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Diabetes Clinical Case Series, Excerpt #9, Endocrinology and Diabetes, The Basics, Part 1

CCU_Endocrinology_and_Diabetes

The Pancreas

  • The pancreas is situated behind the posterior wall of the abdomen
  • It can be divided into:
    • Head: located within the duodenal curve
    • Body connected to the head through a slight constriction (neck)
    • Tail representing tapering of the body as it extends to the left approaching the gastric surface of the spleen
  • The anterior surface of the pancreas is covered by the stomach, whereas the posterior surface is in contact with the large vessels (aorta, inferior vena cava and renal vessels)…
Physiology
The pancreas has an:
  • Exocrine function: secretes hormones into the gastrointestinal system to help with food digestion
  • Endocrine function: the pancreas is the main organ that regulates blood glucose levels.
Pathophysiology
  • Defects in insulin secretion and action result in the development of diabetes mellitus
  • Insulin deficiency is the pathophysiological abnormality in type 1 diabetes (T1DM)
  • Insulin resistance with consequent β-cell dysfunction are the pathophysiological abnormalities in most cases of type 2 diabetes (T2DM).

Classification of diabetes

Type 1 diabetes (5–15% of cases)

  • This is an autoimmune condition, resulting in destruction of pancreatic β-cells
  • Subjects are often young (children or young adults) but the older age group can also be affected
  • Latent autoimmune diabetes of adults (LADA) is also due to autoimmune β-cell destruction but the process is slower than classical T1DM and occurs in an older age group

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Type 2 diabetes (75–85% of cases)

This is due to a combination of:

  • Insulin resistance (usually as a result of obesity)
  • β-cell dysfunction: insulin resistance is compensated for by an increase in insulin production by pancreatic β-cells. Eventually, these cells get ‘worn out’ and their insulin production decreases to a level that is unable to compensate for insulin resistance, leading to high plasma glucose and the development of diabetes.

Type 2 diabetes is on the increase, mainly due to the increased prevalence of obesity and sedentary lifestyle

Secondary causes of diabetes (<5%)

  • Pancreatic destruction
    • Pancreatitis
    • Trauma
    • Pancreatic cancer
    • Cystic fibrosis
    • Haemachromatosis (infiltration of the pancreas with iron)
  • Endocrine disease
    • Acromegaly
    • Cushing’s syndrome

Genetic defects (<5%)

Genetic defect in insulin secretion:

  • Maturity onset diabetes of the young (MODY)
    • An autosomal dominant condition
    • A number of different types have been described, the commonest are due to mutation in genes for hepatic nuclear factor (HNF)1, known as MODY 3, and glucokinase, known as MODY 2
  • Mitochondrial mutations

Genetic defect in insulin action:

  • Resulting in severe insulin resistance (very rare)

Drug induced (<5%)

  • Glucocorticoid treatment: particularly in those receiving high dose of steroids
  • Thiazides

Gestational diabetes (<5%)

  • Diabetes that occurs during pregnancy
  • Resolves spontaneously after giving birth
  • Associated with increased risk of macrosomic (large) babies
  • Affected women are at high lifetime risk of developing T2DM (up to one-third)

From the practical point of view, it is important to distinguish between type 1 and type 2 diabetes as failure to initiate insulin in a type 1 diabetes patient may result in death. 

Clinical presentation

There are a wide range of symptoms, including:

  • Polyuria secondary to osmotic diuresis
  • Polydipsia or increased thirst
  • Visual disturbances: due to changes in the lens, secondary to high glucose levels
  • Repeated skin infections
  • Vaginal candidiasis (thrush) is common in female subjects
  • Tiredness
  • Weight loss (usually in type 1 diabetes)
  • The patient may present with associated complications such as:
    • Myocardial infarction
    • Stroke
    • Renal disease
  • In type 2 diabetes, the disease is commonly clinically silent and is discovered during investigations for other pathologies

During assessment of patients, it is important to differentiate T1DM from T2DM as management of these conditions is entirely different (see Table 20). The following should be taken into account:

  • Detailed history: patients with T1DM present with short history of symptoms (days to weeks), in contrast to individuals with T2DM (months to years)
  • The presence of weight loss, particularly in a younger individual, suggests T1DM
  • Individuals with T1DM tend to be thin (but not always) and those with T2DM tend to be overweight (but not always)
  • Although rare, causes of secondary diabetes should be kept in mind and appropriate investigations should be arranged if necessary
  • The presence of a family history suggestive of an autosomal dominant condition, particularly in those with diabetes at a young age, should alert to the possibility of MODY
  • All patients (particularly older subjects) should be assessed for the presence of complications (macrovascular and microvascular complications, detailed below)
 

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Complications of diabetes

Acute complications

Diabetic ketoacidosis (DKA)

  • DKA is due to the absence of insulin and, therefore, it is mainly seen in patients with T1DM
  • Not uncommonly, DKA is the first presentation of T1DM
  • The absence of insulin results in switching from glucose to fat metabolism (in order to provide energy), a pathway that is associated with accumulation of ketone bodies, which cause metabolic acidosis
  • Therefore, ketoacidosis is characterized by the presence of:
    • Acidosis (due to the accumulation of ketone bodies)
    • Dehydration (due to osmotic diuresis and vomiting, see below)

Diabetic hyperosmolar non-ketotic hyperglycemia (HONK)

  • A complication of T2DM, usually seen in the elderly
  • Characterized by high glucose levels and severe dehydration
  • Acidosis is usually absent
Hypoglycemia
  • This is discussed under the treatment of diabetes below

Chronic complications

Macrovascular (large vessel) complications

Patients with diabetes are at high risk of cardiovascular disease including:

  • Ischemic heart disease (IHD): all newly diagnosed diabetes patients should be assessed for the possibility of IHD
    • History: chest pain or shortness of breath on exertion
    • ECG: previous myocardial infarction, ischemic changes
    • More sophisticated tests if in doubt (exercise test, angiogram)
  • Cerebrovascular disease:
    • History of weakness or slurred speech should alert to the possibility of this diagnosis
    • Any neurological signs will warrant further investigations
  • Peripheral vascular disease
    • History of pain in the legs on exertion
    • Feel the foot pulses

Microvascular (small vessel) complications

These include retinopathy, nephropathy and neuropathy.

  • Retinopathy: the following changes can be observed:
    • Background changes (minor changes): microaneurysms, small intraretinal hemorrhages (dots) and hard exudates due to the leakage of lipids
    • Preproliferative changes (serious changes, need attention): soft exudates (areas of infarction), also known as cotton wool spots, and intraretinal microvascular abnormalities (IRMA), tortuous and dilated looking vessels occurring as a result of retinal ischemia
    • Proliferative changes (very serious changes, need immediate attention): new vessel formation
  • Nephropathy
    • Microalbuminuria: excretion of small amounts of albumin in the urine. This is an early stage of diabetic nephropathy, which can be reversible
    • Macroalbuminuria: excretion of large amounts of albumin in the urine. This is seen in more advanced stages
    • Raised urea and creatinine: indicates renal failure
  • Neuropathy
    • Peripheral: altered sensation in the feet, which predisposes to foot ulcers; Charcot’s osteoarthropathy, results in bone fractures and deformity and can be difficult to diagnose and treat (Fig. 29, colour plate section); and neuropathy can also involve a main nerve or a group of nerves (third nerve palsy for example), causing sensory or motor abnormalities
    • Autonomic: can result in orthostatic hypotension, gastrointestinal symptoms (vomiting, diarrhoea), or erectile dysfunction
 

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Investigations
  1. Confirm the diagnosis of diabetes:
    • Fasting plasma glucose
      • Levels above 126mg/dL.(7.0mmol/L) in the presence of symptoms or two tests above 126mg/dL. (7.0 mmol/L) in the absence of symptoms confirm the diagnosis of diabetes
    • Subjects with fasting glucose 108 mg/dL(6.0mmol/L) but <126mg/dL.(7.0mmol/L) are labeled as having impaired fasting glucose and should undergo a glucose tolerance test (see below)
    • Random plasma glucose
    • Levels above 199mg/dL.(11.0 mmol/L) in the presence of symptoms confirm the diagnosis
    • Oral glucose tolerance test – this should be performed in unclear cases
      • Subjects are given 75 g glucose and plasma glucose is assessed at 0 min and 120 min
        • Individuals with 2-h glucose 140 mg/dL (7.8 mmol/L): diabetes ruled out
        • Individuals with 2-h glucose 199 mg/dL (11.1 mmol/L): diabetes is confirmed
        • Individuals with 2-h glucose 140 mg/dL (7.8 and 11.1): impaired glucose tolerance is present (a prediabetic condition-risk of future diabetes is high)
  2. Differentiate between types of diabetes
    • A careful history is probably the most important tool to differentiate between different types of diabetes
    • Urine dipstick: this is an essential test in all diabetes patients. The presence of heavy ketonuria is indicative of T1DM. Ketonuria may also occur after prolonged fasting.
    • Laboratory tests can be useful in difficult cases:
      • Anti-glutamic acid decarboxylase (GAD) and antityrosine phosphatase (IA-2) antibodies: antibodies against one or both molecules are present in around 80% of patients with T1DM. Their absence does not rule out the diagnosis of T1DM
      • Genetic testing: in suspected MODY commonest are mutations in HNF1(MODY 3) and glucokinase (MODY 2) genes
      • Cases with suspected secondary cause: ferritin levels (hemachromatosis), CT abdomen in pancreatic cancer, Cushing’s syndrome and acromegaly
  3. Investigate for the presence of complications
    • Acute
      • If in doubt whether the patient has early DKA, you can measure venous pH and bicarbonate (bicarbonate 15 mmol/L with or without low pH is diagnostic)
      • Do not miss the diagnosis of acute diabetic ketoacidosis, which may be fatal if not treated appropriately
    • Chronic
      • ECG: this should be done in all newly diagnosed diabetes subjects as silent myocardial infarction is common in this group of patients
      • CT head and carotid Doppler: in case of history of TIA
      • Doppler of peripheral arteries: in case of history or examination suggesting peripheral vascular disease
      • Urinary microalbumin and U&Es to rule out nephropathy
      • Nerve conduction tests: in the presence of atypical neuropathic changes
Treatment

Treatment of type 1 diabetes (T1DM)

Patients with T1DM should be treated with insulin. There are different preparations of insulin, which are briefly discussed here. At present, the main insulin preparations in use are human insulin and insulin analogues. Animal insulin preparations (bovine and pork) are very rarely used these days.

Types of insulin:
  • Human insulin preparations
    • Short (or fast) acting insulin (Actrapid): starts working in 30 min and peaks at 2–4 h after injection, covers up to 6–8 h post injection (Fig. 30)
    • Intermediate acting insulin or NPH insulin (Insulatard): starts working in 2 h and peaks 8 h post injection, covers for 16-20 h (Fig. 31)
    • Mixtures: short and intermediate acting with varied proportions; humulin M1 (10% short and 90% intermediate acting), humulin M3 (30% short and 70% intermediate acting) (Fig. 32)
  • Analogue insulin preparations
    • Ultra-short (or ultra-fast) acting insulins (lispro, aspart, glulisine): start working almost immediately and peak at 1–2 h post injection and cover for around 4 h post injection
    • Long acting insulins (glargine, detemir): relatively flat profile (minimal peak, thus less chance of hypoglycemia), start working in 2 h and last 20–24 h post injection
    • Mixtures: ultra-short acting analogues with intermediate insulin. There are no mixtures with long acting insulin analogues

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How to give insulin injections

There are a number of regimes that can be used in T1DM but the most widely adopted are:

  • Twice daily injections with mixture of insulins (i.e. Novomix 30, Humulin M3, Humalog mix 25) (Fig. 33)
  • Four daily injections of insulin: also called basal bolus regime (Fig. 34)
    • One injection of intermediate or long acting insulin (to cover basal insulin)
    • Three injections of short acting or ultra-short acting insulin with meals (bolus insulin)
    • Basal bolus regime gives better flexibility and has a lower risk of hypoglycemic episodes
In T2DM patients:
  • Single injection of intermediate or long acting insulin can be added to existing oral hypoglycemic agents
  • Above regimes (same as T1DM) can also be used if one injection of insulin is not controlling plasma glucose levels

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How to start a newly diagnosed T1DM patient on insulin

Newly diagnosed patients can be started on two or four injections of insulin after appropriate education, which is best done by the diabetes nurse specialist.

  • Starting total 24-h dose of insulin is usually around 0.3–0.6 unit/kg, divided into:
    • Half to two-thirds of the dose as intermediate/long acting insulin
    • One-third to half the dose as short acting insulin
  • A newly diagnosed patient weighing 70 kg can be started on:
    • Mixture of insulin 12 units morning and 8 units evening
    • Basal bolus: 8–10 units of intermediate/long acting and 2–6 units of fast/ultra-fast acting with meals
  • It is good practice to teach insulin-treated patients carbohydrate counting (assessment of carbohydrate in each meal) to adjust the doses of insulin injections according to meal size.

What are the complications of insulin treatment?

  • Hypoglycemia
    • All patients should be warned about the symptoms of hypoglycemia, which can be very unpleasant including: tremor, sweating, nausea and feeling hungry
    • All patients should be properly educated to learn how to manage a hypoglycemic episode
  • Lipoatrophy and lipohypertrophy at insulin injection sites: the former is rarely seen now but the latter can still occur (Fig. 35, color plate section). Further injection into affected areas should be avoided.

Other than daily injections, are there any other modes of delivery for insulin?

  • Insulin can be delivered by an insulin pump, using a cannula placed in the abdomen (changed every 2–3 days)
    • Insulin is continuously infused with bolus doses given with meals

What to do with a T1DM patient during clinic reviews?

  • Assess diabetes control
    • Review blood glucose diary, paying particular attention to highs and troughs
    • Is there any particular pattern for the sugar readings? For example, high fasting sugar indicates the need for higher doses of intermediate or long acting insulin; high post meal sugars indicate the need for higher short acting insulin before the meal
    • Check HbA1c, which gives an indication of the average diabetes control over the previous 6 weeks
  • Check for associated complications
    • Cardiovascular (particularly in older patients); check blood pressure in all patients
    • Nephropathy (check urine for albumin excretion)
    • Retinopathy (regular retinal examination or photography)
    • Foot examination: pulses and peripheral sensation

Next Text Part 2- The Basics: Treatment of Type 2 Diabetes (T2DM)

Ramzi Ajjan, MRCP, Med Sci, PhD, Senior Lecturer and Honorary Consultant in Diabetes and Endocrinology, Department of Health Clinician Scientist, The LIGHT Laboratories, University of Leeds, Leeds, UK
 

A John Wiley & Sons, Ltd., Publication This edition first published 2011 © 2011 by John Wiley & Sons, Ltd.

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