 41

What are signs and symptoms of hypoglycaemia?

Answer 41

Neurogenic → Triggered by falling glucose levels

• Activated by ANS and mediated by sympathoadrenal release of catecholamines and Ach

Neuroglycopenia → Due to neuronal glucose deprivation

Sign & symptoms include:

• confusion,
• difficulty speaking,
• ataxia,
• paresthesia,
• seizures,
• coma,
• death