Download Insulin-Dependent Diabetes - Wk 1-2

Insulin-Dependent Diabetes
1. Outline the clinical features, natural history and potential longterm complications of IDDM.
Pathogenesis
Type I Diabetes Mellitus is a slowly progressive T-cell mediated autoimmune disease
resulting from the selective destruction of the insulin secreting β-cells in the
Pancreatic Islets of Langerhans. The result is the complete loss of insulin secretion
and production, meaning the individual is not totally dependent upon a supply of
insulin ie Insulin Dependent Diabetes Mellitus (IDDM).
Progressive abnormalities in β-cell function yield an apparent abrupt onset. This is
due to the fact that clinically diagnosed hyperglycaemia is only present when 70-90%
of β-cells have been damaged. Type I diabetes is often termed juvenile-onset diabetes
mellitus as it commonly occurs during childhood and adolescence (but may occur at
any age).
Deficiencies in insulin cause abnormalities with carbohydrate, lipid and protein
metabolism, resulting in the appearance of the classic symptoms – Polyuria,
Polydipsia and Polyphagia.
Progression also sees a rising HbA1c level (within the normal range), impaired fasting
glucose and impaired glucose tolerance levels.
At diagnosis, blood glucose levels are usually high, accompanied by recent weight
loss. Ketoacidosis and Ketonuria may be the first manifestations of the disease. An
exaggerated “Dawn Phenomena” (raised BGL in the morning) is also experience in
IDDM.
There is also evidence that genetic defects, particularly those of chromosome 6 and
11, predispose individuals to diabetes. Defects appear to be polygenic and have links
with the Human Leukocyte Antigen (HLA).
Clinical Features
- Detectable islet cell antibodies and autoantibodies for insulin (Glutamic Acid
Decarboxylase (GAD) and Tyrosine Kinase)
- Islet pathology on biopsy (autopsy) show infiltration of islets with inflammatory
cells and the selective loss of β-cell mass
- Extremely low or undetectable plasma insulin and C-peptide levels
 As insulin is absent, BGL remain high after a meal leading to
HYPERGLYCAEMIA
 Glucose toxicity further damages body organs and tissues and further
complications develop if hyperglycaemia continues
Hyperglycaemia
Hyperglycaemia has 3 main effects;
1. Exerts large amount of osmotic pressure -causes cellular dehydration, thus there is
a sensation of thirst ie polydipsia.
2. Glycosuria - the excretion of glucose into the urine. Ordinarily, urine contains no
glucose because the kidneys are able to reclaim all of the filtered glucose back into
the bloodstream. Blood is filtered by millions of nephrons, the functional units that
comprise the kidneys. In each nephron, blood flows from the arteriole into the
glomerulus, a tuft of leaky capillaries. Bowman's capsule surrounds each glomerulus,
and collects the filtrate that the glomerulus forms. The filtrate contains waste products
(e.g. urea), electrolytes (e.g. sodium, potassium, chloride), amino acids, and glucose.
The filtrate passes into the renal tubules of the kidney. In the first part of the renal
tubule, the proximal tubule, glucose is reabsorbed from the filtrate, across the tubular
epithelium and into the bloodstream. The proximal tubule can only reabsorb a limited
amount of glucose. When the blood glucose level exceeds about 8.9 - 10 mmol/l, the
proximal tubule becomes overwhelmed and begins to excrete glucose in the urine.
Glycosuria leads to excessive water loss into the urine with resultant dehydration, a
process called osmotic diuresis ie Polyuria
3. As glucose is lost in the urine, fuel is lost as it is not getting into the tissues. As a
result, the body still requires food for energy, resulting in Polyphagia.
Lack of Insulin
Insulin actions include;
- Increased glucose uptake by cells
- Increased glucose catabolism ie glycolysis
- Increased glycogen storage and synthesis ie Glycogenesis
- Increased fat synthesis ie Lipogenesis
- Increases a.a. uptake and protein synthesis
- Decreased glycogenolysis, gluconeogenesis, lipolysis, protein catabolism
Therefore a lack of insulin and increased glucagon leads to the activation of
Hormone-sensitive lipases in Adipose Tissue (Fat) resulting in the release and
breakdown of Triglycerides to produce fat and glycerol. Protein breakdown in muscle
also occurs and this all results in weight loss.
The circulating fatty acids are metabolised in the liver to produce Ketone bodies.
Ketone bodies are acidic meaning that if synthesis of ketones exceeds utilisation by
the tissues, there is a drop in pH resulting in Ketoacidosis.
Increased in circulating Fatty Acids also causes fatty liver and an increased in plasma
lipids (dyslipemia and hyperlipidemia) which can have effects on cardiovascular
physiology ie atherosclerosis, hypertension, coronary heart disease.
Acute Complications of Diabetes Mellitus
1. Hypoglycaemia
 Caused by too much insulin, not enough food, skipped or missed meals,
vigorous activity/exercise, excessive alcohol consumption
 Signs and symptoms include, dizziness, headaches, confusion, nausea,
vomiting
 Treatment with simple sugar (sweet drink or soft lolly) – slow consumption as
to avoid overload and hyperglycaemia – if cannot take orally, glucagon
injection
2. Diabetic Ketoacidosis
 Low insulin levels, high glucagon catecholamine and other regulatory
hormones
 Causes increased gluconeogenesis and ketogenesis
 Ketogenesis: Mobilisation of free fatty acids (FFA) from triglyceride stores in
adipose tissue for use as a fuel source leads to accelerated ketone production
and ketosis and acidosis
 Gluconeogenesis: production of glucose in excess of that needed to supply
glucose for the brain and other glucose-dependent tissues produces a rise in
blood glucose levels.
 Symptoms include nausea, vomiting, abdominal or leg pain, drop in pH, rapid
weight loss,
 indicates severe dehydration, due to hyperglycaemia
Chronic Complications of Diabetes Mellitus
Microvascular
- affecting small blood vessels in the body
1. Retinopathy
2. Nephropathy
3. Peripheral/Sensory Nephropathy
Macrovascular
1. Cardiovascular disease
2. Peripheral Vascular Disease
3. Vascular Ulcers
4. Autonomic Neuropathy
Classic Symptoms may include;
- Polyuria, Polydipsia, Polyphagia
- Weight loss
- Lethargy, asthenia
- Fruity ketone breath
- Flushed face
- Blurred vision
- Abdominal pain, nausea, vomiting
- Itchy skin
- Impaired wound healing
- Reduced immune response
Diagnostic Criteria for Diabetes mellitus
1. Classical Symptoms – as mentioned above
2. Plasma Glucose level > 11 mmol/l at least 2 hrs after eating – requires two elevated
values on different days
3. Fasting Plasma Glucose > 8 mmol/l
4. Plasma Glucose levels 2-hr post glucose load > 11 mmol during Oral Glucose
Tolerance Test (OGTT)
5. HbAlc level > 8% (however cannot be used on its own)
Testing and Monitoring BGL
Control vital – improvements in BGL and HbA1c levels reduce the risk of
complications and slow down progression of existing damage
Management via;
1. Glycometer – self monitor of blood glucose levels – pre and post meal to adjust
treatment or detect hyperglycaemia
2. Glycosylated Haemoglobin (HbA1c)
 Better long term indicator of BGL – Red Blood cells contain Hb, and when it
combines with glucose it becomes glycosylated Hb, or HbA1c. Since everyone
has glucose in their blood, everyone has HbA1c, usually at 3-5% of the blood
 Amount of A1c in RBC proportional to the amount of glucose in the blood.
Hence during the high blood sugar levels, such as poorly controlled or
untreated diabetes, HbA1c percentage will be elevated
 Once an RBC is glycosylated it remains that way and, as the lifespan of an
RBC is roughly 120 days, HbA1c levels can be used to give an average of an
individuals blood glucose levels from 1-3 months
3. Fructosamine – is glycosylated serum protein (albumin) that reflects the blood
glucose concentration over the previous 1-3 weeks.