Type 2 Diabetes Mellitus Flashcards
Type 2 diabetes
A condition in which the combination of insulin resistance and beta-cell failure result in hyperglycaemia
Associated with obesity but not always
The resultant chronic hyperglycaemia may initially be managed by changes to diet / weight loss and may even be reversible
With time glucose lowering therapy including insulin, is needed
Traditionally thought to be a condition of late adulthood
Now good evidence that it can present throughout every decade of life
Increasing in all age groups but rapidly in early-adulthood
Stages of development of type 2 diabetes
Normal - fasting glucose less than 6mmol/L
Intermediate - impaired fasting glucose
Diabetes - more than 7mmol/L
Normal - 2-hr glucose (OGTT) < 7.7 mmol/L
Intermediate - Impaired glucose tolerance
Diabetes - more than 11 mmol/L
Normal - HbA1c less than 42mmol/mol
Intermediate - Pre-diabetes or non-diabetic hyperglycaemia
Diabetes - ≥ 48 mmol/mol
Normal - insulin resistance and production low
Intermediate - insulin resistance rising and production high
Diabetes - insulin resistance high and production low
Relative insulin deficiency in type 2 diabetes
Insulin is produced by pancreatic beta-cells but not enough to overcome insulin resistance
There is therefore a relative deficiency of insulin
This is important to understand as it explains why the hyperglycaemia encountered does not cause ketosis under ‘usual’ circumstances
Long duration type 2 diabetes
In long-duration type 2 diabetes, beta-cell failure may progress to complete insulin deficiency
Usually on insulin at this point in any case, but important not to stop as at risk of ketoacidosis
Pathophysiology of type 2 diabetes
Genes and intrauterine environment and adult environment.
Insulin resistance and insulin secretion defects
Fatty acids important in pathogenesis and complications
HETEROGENOUS
People develop T2D at variable BMI, ages and progress differently
In type 2 diabetes, reduced insulin action causes less uptake of glucose into skeletal muscle
Hepatic glucose production is also increased due to both a reduction in insulin action and increase in glucagon action
First Phase Insulin
Lost
No sharp peak after IV glucose challenge
Glucose not just from diet
Impaired insulin-mediated glucose disposal
Excessive glucagon-mediated glucose output
More glucose is put out the more glucose there already is
Relationship between insulin resistance and insulin secretion
Inversely proportional
People developing type 2 diabetes have ‘fallen off the curve’
And for a given degree of insulin sensitivity secrete less insulin
Consequences of insulin resistance
Increased hepatic glucose production
Increased fatty acid uptake from gut in adipocyte - triglycerides form unhealthy types of lipids
Less skeletal muscle glucose uptake
Genetics of type 2 diabetes
Single gene mutation ==> Diabetes (MODY)
‘Born with it, always going to develop diabetes’
Polymorphisms increasing risk of diabetes
‘Not born with it but high risk and may develop later depending on other factors’
Each individual SNP has only a mild effect on risk
Cumulative effect of all SNPs have a bigger effect
What is the role of obesity?
Major risk factor for T2DM Fatty acids and adipocytokines important Central vs visceral obesity 80% T2DM are obese Weight reduction useful treatment
Other associations
Perturbations in gut microbiota
Obesity, insulin resistance T2DM
Bacterial lipopolysaccharides fermentation to short chain FA, bacterial modulation bile acids
Inflammation, signaling metabolic pathways
Most studies correlative
Intra-uterine growth retardation
Hales et al 1991
Weight at age 1 year <8.16kg, 22% had type 2 diabetes of IGT
Weight age 1 year >12.25 kg, 6% had type 2 diabetes or IGT
Presentation of T2DM
Hyperglycaemia Overweight Dyslipidaemia Fewer osmotic symptoms With complications Insulin resistance Later insulin deficiency
Risk factors:
Age PCOS
High BMI Family Hx
Ethnicity Inactivity
Diagnosis of type 2 diabetes
Osmotic symptoms
Infections
Screening test: incidental finding
at presentation of complication
Acute; hyperosmolar hyperglycaemic state,
Chronic; ischaemic heart disease, retinopathy
First line test for diagnosis is HbA1c.
1x HbA1c >=48mmol/L with symptoms
Or
2x HbA1c >=48 mmol/mol if aysymptomatic
Hyperosmolar hyperglycaemic state
Presents commonly with renal failure.
Insufficient insulin (NOT ABSENT) for prevention of hyperglycemia but sufficient insulin for suppression of lipolysis and ketogenesis.
Absence of significant acidosis.
Often identifiable precipitating event (infection, MI).
Unchecked gluconeogensis - hyperglycaemia
Osmotic diuresis - dehydration
Management
Diet Oral medication Structured education May need insulin later Remission / reversal
Prevention diabetes-related complications and their risk factors: Retinopathy Neuropathy Nephropathy Cardiovascular
Principles of a T2DM consultation
Glycaemia: HbA1c, glucose monitoring if on insulin, medication review
Weight assessment
Blood pressure
Dyslipidaemia: cholesterol profile
Screening for complications: foot check, retinal screening
Excess hepatic glucose production drug
Metformin
Resistance to action of circulating insulin drug
Metformin
Thiozolidinediones
Inadequate insulin production for extent of insulin resistance drug
Sulphonylureas
DPP4-inhibitors
GLP-1 Agonists
Excess glucose in circulation drug
Alpha glucosidase inhibitor
SGLT-2 inhibitor
Pioglitazone
Peroxisome proliferator-actived receptor agonists PPAR-γ
Pioglitazone
Insulin sensitizer, mainly peripheral
Adipocyte differentiation modified, weight gain but peripheral not central
Improvement in glycaemia and lipids
Evidence base on vascular outcomes
Side effects of older types hepatitis, heart failure
Incretin effect
Oral glucose given - massive rise in insulin secretion - mediated by GLP 1
Glucagon like peptide-1 (GLP-1)
Gut hormone
Secreted in response to nutrients in gut
Transcription product of pro-glucagon gene, mostly from L-cell
Stimulates insulin, suppresses glucagon
↑ satiety (feeling of ‘fullness’)
Short half life due to rapid degradation from enzyme dipeptidyl peptidase-4 (DPP4 inhibitor)
Used in treatment of diabetes mellitus
Remission of T2DM (not cure)
Gastric bypass surgery has the potential to induce remission of type 2 diabetes
Other aspects of management
Blood Pressure management
Hypertension very common in T2DM
Clear benefits for reduction esp with use of ACE-inhibitors
Lipid management Total cholesterol raised Triglycerides raised HDL cholesterol reduced Clear benefit to lipid-lowering therapy
Present with kidney failure
Hyperosmotic hyperglycaemic state
Insulin sensitiser
Pioglitazone
Oral glucose - increased insulin
Incretin effect
