Diabetes type 2 Flashcards
what is T2 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
which things causes T2 diabetes
Genetics + obesity leading to insulin resistance –> relative insulin deficiency –> hyperglycaemia
when does T2 diabetes present and what is it’s key feature
T2DM may present in youth / young adults
Diabetic ketoacidosis can be a feature of T2DM
Note T2 can develop in youth as well as in later life
Autoimmune diabetes leading to insulin deficiency can present later in life = latent autoimmune diabetes in adults (LADA)
Monogenic diabetes can present phenotypically as Type 1 or Type 2 diabetes (eg. MODY, mitochondrial diabetes)
Diabetes may present following pancreatic damage or other endocrine disease
what is the epidemiology of T2
Prevalence of T2DM varies enormously
Increasing prevalence
Occurring and being diagnosed younger
Greatest in ethnic groups that move from rural to urban lifestyle
What are the stages of development of T2
1) Normal
fasting glucose <= 6 mmol/L
2 h glucose ( OGTT) <7.7 mmol/L
HbA1c <43 mmol/mol
2) intermediate stage
impaired fasting glucose
impaired glucose tolerance
prediabetes / non diabetic hyperglycaemia
3) T2 diabetes
fasting glucose =>7 mmol/L
2 h glucose ( OGTT) / random glucose >=11 mmol/L
HbA1c >=48 mmol/mol
How to diagnose T2
Random glucose of >11,1 with symptoms of diabetes
Note beta cells function declines with T2
what is meant by relative insulin deficiency in T2
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
why does Beta cell function decline with T2
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
What are teh causes if T2
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
how does T2 responded to glucose of Insulin
1) high plasma glucose
2) no response to insulin when more is added
what is first phase insulin release and why it it lost in T2
Previously mentioned that in response to a meal, stored insulin is released and more is produced.
People with T2DM or those who are about to develop diabetes do not have this stored insulin
what does T2 diabetes do to skeletal muscle adn liver function
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
these 2 things cause hyperglycaemia
why do ppl with T2 diabetes have high blood sugar
Decreased Glucose Disposal and Increased HGP Contribute to Increased FPG in T2DM
This slide illustrates how impaired glucose disposal and increased hepatic glucose production (HGP) contribute to increased fasting plasma glucose (FPG) in type 2 diabetes mellitus (T2DM).
The diminished ability to store or oxidize glucose in muscle due to impaired insulin activity reduces the metabolic clearance rate of glucose (top graph), and an excessive amount of glucose is converted to lactate.1 Lactate then returns to the liver to be metabolized back to glucose (Cori cycling). The early increase in FPG in the progression to T2DM is often a result of Cori cycling from the previous night’s meal.
Inadequate insulin action also causes an increased flux of substrates – glycerol and free fatty acids – to the liver, resulting in increased gluconeogenesis.
Inappropriate glucagon secretion induces continued glucose production by stimulating glycogenolysis (release of glucose from glycogen, its stored form) and gluconeogenesis (glucose synthesis) (bottom graph).
Thus, at the liver, impaired insulin-mediated glucose disposal and excessive glucagon-mediated glucose output have the combined effect of increasing FPG in T2DM.
In people with T2DM with FPG levels <140 mg/dL, fasting HGP is less evident, whereas inefficient glucose utilization and inadequate suppression of glucagon following meals lead to abnormal Cori cycling. In those with FPG >140 mg/dL, fasting HGP is increased, further exacerbating the problem.
A dashed yellow line marks the American Diabetes Association’s diagnostic criterion of 126 mg/dL for FPG.
what happens to insulin sensitivity in T2
Is lost so increasing conc of insulin won’t help
what are the consequences of insulin resistance
See
What cytokines are increased in T2 and why
Excess of inflammatory adipokines:
TNF-alpha IL-6: Stimulates lipolysis and VLDL secretion ↑ IR whole body and muscle ↓ adiponectin expression
Endocannabinoids: Insulin inhibits expression in fat Fat IR> ↑ Circulating EC
Leptin: Elevated in obesity ↑ IR whole body muscle and liver ↓ Appetite ↑ Metabolic rate
Resistin: Elevated in obesity and T2DM ↑ IR whole body and liver ↑ Liver TG secretion
Glucocorticoids: ↑ 11-B HSB-I in fat ↑ Fat cell size and IR ↑ Glucose BP lipids
Adiponectin: ↓ Insulin resistance Predicative of diabetes
Fatty acids: Elevated in obesity and T2DM ↑ IR whole body muscle and liver ↓ B cell function ↑ Liver TG secretion ↑ Organ fat, oxidative stress
Apelin: Insulin stimulates expression in fat Elevated in hyperinsulin Cardiovascular effects
Visfatin: Visceral fat ↓ IR whole body
what are the 2 types of genetic mutation that can causes T2
1) Single gene mutation ==> Diabetes (MODY)
‘Born with it, always going to develop diabetes’
2)Polymorphisms increasing risk of diabetes
‘Not born with it but high risk and may develop later depending on other factors’
what is ment by polygenic
T2 diabetes is caused by multiple gene mutations –> the mores of these genes you have the more likely it is
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