Pathophysiology of diabetes mellitus Flashcards
What are the histological changes in the diabetic pancreas
[Left] In T1DM,
autoimmune reaction
against β cells leads to
infiltration of
pancreatic islet by T
cells which eventually
destroys gland.
* [Right] In T2DM,
pancreatic islet is not
usually affected. In
some patients with
long-standing diabetes, there are amyloid deposits (fibres of islet
amyloid polypeptide (IAPP)).
Effect of lack of insulin in T1DM
Glucose transport and utilisation ↑ leading to ↑ glucose.
* Lack of insulin means unopposed ↑ glucagon.
* ↑ protein breakdown leads to:
o ↑ glycogenolysis, gluconeogenesis and hepatic glucose
output.
o ↑ lipolysis, ketogenesis.
* Patient becomes catabolic, dehydrated (because of polyuria) and
there is progressive deterioration (decompensation, diabetic
ketoacidosis and coma).
What are the metabolic disturbances in T1 and T2 diabetes
Metabolic disturbances in T1DM
* Ketone bodies are acidic,
and they cause ketoacidosis.
Can cause brain to fail.
T2DM
* Progressive metabolic
disorder characterised by 𝛽
cell malfunction and insulin
resistance.
* Complex metabolic disorder:
impaired insulin secretion,
insulin resistance, microvascular complications, hypertension, dyslipidaemia, central obesity, macrovascular complications,
impaired insulin secretion.
Describe the interaction of genes obesity and environment
Genes responsible for obesity and insulin resistance interact with
environmental factors (↑ fat/caloric intake and ↓ physical activity),
resulting in development of obesity and insulin resistance. These ↑
secretory demand on β-cells. If β-cells are normal, their function
and mass ↑ in response to this ↑ secretory demand, leading to
compensatory hyperinsulinaemia and maintenance of normal
glucose tolerance. By contrast, susceptible β-cells have a
genetically determined risk, and combination of ↑ secretory
demand and detrimental environment result in β-cell dysfunction
and ↓ β-cell mass, resulting in progression to impaired glucose
tolerance, followed, ultimately, by development of type 2
diabetes. HNF, hepatocyte nuclear factor.
What is the issue of dysfunctional adipose tissue
Type 2 diabetics: adipose tissue deposits in liver and muscles. This
ectopic adipose tissue is dysfunctional and is more inflammatory.
Leads to release of cytokines such as TNF, IL-6 and MCP-1 and
causes necrosis and invasion by macrophages
- Normal glucose tolerant obese patients: fat is less inflammatory as
adipose tissue tends to be outside viscera, subcutaneous tissues.
Far less development of T2DM
What are some complications of diabetes
↑ incidence of CVD.
* Peripheral vascular disease.
* Renal disease (microangiopathy).
* Retinal disease (microangiopathy).
* Lens opacity (cataracts).
* Neuropathy (impaired nerve conductance).
o Autonomic (bladder, stomach, blood vessels, erections).
o Sensory
o Motor
* Skin infections (gangrene, thrush and other yeasts).
* Osteoarthritis
Describe the glycation of proteins in hyperglycaemia
Glucose is a reactive chemical which can link with amides to form
Schiff base. Chemical rearrangement (Amadori rearrangement)
can convert Schiff base into a permanent bond which is known as
an Advanced glycosylation end-product (AGE).
* This can be exploited as a diagnostic tool for diabetes as glycated
haemoglobin can be separated by electrophoresis or
chromatography and area under curve is percentage of HbA1c.
This reflects average glycaemia over past 90 days.
↑ glucose and ↑ lipids leads to AGE effects
Triggers inflammation
* Oxidative stress occurs because mechanism of clearing free
radicals is not working properly. Disposal of SOD leads to
generation of free radicals.
* Activation of renin-angiotensin axis activation produces
aldosterone which can lead to fibrosis leading to vascular
problems.
Describe the oxidation of superoxide dismutase
Glycation of SOD inhibits its activity
* SOD detoxifies free radicals which are generated during cellular
metabolism.
* Glycation of SOD causes accumulation of free radicals and
oxidative stress.
* Oxidative stress can lead to inflammatory biomarkers which leads
to malfunction of various metabolic pathways, which overall leads
to insulin resistance and 𝛽-cell dysfunction.
What is the sorbitol pathway
When glucose levels are high, sorbitol and fructose accumulate in
cells since they diffuse relatively slowly.
* This causes osmotic effects which may damage cells such as lens
cells and nerve cells.
* Sorbitol is an intermediate of glucose being converted to fructose.
It is a non-absorbed sugar which has osmotic effects.
Describe nephropathy
Key target is glomerulus which
functions to retain proteins.
* Thickened basement membrane in
blood vessels and ↑ permeability to
blood proteins leads to proteinuria
and albuminuria.
* This leads to end stage diabetic
nephropathy with excessive scarring
* External surface is granular reflecting
extensive sclerosis of cortical
glomeruli.
* Cut surface shows destruction of renal papillae and scarring
consistent with previous attacks of pyelonephritis.
* Kimmelstiel-Wilson nodules glomerulosclerosis can be seen
(yellow arrows).
Describe diabetic nephropathy
Damaging basement membrane of capillaries causes them to leak,
causing yellow deposits in eye (exudates). When it is sufficiently
weak to cause bleeding, vessels close. Body responds by releasing
EGF to grow new vessels. They are very fragile and have a
tendency to bleed. When they bleed, blood flows into eye and
stops light getting into eye.
How do foot infections occur in diabetes
High levels of glucose make a rich medium for organisms infecting
skin.
* Contributed to by damage to small blood vessels.
* Sensory neuropathy leads to foot numbness and damage (e.g.
from ill-fitting shoes).
* Can lead to ulceration of skin.
* Cause of amputation and disability.
How does the risk of diabetes increase in CVD
↑ risk of CVD in patients with diabetes than in those without.
* Up to 80% of people with diabetes will die from CVD.
* CVD deaths are potentially preventable if action is taken to
address known risk factors.
What is atherosclerosis
[1] High glucose ↑ ROS, oxidises LDLs, ↑ AGEs and activates
angiotensin.
* [2] Causes inflammation of intima media of blood vessels.
* [3] Macrophages are activated and take up LDLs and cholesterols
forming foam cells.
* [4] T-cells and macrophages produce cytokines causing
proliferation of fibroblasts and formation of atherosclerotic
plaque.
