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Diabetes
Diabetes

Diabetes

In this CCC we will discuss:

  • Type 1 diabetes mellitus
  • Type 2 diabetes mellitus
  • Gestational diabetes
  • Diabetes insipidus
  • Complications of diabetes

Overview

Diabetes is an umbrella term for disorders characterised by polyuria. Diabetes mellitus is the more common disorder, however, diabetes insipidus is also important to consider. Pregnancy can also lead to a transient diabetic state and we will also discuss this.

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TYPE 1 DIABETES MELLITUS

Type 1 diabetes mellitus is characterised by hyperglycaemia as a a result of absolute insulin deficiency (hence it may be referred to as insulin dependent diabetes). It accounts for 5-10% of all diabetic cases, and is most common in youth 10-14 years of age (hence it may be referred to as juvenile diabetes).

Pathophysiology

Before we discuss the pathophysiology, let’s recap the physiology of the pancreas:

The pancreas has both exocrine and endocrine functions:

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  • Exocrine function - makes up 85% of the pancreas. The cells of the exocrine pancreas are known as the acinar cells. These acinar cells produce zymogens which are secreted into the pancreatic duct and enter the duodenum via the Ampulla of Vater. These zymogens are activated into certain enzymes such as:
    • Trypsinogen → trypsin (activated by enterokinase) and it is a protease that breaks down peptides and proteins into amino acids.
    • Pancreatic lipase digests triglycerides and monoglycerides into FFAs.
    • Amylase digests starch and maltose.
  • Endocrine function - the cluster of cells that make up the endocrine function of the pancreas are known as the Islets of Langerhans. These islets contain multiple cell types which release polypeptide hormones into our blood stream.

      • There are 6 key polypeptide hormones to remember:

      Cell type
      Hormone
      Function
      Alpha cells
      Glucagon
      Increases blood glucose levels.
      Beta cells
      Insulin
      Decreases blood glucose levels.
      Beta cells
      Amylin
      Slows gastric emptying to prevent spikes in blood glucose levels.
      Gamma cells
      Pancreatic polypeptide
      Associated with GI function.
      Delta cells
      Somatostatin
      Regulated islet cell secretion of other hormones.
      Epsilon cells
      Ghrelin
      Increases appetite.

      Now that we have discussed the normal physiology, let’s understand how things may go wrong:

      Type 1 diabetes usually occurs due to autoimmune destruction of B-cells as a result of autoantibodies against some specific antigens:

    1. Insulin
    2. Glutamic acid decarboxylase (GAD) - an enzyme used to convert glutamic acid → GABA within the pancreas.
    3. Islet auto-antigen-2 (IA-2) - a tyrosine-phosphatase-like molecule.
    4. ZnT8 - a B-cell specific zinc transporter.

This B-cell destruction is sub-clinical for many months/years, and is simply insulitis (inflammation of B-cell). Only when 80-90% of B-cells have been destroyed do we develop hyperglycaemia.

Type 1 diabetic patients are insulin deficient, not insulin resistant. As a result, they are unable to use glucose in their peripheral muscle and adipose tissue, thus leading to glucagon secretion causing gluconeogenesis, glycogenolysis and ketogenesis (within the liver). Ultimately thIs leads to anion gap metabolic acidosis (due to ketone buildup) and hyperglycaemia. Long-term hyperglycaemia leads to vascular issues due to free radical damage and glycosylation of proteins.

Oxidative stress and inflammation is also induced → endothelial dysfunction as it neutralises NO. This aids LDL entry into the vessel wall → atheroma formation.

😷 Presentation

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There are 3 hallmark symptoms of diabetes, we can also call these the 3 P’s of diabetes:

  1. Polyuria - increased urination. Getting up at night to urinate is typical. Children may also present with secondary enuresis (bedwetting in a previously dry child).
  2. Polydipsia - increased thirst. Despite urinating frequently, the patient feels thirsty and may get up at night
  3. Polyphagia - increased hunger. However, with diabetes we have unexplained weight loss also.

Of course hyperglycaemia is always present in diabetes mellitus, this means they will have a random plasma glucose >11.1mmol/l.

Other diagnostic factors include:

  • Young age - highest incidence between 10-14 years old.
  • Lethargy - common in children. may also indicate DKA.
  • Blurred vision
  • Recurrent infections

⚠️ Risk factors

  • Genetic predisposition is the strongest risk factor. HLA-DR3 and HLA-DR4 are implicated with the highest risk. In these susceptible individuals, environmental factors may trigger the autoimmune destruction, for example enteroviridae.
  • Vitamin D supplementation has shown to be protective, however, the relationship still needs to be researched further.
  • It is also more common in European people and less common in Asian individuals.

🔍 Investigations

In adults, a clinical diagnosis can often be made if the patient presents with hyperglycaemia, ketosis, polyuria, polydipsia, rapid weight loss, age <50 years, BMI <25kg/m².

There are a couple of investigations needed to make a diagnosis for T1DM:

🧪
Blood tests:
  1. It is good to get a baseline FBC, U&E and laboratory glucose.
  2. Glucose measures:
    1. Random plasma glucose - can confirm diagnosis in the presence of symptoms (polyuria, polydipsia, unexplained weight loss). A repeat would be needed in most cases. >11.1mmol/L is positive.
    2. Fasting plasma glucose - no caloric intake for at least 8 hours. >7.0mmol/L is positive.
    3. 2-hour plasma glucose may also be measured 2 hours after a 75g oral glucose load. A repeat would be needed in most cases. >11.1mmol/L is positive.
    4. HbA1c - indicates the level of hyperglycaemia over the past 3 months. >6.5% is positive. However, it is less useful for T1DM as it does not reflect a recent rapids rise in glycaemic values.
  3. Plasma ketones - will be raised.
  4. C-peptide - will be low or undetectable. This is the cleaved peptide of proinsulin which is also secreted in the secretory vesicle, and directly reflects AB-insulin measures. It is only recommended by NICE if:
    1. There is difficulty distinguishing T1DM from other types in both adults and children.
    2. In adults: if suspecting T1DM but features are atypical (>50 years, BMI >25kg/m², slow onset).
    3. It should always be paired with a glucose test
  5. Autoimmune markers - any positive result may distinguish it from T2DM.
    1. GAD autoantibodies - present in 80%.
    2. Islet cell autoantibodies - present in 70-80%.
    3. Insulin autoantibodies - found in 90% of children with T1DM, but only 60% of adults.
    4. IA2 autoantibodies
    5. Zn-T8 autoantibodies
💦
Urine dipstick:

A urine dip for glucose and ketones may be done. The urine may have a sweet odour. If the pH is also low, this may indicate DKA and may require the patient to be admitted to hospital for further investigations. Usually, all a urine dipstick warrants is further investigations, however.

🧰 Management

T1DM requires lifelong management and therefore the patient needs to be very involved in their disease management. The patient should be educated and fully understand their condition. This is especially true for children who mature and grow to be independent from their family.

Management involves:

  1. Monitoring
  2. Glycaemic control
👀
Monitoring:
  • Self monitoring - should be performed at least 4 times daily - before each meal and before bed. Monitoring should be increased if the frequency of hypoglycaemic episodes increases, if ill, during and after sport, during pregnancy.
    • Targets are:
      • 5-7mmol/l on waking.
      • 4-7mmol/l before meals and throughout the day.
  • HbA1c - should be performed every 3-6 months.
    • Target is:
      • <48mmol/l (6.5%)
  • Dietary carbohydrate monitoring patients should keep their carbohydrate intake in moderation.
💊
Glycaemic control:
  • 🥇 Basal-bolus insulin

    • These are given as multiple daily injections (MDIs) as a combo of long-acting and short-acting insulins. The regimen needs to be tailored to the patient’s needs, comorbidities and preferences. These are preferred to bidaily mixed insulin injections.

    Basal means injection of a long-acting insulin. These are slow-release insulins that work by binding to albumin, or by forming microcrystals that become more soluble at acidic pHs. They give constant background insulin throughout the day. Twice-daily insulin detemir is first-line.

    Bolus refers to injection of rapid-acting insulin. These are injected before meals.

    We will discuss the types of medication below.

  • Metformin - 500mg OD may be considered as an adjunct in adults with a BMI >25kg/m²
  • 🥈 Fixed-dose insulin - may be given when patients are already doing well on a fixed-dose regimen and cannot manage a MDI regimen.
  • Insulin pumps

      • These are devices that infuse insulin at different rates. They are alternatives to basal-bolus regimens. They push insulin through a cannula which is replaced every 2-3 days at different sites (to prevent lipdystrophy). They are indicated in children >12 years old who are having difficulty controlling their HbA1c. They are advantageous as they provide better glycaemic control and allow flexibility with eating with less injections required.

      There are 2 types of pumps:

    1. Tethered pumps - with replaceable infusion sets and insulin. They are not attached to the person’s belt or waist. There is a visible tube that connects from the pump to the insertion site.
    2. Patch pumps - sit directly on the skin without visible tubes. They are disposable once finished.
      3. image
💊
Insulin medications:

Rapid-acting insulins:

These reduce insulin aggregation and reduce hypoglycaemic risk. They are rapid acting as they make changes to a few amino acids on recombinant insulin to prevent hexameter/dimmer formation, thus are more soluble. They are given before meals.

  1. Insulin aspart
  2. Insulin lispro
  3. Insulin glulisine

Long-acting insulins:

These are slow-release insulins that provide night time cover and background cover throughout the day. They are typically given in the evening.

  1. Insulin detemir
  2. Insulin glargine
  3. Insulin degludec
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🚨 Complications

We will discuss complications at the end, but the main complications include:

  • Hyperglycaemia
  • Hypoglycaemia
  • Macrovascular changes
  • Microvascular changes
  • DKA
  • Diabetic nephropathy
  • Diabetic neuropathy
  • Diabetic retinopathy
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TYPE 2 DIABETES MELLITUS

Pathophysiology

Type 2 diabetes mellitus is characterised by insulin resistance (and a relative deficiency of insulin due to an excess of adipose tissue, but not to the degree of T1DM). It is accelerated by ageing and obesity. Therefore weight loss can delay or prevent onset in obese patients.

Increased exposure to glucose and insulin develops resistance, thus requiring more insulin to produce a response from adipocytes and skeletal muscle in order for them to take up and use glucose. Beta-cells become “fatigued” by producing excessive insulin and they start to produce less as a result. Therefore, when exposed to more glucose we get hyperglycaemia. Chronic hyperglycaemia can lead to microvascular and macrovascular complications.

The mechanisms for these complications probably occurs due to an accumulation of advanced glycation end products (AGEs) which results in oxidative stress and inflammation.

😷 Presentation

It is very common for T2DM to be asymptomatic and only picked up on screening. However, it too presents with polyuria, polydipsia, and unintentional weight loss in many patients.

  • Fatigue
  • Opportunistic infections - this is because these opportunistic bacteria thrive with higher glucose concentrations.
    • Candidal infections - most commonly in the vaginal, penile and skin fold regions.
    • Skin infections - such as cellulitis or abscesses.
    • UTIs
  • Blurred vision
  • Paraesthesias - may occur with prolonged undiagnosed diabetes due to neuropathy.
  • Acanthosis nigricans - on the neck, axilla, groin regions. Especially in obese patients.

⚠️ Risk factors

  • Increasing age
  • Diet
  • Sedentary lifestyle
  • Obesity - mean BMI at diagnosis is 32kg/m2. Weight loss has shown to delay or decrease risk of diabetes.
  • Gestational diabetes - about 50% of women who have gestational diabetes will develop diabetes within 10 years of delivery.
  • Pre-diabetes (non-diabetic hyperglycaemia)
  • Family history
  • Non-white ethnicity - most common in Hispanic, African, East Asian and South Asian ethnicities.
  • PCOS - screening needs to be done for these patients.
  • Dyslipidaemia
  • Cardiovascular disease - patients with CVD need to be screened as there is a high prevalence of CVD in diabetics.
  • Stress - as stress causes glucose elevation and some evidence says it may predispose one to T2DM.

🔍 Investigations

🍪
Glycaemic testing:
  1. Random plasma glucose - can confirm diagnosis in the presence of symptoms (polyuria, polydipsia, unexplained weight loss). A repeat would be needed in most cases. >11.1mmol/L is positive.
  2. Fasting plasma glucose - no caloric intake for at least 8 hours. >7.0mmol/L is positive.
  3. 2-hour plasma glucose may also be measured 2 hours after a 75g oral glucose load. A repeat would be needed in most cases. >11.1mmol/L is positive.
  4. HbA1c - indicates the level of hyperglycaemia over the past 3 months. >48mol/mol (>6.5%) is positive. However, it is less useful for T1DM as it does not reflect a recent rapids rise in glycaemic values.
☝
Other investigations to consider:
  • Ketones - to assess for DKA.
  • Album-to-creatinine ratio - anything >3mg/mmol may indicate clinically relevant proteinuria as seen in diabetic nephropathy.
  • eGFR
  • ABPI - to assess for PAD.
  • LFTs - as about 40-70% of diabetics have NAFLD.

🧰 Management

🥗
Lifestyle modification:

Dietary changes and lifestyle modifications need to be emphasised upon diagnosis. This includes:

  • Dietary advice
    • High fibre, low glycaemic index carbohydrates
    • Lowering intake of saturated fats and trans fatty acids.
    • Increase low-fat dairy and oily fish products.
  • Weight loss - if the patient is overweight, target weight loss at 5-10% initially.
  • Smoking cessation
  • Alcohol reduction
  • Encourage sleep quality
🍫
Glycaemic control:
  1. Agree on glycaemic target (HbA1c) - these should be agreed with patients to encourage motivation. It should also be checked every 3-6 months, and once stable it should be checked every 6 months. However, NICE promotes case-by-case targets with consideration to the patient’s individual factors
    2. Management
    HbA1c target
    Lifestyle
    48mmol/mol (6.5%)
    Lifestyle + metformin
    48mmol/mol (6.5%)
    Lifestyle + any drug that may cause hypoglycaemia
    53mmol/mol (7.0%)
    Patient already on one drug but HbA1c has risen to 58mmol/mol (7.5%)
    53mmol/mol (7.0%)
  2. Rescue therapy at initial diagnosis - if symptomatic at initial diagnosis rescue therapy should be given alongside longer-term therapies (such as metformin), however, these take longer to take effect, that is why we give rescue therapy in the form of:
    1. Insulin
    2. Sulfonylurea
  1. Drug therapy - this is given for long-term management alongside lifestyle modification. Let’s discuss the drug therapies below.
🥇
Initial drug therapy:
  • Metformin - 500mg OD is the first-line drug of choice for T2DM. It should be titrated up slowly to prevent GI upset, maximum 2000mg/day.
    • It can be given as an immediate-release form, but if this is not tolerated a modified-release formulation may be trialled.
  • SGLT2 inhibitors - should be given in addition to metformin in the following cases:
    • Patient at high risk of developing CVD (QRISK >10%)
    • Patient already has CVD
    • Patient has chronic heart failure.

      • If an SGLT2 inhibitor is given, metformin should first be titrated up before introducing the agent.

      image

If metformin is contraindicated, we should give:

  • DPP-4 inhibitors

OR

  • Pioglitazone

OR

  • Sulfonylurea

OR

  • SGLT2 inhibitor - if the patient is at risk of CVD or has CVD/HF.
🥈
Second-line therapy:

If monotherapy hasn’t worked and the HbA1c has risen to 58mmol/mol then dual therapy is indicated with metformin being the steadfast option.

  • Metformin + DPP-4 inhibitor/pioglitazone/sulfonylurea/SGLT-2 inhibitor (if at risk of CVD or patient has chronic HF or established CVD)

If metformin is contraindicated, we should give:

  • DPP-4 inhibitor + pioglitazone/sulfonylurea

OR

  • Pioglitazone + sulfonylurea
🥉
Third-line therapy:

Triple therapy may be indicated with metformin + 2 other drugs mentioned above.

NICE recommends consideration of insulin therapy ± SGLT-2 inhibitor. Metformin should be continued throughout.

  • Isophane insulin - taken at bed-time or twice daily is recommended.
🔥
Further therapy:

If triple therapy is refractory or not tolerated, one of the drugs may be switched for a GLP-1 mimetic, especially if the patient is >35kg/m2.

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⚠️
Risk-factor modification:
  • Hypertension - targets are the same as for patients without T2DM
    • ACEIs (-pril) or ARBs (-sartan) are first-line. ARBs are preferred if the patient is of African or Afro-Caribbean origin.
  • Antiplatelets - only offered if the patient has existing CVD.
    • Aspirin - 75mg OD
    • Clopidogrel - 75mg OD
  • Lipid management - if the patient has a 10 year CVS risk >10% according to QRISK2 then they can be offered a statin.
    • Atorvostatin - 20mg OD.
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Dear future Sarmad,

Please add in the MOAs of the drugs as well as their adverse effects when you have the strength to do so.

Kind regards,

Present Sarmad (20/11/2022)

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GESTATIONAL DIABETES
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Pathophysiology

Gestational diabetes refers to diabetes that develops during pregnancy. It occurs in 1 in 20 pregnancies.

Similar to type 2 diabetes mellitus, it is due to reduced insulin sensitivity. It generally resolves after delivery.

The largest complication of gestational diabetes is macrosomia (large baby) which can complicate birth, especially increasing risk of shoulder dystocia (when baby is delivered but shoulder gets stuck behind the pubic bone).

⚠️ Risk factors

  • Previous gestational diabetes
  • BMI >30
  • Previous macrosomic baby
  • Ethnic origin - black Caribbean, Middle Eastern and South Asian
  • Family history of diabetes (1º relative)

👀 Screening

NICE recommends a 75g 2-hour oral glucose tolerance test (OGTT) between 24-48 weeks gestation to high risk women.

What qualifies a women as high risk?

One or more of the following risk factors:

  1. BMI >30kg/m2
  2. Previous baby weighing >4.5kg
  3. Family history of diabetes mellitus
  4. Family origin in an area of high prevalence of diabetes (black Caribbean, Middle Eastern and South Asian)
  5. Features that suggest GDM
    1. Large for date fetus
    2. Polyhydramnios
    3. Glucose on urine dipstick

If a women has had a previous gestational diabetes, they should be offered early self-monitoring of blood glucose or an OGTT as soon as possible.

🔍 Investigations

🍫
Glycaemic testing:
  1. 2-hour OGTT - >7.8mmol/L is positive for GDM.
  2. Fasting glucose - >7.8mmol/L is also positive for GDM.

💡 Just remember 5-6-7-8!

🧰 Management

👨🏽‍⚕️
Management of gestational diabetes:
  1. Newly diagnosed women need to be seen in a diabetic and antenatal clinic.
  2. Education of self-monitoring of blood glucose
    1. Fasting - 5.3mmol/L
    2. 1 hour after meal - 7.8mmol/L
    3. 2 hour after meal - 6.4mmol/L
  3. Dietary advice - eating foods with low glycaemic index.
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If fasting plasma glucose >7mmol/L:
  1. Insulin - needs to be given immediately as rescue therapy to get it under control immediately.
    1. Insulin isophane - is recommended first-line by NICE. It is given once at night, or twice daily.
    2. Insulin glargine/insulin detemir - are also commonly used.
  2. Metformin - 500mg OD metformin can be considered according to NICE, as an adjunct with insulin. However, this is an off-label use of metformin.

If fasting plasma glucose is 6-6.9mmol/L but there is evidence of macrosomia or polyhydramnios then follow the same protocol.

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If fasting plasma glucose <7mmol/L:
  1. Trial diet and exercise should be offered
    1. If glucose targets are not met within 1-2 weeks → start metformin.
      1. If glucose targets are still not met → add insulin (rapid-acting insulin).

If fasting plasma glucose is 6-6.9mmol/L but there is evidence of macrosomia or polyhydramnios then follow the protocol above.

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Pre-existing diabetes management:
  • Weight-loss if BMI >27kg/m2.
  • Stop oral antihyperglycaemic agents (besides metformin) and replace them with insulin (sliding-scale insulin regime).
  • Folic acid 5mg/day until 12 weeks gestation.
  • Anomaly scan at 20 weeks
  • Glycaemic control of course.
  • Retinopathy screening - through ophthalmology referral performed at 28 weeks gestation.
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DIABETES INSIPIDUS

Pathophysiology

Diabetes insipidus is when you lack ADH/AVP (arginine vasopressin) or lacks response to ADH which leads → polyuria (excessively hypotonic as well) and polydipsia.

It can be classified as either:

  1. Nephrogenic diabetes insipidus - collecting ducts do not respond to ADH.
  2. Cranial diabetes insipidus - when the hypothalamus does not produce ADH for the posterior pituitary to secrete.

Nephrogenic diabetes insipidus

May be caused by:

  • Drugs - lithium
  • Genetics - mutations of the AVPR2 gene on the X chromosome, which codes for the ADH receptor.
  • Intrinsic renal disease - such as pyelonephritis, sickle-cell, obstruction.
  • Electrolyte imbalances - hypercalcaemia, hypokalaemia, hyperglycaemia.

Cranial diabetes insipidus

May be idiopathic, but can be caused by:

  • Brain tumours - craniophyaryngiomas
  • Head injury
  • Cerebral malformations
  • Infections - meningitis, encephalitis, tuberculosis.
  • Brain surgery - especially on pituitary.
  • Radiotherapy
  • Infiltration - sarcoidosis, histiocytosis X
  • Haemochromatosis
☝
Primary polydipsia

Primary polydipsia occurs when the patient has a normally functioning ADH system but are drinking excessive water due to excessive urine production.

😷 Presentation

Polyuria and polydipsia.

🔍 Investigations

💧
Diagnosing diabetes insipidus:
  1. Serum osmolality - elevated (>295mOsmol/kg)
  2. Urine osmolality - low.

With these 2 factors, we can suspect DI. Confirmation will be done with a water deprivation test.

  1. Water deprivation test - you do not drink any water for several hours and urine output is monitored hourly. A positive test would be when urine osmolality is low and urine output remains high. Synthetic ADH is administered 8 hours later and osmolality is measured again.
    2. Diagnosis
    Osmolality with deprivation
    Osmolality after ADH
    Cranial DI
    Low
    High
    Nephrogenic DI
    Low
    Low
    Primary polydipsia
    High
    High

🧰 Management

  • Treat underlying cause.
  • Promote oral fluids/IV fluids if there is hypernatraemia.
  • Central DI - can be treated with desmopressin.
  • Nephrogenic DI - can be treated with thiazide diuretics and low salt/protein diet.