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Diabetes Mellitus

Anatomy of the pancreas

Retroperitoneal

Posterior to greater curvature of the stomach

Head, body and a tail.

Blood supply: superior and inferior pancreaticoduodenal arteries


arising from gastroduodenal artery and superior mesenteric artery.

Endocrine and exocrine functions

Islet of Langerhan cells:

Alpha (A): Glucagon

Beta (B): Insulin

Delta (D): Somatostatin

F cells: Pancreatic

Insulin

Effect on tissues: short term and long-term

Derived from proinsulin, which is synthesised in the rER.

Converted to insulin in the Golgi apparatus as result of proteolytic


enzyme cleavage.

Stored in granules in B cells until secreted into blood stream by


exocytosis.

Glucagon

Synthesised by alpha cells of the pancreatic islets and released


from them by exocytosis

Response to glucose deficiency

Raise levels of glucose

Major target: liver. Hepatic glycogenolysis is stimulated glycogen


synthesis is inhibited in response to glucagon. Hepatic uptake of
amino acids and glyconeogenesis (glucose from amino acid) are
enhanced.

Lipolytic effect mobilise fatty acids and glycerol from adipose


tissues.

Effect of blood glucose on insulin


and glucagon

Fasting: plasma glucose is low, insulin is low.

Following a meal: insulin secretion rises as plasma glucose rises.


Peaks 30-60 mins after eating.

Biphasic release: early rise reflects the release of available insulin.


Latter rise: depend on synthesis of new insulin in response to glucose
load.

Declines after food.

Insulin: uptake of glucose by insulin-responsive cells by translocating


GLUT-4 from vesicles to cell membrane. Glucose absorption
increases -> Glycolysis.

Type 1 Diabetes Mellitus

Usually teenagers but can affect ANY age

Insulin deficiency from autoimmune destruction of insulin-secreting


pancreatic B cells. CD4+ and CD8+ T cells, B cells and activation of
the innate immune system.

Autoantibodies: islet cell antibodies and anti-glutamic acid


decarboxylase

Association: other autoimmune diseases

Genetic contribution: increased risk if family history

Possible viral trigger

Environmental influence: only ~30% in identical twins

Pathogenesis

Lack of insulin

Prevents uptake of blood glucose: saturation of renal glucose


carriers so glycosuria -> osmotic diuresis (reduced reabsorption of
water) -> polyuria.

Increase in glycogen breakdown

Increase in rate of gluconeogenesis -> weight loss and


hyperglycaemia

Increased fatty acid oxidation -> Ketogenesis and ketouria ->


metabolic acidosis = diabetic ketoacidosis.

T1DM: Clinical Features

Weight loss

Polyuria

Polydipsia

Visual blurring

Genital thrush

Diabetic ketoacidosis medical emergency. Hyperglycaemic.


Ketones in urine.

Raised fasting glucose: >7mmol/L or random >11.1mmol/L

Investigation: oral glucose tolerance test 2h value >11.1mmol/L

Management: types of insulin


Subcutaneous insulin: short -, medium- or long-acting
1.

Ultra-fast acting e.g. Humalog, Novorapid: inject at the start of each


meal helps to match what is eaten.

2.

Isophane insulin (variable peak at 4-12h)

3.

Pre-mixed insulin, with ultra-fast component e.g. NovoMix 30

4.

Long acting recombinant human insulin analogues: bedtime in type


1 or type 2 DM. Good if nocturnal hypoglycaemia is an issue.

Management insulin
regimens

The regimens are tailored to the individual and must suit them in
order to maintain good control

BD biphasic regimen: twice daily insulin i.e. NovoMix 30 type 2 DM


or type 1 DM with regular lifestyle

QDS: before meals ultra-fast insulin + bedtime long-acting analogue


allows type 1 DM to have flexible lifestyle

OD before bed long acting insulin: good for switching from tablets to
insulin in T2DM

DAFNE training courses with the aim to improve glycaemic control

Monitoring blood glucose


levels

Fingerprick glucose: at the time

HbA1c: glycated haemoglobin; reflects mean glucose level over


the past 8 weeks

Increased complications with rising HbA1c

Neuropathy

Decreased sensation in
stocking distribution.

Neuropathy + poor wound


healing leads to foot ulcers:
painless, punched out ulcer

Nephropathy

High level of glucose in the urine

Osmotic diuresis: more water thus increasing urine volume

Increased volume results sodium chloride in urine

Macula densa to release more renin

Leads to vasoconstriction leading to infarction and reduced renal


function

Microalbuminuria reflects early renal disease and increased


vascular risk

Can lead to renal failure and need for dialysis

Retinopathy

Hyperglycaemia damages blood vessels reducing permeability of


the vessels.

Background retinopathy: microaneurysms, haemorrhage and hard


exudates (lipid deposits)

Pre-proliferative retinopathy: cotton wool spots, haemorrhages,


venous beading. Retinal ischaemia.

Proliferative retinopathy: new vessels form as retina signals


ischaemia. These have fragile walls and prone to damage leading
to leaking blood.

Maculopathy: damage causes fluid to leak from damaged blood


vessels causing macula to swell.

T2DM Epidemiology

Rates of type 2 diabetes mellitus is increasing

Most over 40 years but now also teenagers

Cause: reduced insulin secretion +/- insulin resistance

Associations: obesity, lack of exercise, calorie and alcohol excess

>80% concordance in identical twins = stronger genetic influence


than T1DM

T2DM: Clinical Features

Polyuria

Polydipsia

Weight loss

Lack of energy

Visual blurring: glucose affecting refraction

Inflammation of genitals: candida

Complications

T2DM: Pathophysiology

Insulin released

Still bind to receptor

Type 2 diabetes: person cannot secrete enough insulin to overcome


this resistance.

Fewer beta cells: under strain

Causes secondary effect on liver: less glucose enters liver cells so


liver begins glycogenolysis and raises blood glucose even more.

Obesity and insulin resistance

Obesity = increased visceral adiposity

Increased secretion of pro-inflammatory cytokines

Accumulation of fat in liver: Non-alcoholic fatty liver disease


causing increased rate of release of free fatty acids may cause
insulin resistance

Beta-cell exhaustion and depletion reduces insulin secretion

Metabolic syndrome: central obesity, hypertension,


hyperglycaemia, dyslipidaemia

Presence of mild inflammation makes it different from simple


obesity.

Other mechanisms to consider

Mutation of genes encoding insulin receptors

Circulating autoantibodies to the extracellular domain of the insulin


receptor

Risk factors for insulin resistance: obesity, metabolic syndrome, TB


drugs, pregnancy, renal failure, cystic fibrosis, polycystic ovarian
syndrome, acromegaly and Cushings.

Management

Lifestyle: low sugar diet, high starchy COH diet, high fibre, low in fat,
low protein.

Lifestyle + metformin

Lifestyle + metformin + further drugs

Lifestyle + metformin + further drugs + insulin

Classes of anti-diabetic drugs


Main classes:

Biguanide e.g. metformin: increases insulin sensitivity, mechanism unclear;


reduces gluconeogenesis and thus reduced glucose output from the liver so
insulin sensitivity is increased. Cannot cause hypoglycaemia.

Sulfonylurea e.g. gliclazide: stimulate the beta cells of the pancreas to produce
more insulin.

Glitazone e.g. pioglitazone: interact with PPARy involved with lipid metabolism
and insulin action. Theory lower circulation of free fatty acids and therefore
promote glucose utilisation by muscle cells.

Glucagon-like peptide analogues e.g. exenatide: enhances secretion of insulin,


suppresses glucagon and slows gastric emptying.

Alpha-glucosidase inhibitors e.g. acarbose: inhibit breakdown of carbohydrates


in gut so glucose is not absorbed.

Hyperosmolar hyperglycaemic
state

Similar to diabetic ketoacidosis

Aetiology: infection, myocardial infarction, stroke.

Hyperglycaemia and increased serum osmolarity polyuria (result


of osmotic diuresis) volume depletion/ dehydration

Presence of some insulin prevent ketoacidosis occurring through


lipolysis.

Management: IV fluids, electrolyte replacement (esp. potassium),


and insulin once potassium level is sufficient.

Macrovascular complications

As well as microvascular complications!!!

Stroke, renovascular disease, limb ischaemia, myocardial infarction

Increased production of free radicals

Increased inflammation and adhesion molecules that facilitate


monocyte adhesion to endothelial cells. Monocytes >>
macrophages >> foam cells

Increases vasoconstrictors

Increased gene transcription for LDL cholesterol

Type 1 v. Type 2 diabetes

Type 1 DM

Type 2 DM

Often starts before puberty

Older patients (usually)

HLA D3 and D4 linked

No HLA association

Autoimmune B cell
destruction

Insulin resistance/ B cell


dysfunction

Polydipsia, polyuria, weight


loss, ketosis

Asymptomatic/
complications i.e. MI

Untreated diabetics may result


in all of the following except:
a)

Blindness

b)

Cardiovascular disease

c)

Kidney disease

d)

Tinnitus

Among female children and


adolescents, the first sign of
type 1 diabetes may be:
a)

Rapid weight gain

b)

Constipation

c)

Genital candidiasis

d)

Insomnia

Hyperinsulinaemia may be
caused by all of the following
except:
a)

An insulinoma

b)

Nesidioblastosis

c)

Insulin resistance

d)

Type 1 diabetes

Which of the following diabetes drugs


acts by decreasing the amount of
glucose produced by the liver?
a)

Sulfonylureas

b)

Glitazones

c)

Biguanides

d)

Alpha-glucosidase inhibitors

Which of the following regimens


may offer the best blood glucose
control for T1DM?
a)

A single anti-diabetic drug

b)

Once daily insulin injections

c)

A combination of oral anti-diabetic medications

d)

Three or four injections per day of different insulin

Urinalysis in an undiagnosed
diabetic may show
a)

Glucose and ketones in the urine

b)

Glucose and high amounts of bilirubin in the urine

c)

Ketones in the urine

d)

Ketones and adrenaline in the urine

If a person has a fasting plasma glucose of


6.8mmol/L and a 2hr post-prandial plasma glucose
of 11.6mmol/L, should this person be suspected of
having diabetes?
a)

Yes

b)

No

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