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2A Medicine Sam > Diabetes > Flashcards

Diabetes Flashcards

1
Q

Define Diabetes Mellitus

A

Syndrome of chronic hyperglycaemia due to relative insulin deficiency, resistance or both

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2
Q

What types of complications are associated with diabetes?

A

Hyperglycaemia results in serious microvascular (retinopathy, nephropathy, neuropathy) or macrovascular (strokes, renovascular disease, limb ischaemia and heart disease) problems

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3
Q

What are normal levels of blood glucose?

A

Blood glucose levels should be between 3.5-8.0mmol/L under all conditions

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4
Q

What is the main organ involved in glucose homeostasis and what is its role?

A

The liver is the principal organ of glucose homeostasis:

  • Stores & absorbs glucose as glycogen - in post-absorptive state
  • Performs gluconeogenesis from fat, protein and glycogen
  • If blood glucose is HIGH then the liver will make glycogen (convert
    glucose to glycogen) in a process called glycogenesis - in the long term
    the liver will make triglycerides (lipogenesis)
  • If blood glucose is LOW then the liver will split glycogen (convert
    glycogen to glucose) in process called glycogenolysis - in the longer
    term the liver will make glucose (gluconeogenesis) from amino acids/
    lactate
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5
Q

How much glucose is produced daily?

A

200g is produced and utilised each day with more than 90% derived from liver glycogen and hepatic gluconeogenesis and the remainder from renal gluconeogenesis

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6
Q

Where is glucose utilised?

A
  • The brain is the MAJOR CONSUMER of glucose and its function depends on
    an uninterrupted supply of this substrate
  • Tissues such as muscle and fat have insulin-responsive glucose
    transporters and absorb glucose in response to postprandial (post-meal)
    peaks in glucose and insulin
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7
Q

Why is the brain so reliant on just glucose and no other energy forms?

A
  • fatty acids (which can be turned into ketones and then acetyl-CoA for Krebs) cannot cross the blood brain barrier
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8
Q

How is glucose utilised in muscles?

A

Either stored as glycogen or metabolised to lactate or CO2 and H2O

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9
Q

How is glucose utilised in adipose tissue?

A

Fat uses glucose as a substrate for triglyceride synthesis. Lipolysis of triglyceride releases FA and glycerol which is used in hepatic gluconeogenesis

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10
Q

What are some of the roles of insulin?

A
  • Suppresses hepatic glucose output - decreases glycogenolysis &
    gluconeogenesis
  • Increases glucose uptake into insulin-sensitive tissues:
    • Muscle - glycogen & protein synthesis
    • Fat - fatty acid synthesis
    • Suppresses:
      • Lipolysis
      • Breakdown of muscles (decreased ketogenesis)
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11
Q

What is meant by biphasic insulin release?

A

B-cells can sense the rising glucose levels and aim to metabolise it
by releasing insulin - glucose levels are the major controlling factor
in insulin release!

  • First phase response is the RAPID RELEASE of stored insulin
  • If glucose levels remain high then the second phase is initiated. This
    takes longer than the first phase due to the fact that more insulin
    must be synthesised.
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12
Q

What are some of the roles of glucagon?

A
  • Increases hepatic glucose output - increases glycogenolysis & gluconeogenesis
  • Reduces peripheral glucose uptake
  • Stimulates peripheral release of gluconeogenic precursors e.g. glycerol & amino acids
  • Stimulates:
    • Muscle glycogenolysis & breakdown (increased ketogenesis)
    • Lipolysis
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13
Q

What are some other counter-regulatory hormones that are involved in diabetes?

A

Adrenaline, Cortisol, and GH which increase glucose production in the liver and reduce the utilisation in fat and muscle

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14
Q

How is insulin formed and explain C peptides

A
  • Insulin is coded for on CHROMOSOME 11 produced in the BETA CELLS of
    the ISLETS of LANGERHANS of the PANCREAS:
    • Proinsulin is the precursor of insulin
    • It contains the Alpha & Beta chains of insulin which are joined together
      by a C PEPTIDE
    • When insulin is being produced, the proinsulin is cleaved from its C
      peptide and is then used to make insulin which is then packaged into
      insulin secretory granules
    • Thus when there is insulin release there will also be a high level of C
      peptide in the blood from the cleavage of the proinsulin from it
    • Synthetic insulin DOES NOT have C peptide - thus the presence of C
      peptide in the blood determines whether release is natural (then C peptide
      will be present) or synthetic (then C peptide will not be present)
    • After secretion, insulin enters the portal circulation and is carried to the
      liver, its prime target organ
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15
Q

What are the main roles of insulin in the fed and fasting state?

A
  • In the fasting state - its main action is to regulate glucose release by the liver
  • In the post-prandial state - its main action is to promote glucose uptake by fat and muscle
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16
Q

How does glucose get into cells?

A

A family of specialised glucose-transporter (GLUT) proteins carry glucose
through the membrane and into cells.

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17
Q

Explain GLUT-1 transporters

A
  • Enables basal NON-INSULIN-STIMULATED glucose uptake into many cells
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18
Q

Explain GLUT-2 transporters

A

Found in BETA-CELLS of the pancreas
Transports glucose into the beta-cell - enables these cells to SENSE GLUCOSE LEVELS
It is a low-affinity transporter, that is, it only allows glucose in when there is a high concentration of glucose i.e. when glucose levels are high and thus WANT insulin release
In this way, via GLUT2, beta-cells are able to detect high glucose levels and thus release INSULIN in response
Also found in the renal tubules and hepatocytes

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19
Q

Explain GLUT-3 transporters

A

Enables NON-INSULIN-MEDIATED glucose uptake into BRAIN, NEURONS & PLACENTA

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20
Q

Explain GLUT-4 transporters

A

Mediates much of the PERIPHERAL ACTION of INSULIN
It is the channel through which glucose is taken up into MUSCLE and ADIPOSE TISSUE cells following stimulation of the insulin receptor by INSULIN binding to it

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21
Q

What is the role of the insulin receptor in glucose transport?

A
  • This is a glycoprotein, coded for on the short arm of chromosome 19, which
    straddles the cell membranes of many cells
  • When insulin binds to the receptor it results in the activation of tyrosine
    kinase and initiation of a cascade response - one consequence of which is
    the migration of the GLUT-4 transporter to the cell surface and increased
    transport of glucose into the cell
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22
Q

What conditions might diabetes be secondary to?

A
  • Pancreatic pathology e.g. total pancreatectomy, chronic pancreatitis, haemochromatosis
  • Endocrine disease e.g. Acromegaly and Cushing’s disease
  • Drug induced commonly by thiazide diuretics and corticosteroids
  • Maturity onset diabetes of youth (MODY):
    • Autosomal dominant form of type 2 diabetes - single gene defect altering beta cell function
    • Tends to present <25 yrs with a positive family history
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23
Q

Brief description of Type 1 DM

A

The type 1 diabetic is young, has insulin deficiency with no resistance and immunogenic markers

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24
Q

Brief description of Type 2 DM

A

Common in all populations enjoying an affluent lifestyle and is also increasing in frequency - particularly in adolescents - resistance to insulin

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25
Q

Where is T1DM most common?

A

Most prevalent in Northern European countries, particularly Finland and the incidence is increasing in most populations

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26
Q

What is T1DM?

A

Type 1 diabetes mellitus (T1DM) is a metabolic disorder characterised by hyperglycaemia due to an absolute deficiency of insulin. This is caused by an autoimmune destruction of beta cells of the pancreas

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27
Q

Epidemiology of T1DM

A

Typically manifests in childhood with peak incidence around puberty, usually below 30 y/o, patient is usually lean, increased in Northern Europe especially Finland and incidence is increasing in all populations particularly in children

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28
Q

Aetiology of T1DM

A
  • AUTOIMMUNE - Auto-antibodies forming against insulin and islet beta cells - INSULITIS
  • Idiopathic - Uncommon form that is characterised by the absence of antibodies
  • Genetic susceptibility - HLA-DR3-DQ2 or HLA-DR4-DQ8
  • Association found with enterovirus
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29
Q

Risk Factors for T1DM

A

Northern European, Family History (HLA-DR3-DQ2 or HLA-DR4-DQ8). Its associated with other autoimmune diseases e.g. Autoimmune thyroid, Coeliac, Addisons, Pernicious anaemia. Environmental factors e.g. Diet, Enterovirus, Vit D deficiency, Cleaner environment in childhood

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30
Q

Pathophysiology of T1DM

A

Chronic insulin deficiency means the continued breakdown of liver glycogen (which makes glucose and ketones) which leads to glycosuria and ketonuria. Impaired glucose clearance in skeletal muscle and fat. When blood glucose is above 10mmol/L the body can’t absorb any more glucose so you get polyuria and polydipsia (the body attempt to clear glucose). Patients require insulin as they are prone to DKA. Eventual complete B cell destruction results in the absence of serum C-peptide

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31
Q

Explain DKA

A

reduced glucose supply drives the formation of ketone bodies as a source of energy. Ketones are strong acids and lower the pH of the blood which impairs Hb ability to bind to O2, AKI and other complications - EMERGENCY

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32
Q

Signs of T1DM

A

BMI lower than 25 kg/m2, Glycosuria, Ketonuria, Failure to thrive in children, Glove and stocking sensory loss (peripheral neuropathy), Reduced visual acuity, Diabetic retinopathy, Diabetic foot disease (reduced peripheral pulse, calluses, ulceration and Charcot foot (weak foot bones prone to breakages)

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33
Q

Symptoms of T1DM

A

Polydipsia, Polyuria, Nocturia, Weight loss, Lethargy, Recurrent Infections, Evidence of complications (blurred vision or parasthesia)

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34
Q

1st line investigations for T1DM

A

Primary:
Random blood glucose taken at any time of day with 11mmol or more being diagnostic.
Fasting blood glucose as well with 7 or above being diagnostic - for symptomatic patients, one test is diagnostic but asymptomatic requires two abnormal results.

Borderline:
Oral glucose tolerance test - above 11mmol two hours after a 75g oral glucose load is diagnostic, between 7.8-11 is pre-diabetes.
HbA1C: measures the amount of glycated Hb. More than 48 mmol/mol suggests hyperglycaemia over preceding three months

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35
Q

What other investigations could be considered for T1DM

A

C-peptide - NICE says only measure in atypical patients e.g. age over 50 or high BMI

Autoantibodies - only if atypical. If positive it suggests autoimmune beta cell destruction. Autoantibodies may be found against the following: GAD, Insulin, Islet cells, Islet antigens and Zinc transporters

VBG: if concerned about DKA e.g. systemically unwell or vomiting, this can reveal metabolic acidosis

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36
Q

Diagnostic criteria for T1DM according to NICE

A

NICE guidelines stipulate a diagnosis should be made taking into accountclinical featuresand evidence of hyperglycemia, e.g.random glucose ≥ 11.1 mmol/L**. Additionally, NICE state that type 1 diabetic will usually have one of the following:

  • Ketosis
  • Rapid weight loss
  • Age of onset < 50 years
  • BMI < 25 kg/m2
  • Personal and/or family history of autoimmune disease
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37
Q

Differential diagnosis for T1DM

A
  • Monogenic diabetes: maturity onset diabetes of the young (MODY) - should be suspected in cases of diabetes in non-obese, young patients (adolescence or young adult) with family history of diabetes in two or more successive generations.
    • C peptide will be present, autoantibodies will be absent
  • Neonatal diabetes: diabetes diagnosed under 6 months of age.
    • Genetic testing with majority of mutations in the genes encoding the adenosine triphosphate-sensitive potassium channel and the insulin gene.
  • Latent autoimmune diabetes in adults (LADA): Typical age of onset of diabetes is over 30 years old. Patients are usually non-obese and respond initially to lifestyle modifications and oral agents. Production of insulin gradually decreases (between 6 months and 5 years), such that treatment with insulin is required.
    • Low to normal initial C-peptide level.
    • Can be positive for at least 1 of the 4 antibodies commonly found in type 1 diabetic patients.
  • Type 2 diabetes: Older age and slow onset, obesity, a strong family history, absence of ketoacidosis, and initial response to oral anti-hyperglycaemic drugs are typical of type 2 diabetes.
    • C peptide present, autoantibodies absent
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38
Q

1st line management for T1DM

A

Lifestyle:

  • Educate patient on disease and risk
  • Maintain lean weight, stop smoking and take care of feet (to reduce gangrene
    risk)
  • Patients should be educated regarding carbohydrate counting. This is a technique which allows the insulin dose to be matched to intake
  • NICE recommend that dietary advice should be tailored to the patient’s personal needs and culture

Insulin therapy (refer to other notes tab for types of insulin):

Basal-bolus regimen: the first-line regimen of choice, whereby a long-acting insulin is given regularly (basal) and supplemented with a rapid-acting insulin before each meal (bolus)

  • Basal:Levemir (Detemir) is the first line basal insulin given twice-daily. Lantus (Glargine) once-daily is an alternative
  • Bolus:Humalog (Lispro) or Novorapid (Aspart) are examples
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39
Q

Adjunctive therapies for T1DM

A
  • Mixed insulin regimen:a mixture of a short or rapid-actingandintermediate-acting insulin. It is given twice daily and used in those who cannot tolerate multiple injections as part of a basal-bolus regimen
  • Continuous insulin infusion:indicated if the patient has disabling hypoglycaemia or persistently hyperglycaemic (HbA1c>69mmol/mol) on multiple injection insulin therapy
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40
Q

Complications of insulin therapy

A
  • Hypoglycaemia - most common (also caused by SULFONYLUREA - antidiabetic drug)
  • Injection site - lipohypertrophy
  • Insulin resistance - mild and associated with obesity
  • Weight gain - insulin makes people feel hungry
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41
Q

Regular monitoring for T1DM

A
  • HbA1c:measure every 3-6 months with a target of≤48 mmol/mol
    • NICE advises that the target can be tailored based on personal daily activities, aspirations, the likelihood of complications, comorbidities, occupation and history of hypoglycaemia
  • Self-monitoring:should be tested at least4 times a day, including before meals and before bed; more frequent monitoring may be required during periods of illness. Targets are as follows:
    • On waking:5–7 mmol/L
    • Other times of the day including before meals: 4–7 mmol/L
    • Bedtime:this target should be personalised and depends on the timing of the last meal
42
Q

Annual monitoring for T1DM

A

On an annual basis (more frequently if required), patients should receive a diabetic review. This includes assessment of injection site problems, retinopathy, nephropathy, diabetic foot problems (e.g. neuropathic problems), cardiovascular risk factors and thyroid disease.

  • Retinopathy:annual screening
  • Nephropathy:renal function (eGFR) and albumin:creatinine ratio (ACR)
  • Diabetic foot problems:full examination including footwear, monofilament assessment of neuropathy, vascular assessment +/- dopplers.
  • Cardiovascular risk factors:primary/secondary prevention strategy with optimisation of blood pressure, lipids, weight, smoking and others
  • Thyroid disease:screening blood test
43
Q

Complications of T1DM

A
  • DKA
  • Hypoglycaemia - complication of insulin treatment, especially insulin doses without a meal.
  • Diabetic kidney disease - involves glomerular mesangial sclerosis leading to proteinuria and progressive decline in glomerular filtration.
  • Retinopathy
  • Peripheral or autonomic neuropathy
  • Cardiovascular disease - increased risk of atherosclerosis, hyaline arteriolosclerosis etc
  • Summary of micro- and macrovascular complications
44
Q

Prognosis for T1DM

A

Overall, cardiovascular disease is the leading cause of death in these patients. With good control of blood glucose levels, the risk of complications can be reduced. Life-expectancy is reduced by 13 years but this is dependent on glucose control.

45
Q

Explain the three types of insulin

A

Short acting soluble insulins -

  • Start working within 30-60 minutes and last for 4-6 hours
  • Given 15-30 minutes before meals in patients on multiple dose regimens and by continuous IV infusion in labour, during medical emergencies, at the time of surgery and in patients using insulin pumps

Short acting insulin analogues -

  • Human insulin analogues (insulin aspart, insulin lispro, insulin glulisine) have a faster onset and a shorter duration than the soluble insulin but overall DO NOT IMPROVE DIABETIC CONTROL
  • Have a reduced carry-over effect compared to soluble insulin and are used with the evening meal in patients who are prone to nocturnal hypoglycaemia

Longer acting insulin -

  • Insulin premixed with retarding agents (either protamine or zinc) precipitate crystals
  • Can be intermediate (12-24 hrs) or long-acting (more than 24hrs)
46
Q

Define T2DM

A

type 2 diabetes mellitus is characterised by insulin resistance and less severe insulin deficiency

47
Q

Epidemiology of T2DM

A
  • Common in all populations enjoying an affluent lifestyle - has increased in incidence due to the ageing population and increasing obesity in the Western world
  • Older - usually >30 yrs of age - but teenagers are starting to get it
  • Often overweight around the abdomen
  • More prevalent in South Asian, African and Caribbean ancestry
  • Middle eastern and Hispanic Americans also more at risk
  • M>F
48
Q

Aetiology of T2DM

A
  • Decreased insulin secretion +/- increased insulin resistance
  • Associated with obesity, lack of exercise, calorie and alcohol excess
  • No immune disturbance
  • No HLA disturbance but there is a stronger genetic link
  • Polygenic disorder
49
Q

Risk factors for T2DM

A
  • Family history - genetics. 75% risk if both parents have T2DM
  • Increasing age
  • Obesity and poor exercise - can trigger DMT2 in genetically susceptible
    individuals
  • Ethnicity - Middle Eastern, South-east Asian and Western pacific
  • Obesity
  • Hypertension
  • Dyslipidemia - especially with low high-density lipoprotein (HDL) and/or high triglycerides
  • Gestational Diabetes
  • Polycystic ovary syndrome
  • Drugs: corticosteroids, thiazide diuretics
50
Q

Pathophysiology of T2DM

A
  • Type 2 diabetes is associated with central obesity, hypertension, hypertriglyceridaemia, decreased high-density lipoprotein (HDL) cholesterol, disturbed homeostatic variables and modest increases in a number of pro-inflammatory markers
  • Insulin binds normally to its receptor on the surface of cells in DMT2 just like in healthy people - thus insulin resistance develops post-receptor i.e. not caused by a problem with insulin binding to receptor
  • Circulating insulin levels are typically higher than in non-diabetics following diagnosis and tend to rise further, only to decline again after months or years due to eventual secretory failure - phenomenon is known as the Starling curve of the pancreas.
    • Initial compensatory mechanism is hyperplasia and hypertrophy of beta cells to secrete more insulin. This is then exhausted and leads to hypoplasia and hypotrophy.
  • At the time of diagnosis the Beta cell mass is reduced to about 50% of normal
  • Almost all patient show amyloid deposition in the islets of the pancreas at autopsy derived from a peptide known as amyloid or islet amyloid polypeptide which is co-secreted with insulin by beta cells. When beta cells hypertrophy and undergo hyperplasia to release more insulin as a compensatory mechanism, they also secrete more amylin.
  • Abnormalities of insulin secretion manifest early in the course of DMT2
  • An early sign is loss of the first phase of the normal biphasic response to insulin
  • Circulating insulin levels are higher than in healthy controls - but are still inadequate to restore glucose homeostasis
  • Hyperglycaemia and lipid excess are toxic to beta cells (glucotoxicity) and this is thought to result in further beta cell loss and further deterioration or glucose homeostasis
  • Don’t tend to develop diabetic ketoacidosis as even a small amount of insulin can halt the breakdown of fat & muscle into ketones
51
Q

Signs of T2DM

A
  • Acanthosis nigricans - characterised by blackish pigmentation at the nape of the neck and in the axillae
  • Glove and stocking sensory loss
  • Reduced visual acuity
  • Diabetic retinopathy
  • Diabetic foot disease
    • Reduced peripheral pulses
    • Calluses
    • Ulceration
    • Charcot joint
52
Q

Symptoms of T2DM

A
  • Weight loss
  • Polyuria
  • Polydypsia
  • Lethargy
  • Recurrent infections
  • Evidence of complications e.g. blurred vision or paresthesia
53
Q

1st line investigations for T2DM

A

Same as for T1DM

54
Q

Other investigations for T2DM

A
  • Fasting lipids:patients with diabetes often have dyslipidaemia
  • U&Es:reduced eGFR may be seen due to diabetic nephropathy
  • Urine albumin:creatinine ratio:diabetic nephropathy leads to protein leaking through the glomerular basement membrane
55
Q

Diagnostic Criteria for T2DM

A

Diagnosing T2DMrequires an elevated plasma glucose sample and/or HbA1c on one occasion if symptomatic or two occasions if asymptomatic.

The WHO diagnostic criteria also contain apre-diabetic phase which comprisesimpaired fasting glucose (IFG)andimpaired glucose tolerance (IGT). Both of these confer an increased risk of developing diabetes mellitus.

  • Patients with IFG: raised fasting glucose andnormalOGTT
  • Patients with IGT: raised OGTT, and may or may not have a raised fasting glucose
56
Q

Differential Diagnosis for T2DM

A
  • Pre-diabetes
  • T1DM
  • LADA - can be mistaken due to late onset
  • Monogenic diabetes - MODY
  • Ketosis-prone diabetes - idiopathic diabetes. Unprovoked ketosis or ketoacidosis. Some patients may have type 2 presentation.
  • Gestational diabetes
57
Q

1st line management for T2DM

A

Target HbA1c with lifestyle management is48 mmol/mol(6.5%). Metformin should be commenced if HbA1crises above this.

  • High fibre, low glycaemic index sources of carbohydrates
  • Include low-fat dairy products and oily fish
  • Control intake of trans and saturated fats, and limit sucrose-containing foods
  • Discourage the use of foods marketed specifically for people with diabetes
  • Aim for an initial weight loss of 5-10%

Anti-diabetic medications:

There are a number of choices with metformin used first line.

  • Metformin
    • First-line agent and target HbA1c with metformin is48 mmol/mol(6.5%). Iflevel rises above this, the dose should be increased
    • Dual therapy (with a second anti-diabetic drug) should be commenced if HbA1Crises above58 mmol/mol(7.5%) despite maximal dose (1g BD)
    • If not tolerated, monotherapy with an alternative anti-diabetic should be used and then further anti-diabetic agents added in as the HbA1c rises above 58mmol/mol (7.5%)
58
Q

Adjunctive therapy for T2DM

A

Triple therapy and insulin:

  • If the HbA1C is >58 mmol/mol(7.5%)despite dual therapy, either triple therapy can be commenced,orinsulin treatment can be considered
  • If triple therapy fails, metformin with a sulfonylurea and GLP-1 mimetic may be used if any of the following apply:
    • BMI ≥ 35 kg/m2andspecific psychological or other medical problems associated with obesity
    • BMI < 35 kg/m2for whom insulin therapy would have significant occupational implications
    • BMI < 35 kg/m2andweight loss would benefit other significant obesity‑related comorbidities
  • NICE suggest commencing anintermediate-acting insulin with metformin, with the need for all other anti-diabetic agents to be reviewed. A long-acting insulin may be used as an alternative.

Controlling other factors:
- Ramipril for BP control
- Statins for hyperlipidaemia control
- Orlistat - to promote weight loss in pt’s who are obese

59
Q

Summarise T2DM treatment

A

Metformin initially.

If this fails to reduce the HBA1C to below 58 then add on a dual therapy which could either be a DPP-4 inhibitor (e.g. sitagliptin) OR pioglitazone (a thiazolidinedione that reduces peripheral insulin resistance) OR sulfonylurea (e.g. Gliclazide) OR an SGLT2 inhibitor e.g. dapagliflozin.

If they’re still above 58 then consider triple therapy or insulin based therapy

Adjunctive: Lifestyle changes, Ramipril for BP, Diet and exercise, weight loss medication

60
Q

Complications of T2DM treatment

A

Hypoglycaemia, Injection side lipohypertrophy, side effects of metformin e.g. anorexia, diarrhoea, nausea, abdominal pain

61
Q

How does metformin work?

A
  • Reduces rate of gluconeogenesis in the liver
  • Increases cells sensitivity to insulin
  • Helps with weight issues
  • Reduces CVS risk in diabetes
62
Q

How do Sulfonylureas work?

A
  • Promotes insulin secretion
  • These are ineffective in patients without a functional beta-cell mass
  • Avoided in pregnancy
  • Effect wears off as beta-cell mass declines
63
Q

Monitoring for T2DM?

A

HbA1c: measure every 3-6 months until the HbA1c is stable on unchanging therapy, after which it can be measured 6 monthly. The targets are dependent on the treatment and summarised below, however, NICE states that these can be tailored on a case by case basis

  • Self-monitoring: not routine and only indicated in the following circumstances:
    • On insulin therapy
    • Evidence of hypoglycaemic episodes
    • At risk of hypoglycaemia whilst operating machinery or driving
    • Pregnant or planning pregnancy
64
Q

Explain the complications of T2DM and split them into Macrovascular, Microvascular, Acute and Other

A

Macrovascular:
- IHD, Heart failure, Peripheral vascular disease, Stroke

Microvascular:
- Neuropathy: Mononeuropathy, Polyneuropathy (glove and stocking), Amyotrophy (painful proximal lower limb muscle wasting), Autonomic neuropathy (gastroparesis, ED, postural hypotension)
- Renal: Diabetic nephropathy and CKD
- Retinopathy: Non proliferative vs proliferative, Maculopathy

Other:
- Carpal tunnel syndrome, Open-angle glaucoma, Cataracts

Acute:
- Hyperosmolar hyperglycaemic state

65
Q

Prognosis for T2DM

A

Survival depends on glucose control and management of cardiovascular risk factors. Adults with type 2 diabetes are twice as likely to die of stroke or myocardial infarction compared to those without diabetes

66
Q

Define Diabetic Ketoacidosis (DKA)

A

Diabetic ketoacidosis (DKA) is an acute metabolic complication of diabetes that is potentially fatal and requires prompt medical attention for successful treatment. It is characterised by absolute insulin deficiency and is the most common acute hyperglycaemic complication of type 1 diabetes mellitus.

67
Q

Epidemiology of DKA

A
  • It is estimated that there are more than 20,000 cases per year in the UK
  • It is suspected that 4% of patients with T1DM develop DKA each year and up to 14% of diabetes related hospital admissions are the result of DKA.
  • The condition is also being increasingly recognised in type 2 diabetes mellitus. This isn’t common as there is residual beta cell function and so some insulin presence.
  • DKA at diagnosis was more common in children aged below 10 years, and in non-white than in white people.
68
Q

Risk factors for DKA

A
  • Infection
  • Undiagnosed diabetes
  • Inadequate insulin or non-adherence to insulin therapy
  • Myocardial Infarction
  • Physiological stress: e.g. trauma or surgery
  • Other co-morbidities: e.g. hypothyroidism and pancreatitis
  • Drugs that affect carbohydrate metabolism: e.g. corticosteroids, diuretics and salbutamol
69
Q

Pathophysiology of DKA

A

Diabetic ketoacidosis (DKA) is a metabolic state which occurs as a complication oftype 1 diabetes(and rarely T2DM). DKA is considered a medical emergency associated with the triad of significanthyperglycaemia,acidosisandketonaemia, resulting in dehydration and electrolyte imbalances.

The lack of insulin means the body is unable to utilise glucose. This leads to accumulation of glucose within the blood resulting in hyperglycaemia. As glucose cannot be used there is an increase in hepatic glucose production through the breakdown of glycogen stores (glycogenolysis) and increased formation of glucose from other substrates (gluconeogenesis).

This is coupled with an increase in counter-regulatory hormone release (e.g. cortisol, glucagon, growth hormone), which exacerbates the hyperglycaemia and drives the production of alternative energy sources.

The lack of utility of glucose leads to the break down of fats (lipolysis) that increases serum free fatty acids. Fatty acids can be used as an alternative energy source through ketogenesis.

This increases the levels of ketone bodies (acetone, beta-hydroxybutyrate and acetoacetate) within the blood leading to ketonaemia. The main ketone body within DKA is 3-beta-hydroxybutyrate. Ketone bodies are weak acids, which can lead to significant acidosis and severe illness in increasing quantities.

As DKA progresses, the raisedplasma glucose leads to osmotic diuresis and profound hypovolaemia that is exacerbated by vomiting. This can lead to major electrolyte derangements, reduced consciousness and eventually death if not managed urgently.

70
Q

Signs of DKA

A
  • Fruity smell of acetone on breath
  • Dehydration
    • Mild: only just detectable
    • Moderate: dry skin and mucus membranes; reduced skin turgor
    • Shock: tachycardia, hypotension (late), drowsiness, reduced urine output
  • Kussmaul respiration: deep, labored breathing trying to reverse the metabolic acidosis
  • Hypotension
  • Abdominal tenderness
  • Reduced consciousness/ com
71
Q

Symptoms of DKA

A
  • Abdominal pain
  • Leg cramps
  • Headache
  • Nausea and vomiting
  • Polyuria
  • Polydipsia
  • Weight loss
  • Inability to tolerate oral fluids
  • Lethargy
  • Confusion
72
Q

1st line investigations for DKA

A
  • Laboratory glucose: > 11.0 mmol/L
  • Venous/arterial blood gas: quickest way to ascertain pH and HCOlevels. ABG may be used as the initial blood gas sample for diagnosis, but later samples should be venous if possible - pH < 7.3 or bicarbonate < 15 mmol/L
  • Ketone testing: capillary blood ketone ≥ 3 mmol/L or urinary ketones+++ or above
73
Q

Other investigations for DKA

A

To confirm DKA, DKA precipitants and monitor complications:

  • Urine dip:glycosuria and ketonuria
  • U&Es:electrolyte derangement and acute kidney injury due to dehydration
  • FBC and CRP:raised inflammatory markers may suggest underlying infection as a precipitant
  • LFTs
  • Troponin
  • Infection screen: if an infection is the suspected trigger
  • ECG
  • Imaging: chest xray
74
Q

Diagnostic criteria for DKA

A

For a diagnosis to be made, hyperglycaemia, acidosis, and ketonaemia must be present.

As per NICE, it is possible to have DKA with normal blood glucose levels, particularly in children and young people on insulin therapy. Furthermore, low blood ketone levels (< 3 mmol/L) do not always exclude DKA.

75
Q

Differential Diagnosis for DKA

A
  • Hyperosmolar hyperglycaemic state - Patients are typically older than patients with DKA and are usually patients with type 2 diabetes.
  • Lactic acidosis - The presentation is identical to that of DKA. In pure lactic acidosis, the serum glucose and ketones should be normal and the serum lactate concentration should be elevated.
  • Starvation ketosis - Starvation ketosis results from inadequate carbohydrate availability resulting in physiologically appropriate lipolysis and ketone production.
  • Alcoholic ketoacidosis - these are people with long-standing alcohol use disorder for whom ethanol has been the main caloric source for days to weeks. The ketoacidosis occurs when for some reason alcohol and caloric intake decreases.
  • Salicylate poisoning - Salicylate intoxication produces an anion gap metabolic acidosis usually with a respiratory alkalosis.
  • Ethylene glycol/methanol intoxication - Methanol and ethylene glycol also produce an anion gap metabolic acidosis without hyperglycaemia or ketones.
  • Uraemic acidosis - elevated serum urea and creatinine with normal plasma glucose. The pH and anion gap are usually mildly abnormal.
76
Q

1st line management for DKA

A
  • ABC’s
  • IV fluids (0.9% saline) are priority as patients with DKA are fluid deplete by 5-8 litres. Duration of infusion will differ. For example, slower fluid replacement may be required in younger patients (18 to 25 years old) due to the increased risk of cerebral oedema, as well as those with heart failure.
  • Insulin infusion: 0.1 units/kg/hr. Once glucose level < 14 mmol/L: add 10% glucose. Do notstop long-acting insulin
  • Potassium replacement (KCl):In DKA, even if serum potassium levels are normal, total body potassium is low. Insulin therapy and correction of acidosis causes a further reduction in serum potassium, hence replacement and monitoring are key.
77
Q

Adjunctive DKA therapy

A

Anticoagulation: patients are at increased risk of Venous thromboembolic disease (VTE)

78
Q

Summarise DKA treatment

A

Suspect DKA? > Clinical assessment > Fluid resuscitation + Insulin + Electrolyte monitoring > Monitor

Target:
Ketones to fall by 0.5 mmol/l/h
Bicarb to rise by 3 mmol/l/h
Glucose to fall by 3 mmol/l/h

79
Q

Monitoring for DKA

A

Glucose, pH, bicarbonate, ketone levels, and electrolytes should be closely monitored throughout, 1-2 hourly

80
Q

Complications for DKA

A
  • Hypokalaemia - K+ moves out of cell, as H+ moves into cell. The lack of insulin means more K+ is lost from the cell. This may also cause arrhythmias
  • Hypoglycaemia
  • Cardiovascular: Venous thromboembolism
  • Renal:acute kidney injury
  • Iatrogenic (due to treatment):Cerebral oedema, pulmonary oedema, central pontine myelinolysis, hypokalaemia, hypoglycaemia; due to inappropriate fluid replacement
  • Gastrointestinal: gastric stasis
  • Non-anion gap hyperchloraemic acidosis - this occurs due to urinary loss of ketoanions needed for bicarbonate regeneration, and also increased reabsorption of chloride secondary to intensive administration of chloride-containing fluids.
81
Q

Prognosis for DKA

A

Fortunately, mortality has decreased in the UK from 8% to < 1%. In children and young adults, cerebral oedema is the most common cause of death. In adults, the most common causes of death include severe hypokalaemia, ARDS, and co-morbid conditions such as pneumonia, sepsis and acute myocardial infarction.

82
Q

Define Hyperosmolar Hyperglycaemic state

A

Hyperosmolar hyperglycaemic state (HHS) is characterised by profound hyperglycaemia, hyperosmolality and volume depletion in the absence of significant ketoacidosis, and is a serious complication of diabetes (T2DM).

83
Q

Epidemiology of HHS

A
  • The incidence of HHS is not precisely known but is thought to make up less than 1% of diabetes-related hospital admissions
  • Usually occurs in the elderly but is increasingly recognised in younger patients.
  • The average age of presentation is 60 years old and it is associated with a 15-20% mortality.
  • HHS is often the first the presentation of type 2 diabetes mellitus in up to 20-30% of cases.
84
Q

Risk factors/precipitants of HHS

A
  • Infection
  • Myocardial infarction
  • Stroke
  • Poor medication compliance
  • Vomiting
  • High-dose steroids - can increase blood glucose
85
Q

Pathophysiology of HHS

A

HHS is usually triggered by a precipitant, most commonly infection.

In HHS, the relative lack of insulin is coupled with a rise in counter-regulatory hormones (e.g. cortisol, growth hormone, glucagon) that leads to a profound rise in glucose.

These patients retain a certain level of insulin, which prevents the development of ketosis that epitomises DKA. However, the level of insulin is inadequate to prevent profound hyperglycaemia.

The excessive glucose leads to massive osmotic diuresis within the kidneys with the loss of essential electrolytes such as sodium and potassium. This is because the proximal tubules within the kidneys only have a certain capacity for reabsorption of glucose. Once this is reached, the remaining glucose is passed through the renal nephrons causing diuresis.

As water is lost, there is profound dehydration and reduced circulating volume, resulting in hyperosmolarity and marked hyperglycaemia.

The increase in osmolality increases compensatory mechanisms such as release of anti-diuretic hormone (ADH) and stimulation of thirst. However, if this cannot compensate for the renal water loss (e.g. elderly patients with co-morbidities) then hypovolaemia develops with progression to acute kidney injury, electrolyte disturbances, hypotension and coma.

The hyperosmolar state of the condition leads to hyperviscosity that increases the risk of arterial and venous thrombosis**(e.g. stroke, DVT).

86
Q

Signs of HHS

A
  • Reduced GCS - reduced consciousness/ coma
  • Dehydration - tachycardia and hypotension, dry mucous membranes, reduced skin turgor
  • Could be confused for a stroke - e.g. hemiparesis
  • Seizures
87
Q

Symptoms of HHS

A
  • Generalised weakness
  • Leg cramps
  • Lethargy
  • Confusion
  • Hallucinations
  • Headache
  • Visual disturbances
  • Polyuria
  • Polydipsia
  • Nausea, vomiting and abdominal pain: possible, but more common in DKA
88
Q

1st line investigation for HHS

A

The key investigations for management of HHS include a laboratory glucose, urea & electrolytes blood test (electrolyte derangement and AKI due to dehydration), ABG/VBG (hyperglycaemia without a metabolic acidosis) and a blood or urinary ketone level.

89
Q

Other investigations for HHS

A
  • Urine dip:glycosuria
  • Serum osmolality:if laboratory testing is not available, use the formula:
    • 2Na++ glucose + urea
  • FBC and CRP:raised inflammatory markers may suggest underlying infection as a precipitant
90
Q

Diagnostic criteria for HHS

A

Hyperglycaemia - more than 30 mmol/L without significant hyperketonaemia and without acidosis

Hyperosmolality - more than 320 mosmol/kg

Hypovolaemia

91
Q

Differential diagnosis for HHS

A
  • DKA
  • Lactic acidosis
  • Alcohol ketoacidosis
  • Ingestion of toxic substances
  • Paracetamol overdose
  • Salicylate overdose
  • Seizures
  • Stroke
92
Q

First line management for HHS

A

ABC’s, IV fluid

93
Q

Adjunctive therapy for HHS

A

Insulin (if IV fluid doesn’t fix it)

Potassium replacement

Anticoagulation therapy - low molecular weight heparin for full duration of visit to reduce VTE risk

94
Q

Monitoring for HHS

A
  • Serum osmolalityis the most important parameter (to which glucose and sodium are the main contributors);fluid replacement aloneis usually sufficient to reduce osmolality
  • Rapid changes to osmolality must be avoided to preventcentral pontine myelinolysisandcardiovascular collapse
  • If laboratory osmolarity testing is not available, use the formula2Na++ glucose + urea
  • Maintain an accurate fluid balance chart and initiallyplotosmolalityhourly
  • Rising sodiumis only a concern if the osmolality isNOTdeclining concurrently
  • The rate of fall of plasma sodiummust not exceed10 mmol/L in 24 hours
  • Plasma glucose aim:a reduction of4-6 mmol/houris considered safe, with an overall goal of10-15 mmol/L
95
Q

Complications of HHS

A
  • Cardiovascular: venous thromboembolism,arrhythmias (hyper/hypokalaemia), myocardial infarction
  • Neurological:stroke and seizures
  • Renal:acute kidney injury
  • Iatrogenic (due to treatment): cerebral oedema or central pontine myelinolysis; due to rapid correction of osmolality.Cardiovascular collapsemay occur if insulin is administered prior to adequate fluid replacement.
96
Q

Prognosis for HHS

A

HHS has significantly higher mortality than DKA, with estimates at 5-20% in HHS compared to <1% for DKA. This is predominantly due to the fact that HHS develops over days and is associated withprofound dehydrationandsignificant electrolyte abnormalities.

Furthermore, HHS can be complicated byvascular complicationssuch as MI, peripheral arterial thrombosis and stroke due to hyper-viscosity. In addition, neurological manifestations such asseizuresare more common in HHS than DKA.

97
Q

Explain diabetic eye disease (Presentation, Referral, Screening, Emergencies)

A

The GP should immediately refer patients to thelocal eye screening unitupon diagnosis and the patient should be seen within 3 months.

Annual screeningshould take place thereafter if no changes are found.

A referral to an ophthalmologist is warranted if there is evidence of pre-proliferative or proliferative retinopathy, or evidence of maculopathy.

An emergency review by an ophthalmologist is required if any of the following are present:

  • Acute reduction in acuity
  • Rubeosis iridis
  • Vitreous haemorrhage
  • Retinal detachment
98
Q

Explain diabetic foot disease (Presentation, Referral, Screening, Emergencies)

A

The risk of diabetic foot disease should be assessed on diagnosis, and at leastannuallythereafter by the GP. Assessing risk involves a full examination of both feet, assessing theneurovascular statusincluding an ankle-brachial pressure index. NICE stipulate a10g monofilamentmust be used to assess sensation.

Patients deemed low risk can bescreened annually. Referral to thelocal foot protection serviceis indicated if either moderate or high risk. This is a service led by podiatrists with MDT input from multiple specialities including vascular surgeons and diabetologists. The servicemust see moderate-risk patients within8 weeks, and high-risk patients within4 weeks.

99
Q

Explain diabetic nephropathy (Presentation, Referral, Screening, Emergencies, Treatment)

A

Diabetes can cause chronic kidney disease (CKD), hence, patients should have theireGFRcheckedannually, as well as a urinaryalbumin:creatinine ratio.

Renoprotective therapy:

  • ACEi:patients with diabetesand CKD should be started on anACE inhibitor(ACEi) due to its renoprotective effects
  • Aim for a target BP of130/80 mmHgif CKD anddiabetes are both present
  • Even if the patient has a normal BP, they should still be started on an ACEi if there is evidence of CKD
100
Q

Explain Diabetic Cardiovascular risk (Presentation, Referral, Screening, Emergencies, Treatment)

A

All patients should be given lifestyle advice, with a particular emphasis on smoking cessation.

Statin therapy:primary prevention with atorvastatin 20mg

  • T1DM:should be considered in all patients and given ifanyof the following are present:
    • > 40 years
    • Diabetes for > 10 years
    • Diabetic nephropathy
    • Other cardiovascular risk factors
  • TD2M:as for non-diabetics, calculate the QRISK2 score and, if ≥10%, commence therapy

Anti-hypertensive therapy:

  • ACEiis first-line, irrespective of age
  • Target BP:140/90 mmHg in patients without CKD, or 130/80 mmHg in patients with CKD

2A Medicine Sam (12 decks)

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