Endocrinology

Pancreatic Endocrine disease and Diabetes

Diabetes Mellitus

Anatomy and physiology

The pancreas function by weight is

  • Exocrine - 98%
  • Endocrine - 2%

Releases

  • A (alpha) cells release Glucagon
  • B (beta) cells are commonest (60%) and release Insulin and C-peptide
  • D (delta) cells (10%) release somatostatin
  • F cells release pancreatic polypeptide and are situated mainly in the head of pancreas

Endocrine function

  • Control by Islets of Langerhans and other hormones Insulin released along with C-peptide from B cells and acts via portal system predominantly on Liver and also through peripheral tissues
  • Insulin half life is 5 minutes but can be increased by the addition of zinc or modifications to the molecule
  • Glucagon released from the A cells. Somatostatin released from D cells
  • The cells are closely related in the islets in the sequence B-> A -> D
  • Glucagon stimulates Insulin secretion and somatostatin inhibits insulin and glucagon release

Blood glucose

  • Normal values are 3.5-8 mmol/l
  • Fasting level > 7.0 = Diabetes (should be confirmed on two separate days if no other evidence)
  • Random level (or 2 hrs after 75 g Glucose) > 11.1 = Diabetes (should be confirmed on two separate days if no other evidence)
  • Fasting level of 5.6-7.0 mmol/l is called impaired fasting glucose
  • A random level or post 75 g glucose of 8.1-11.1 is termed impaired glucose tolerance

Glyosylated Haemoglobin

  • Haemoglobin can become non enzymatically glycosylated in proportion to the availability of circulating glucose
  • Normal Adult Hb is HbA and this glycosylated variety called HbA1 or an even more specific fraction called HbA1C
  • It represents the average levels of glucose over the preceding 6 weeks. Target levels for HbA1C are 7%
  • Insulin resistance simply means that for some reason the effects of Insulin are counteracted possibly at a cell signalling level so that more is needed to do the same job as before

    Glucose homeostasis - maintain a level of 3-5 mmol/l

    The body has to cope with an ever changing demand and supply of glucose

    • Reduced supply with starvation
    • Increased demand with exercise
    • Increased supply after a meal
    • Increased glucose as a stress response to illness,trauma, surgery

    Response to hyperglycaemia - largely mediated by Insulin

    • Insulin mediates converting glucose to glycogen in liver
    • Insulin stimulates protein synthesis in liver and muscle
    • Insulin increases formation of triglycerides in liver and fatty tissue

    Response to fasting - largely mediated by Glucagon

    • Protein breakdown in muscle
    • Breakdown of fat in adipose tissue - lipolysis
    • Glucose production by liver
    • Glycogen breakdown in liver
    • Ketones produced in liver

    Glucose homeostasis is basically Insulin lowering blood glucose and Glucagon raising it

    Glucagon

    • Glucagon is a 29 Amino acid formed from proglucagon in pancreatic A cells
    • Islet cell hormone which acts opposing Insulin. Half life 5-10 minutes.
    • Stimulates Glycogenolysis, Gluconeogenesis, Lipolysis and ketone formation
    • Used therapeutically to treat acute hypoglycaemia in those unable to receive oral or IV glucose
    • Glucagon release stimulated by amino acids, Cortisol, exercise, infections, CCK, Gastrin
    • Immediate action is on liver stimulating glycogenolysis glycogen to glucose
    • In large doses it is a cardiac inotrope

    Insulin molecule

    Summary

    • 51 Amino acid protein Insulin is released from pancreatic B cells
    • Half life of 5 minutes and is released in response to rising blood glucose

    Production

    • Gene for Insulin is on the short arm of chromosome 11
    • Occurs in the endoplasmic reticulum of the B cells of the Islets of Langerhans in the pancreas > It is then transported to the golgi apparatus and stored as membrane bound granules which can be expelled by exocytosis.

    Structure

    • Preproinsulin -> Proinsulin -> Insulin and C-peptide released.
    • C-peptide is a guide to B cell function.
    • Insulin molecule has 2 polypeptide chains connected by 2 disulphide bridges
    • A chain 21 AAs and B chain 30 AA

    Release of Insulin is controlled by circulating glucose levels on B cells

    • Glucose enters pancreatic beta cells via the GLUT-2 transporter and is phosphorlyated by glucokinase
    • Glycolysis and mitochondrial metabolism produces ATP which closes ATP sensitive K channels causing membrane depolarisation and calcium influx
    • Calcium influx facilitates exocytosis and release of insulin and increased Insulin release by beta cells of the Islets into the portal circulation
    • There is a biphasic response with an early first peak and later sustained second phase of insulin release
    • Liver reduces gluconeogenesis and increases glycogen storage

    Insulin receptor

    • Insulin binds to its receptor which are found on many different cell types not all concerned with glucose uptake
    • The receptor is made up of two alpha and two beta glycoprotein subunits coded by a gene on chromosome 19
    • The alpha subunits bind the insulin and the beta subunits have tyrosine kinase activity
    • This causes localised autophosphyrlation and manifests the effects of insulin
    • Action is through secondary messengers to regulate glucose transport, protein and glycogen synthesis
    • The insulin-receptor complex is internalised by endocytosis and broken down.
    • Insulin is then internalised with its receptor into a clathrin lined endosome and broken down by lysosome

    Actions of Insulin are generally anabolic building up muscle, laying down fat

    • Acts on liver, fats and muscle cells
      • Stimulates glucose entry, Increased glycogen synthesis
      • Increased fat synthesis
      • Reduces fat breakdown (lipolysis) (Increased obesity seen in Type 2 DM treated with insulin)
      • Increased K+ uptake
    • On Muscle cells
      • Increased glucose entry and glycogen synthesis
      • Increased uptake of amino acids and ketones
      • Stimulates cell growth and differentiation
      • Increased DNA and RNA synthesis
    • General
      • Stimulates amino acid uptake within liver and muscle
      • Increases protein synthesis
      • Decreases protein breakdown
      • Increased cell growth

    Glucose entry "transport" into cells as it does not freely pass across the cell membrane as the molecule is too big is carried by facilitated diffusion via a variety of glucose transporters

    • Glut-1 - present throughout the body and brings basal levels of glucose into cells
    • Glut-2 found in beta cells
    • Glut-3 basal glucose uptake in brain but not insulin regulated
    • Glut-4 insulin mediated glucose uptake in muscles and adipose tissue
    • Glut-8 blastocyst development

    Cerebral Blood glucose

    • Brain consumes 80% of total body glucose which is its main energy source - The process is independent of Insulin

    Diabetes Mellitus

    Introduction

    Introduction

    • A disease typified by chronic hyperglycaemia due to a complete or relative insulin deficiency
    • It affects 6% of the population with increasing incidence of Type 2 and MODY from increasing obesity.
    • Diagnosis of Diabetes is based on laboratory testing of blood glucose - Normal values are 3.5-8 mmol/l

    Aetiology

    • Microvascular disease causes morbidity - retinopathy, neuropathy (related to poor glycaemic control)
    • Macrovascular disease causes death with IHD, Stroke and is also related to Hypertension, lipids, smoking.

    Criteria for diagnosing diabetes - It is a laboratory diagnosis

    • Fasting Blood glucose >=7.0 mmol/l (6-7 mmol/l= Impaired fasting glucose)
    • Random or 2-h post glucose load >=11.1 mmol/l (7.8-11.1 mmol/l = Impaired glucose tolerance)
    • Repeat on another day when asymptomatic or a single reading
    • Hba1c is not part of the diagnosis but glycosylated Hb gives an idea of glucose levels over the preceding 2-3 months and the target value is < 7.2 %

    Different Types

    • Type 1 Diabetes - autoimmune destruction of islet cells leads to hyperglycaemia and possibly even DKA. Insulin levels very low/absent
    • Type 2 Diabetes - resistance to the effects of Insulin and pancreas fails to supply increased insulin demand. Insulin detectable.
    • Secondary diabetes - damage to the pancreas or use of drugs or illnesses that raise blood sugar
    • Gestational diabetes - diabetes seen in pregnancy with its own risks to mother and fetus
    • Maturity onset diabetes of the young (MODY) - onset of type 2 DM in those under 25 with a family history. Genetic defects discussed below.

    Effects

    • Poor glycaemic control seems to parallel microvasculature disease and was reduced by 50% in the DCCT trial

    Management

    • Good glycaemic control through diet and exercise and medications and insulin
    • Good BP control is also vitally important

    Impaired fasting glucose and Impaired glucose tolerance are perhaps borderline diabetes. They are not associated with microvascular disease but they increase the risk of macrovascular disease. Some people move from IGT to diabetes and some return to normal glucose tolerance.

    Either of these is diagnostic if repeated on two separate days

    • Random blood glucose > 11.1 mmol/l
    • Fasting blood glucose > 7.0 mmol/l
    • Plasma glucose > 11.1 mmol/l 2 hours after 75 g glucose

    Type 1 Diabetes formerly "Insulin dependent diabetes"

    Introduction

    • Seen in 1 in 1000.

    Aetiology

    • Autoimmune illness associations with other autoimmune conditions
    • Antibodies to Islet cells and GAD are found
    • Genetic predisposition - identical twins 50% concordance
    • Increased in those with HLA DR3/4 DQ8

    Pathology

    • Autoimmune destruction of pancreatic B cells

    Presentation

    • Sudden onset in childhood and young adults. Usually thin with recent weight loss
    • Usually severe symptoms even presenting with Diabetic ketoacidosis
    • Significant weight loss, polyuria and polydipsia, Hyperglycaemia or glycosuria, Vaginal candidiasis, balanitis
    • Later may develop renal disease, Retinopathy and Nephropathy

    Investigations

    • Confirm diagnosis Random blood glucose > 11.1 mmol/l
    • Confirm diagnosis Fasting blood glucose > 7.0 mmol/l

    Management

    • All need Insulin from start

    Type 2 Diabetes formerly "Non insulin dependent diabetes"

    Introduction

    • Seen in 1 in 35. Commonest form of diabetes - many have no symptoms and are undiagnosed and 20% have retinopathy at diagnosis

    Aetiology

    • Insulin resistant - cells do not respond to insulin
    • No antibodies.

    Presentation

    • 80% are obese and middle aged and over. Present with asymptomatic hyperglycaemia. Do not go into DKA
    • They may have had diabetes for several years so may already have vascular complications
    • May have weight loss, polyuria and polydipsia, Hyperglycaemia or glycosuria, Vaginal candidiasis, balanitis
    • Later may develop renal disease, Retinopathy and Nephropathy

    Investigations

    • Confirm diagnosis Random blood glucose > 11.1 mmol/l
    • Confirm diagnosis Fasting blood glucose > 7.0 mmol/l

    Management

    • Manage initial with diet and exercise, smoking cessation and BP management
    • Some may need oral hypoglycaemic agents
    • A few will need to be started on Insulin if these other measures fail
    Type 1 Type 2
    0.25% 5% population
    Autoantibodies found to Islet cells, Insulin and Glutamic acid decarboxylase and tyrosine phosphatase before onset of diabetes. Autoimmune disease- cell mediated destruction 80% are associated with obesity and older age Being seen in younger patients as obesity more prevalent.
    50% twin concordance 95% twin concordance
    Average onset Aged 12 Average onset aged 60

    Childhood and young adults

    Usually thin rather than obese

    Present with hyperglycaemia and Diabetic ketoacidosis

    Weight loss, polyuria and polydipsia, Hyperglycaemia or glycosuria, Vaginal candidiasis, balanitis

    Slow insidious onset in middle aged and older patients who are often obese

    Hyperglycaemic symptoms

    Emergencies : May precipitate

    Hyperosmolar non ketotic coma

    Diabetic ketoacidosis is not seen as even low levels of insulin will suppress ketogenesis

    Diabetic ketoacidosis Renal disease, Retinopathy and Nephropathy seen after 10 years affects 35%

    May present with complications of Renal disease, Retinopathy and neuropathy may be seen before 10 years

    Commoner in Asians

    Absent C-peptide Detectable C-peptide
    Insulin from diagnosis, Diet, weight loss
    • Metformin
    • Oral hypoglycaemic agents
    • Insulin sometimes

    Secondary diabetes

    Introduction

    • Caused by pancreatic damage or release of hormones that act in opposition to insulin and increase blood sugar

    Causes

    • Pregnancy (Gestational diabetes), Haemochromatosis
    • Steroids, Cushing's syndrome, Acromegaly, Phaeochromocytoma
    • Chronic pancreatitis, Pancreatectomy, Pancreatic cancer, Cystic fibrosis

    Associations with raised incidence of diabetes

    • Down's syndrome, Klinefelter's syndrome, Turner's syndrome
    • Huntington's chorea, Myotonic dystrophy, Friedreich's ataxia
    • Prader-willi syndrome, Wolfram syndrome

    Maturity onset diabetes of the young

    Introduction

    • Autosomal dominant inherited so family history possible

    Types

    • MODY 1 : Defect on Chromosome 20 affecting hepatic nuclear factor
    • MODY 2 : Defect in glucokinase gene on chromosome 7
    • MODY 3 : Another defect affecting function of hepatic nuclear factor gene (HNF) on chromosome 12

    Symptoms and signs

    Early Symptoms and presentation

    • Weight loss, polyuria and polydipsia due to Hyperglycaemia
    • Vaginal candidiasis, balanitis
    • Glycosuria on random testing
    • Diabetic ketoacidosis with Type 1 Diabetes
    • HONK with Type 2 Diabetes/MODY

    Long term complications

    • These are seen within 10 years of diagnosis of Type 2 DM and slightly later in those with Type 1 DM
    • Several trials have shown benefits with blood pressure management and improved glycaemic control

    Vascular Disease (Macrovascular)

    • Stroke (Ischaemia and haemorrhagic)
    • Myocardial infarction, Angina
    • Peripheral vascular disease - intermittent claudication.
    • Impotence (multifactorial)

    Nephropathy

    • There is initial increase in GFR (hyperfiltration) followed by Microalbuminuria (30-300 mg/day which is not detectable by dipstick) is first detectable sign.
    • Pathology is Kimmelstiel-Wilson glomerulosclerosis lesion.
    • Worsening proteinuria. Creatine rises late in disease.

    Management

    • Aggressive early treatment with ACEI slows progression and AT2 blockers also used with the aim to keep BP < 130/80 (UKPDS trial) or below.
    • Some will need dialysis and transplantation (usually when creatinine reaches 500 umol/l) and Nephrology involvement should be early to plan renal replacement therapy. Increased risk of renal papillary necrosis with diabetes Timing of End stage renal failure can be determined by plotting 1/creatinine with time

    Diabetic eye disease

    Introduction

    • Affects 30% of diabetics. Rare in Type 1 at presentation but common in those with Type 2 at presentation

    Aetiology

    • Thickening of capillary basement membrane and loss of pericytes
    • Extravasation of blood and protein and capillary occlusion and ischaemia.

    Clinical manifestations of diabetic eye disease

    • Blurred vision from osmotic changes in lens related to hyperglycaemia
    • Background retinopathy- red dots (microaneurysms), blots (intraretinal bleeds), hard exudates (lipid deposits)
    • Maculopathy - Oedema and ischaemia, haemorrhages and hard exudates around the macula can threaten vision so urgent refer to ophthalmologist for Flourescin angiography.
    • Preproliferative retinopathy - Cotton wool spots due to infarcts, venous beading
    • Intraretinal microvascular abnormalities
    • Proliferative retinopathy- new vessels (neovascularisaiton) near or on optic disc (NVD) or elsewhere (NVE)
    • Rubeosis iridis and neovascular glaucoma.
    • Vitreous haemorrhage : Vitrectomy may be needed if haemorrhage or scar or opacity in vitreous
    • Focal lesions can be treated with focal laser therapy and diffuse lesions with macular grid of laser to focusing on areas of microaneurysms
    • Panretinal photocoagulation ablates the entire retina except areas for central vision, the macula and its nerve efferents.
    • Cataract and Glaucoma
    • Cranial nerve lesions - IIIrd (pupil unaffected) , IV and VIth

    Diabetic foot disease

    Introduction

    • Damage is due to a combination of vascular insufficiency and peripheral sensory neuropathy. Vascular problems both at microvascular and macrovascular level
    • Osteomyelitis if wounds extend to bony level - Needs swabs, culture, MRI and IV antibiotics. CRP elevated.
    • Charcot's deformities - abnormal stresses due to motor weakness, loss of sensation and increased blood flow from autonomic neuropathy can lead to microfractures. There is glycosylation of connective tissues which causes stiffness. Bisphosphonates may help to reduce microfractures. Result is damage to mid-foot and forefoot.
    • Foot ulcers - abnormal positions and skin trauma due to motor weakness, loss of sensation
    • Detection of Peripheral sensory neuropathy as patients can be more alert to important injuries which would go unrecognised and unnoticed Good foot care important . Chiropody for nail and foot care. Never walking barefoot. Visual inspection of feet for injury. Early referral and expert

    Management

    • Ischaemia - Poor wound healing, Ulcers. Hospitalisation and rest
    • Doppler studies, Angiography. Vascular reconstruction, amputation.
    • MRI if ? Osteomyelitis. Best to have diabetology with orthopaedic management

    Neurology (often due to microvascular damage to vasa nervorum of the nerves)

    • Stroke/TIA is commoner
    • Distal sensorimotor neuropathy of the legs (sensation affected most) such that patient unaware of damage which can lead to infections due to distal Axonal damage and patch demyelination. Progressive. Always test pinprick, touch sensation, vibration and tendon reflexes (ankle jerk often lost)
    • Mononeuritis multiplex
    • Mononeuropathies e.g. Cranial nerve palsies (IIIrd and VIth), Peripheral nerve lesions . May improve after 3-6 months
    • Acute painful neuropathy - neuralgic pain often in lower limbs at night. Bed clothes tender. Try Amitriptyline initially. Gabapentin and lamotrigine for chronic pain and Carbamazepine and Phenytoin for lancinating pain. TENS may help. May improve after 6-12 months
    • Autonomic neuropathy - postural hypotension, impotence, diarrhoea, nausea, vomiting, gastric stasis. Most often asymptomatic.
    • Diabetic amyotrophy with pain and wasting of quadriceps
    • Neuropathic bladder with painless retention - needs intermittent self catheterisation

    Infections

    • There is impaired polymorph function and hyperglycaemia
    • Candidiasis - oral, vaginal, balanitis
    • Boils, abscesses, cellulitis
    • Increased risk of TB

    Miscellaneous

    • Insulin injections - localised lipohypertrophy
    • Necrobiosis lipoidica - yellow/reddish shiny waxy plaques over the shins
    • Vitiligo - discolouration and loss of pigmentation
    • Granuloma annulare -similar to Necrobiosis and some doubt its association with diabetes
    • Acanthosis nigricans - dark velvety rash seen under axillae and groin associated with insulin resistance
    • Diabetic cheiroarthropathy - scleroderma like thickening and contractures of skin in fingers cannot oppose fingers with "prayer sign"
  • Hypoglycaemia
    • The aim is to get the HbA1c < 7.2% but with minimal risk of hypoglycaemia
    • The tighter diabetic control is the greater the risk of hypoglycaemia.
    • Confusion, odd erratic behaviour, drowsiness, coma and death. Road traffic accidents.
  • Symptoms when Blood glucose < 2.8 mmol/L
    • Hypoglycaemia is an important side effect of diabetic therapies except metformin
    • It causes causes accidents and death and prolonged neuroglycopenia will cause brain damage.
    • Give oral glucose e.g. dextrose tablets, milk, and then biscuits to boost glucose
    • Buccal gel called lucogel can be used when swallowing not possible.
    • IV dextrose can be given usually 20-50 mls of 50% dextrose
    • 1 mg of IM glucagon can also be tried.
  • General Management

    • Lifestyle, Weight loss, Smoking cessation, exercise
    • Blood sugar control aim Hba1C < 7%
    • Team approach - Physician, Dieticians, Community/Inpatient Diabetic Specialist nurses, Ward nurses, Chiropody, Vascular surgeons, Orthopaedic surgeons
    • Diet - low in refined sugar and high in complex carbohydrates e.g. pasta High fibre and low fat. Aim for a BMI 20-25
    • Foot care - never walking barefoot, checking feet routinely in case of injury and chiropody especially if evidence of peripheral neuropathy and decreased pain sensitivity.
    • Blood pressure control is paramount - ACE Inhibitors and AT2 Blockers preferred
    • Target is < 130/80 mmHg or 120/70 mmHg if nephropathy
    • Sick Day Rules - advice must be given to all diabetics on how to manage acute illness
    • Physiological Stress from any cause e.g
    • infection, trauma or other illness leads to hyperglycaemia and in Type 1 DM DKA can quickly develop which can
    • Hyperosmolar non ketotic coma can be seen in those with Type 2 DM
    • Diabetic treatment must be increased and fluid balance maintained Diabetics must be advised to continue their insulin and if unable to eat and drink to get medical help who may need admission for IV fluids and insulin.

    Drugs Management

    • Low dose Aspirin for those at increased cardiovascular risk
    • Statin - Secondary prevention target Total Cholesterol < 4.5 mmol/l and LDL < 2.6 mmol/l and TG < 1.5 mmol/l
    • Metformin is preferred in the obese and sensitises end organs to insulin and reduces liver gluconeogenesis and does not cause hunger in fact it can help with weight reduction. Can cause GI upset and lactic acidosis and not used with Creatinine > 150 umol/l or severe heart or renal or liver disease. Does not cause hypoglycaemia.
    • Sulphonyureas stimulate insulin release and so can cause hypoglycaemia. Short acting agents are safest.Reduce microvascular complications eg retinopathy
    • Repaglinide (Meglitinides) increase insulin release with meals
    • Glitazones : Add on therapy can worsen heart failure.
    • Alpha glucosidase inhibitors can block carbohydrate uptake in gut with resulting GI side effects of bloating, flatulence and diarrhoea
    • Insulin add on therapy if control inadequate consists of differing regimens that try to mimic daily insulin levels and are practical. Aim for target of 4-10 mmol/l.
    • Pancreatic islet cell transplantation is experimental
    • Insulin regimens: insulin is needed in all of those with Type 1 Diabetes. It is used in type 2 when other measures have failed to control the HbA1C.


    Insulin

    Insulin may be used in all types of diabetes to improve control. The aim is to optimise control and to avoid hypoglycaemia. Remember hypoglycaemia can kill especially in those who drive. In a young and motivated patient an Insulin pen is used and patients use a basal dose of long acting with three bolus doses of short acting at meal times throughout the day. Well motivated Patients can take responsibility for fine tuning control around food intake and exercise. This is the basal bolus method. In older patients where injections are more difficult then insulin may be given using 2-3 injections per day with a mixture of longer acting insulins. There are many different regimens but the idea is to have a basal level and small increases in insulin to match meals.

    Examples

    • Regimen A : Young person tight control : Basal-Bolus - a long acting basal dose of Insulin once daily often at night + 3 short acting insulin boluses 20 minutes pre meals
    • Regimen B : Twice daily insulins (2/3rds of daily dose given pre-breakfast and 1/3rd pre evening meal)with each dose containing a short and medium acting insulin e.g. Mixtard 30 with 70% medium and 30% short acting
    • Regimen C: Older patient Type II diabetes - once daily long acting e.g. glargine insulin
    • Regimen D: Continuous subcutaneous infusion (insulin pumps) uncommon in UK. Concerns over pump failure and hypoglycaemia

    Sick day rules

    Sick Day Rules - this advice must be given to all but especially Type 1 diabetics on how to manage acute illness. Basically never stop taking Insulin. Insulin requirements are higher in acute illness. If you cannot tolerate oral intake or severe vomiting or diarrhoea then you need admission for IV fluids. Patients should come to A&E, by ambulance if they need. It will not take long for DKA to occur in an ill patient not receiving insulin. DKA can kills and in others can cause cerebral oedema and brain damage. Prevention is so important.

    Diabetes and surgery

    • Fast and first on morning list
    • Stop oral hypoglycaemic agents and give insulin if hyperglycaemia.
    • Give 500 ml of 5% dextrose and 10 mmol KCl
    • Then commence Insulin in 0.9% NaCl and Insulin at 1 u/hour then titrated to glucose level.

    Sliding scale - alter as required

    Blood Glucose mmol/l Insulin rate in Units/hour
    0-4.0 No insulin
    4.1-7.0 1
    7.1-11.1 2
    11.1-17.0 4
    >17.1 6 and medical review and check Insulin line and venflon

    Diabetic ketoacidosis

    Introduction

    • DKA can cause of death as well as brain damage in Type 1 diabetics
    • Early recognition and treatment if not prevention are key

    Causes

    • New Type 1 diabetic presenting
    • Infection and failure to follow sick day rules Inappropriate changes to insulin therapy Myocardial infarction Non compliance with treatment

    Pathophysiology

    • Lack of insulin causes cells to be starved of glucose who then switch to fatty acid breakdown generating ketones causing a metabolic acidosis
    • High sugar causes massive polyuria and dehydration

    Clinical

    • Profound dehydration, poor skin turgor, polyuria from osmotic effects of glucose, hypotension, hypovolaemia
    • Kussmaul's respiration - hyperventilating to get rid of CO2 to compensate for metabolic acidosis
    • Acetone smell on breath from ketones
    • Signs of sepsis, reduced GCS

    Investigations

    • Blood sugar > 11.1 mmol/L
    • Urinalysis - ketones +++ Glucose +++ possible signs of infection
    • pH - low often < 7.1 ,HCO3 low,PCO2 low, base excess < -10
    • Elevated Urea and Creatinine - severely dehydrated and prerenal failure
    • CXR - look for infection, consolidation
    • CT scan - may show cerebral oedema
    • ECG troponin if any suggestion of MI which can rarely precipitate DKA

    Management

    • Fluid replacement - 1 L N Saline in 30 minutes, 1 L over 1 hour then 1 L every 2 hours until volume replaced
    • Consider HDU and arterial and Central venous monitoring, Urinary catheter, NG tube if vomiting.
    • Insulin give 50 units in 50 ml of N-saline at 8-10 mls/hour. Some give initial bolus of 8 u IM (not subcutaneous)
    • Replace Potassium which moves into cells with glucose when Insulin given usually 20 KCL per litre of saline. Monitor levels 4 hourly. Once Blood sugar is 15 mmol/l then switch to 5% dextrose. Lower glucose by 5 mmol/hr so that the speed of osmotic shifts is reduced.
    • If GCS falls then consider Cerebral oedema and CT scan. Prognosis poor. Dexamethasone and mannitol can be given.
    • Some give IV bicarbonate if pH < 7.0 but unproven indication
    • IV antibiotics to treat infection
    • Most cases can be prevented by good education through diabetic team

    Hyperosmolar Non ketotic hyperglycaemia

    Introduction

    • Seen in older Type 2 Diabetics with a 50% mortality

    Causes

    • New presentation, Infection, Stress e.g. Myocardial infarction
    • Non compliance with treatment

    Pathophysiology

    • In type 2 diabetes there is enough Insulin present to prevent ketogenesis
    • The problem then becomes one of massive hyperglycaemia and osmotic diuresis

    Clinical

    • Profound dehydration, poor skin turgor
    • Polyuria from osmotic effects of glucose, hypotension, hypovolaemia
    • Signs of sepsis, reduced GCS

    Investigations

    • Blood sugar > 11.1 mmol/L usually > 30 and as high as 60 or 70 mmol/l
    • Urinalysis - no or very slight trace of ketones Glucose ++++ possible signs of infection
    • pH - normal and HCO3 normal.
    • Elevated Urea and Creatinine - severely dehydrated and prerenal failure
    • Hypernatraemia > 160 mmol/l
    • CXR - look for infection, consolidation
    • ECG, troponin if any suggestion of MI which can precipitate HONK

    Management

    • Fluid replacement - 1 L N Saline in 60 minutes, 1 L over 2 hours then 1 L every 4 hours until volume replaced
    • Consider HDU and arterial and Central venous monitoring, Urinary catheter, NG tube if vomiting.
    • Insulin give 50 units in 50 ml of N-saline at 3-5 mls/hour and some give initial bolus of 8 u IM (not subcutaneous)
    • Replace Potassium which moves into cells with glucose when Insulin given
    • Give 20 KCL per litre of saline and Monitor levels 4 hourly.
    • Once Blood sugar is 15 mmol/l then switch to 5% dextrose
    • Lower glucose by 5 mmol/hr so that the speed of osmotic shifts is reduced
    • Low molecular weight heparin prophylactic VTE dose IV antibiotics to treat infection
    • Most causes can be prevented by good education through diabetic team ?

    Hypoglycaemia

    Causes

    • Diabetic therapy with Insulin, Sulphonylureas
    • Insulinomas, Addison's disease, Quinine, Excess alcohol
    • von Gierke's disease (A Glycogen storage disease)
    • Liver failure, Dumping after gastric surgery - excessive insulin response mismatched to food
    • Tumours - sarcomas, hepatoma release Insulin like growth factor -1

    Clinical

    • Hypoglycaemia - feeling of hunger, panic, sweating, palpitations, weakness
    • Abnormal behaviour, proceeds to coma and death.
    • Fasting hypoglycaemia - need to keep eating to maintain blood sugar.

    Investigations

    • Overnight fasting glucose and Insulin levels with any hypoglycaemia and C-peptide
    • 72 hour fast - measure Insulin, Glucose and C-peptide
    • Insulin > 3 microunits/ml and Glucose < 3.0 mmol/l suggests inappropriate Insulin level
    • A matching C-peptide rise suggests endogenous insulin
    • Radiolabelled somatosatin and abdominal CT/MRI to localise tumours

    Management

    • Tumours are resected if possible
    • Diazoxide reduces insulin release
    • Octerotide and similar somatosatin analogues can limit symptoms

    Causes of hyperprolactinaemia

    • Prolactinoma usually give highest levels > 3000 mU/L
    • Damage or pressure on pituitary stalk ? pituitary tumours, craniopharyngiomas
    • Pregnancy and breast feeding
    • Nipple stimulation or chest wall injury
    • Dopamine blockers - Metoclopramide, phenothiazines (many psychotropic drugs block dopamine)
    • Cirrhosis and liver failure
    • Hypothyroidism

    Complications of Diabetes

    Microangiopathy - related to duration and degree of hyperglycaemia

    • Diabetic retinopathy
    • Diabetic nephropathy
    • Autonomic neuropathy

    Macroangiopathy

    • Ischaemic heart disease
    • Strokes
    • Peripheral vascular disease

    Biological functions using 7TM receptors

    • Senses - Smell, Taste, Vision
    • Neurotransmission
    • Hormone secretion
    • Chemotaxis
    • Exocytosis
    • Embryogenesis
    • Cell growth
    • Cell differentiation
    • Carcinogenesis
    • Viral infections

    Diabetic reviews

    Measure

    • Blood pressure
    • HbA1C
    • Weight
    • Lipids
    • Visual acuity
    • Fundoscopy/Retinal photo
    • Urine for proteinuria
    • Pulses in feet and peripheral vascular disease
    • State of feet - ulcers, check sensation

    Discuss

    • Monitoring and treatment
    • Side effects of medications
    • Frequency of hypoglycaemia
    • Insulin administration issues
    • Sexual advice/problems
    • Complications
    • Management of hypertension

    Referrals

    • Chiropody
    • Nephrology
    • Ophthalmology
    • Vascular surgeons
    • Orthopaedics ? foot ulcers
    • Tissue viability
    • Community diabetic/district nurse for ulcer management

    Type 2 Diabetes Management summary

    • Weight loss
    • Antihypertensives for BP reduction
    • HbA1C < 7%
    • Lipids - Statin
    • Aspirin 75 mg od
    • Smoking cessation
    • If obese start Metformin first and increase dose over several months
    • If non obese start with Sulphonylurea e.g. Gliclazide
    • If HbA1C remains elevated combine Metformin + Sulphonlyurea
    • Increase to maximal doses if needed
    • Consider adding Glitazone
    • HbA1C remains > 7% then consider adding Insulin

    Nephropathy in Diabetes

    • 20% of Type 2 Diabetics have nephropathy on presentation
    • Seen eventually in all types of diabetes
    • Commonest cause of End stage renal disease in UK
    • Microalbuminuria 30-300 mg/day : (Dipstick negative - needs a special test) this is risk factor for nephropathy and macrovascular complications
    • Many use albumin/creatinine ratio (ACR) microalbuminuria is defined as ACR > 3.5 mg/mmol (female) or ?2.5 mg/mmol(male),[
    • Macroalbuminuria > 300 mg/day: Dipstick positive. suggests established nephropathy
    • Nephrotic > 3g/day

    Prevention

    • Lower Blood pressure
    • Lower Blood pressure
    • Lower Blood pressure
    • Use ACEI or ARB
    • Avoid metformin if Creatinine > 150 umol/L
    • Renal replacement when Creatinine around 500 umol/l

    Neuropathy in Diabetes: microvascular complication seen in all types of diabetes due to damage to vasa nervorum

    • Distal Symmetrical polyneuropathy - painful, stabbing nand burning pain with reduced ankle jerks
    • Assess using inability to feel a 10 g monofilament
    • Mononeuropathy e.g. single peripheral nerve or cranial nerve (III,IV and VI) with diplopia
    • Mononeuritis multiplex - same as before only multiple
    • Proximal motor neuropathy often at thigh (amyotrophy)
    • Acute painful neuropathy
    • Autonomic neuropathy - BP drop > 30 mmHg on standing, loss of sinus arrhythmia
  • Causes of secondary Diabetes

    • Pregnancy (Gestational diabetes)
    • Haemochromatosis
    • Steroids
    • Cushing's syndrome
    • Acromegaly
    • Phaeochromocytoma
    • Chronic pancreatitis
    • Pancreatectomy
    • Pancreatic cancer
    • Cystic fibrosis
    • Partial lipodystrophy
    • Polycystic ovaries

    Complications of Diabetes

  • Microangiopathy - related to duration and degree of hyperglycaemia
    • Diabetic retinopathy
    • Diabetic nephropathy
    • Autonomic neuropathy
  • Macroangiopathy
    • Ischaemic heart disease
    • Strokes
    • Peripheral vascular disease
  • Diabetic reviews

  • Measure
    • Blood pressure
    • HbA1C
    • Weight
    • Lipids
    • Visual acuity
    • Fundoscopy/Retinal photo
    • Urine for proteinuria
    • Pulses in feet and peripheral vascular disease
    • State of feet - ulcers, check sensation
  • Discuss
    • Monitoring and treatment
    • Side effects of medications
    • Frequency of hypoglycaemia
    • Insulin administration issues
    • Sexual advice/problems
    • Complications

      Management of hypertension

  • Referrals
    • Chiropody
    • Nephrology
    • Ophthalmology
    • Vascular surgeons
    • Orthopaedics ? foot ulcers
    • Tissue viability
    • Community diabetic/district nurse for ulcer management
  • Type 2 Diabetes Management summary

    • Weight loss
    • Antihypertensives for BP reduction
    • HbA1C < 7%
    • Lipids - Statin
    • Aspirin 75 mg od
    • Smoking cessation
    • If obese start Metformin first and increase dose over several months
    • If non obese start with Sulphonylurea e.g. Gliclazide
    • If HbA1C remains elevated combine Metformin + Sulphonlyurea
    • Increase to maximal doses if needed
    • Consider adding Glitazone
    • HbA1C remains > 7% then consider adding Insulin

    Nephropathy in Diabetes

    • 20% of Type 2 Diabetics have nephropathy on presentation
    • Seen eventually in all types of diabetes
    • Commonest cause of End stage renal disease in UK
      • Microalbuminuria 30-300 mg/day : (Dipstick negative - needs a special test) this is risk factor for nephropathy and macrovascular complications
      • Many use albumin/creatinine ratio (ACR) microalbuminuria is defined as ACR =3.5 mg/mmol (female) or =2.5 mg/mmol(male),[
      • Macroalbuminuria > 300 mg/day: Dipstick positive. suggests established nephropathy
      • Nephrotic > 3g/day
    • Prevention
      • Lower Blood pressure
      • Lower Blood pressure
      • Lower Blood pressure
      • Use ACEI or ARB
      • Avoid metformin if Creatinine > 150 umol/L
      • Renal replacement when Creatinine around 500 umol/l