Diabetes Revision Lecture 2nd Year 2014

8/10/2019 Diabetes Revision Lecture 2nd Year 2014

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Diabetes Mellitus


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Anatomy of the pancreas

Retroperitoneal

Posterior to greater curvature of the stomach

Head, body and a tail.

Blood supply: superior and inferior pancreaticoduodenal arteriesarising 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


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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 proteolyticenzyme cleavage.

Stored in granules in B cells until secreted into blood stream byexocytosis.


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Glucagon

Synthesised by alpha cells of the pancreatic islets and releasedfrom them by exocytosis

Response to glucose deficiency

Raise levels of glucose

Major target: liver. Hepatic glycogenolysis is stimulatedglycogensynthesis is inhibited in response to glucagon. Hepatic uptake of

amino acids and glyconeogenesis (glucose from amino acid) areenhanced.

Lipolytic effectmobilise fatty acids and glycerol from adiposetissues.


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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 glucoseload.

Declines after food. Insulin: uptake of glucose by insulin-responsive cells by translocating

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


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Type 1 Diabetes Mellitus

Usually teenagers but can affect ANY age

Insulin deficiency from autoimmune destruction of insulin-secretingpancreatic B cells. CD4+ and CD8+ T cells, B cells and activation ofthe innate immune system.

Autoantibodies: islet cell antibodies and anti-glutamic aciddecarboxylase

Association: other autoimmune diseases Genetic contribution: increased risk if family history

Possible viral trigger

Environmental influence: only ~30% in identical twins


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Pathogenesis

Lack of insulin

Prevents uptake of blood glucose: saturation of renal glucosecarriers so glycosuria -> osmotic diuresis (reduced reabsorption ofwater) -> 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.


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T1DM: Clinical Features

Weight loss

Polyuria

Polydipsia

Visual blurring

Genital thrush

Diabetic ketoacidosismedical 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


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Management: types of insulin

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

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


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Managementinsulin

regimens

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

BD biphasic regimen: twice daily insulin i.e. NovoMix 30type 2 DMor type 1 DM with regular lifestyle

QDS: before meals ultra-fast insulin + bedtime long-acting analogueallows type 1 DM to have flexible lifestyle

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

DAFNE training courses with the aim to improve glycaemic control


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Monitoring blood glucose

levels

Fingerprick glucose: at the time

HbA1c: glycated haemoglobin; reflects mean glucose level overthe past 8 weeks

Increased complications with rising HbA1c


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Neuropathy

Decreased sensation instocking distribution.

Neuropathy + poor woundhealing leads to foot ulcers:painless, punched out ulcer


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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 renalfunction

Microalbuminuria reflects early renal disease and increasedvascular risk

Can lead to renal failure and need for dialysis


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Retinopathy

Hyperglycaemia damages blood vessels reducing permeability ofthe vessels.

Background retinopathy: microaneurysms, haemorrhage and hardexudates (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 leadingto leaking blood.

Maculopathy: damage causes fluid to leak from damaged bloodvessels causing macula to swell.


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T2DMEpidemiology

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 influencethan T1DM


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T2DM: Clinical Features

Polyuria

Polydipsia

Weight loss

Lack of energy

Visual blurring: glucose affecting refraction

Inflammation of genitals: candida

Complications


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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.


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Obesity and insulin resistance

Obesity = increased visceral adiposity

Increased secretion of pro-inflammatory cytokines

Accumulation of fat in liver: Non-alcoholic fatty liver diseasecausing increased rate of release of free fatty acids may causeinsulin resistance

Beta-cell exhaustion and depletion reduces insulin secretion

Metabolic syndrome: central obesity, hypertension,hyperglycaemia, dyslipidaemia

Presence of mild inflammation makes it different from simpleobesity.


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Other mechanisms to consider

Mutation of genes encoding insulin receptors

Circulating autoantibodies to the extracellular domain of the insulinreceptor

Risk factors for insulin resistance: obesity, metabolic syndrome, TBdrugs, pregnancy, renal failure, cystic fibrosis, polycystic ovariansyndrome, acromegaly and Cushings.


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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


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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 soinsulin sensitivity is increased. Cannot cause hypoglycaemia.

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

Glitazone e.g. pioglitazone: interact with PPARy involved with lipid metabolismand insulin action. Theorylower circulation of free fatty acids and thereforepromote 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 carbohydratesin gut so glucose is not absorbed.


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Hyperosmolar hyperglycaemic

state

Similar to diabetic ketoacidosis

Aetiology: infection, myocardial infarction, stroke.

Hyperglycaemia and increased serum osmolarity polyuria (resultof osmotic diuresis) volume depletion/ dehydration

Presence of some insulin prevent ketoacidosis occurring throughlipolysis.

Management: IV fluids, electrolyte replacement (esp. potassium),and insulin once potassium level is sufficient.


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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 facilitatemonocyte adhesion to endothelial cells. Monocytes >>

macrophages >> foam cells

Increases vasoconstrictors

Increased gene transcription for LDL cholesterol


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Type 1 v. Type 2 diabetes

Type 1 DM

Often starts before puberty

HLA D3 and D4 linked

Autoimmune B celldestruction

Polydipsia, polyuria, weightloss, ketosis

Type 2 DM

Older patients (usually)

No HLA association

Insulin resistance/ B celldysfunction

Asymptomatic/complications i.e. MI


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Untreated diabetics may result

in all of the following except:

a) Blindness

b) Cardiovascular disease

c) Kidney disease

d) Tinnitus


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Among female children andadolescents, the first sign of

type 1 diabetes may be:

a) Rapid weight gain

b) Constipation

c) Genital candidiasis

d) Insomnia


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Hyperinsulinaemia may becaused by all of the following

except:

a) An insulinoma

b) Nesidioblastosis

c) Insulin resistance

d) Type 1 diabetes


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Which of the following regimensmay 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


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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


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If a person has a fasting plasma glucose of6.8mmol/L and a 2hr post-prandial plasma glucoseof 11.6mmol/L, should this person be suspected ofhaving diabetes?

a) Yes

b) No

Diabetes Revision Lecture 2nd Year 2014

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