26. Diabetes & Hypoglycaemia Flashcards
How are blood glucose levels maintained?
- dietary carbohydrate
- glycogenolysis
- gluconeogenesis
What is the liver’s role in blood glucose homeostasis?
After meals - stores glucose as glycogen
During fasting - makes glucose available through: - glycogenolysis ~ breakdown of glycogen store to glucose
- gluconeogenesis ~ making glucose from non-glucose sources, e.g. lactate, alanine, glycerol
Why is it important to maintain glucose levels?
Brain and erythrocytes require continuous supply: – therefore avoid deficiency.
High glucose and metabolites cause pathological changes to tissues; e.g. micro/macro vascular diseases, neuropathy: – therefore avoid excess.
What are the metabolic effects of insulin?
LIVER:
- ↑ amino acid uptake
- ↑ glycogen synthesis
- ↑ fatty acid synthesis
- ↓ ketogenesis
- ↓ gluconeogenesis
- ↓ glycogenolysis
ADIPOSE TISSUE:
- ↑ lipogenesis
- ↓ lipolysis
MUSCLE:
- ↑ amino acid uptake
- ↑ glycogen synthesis
- ↓ protein breakdown
GENERALISED TISSUE EFFECTS:
- ↑ glucose uptake
Briefly, describe diabetes mellitus
It is a metabolic disorder characterised by chronic hyperglycaemia, glycosuria and associated abnormalities of lipid and protein metabolism:
- hyperglycaemia result of increased hepatic glucose production and decreased cellular glucose uptake
- blood glucose > ~ 10mmol/L exceeds renal threshold – glycosuria
How would you diagnose diabetes mellitus?
In the presence of symptoms: (polyuria, polydipsia & weight loss for Type I)
- Random plasma glucose ≥ 11.1mmol/l (200 mg/dl ).
- OR fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl) Fasting is defined as no caloric intake for at least 8 h
- OR oral glucose tolerance test (OGTT) - plasma glu ≥ 11.1 mmol/l
In the absence of symptoms:
- test blood samples on 2 separate days
What are the blood serum levels of IGT (prediabetes) and IFG?
Impaired Glucose Tolerance (IGT)
- Fasting plasma glucose 6.1-6.9mmol/L**
- OGTT value of 7.8 – 11.1 mmol
Impaired Fasting Glycaemia (IFG)
- Fasting plasma glucose ‹ 7.0 mmol/L**
- and OGTT value of < 7.8
** OGTT used in individuals with fasting plasma glucose of ‹ 7.0 mmol/L to determine glucose tolerance status.
How would you perform the oral glucose tolerance test?
OGTT should be carried out:
- in patients with IFG
- in unexplained glycosuria
- in clinical features of diabetes with normal plasma glucose values
- for the diagnosis of acromegaly
75g oral glucose and test after 2 hour
Blood samples collected at 0 and 120 mins after glucose
Subjects tested fasting after 3 days of normal diet containing at least 250g carbohydrate
List the different classifications of diabetes
Type 1:
Insulin secretion is deficient due to autoimmune destruction of β-cells in 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
Describe the presentation of type 1 DM
Predominantly in children and young adults; but other ages as well.
- Sudden onset (days/weeks)
- Appearance of symptoms may be preceded by ‘prediabetic’ period of several months
- Commonest cause is autoimmune destruction of β-cells
- interaction between genetic and environment factors
- strong link with HLA genes within the MHC region on chrom. 6
Describe the pathogenesis of type 1 DM
HLA class II cell surface present as foreign and self antigens to T-lymphocytes to initiate autoimmune response
Circulating autoantibodies to various -cell antigens against:
- glutamic acid decarboxylase
- tyrosine-phosphatase-like molecule
- Islet auto-antigen
The most commonly detected antibody associated with type 1 DM is the islet cell antibody
More than 90% of newly diagnosed persons with type 1 DM have one or another of these antibodies.
Destruction of pancreatic ß-cell causes hyperglycaemia due to absolute deficiency of both insulin & amylin.
Amylin, a glucoregulatory peptide hormone co-secreted with insulin.
lowers blood glucose by slowing gastric emptying, & suppressing glucagon output from pancreatic cells.
What does insulin deficiency cause?
- increased hepatic output and impaired glucose uptake – hyperglycaemia
- Increased glucose osmotic effect and causes diuresis, dehydration and circulatory collapse
- Increased lipolysis blood level of ketone bodies formation (DKA) and metabolic acidosis.
Describe the presentation of type 2 DM
• Slow onset (months/years)
• Patients middle aged/elderly ~ prevalence increases with age
• Strong familiar incidence
• Pathogenesis uncertain ~ insulin resistance; β-cell dysfunction:
- may be due to lifestyle factors - obesity, lack of exercise
What are the metabolic complications of type 2 DM?
Hyper-osmolar non-ketotic coma (HONK) [Hyperosmolar Hyperglycaemic State (HHS)]. This can lead to:
- Development of severe hyperglycaemia
- Extreme dehydration
- Increased plasma osmolality
- Impaired consciousness
- No ketosis
- Death if untreated
What is the aim of monitoring glycaemic control?
Aim: to prevent complications or avoid hypoglycaemia
Self-monitoring to be encouraged:
- Capillary blood measurement
- urine analysis: glucose in urine gives indication of blood glucose concentration above renal threshold
3-4 months: blood HbA1c (glycated Hb; covalent linkage of glucose to residue in Hb.
Others: urinary albumin (index of risk of progression to nephropathy).
What are some long term complications of diabetes mellitus?
Occur in both type 1 and type 2 DM
Micro-vascular disease:
- retinopathy, nephropathy, neuropathy
Macro-vascular disease:
- related to atherosclerosis heart attack/stroke
Exact mechanisms of complications are unclear
Define hypoglycaemia
Defined as plasma glucose < 2.5 mmol/L
Hypoglycaemia in diabetes
Hypoglycaemia in patients without diabetes
What are some causes of hypoglycaemia?
Drugs are the most common cause:
- insulin & insulin secretagogues
- Alcohol, beta blockers ACE inhibitors
Endocrines disease; e.g. cortisol disorder
Inherited metabolic disorders, e.g. glycogen storage diseases, galactosaemia, hereditary fructose intolerance.
Insulinoma
Others: severe liver disease, non-pancreatic tumours (beta cell hyperplasia), renal disease (metab. acidosis, reduced insulin elimination).
List three types of inherited metabolic diseases
1) Glycogen storage disease type l (von Gierke’s disease);
- deficiency of G-6-Phosphatase: impaired glucose release from glycogen
2) Galactosaemia:
- deficiency of galactose-1-phosphate uridyl transferase: liver damage
3) Hereditary fructose intolerance:
- deficiency of fructose-1-phosphate adolase B: accumulation of fructose-1-phosphate in liver
Describe glycogen storage disease type Ia
- Autosomal recessive disorder;
- Glucose synthesis from glycogen or by gluconeogenesis is blocked.
- presents in early infancy; manifested in severe fasting hypoglycaemia as only source of glucose is dietary carbohydrate.
- accumulation of glycogen causes hepatomegaly; inability to produce glucose from lactate causes acidosis.
- Treatment: uncooked cornstarch; a slow releasing glucose prep.
Describe galactosaemia
- Autosomal recessive disorder
- Defects in 3 enzymes can cause galactosaemia; most common is galactose-1-phosphate uridyl transferase deficiency.
•Deficiency of G-1-PUT impairs conversion of galactose-1-phosphate to glucose-1-P.
- Gal-1-phosphate accumulates in liver - toxicity
- Hypoglycaemia; and vomiting/diarrhoea after starting milk feeds
- Galactose excreted in urine.
- Treatment - exclude galactose from diet.
Describe hereditary fructose intolerance.
•Autosomal recessive disorder.
•Deficiency of fructose 1-phosphate aldolase B
- ingested fructose accumulates – inhibits glycogenolysis at phosphorylase step.
- Severe hypoglycaemia and vomiting after ingesting fruit, sweetened foods.
- Fructose detected in urine
- Benign fructose intolerance: – this due to absence of fructokinase
Describe the responses to falling glucose levels in fasting
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.
Glucose Counter-Regulatory Hormones:
- Glucagon: Secreted by α-cells of pancreas in response to hypoglycaemia stimulates glycogenolysis and gluconeogenesis
- Cortisol: Gluconeogenesis
Symptoms of hypoglycaemia are divided into 2 categories, what are they?
1) Neurogenic (autonomic):
- triggered by falling glucose levels
- activated by ANS & mediated by sympathoadrenal release of catecholamines and Ach
2) Neuroglycopaenia:
- due to neuronal glucose deprivation.
Sign & symptoms include:
- confusion,
- difficulty speaking,
- ataxia,
- paresthesia,
- seizures,
- coma,
- death
What are some complications of type 1 DM?
- hyperglycaemia (too much glucose in the blood)
- polyphagia (excessive eating or appetite)
- glycosuria (excess sugar in the urine)
- polyuria (excessive urination)
- volume depletion
- polydipsia (excessive thirst)
- increased lipolysis
- increased FFAs
- increased FFA oxidation (liver)
- ketoacidosis (DKA)
- diabetic coma
