Diabetes and Hypoglycaemia Flashcards
How are blood glucose levels maintained?
- dietary carbohydrate
- glycogenolysis
- gluconeogenesis
What is the liver’s role in blood glucose homeostasis?
After meals, the liver stores glucose as glycogen.
During fasting the liver 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 o maintain glucose levels?
The brain and erythrocytes require a continuous supply – therefore need to avoid deficiency.
High glucose and metabolites cause pathological changes to tissues: e.g. micro/macro vascular diseases, neuropathy: – therefore also need to avoid excess.
What are the metabolic effects of insulin?
IN THE LIVER:
- ↑ amino acid uptake
- ↑ glycogen synthesis
- ↑ fatty acid synthesis
- ↓ ketogenesis
- ↓ gluconeogenesis
- ↓ glycogenolysis
IN ADIPOSE TISSUE:
- ↑ lipogenesis
- ↓ lipolysis
IN THE 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 results due to the increased hepatic glucose production and decreased cellular glucose uptake
- blood glucose > ~10mmol/L, exceeds renal threshold = glycosuria
What is the prevalence of diabetes mellitus?
Globally, 422 million people currently have diabetes; this is estimated to increase by 2035 (WHO, 2014).
In UK in 2018, ~ 3.8 million diagnosed with DM.
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 is 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 hours.
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.
It presents 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 B-cells
- interaction between genetic and environment factors
- strong link with HLA genes within the MHC region on chromosome 6
Describe the pathogenesis of Type 1 DM.
HLA class II cell surface present as foreign and self antigens to T-lymphocytes to initiate an autoimmune response.
There are 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 is a glucoregulatory peptide hormone co-secreted with insulin. It lowers blood glucose by slowing gastric emptying, & suppressing glucagon output from pancreatic cells.
Describe the presentation of Type 2 DM.
- low 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?
You are in a Hyper-osmolar non-ketotic coma (HONK)
[Hyperosmolar Hyperglycaemic State (HHS)]. which 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?
They occur in both type 1 and type 2 DM.
- micro-vascular disease:
retinopathy, nephropathy, neuropathy - macro-vascular disease:
related to atherosclerosis heart attack/stroke
The exact mechanisms of the complications are unclear.
What are some causes of hypoglycaemia?
Drugs are the most common cause:
- insulin & insulin - secretagogues
- alcohol, beta blockers CAE 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 (metabolic 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.
- it’s an autosomal recessive disorder
- glucose synthesis from glycogen or by gluconeogenesis is blocked.
- it 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.
Descrieb galactosaemia.
- it’s an 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.
- it’s an 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 is 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: increased gluconeogenesis
Symptoms of hypoglycaemia are divided into two categories, what are they?
1) Neurogenic (automatic)
- triggered by falling glucose levels
- activated by ANS and mediated by sympathoadrenal release of catecholamines and Ach
2) Neuroglycopaenia:
- due to neuronal glucose deprivation
SIGNS AND SYMPTOMS INCLUDE:
- confusion
- difficulty speaking
- ataxia (coordination and balance affected)
- paresthesia (abnormal dermal sensation with no apparent physical cause)
- seizures
- coma
- death
What are some complicaions of Type 1 DM?
- hyperglycaemia
- polyphagia
- glycosuria
- polyuria
- volume depletion
- polydipsia
- increased lipolysis
- increased free fatty acids (FFAs)
- increased FFA oxidation (liver)
- ketoacidosis (DKA)
- DIABETIC COMA
