Pathophysiology and treatment of type 1 diabetes Flashcards
(47 cards)
When autoimmune Type 1 diabetes presents later in life (>decades), what is it called?
Latent autoimmune diabetes in adults (LADA)
State two monogenic causes of diabetes (hereditary form of DM).
Present as T1DM/T2DM?
Mitochondrial Diabetes
Maturity Onset Diabetes of the Young (MODY)
- Can present phenotypically as Type 1 or Type 2 diabetes
What conditions and triggers are required for the onset of type 1 diabetes mellitus?
Environmental trigger in the presence of a genetic predisposition => autoimmune attack of the beta cells
May present following pancreatic damage or other endocrine disease.
Name three endocrine diseases that are associated with diabetes.
Phaeochromocytoma
Cushing’s Syndrome
Acromegaly
Which type of diabetes has a bigger genetic component?
Type 2 Diabetes Mellitus
What can be measured in the blood to give an indication of beta cell mass/insulin production? Why?
C-peptide
Proinsulin is cleaved in Golgi to form insulin and C-peptide and the two components are stored together in secretory granules in cytoplasm
In the pathogenesis of T1DM, what is one of the first pathological signs?
Loss of first phase insulin release
When the β-cells are stimulated and the stimulus is maintained, there is a biphasic pattern of insulin release (initial sharp rise in insulin release over a period of 10 minutes; second release of insulin which reaches a plateau approximately 2–3 hours later)
Why is T1DM described as a ‘relapsing-remitting’ disease?
Over time the beta cell mass appears to reduce, then stabilise, then reduce again (until hypoglycaemic state)
There is a theory that this is due to the imbalance in effector T-cells and regulatory T-cells
State the reasons why knowledge of the immune basis of T1DM is important
- Increased prevalence of other autoimmune disease (associated with diabetes)
- Risk of autoimmunity in relatives
- Measurement of auto antibodies can be useful clinically (in diagnosing)
- Immune modulation offers the possibility of novel treatments
What are the histological features of T1DM?
Lymphocyte infiltration of beta cells
On which chromosome is the HLA found?
Chromosome 6
In terms of the antigen types encoded by different HLA gene regions, what are the major genetic determinants of T1DM?
The major genetic determinants of T1D are polymorphisms of class II HLA genes encoding DQ and DR.
Specifically, the DR3 and DR4 alleles of the HLA-DR region => most significant risk
What are the markers of diabetes (which are not used in clinical practice)?
- Islet cell antibodies (ICA)
- Glutamic acid decarboxylase (GADA)
Not used:
- Insulin antibodies (IAA)
- Insulinoma-associated-2 autoantibodies (IA-2A)-receptor like family
State some symptoms of T1DM
- Polyuria
- Nocturia
- Polydipsia
- Blurring of vision
- Thrush (due to increased risk of infection)
- Weight loss
- Fatigue
What are the signs of T1DM?
- Dehydration
- Cachexia
- Hyperventilation (Kussmaul breathing)
- Smell of ketones (‘like nail polish’)
- Glycosuria
- Ketonuria
What does insulin have a negative effect on (inhibitory effects)?
- Decreases hepatic glucose output (glycogenolysis + gluconeogenesis)
- Inhibits glucagon release (via paracrine stimulation of alpha cells)
- Inhibits lipolysis and hence ketogenesis in liver (since the release of fatty acids and transport to liver is required for beta-oxidation to acetyl-CoA and then subsequent conversion to ketone bodies)
What does insulin have a positive effect on (stimulatory effects)?
- Increases GLUT4* mediated glucose uptake (in muscle and adipose tissue)
- Stimulates glycolysis
- Stimulates glycogenesis
- Stimulates amino acid uptake
- Stimulates protein synthesis (via an indirect genomic effect)
- Stimulates lipogenesis
State 4 other hormones that increase hepatic glucose output.
Catecholamines
Cortisol
Growth Hormone
Glucagon
Describe the factors that control insulin release. Outline the mechanism by which glucose (and certain amino acids) stimulate insulin release from beta cells
Note that there are two levels of insulin secretion - basal secretion (since some cells are dependent on the insulin- dependent GLUT4 transporters in order to receive sufficient intracellular glucose) and enhanced release when blood glucose levels rise (e.g. post-prandial)
- As the blood glucose level rises insulin output increases*
- Certain amino acids (glycine, alanine and arginine) directly stimulate insulin release
- Free fatty acids (FFA) are generally potent enhancers of glucose-stimulated insulin granule secretion/exocytosis (acting via GPCRs)
- Incretins (gastrointestinal hormones) stimulate insulin production and β-cell mass (e.g. by cell proliferation) e.g. gastrin, cholecystokinin, GLP1
- Sympathetic stimulation is associated with an inhibition of insulin secretion while parasympathetic (vagal) activity stimulates its release (these effects are indirect and involve the islet vasculature, so no direct innervation of islet cells)
- Glucagon appears to have a stimulatory effect on insulin release, while somatostatin from the δ-cells is inhibitory
- Glucose enters beta via GLUT2 and are converted to glucose-6-phosphate by glucokinase; further metabolism of G6P (glycolysis + kreb’s) produces ATP; ATP closes ATP-sensitive potassium channels in the cell membrane;
transient build-up of K+ in the cell => membrane depolarisation => activates voltage-dependent calcium channels which open; influx of calcium ions down its concentration gradient is associated with
the movement of granules (containing insulin and C-peptide) towards the cell membrane, the fusion of the
granule membrane with the plasma membrane and the release of granule contents into the bloodstream by exocytosis
State the actions of glucagon and describe the control of its release
- Stimulates glycogenolysis and gluconeogenesis, increasing blood glucose concentration
- Stimulates the breakdown of triglycerides to fatty acids in adipose tissue. The accompanying increase in glycerol production then feeds into the gluconeogenic pathway in the liver
Control:
- Stimulus for glucagon release is a fall in the blood glucose level (e.g. during fasting).
- The same gastrointestinal hormones that enhance insulin release (e.g. cholecystokinin) also stimulate glucagon release
- Increased sympathetic activity is associated with
stimulated glucagon release
- Insulin itself has an inhibitory effect on glucagon release probably at least partly by a paracrine effect, and this probably explains why the glucagon levels in untreated diabetic patients tend to be higher than would be expected for the given raised blood glucose concentration
- Somatostatin from the δ-cells also has an inhibitory effect on glucagon release
Describe how insulin deficiency leads to polyuria, dehydration, and polydipsia and diabetic ketoacidosis (DKA). Explain the associated symptoms/signs
- The lack of insulin + corresponding elevation of glucagon => increased HGO; High glucose levels spill over into the urine (surpasses renal threshold for glucose absorption), taking water and solutes (such as sodium and potassium) along with it in a process known as osmotic diuresis. This leads to polyuria, dehydration (when can’t drink enough or vomiting), and polydipsia.
- The absence of insulin => release of free fatty acids from adipose tissue (lipolysis), which are converted via beta oxidation (in the mitochondria of liver cells) into acetyl CoA.
- If the amounts of acetyl-CoA generated challenge the processing capacity of the TCA cycle; i.e. if activity in TCA cycle is low due to low amounts of intermediates such as oxaloacetate, acetyl-CoA is then used instead in biosynthesis of ketone bodies.
- The ketone bodies, however, have a low pKa and therefore turn the blood acidic (metabolic acidosis).
- The body initially buffers the change with the bicarbonate buffering system of the blood, but this system is quickly overwhelmed and other mechanisms must work to compensate for the acidosis. One such mechanism is hyperventilation to lower the blood carbon dioxide levels (a form of compensatory respiratory alkalosis). This hyperventilation, in its extreme form, may be observed as Kussmaul breathing.
Other clinical signs: ketonuria, abdominal pain, vomiting => coma (look for precipitating factor)
What is the defining/diagnostic biochemical feature of insulin deficiency? But under what circumstances may this be a normal observation, and when would you diagnose someone with DKA? Why is DKA uncommon in T2DM?
Elevated ketone bodies
Ketosis also occurs due to increased stress hormones and fasting e.g. in a non-diabetic subject say at 6.00am in the morning before breakfast. The diagnosis of ketoacidosis is made on the combination of hyperglycaemia, ketones in the urine and a metabolic acidosis on blood gas analysis (low pH, low bicarbonate, low PC02).
DKA is common in T1DM. In T2DM, insulin production is present but is insufficient to meet the body’s requirements as a result of end-organ insulin resistance. Usually, these amounts of insulin are sufficient to suppress ketogenesis. If DKA occurs in someone with type 2 diabetes, their condition is called “ketosis-prone type 2 diabetes” but is very rare.
State some long-term complications of T1DM.
Neuropathy
Nephropathy
Retinopathy
Vascular Disease
What is the main treatment for T1DM?
Exogenous insulin (SC injection)
