Diabetes Mellitus

Question 1

Summarise T2DM

Answer 1

The cornerstone of therapy for all patients with diabetes is a personalised self-management programme, usually developed with the patient by a diabetes education nurse or nutritionist.

Lifestyle changes plus metformin are initial antihyperglycaemic therapy for most patients. Glycaemic goals and treatment choices are individualised.

Selected glucose-lowering drugs reduce all-cause and cardiovascular mortality. Addition of a sodium-glucose co-transporter 2 (SGLT2) inhibitor or glucagon-like peptide-1 (GLP-1) agonist is recommended in patients with long-standing suboptimal glycaemic control plus established cardiovascular and/or renal disease.

Blood pressure control, lipid management, smoking cessation, and glycaemic management reduce the risk of macrovascular complications such as heart attack and stroke. Glycaemic control and blood pressure management reduce the risk of microvascular complications (neuropathy, nephropathy, retinopathy).

Question 2

Define T2DM

Answer 2

Type 2 diabetes mellitus is a progressive disorder defined by deficits in insulin secretion and action that lead to abnormal glucose metabolism and related metabolic derangements.[1] Although the aetiologies of type 1 and type 2 diabetes differ dramatically, both lead to hyperglycaemic states, and both share common macrovascular (coronary heart, cerebrovascular, and peripheral vascular disease) and microvascular (retinopathy, nephropathy, and neuropathy) complications. Type 2 diabetes is most often diagnosed following routine screening. It is preceded by a state of pre-diabetes, which is defined by a single fasting plasma glucose of 5.6-6.9 mmol/L (100-125 mg/dL) or a HbA1c of 39-46 mmol/mol (5.7% to 6.4%) in the absence of diabetes. Diabetes diagnosis is based on two confirmed values of: fasting plasma glucose >6.9 mmol/L (125 mg/dL); HbA1c of 48 mmol/mol (6.5%) or greater; or (less commonly) abnormal glucose tolerance test results, or a random plasma glucose of ≥11.1 mmol/L (≥200 mg/dL) plus symptoms of hyperglycaemia. A single blood sample is sufficient to establish a diabetes diagnosis if assays of both HbA1c and fasting plasma glucose meet criteria for diabetes diagnosis.

Question 3

Describe the rise in the prevalence of T2DM worldwide

Answer 3

Diabetes prevalence is increasing worldwide, compounded by population growth and an ageing population.[3] In 1980, the global age-standardised diabetes prevalence was 4.3%.[3] In 2017, the global age-standardised diabetes prevalence was estimated at 8.6%.[4] Survey data of diabetes in adults does not separate type 1 and type 2 diabetes, but most cases of diabetes (around 90%) are type 2.[3] However, while the overall burden of diabetes is increasing, trends in the incidence rate of diabetes plateaued and now appear to be decreasing. Data from the US National Health Interview Survey documented that the incidence of age-adjusted, diagnosed diabetes decreased from 2007 to 2017, from 7.8 to 6.0 per 1000 adults

Question 4

What factors have been responsible for the recent increase in cases of T2DM worldwide

Answer 4

Incidence and prevalence of type 2 diabetes have risen steadily since 1950, driven by increasing prevalence in obesity and being overweight.[6] In the US in 2017, type 2 diabetes had a prevalence of 8.5%.[7] In the UK, prevalence rates of type 2 diabetes increased from 3.21% in 2004 to 5.26% in 2014, and incidence rates remained stable.[8] Clinical onset is usually preceded by many years of insulin resistance and hyperinsulinaemia before elevated glucose levels are detectable

Question 5

At what stage in life are patients with T2DM often diagnosed

Answer 5

Patients with type 2 diabetes have a very high risk of concurrent hypertension (80% to 90%), lipid disorders (70% to 80%), and overweight or obesity (60% to 70%).[9] When diabetes is diagnosed at age 40 years, men lose an average of 5.8 years of life, and women lose an average of 6.8 years of life, highlighting the importance of primary prevention of diabetes.[10] However, onset of diabetes at older ages has much less effect on life expectancy if acceptable glucose, blood pressure, and lipid control can be achieved and maintained.

Question 6

Describe the aetiology of T2DM

Answer 6

Type 2 diabetes often presents on a background genetic predisposition and is characterised by insulin resistance and relative insulin deficiency. Insulin resistance is aggravated by ageing, physical inactivity, and overweight (body mass index [BMI] 25-29.9 kg/m²) or obesity (BMI >30 kg/m²). Among obese patients, weight loss often reduces the degree of insulin resistance and may delay diabetes onset or ameliorate diabetes severity and thereby reduce risk of long-term complications. Insulin resistance affects primarily the liver, muscle, and adipocytes, and it is characterised by complex derangements in cellular receptors, intracellular glucose kinase function, and other intracellular metabolic processes.[6] The complexity and variety of these intracellular derangements suggest that what is now classified as type 2 diabetes may be in fact a larger group of conditions that await future definition.

Question 7

Describe the pathophysiology of T2DM

Answer 7

The precise mechanism by which the diabetic metabolic state leads to microvascular and macrovascular complications is only partly understood but probably involves both uncontrolled blood pressure (BP) and uncontrolled glucose, increasing the risk of microvascular complications such as retinopathy and nephropathy. Mechanisms may involve defects in aldose reductase and other metabolic pathways, damage to tissues from accumulation of glycated end products, and other mechanisms. With respect to macrovascular complications, high BP and glucose raise risk, but so do lipid abnormalities and tobacco use. One unifying theory postulates the existence of a metabolic syndrome that includes diabetes mellitus, hypertension, dyslipidaemias, and obesity, and predisposes to coronary heart disease, stroke, and peripheral artery disease.[6] However, this theory is not universally accepted as more clinically useful than assessing individual cardiovascular risk factors

Question 8

Describe a typical case history for T2DM

Answer 8

An overweight 55-year-old woman presents for preventative care. She notes that her mother died of diabetes, but reports no polyuria, polydipsia, or weight loss. BP is 144/92 mmHg, fasting blood sugar 8.2 mmol/L (148 mg/dL), HbA1c 65 mmol/mol (8.1%), LDL-cholesterol 5.18 mmol/L (200 mg/dL), HDL-cholesterol 0.8 mmol/L (30 mg/dL), and triglycerides 6.53 mmol/L (252 mg/dL).

Question 9

Describe some other presentations of T2DM

Answer 9

Patients with type 2 diabetes can also present with symptoms such as blurred vision; fatigue; erectile dysfunction; urinary tract or candidal infections; dry itchy skin; paresthaesias; increased urination, thirst, and appetite; or unexplained weight loss.

Question 10

When is T2DM most commonly diagnosed

Answer 10

Type 2 diabetes is most often diagnosed on routine screening. Strong risk factors, which also indicate the need for screening, include: older age; overweight/obesity; black, Hispanic, or Native American ancestry; family history of type 2 diabetes; history of gestational diabetes; presence of pre-diabetes; physical inactivity; polycystic ovary syndrome; hypertension; dyslipidaemia; or known cardiovascular disease.[2] Symptomatic patients may present with: fatigue; polyuria, polydipsia, polyphagia, or weight loss (usually when hyperglycaemia is more severe [e.g., >16.6 mmol/L, >300 mg/dL]); blurred vision; paraesthesias; unintentional weight loss; nocturia; skin infections (bacterial or candidal); urinary infections; or acanthosis nigricans

Question 11

Describe four tests that can be used to diagnose T2DM

Answer 11

One of four tests can be used to establish a firm diagnosis of diabetes:[2]

Fasting plasma glucose (FPG) >6.9 mmol/L (>125 mg/dL)
Random plasma glucose ≥11.1 mmol/L (≥200 mg/dL) with diabetes symptoms such as polyuria, polydipsia, fatigue, or weight loss
2-hour post-load glucose ≥11.1 mmol/L (≥200 mg/dL) on a 75 g oral glucose tolerance test
HbA1c ≥48 mmol/mol (≥6.5%).

Question 12

What is important to remember about testing for T2DM

Answer 12

All of these require confirmation with a second test, which may be the same test or a different test. This means a single blood sample is sufficient to establish a diabetes diagnosis if assays of both HbA1c and fasting plasma glucose meet criteria for diabetes diagnosis.[2] Some variability in HbA1c results is possible as a result of such factors as increased red blood cell turnover (e.g., sickle cell anaemia), factors related to ancestry,[43] or laboratory variation.

Question 13

Describe how sometimes it’s difficult to differentiate between type 1 and type 2 diabetes mellitus in patients

Answer 13

Some individuals cannot be clearly classified as having type 1 or type 2 diabetes at the time of diagnosis.[2] However, at initial diagnosis of diabetes, it is important to determine if immediate treatment with insulin is required. Type 1 diabetes can occur at any age but usually is diagnosed in younger (age <35 years), thinner patients, and has a more rapid onset and often more severe symptoms. Around one third of patients with newly diagnosed type 1 diabetes present with diabetic ketoacidosis (DKA).[44] However, DKA may also occur in type 2 diabetes, particularly if there is an underlying infection.[45][46] Urine ketones should be checked if patients are symptomatic of hyperglycaemia (polyuria, polydipsia, weakness) and volume depletion (dry mucous membranes, poor skin turgor, tachycardia, hypotension, and, in severe cases, shock) at diagnosis or throughout course of disease.

Question 14

Describe C-peptide

Answer 14

C-peptide is produced in equal amounts to insulin and is the best measure of endogenous insulin secretion in patients with diabetes. There is no role for routine testing for C-peptide for diagnosis of diabetes, but measuring C-peptide may be useful in differentiating type 1 and type 2 diabetes.[47] The best evidenced C-peptide test is the glucagon stimulation test (GST), but non-fasting ‘random’ blood C-peptide has been shown to correlate with fasting C-peptide and post-GST samples in subjects with well-defined type 1 or type 2 diabetes.[48] Development of absolute insulin deficiency is a key feature of type 1 diabetes, which results in low (<0.2 nanomol/L) or undetectable levels of plasma C-peptide.[2][47] A GST or non-fasting ‘random’ blood C-peptide level >1 nanomol/L suggests type 2 diabetes.[47] C-peptide results must be interpreted in clinical context of disease duration, comorbidities, and family history

Question 15

Describe how we can evaluate the disease and the risk of both macro- and microvascular complications

Answer 15

Blood pressure, smoking status, and fasting lipid levels should be assessed. Baseline urine albumin/creatinine ratio and serum creatinine with estimated glomerular filtration rate (eGFR) are also indicated, as signs of chronic kidney disease may be present at diagnosis.[2] Clinical assessment of cardiac, carotid, and peripheral circulation, with ECG and vascular investigation (e.g., an ankle-brachial index) can be considered at diagnosis.[2][41] Examination of the feet, including assessment of ankle reflexes, pulses, vibratory sensation, and monofilament touch sensation, and a dilated retinal examination, should be part of the evaluation.[2] HbA1c, lipid levels, blood pressure, urine albumin excretion, renal function, and clinical assessment are monitored at periodic intervals.

Question 16

Describe some key diagnostic features of T2DM in the history and exam

Answer 16

presence of risk factors
Key risk factors include older age; overweight/obesity; black, Hispanic, or Native American ancestry; family history of type 2 diabetes; history of gestational diabetes; presence of pre-diabetes; physical inactivity; polycystic ovary syndrome; hypertension; dyslipidaemia; or known cardiovascular disease.

One unifying theory postulates the existence of a metabolic syndrome that includes diabetes mellitus, hypertension, dyslipidaemias, and obesity, and predisposes to coronary heart disease, stroke, and peripheral artery disease.[49] However, this theory is not universally accepted as more clinically useful than assessing individual cardiovascular risk factors.[50]

asymptomatic
It is very common for type 2 diabetes to be asymptomatic and detected on screening. Symptoms, when present, may indicate more overt hyperglycaemia.

candidal infections
Most commonly vaginal, penile, or in skin folds.

skin infections
Cellulitis or abscesses.

urinary tract infections
Cystitis or pyelonephritis.

Question 17

Describe some other diagnostic features of T2DM

Answer 17

fatigue
Increased fatigability may be an early warning sign of progressive cardiovascular disease; clinicians should have a low threshold for cardiac evaluation.

blurred vision
Due to elevated glucose.

Question 18

Describe some uncommon diagnostic features of T2DM

Answer 18

polydipsia
Usually in patients with fasting plasma glucose >16.6 mmol/L (>300 mg/dL), HbA1c >95 mmol/mol (>11%).

polyphagia
Usually in patients with fasting plasma glucose >16.6 mmol/L (>300 mg/dL), HbA1c >95 mmol/mol (>11%).

polyuria
Usually in patients with fasting plasma glucose >16.6 mmol/L (>300 mg/dL), HbA1c >95 mmol/mol (>11%).

paraesthesias
May occur in the extremities as a result of neuropathy in those with prolonged undiagnosed diabetes.

nocturia
Due to glucose-induced diuresis.

unintentional weight loss
If marked hyperglycaemia is present.

acanthosis nigricans
A velvety, light brown-to-black marking, usually on the neck, under the arms, or in the groin. Can occur at any age. Most often associated with obesity.

Question 19

Describe some genetic and ethnic risk factors for T2DM

Answer 19

family history of type 2 diabetes
Although the specific genetic profile that confers risk has yet to be fully elucidated, epidemiological observations leave little doubt of a substantial genetic component.[6]

non-white ancestry
Prevalence of diabetes varies by ethnic group. Differential prevalence rates have been observed for European Americans, Hispanic Americans, and African-Americans,[16] with people of African, Hispanic, or American-Indian ancestry at higher risk of diabetes compared with white people.[17] In the UK, type 2 diabetes is more common in people of African, African-Caribbean, and South Asian family origin.[18] South Asian and East Asian people are at increased risk of developing type 2 diabetes, probably due to an interplay of diet, lifestyle, and genetic factors

Question 20

Describe the risks of pre-diabetes and gestational diabetes

Answer 20

gestational diabetes
About 50% of women who have gestational diabetes mellitus will go on to develop overt diabetes mellitus within 10 years of delivery.[15]

pre-diabetes
Major risk factor for onset of type 2 diabetes. Progression from pre-diabetes to overt type 2 diabetes occurs at the rate of about 2% to 4% per year

Question 21

Describe some other strong risk factors for T2DM

Answer 21

older age
Older patients are at increased risk. However, the incidence of type 2 diabetes in children and adolescents is increasing.[12]

overweight/obesity
Appears to be the precipitating factor leading to clinical expression of diabetes. The mean body mass index (BMI) at the time of diagnosis of diabetes in several studies is around 31 kg/m², and there is a graded increase in risk of diabetes with increasing BMI.[13] Clinical trials have shown that weight loss is associated with delayed or decreased onset of diabetes in high-risk adults

While the impact on increased risk of diabetes is mediated in part through obesity/overweight, several interventions studies indicate that increased levels of physical activity delay or decrease onset of diabetes in high-risk adults

olycystic ovary syndrome
Elevated risk; should be periodically screened for diabetes.[2]

hypertension
Often associated with type 2 diabetes. Periodic screening is recommended in people with essential hypertension due to increased prevalence of diabetes.[2]

dyslipidaemia
Especially with low high-density lipoprotein (HDL) and/or high triglycerides: periodic diabetes screening is recommended due to the high prevalence of diabetes in patients with dyslipidaemia\

cardiovascular disease
Periodic diabetes screening is recommended due to the high prevalence of diabetes in patients with peripheral vascular and coronary artery disease.[2]

American College of Cardiology/American Heart Association statements identify a number of additional risk factors for atherosclerotic cardiovascular disease, which include: C-reactive protein ≥2 mg/L; coronary artery calcium score ≥100 Agatston units or ≥75% for age, sex, and ethnicity; and ankle-brachial index <0.9.[27]

stress
Stress provokes release of hormones that elevate glucose, and there is some evidence that life stress may predispose to onset of type 2 diabetes.

Question 22

Describe the use of HbA1c as a 1st line investigation

Answer 22

Confirm with a repeat HbA1c or another diagnostic test.[2] HbA1c is also used to monitor glycaemic control, usually every 3 months.

Result:
48 mmol/mol (6.5%) or greater

Question 23

Describe the use of fasting plasma glucose as a first line investigation

Answer 23

Order after a minimum 8-hour fast. Confirm an elevated result with an HbA1c (which can be done on the same sample), a second fasting plasma glucose, or another diabetes diagnostic test

Result;
>6.9 mmol/L (>125 mg/dL)

Question 24

Describe random plasma glucose as a first line investigation

Answer 24

Non-fasting test. Convenient, but less accurate than either fasting plasma glucose, HbA1c, or 75 g oral glucose tolerance test.[2] Used for rapid assessment of glucose status if symptoms such as polyuria, polydipsia, or weight loss are present.

Result:
≥11.1 mmol/L (≥200 mg/dL)

Question 25

Describe 2-hour post load glucose as a first line investigation

Answer 25

More costly and inconvenient than fasting plasma glucose or HbA1c. Diabetes should be confirmed on a separate occasion with another diagnostic test.

Result:
≥11.1 mmol/L (≥200 mg/dL)

Question 26

Describe how you may consider fasting lipid profile

Answer 26

Dyslipidaemia is common in type 2 diabetes.

Result:
may show high LDL, low HDL, and/or high triglycerides

Question 27

Describe how you may consider measuring urine ketones

Answer 27

Urine ketones should be checked if patients are symptomatic of hyperglycaemia (polyuria, polydipsia, weakness) and volume depletion (dry mucous membranes, poor skin turgor, tachycardia, hypotension, and, in severe cases, shock) at diagnosis or throughout course of disease. Ketoacidosis is a common presentation of type 1 diabetes, but can also occur in type 2 diabetes

Result:
positive in instances of ketoacidosis

Question 28

Describe how you may consider random C-peptide

Answer 28

Not done routinely for diagnosis of diabetes, but may be useful in differentiating type 1 and type 2 diabetes.[47] Absolute insulin deficiency is a key feature of type 1 diabetes, which results in low (<0.2 nanomol/L) or undetectable levels of plasma C-peptide.[2][47] C-peptide results must be interpreted in clinical context of disease duration, comorbidities, and family history.

Result:
>1 nanomol/L

Question 29

Describe how you may consider urine albumin secretion

Answer 29

Indicates nephropathy and suggests possible other microvascular damage. Monitored yearly.

May be assessed with albumin-to-creatinine ratio in a random urine sample

Result:
may be increased

Question 30

Describe how you may measure serum creatinine and eGFR

Answer 30

GFR is calculated according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) or Modification of Diet in Renal Disease (MDRD) formulas. The CKD-EPI formula is now recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI) because it removes bias at higher GFR levels, allowing for reporting across a full range

Result:
may show renal insufficiency

Question 31

Describe how you may consider doing an ECG

Answer 31

Baseline assessment. A normal ECG does not rule out coronary artery disease. Patients with an abnormal resting ECG may require further cardiac investigation

Result:
May indicate prior ischaemia

Question 32

Describe how you may consider an ankle-brachial index

Answer 32

A non-invasive tool to detect peripheral arterial disease (PAD), which has a high prevalence in patients with diabetes. The American Diabetes Association recommends that ABI should be performed in patients with symptoms of PAD.[2] Can be used to screen for PAD.

Result:
≤0.9 is abnormal

Question 33

Describe how you may consider a dilated retinal examination

Answer 33

Patients should be referred to an ophthalmologist at the time of diagnosis of type 2 diabetes

May show retinopathy

Question 34

Describe how pre-diabetes is a differential.

Answer 34

Patients with pre-diabetes often have no specific differentiating signs or symptoms.

Fasting plasma glucose level is 5.6 to 6.9 mmol/L (100-125 mg/dL) in pre-diabetes.

2-hour post-load glucose after 75 g of oral glucose is 7.8 to 11.0 mmol/L (140-199 mg/dL) in pre-diabetes.

HbA1c of 38-47 mmol/mol (5.7% to 6.4%) indicates pre-diabetes and high risk of future diabetes

Question 35

Describe how T1DM is a differential

Answer 35

Onset often at age <35 years, but can occur in older individuals.

Many patients are not obese.

More commonly presents with symptoms (polyuria, polydipsia, weight loss, generalised weakness, blurred vision) and ketosis, rather than being detected by screening

Urine ketones are often present in type 1 diabetes, but may be positive in type 2 diabetes if there is severe volume depletion.

Low (<0.2 nanomol/L) or absent C-peptide level.

One or more auto-antibodies (antiglutamic acid decarboxylase [GAD] antibodies, islet cell antibodies [ICA], insulin auto-antibodies, auto-antibodies to the tyrosine phosphates IA-2 and IA-2beta) are present in 85% of patients with type 1 at the time of diagnosis, but may disappear within a few years.[51] Type 1 diabetes is defined by the presence of one or more of these autoimmune markers, but testing is usually not required for diagnosis.

Glucose screening criteria cannot be used to differentiate type 1 and type 2 diabetes, as they are identical.

Question 36

Describe how latent autoimmune diabetes in adults (LADA) is a differential

Answer 36

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.[52]

LADA is considered a subset of type 1 diabetes; however, patients with LADA are frequently misclassified as having type 2 diabetes.

Positive for at least 1 of the 4 antibodies commonly found in type 1 diabetic patients (ICAs and auto-antibodies to GAD65, IA-2, and insulin).

Question 37

Describe how monogenic diabetes is a differential

Answer 37

Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes and affects 1% to 2% of people with diabetes.[54]

MODY is caused by mutation of a single gene (i.e., monogenic). As of 2011, at least 11 forms of MODY are known.[55]

It has autosomal dominant inheritance and 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.[55]

Patients are often misclassified as type 1 or type 2 diabetes. Insulin treatment is often not needed.

Genetic testing in patients with high index of suspicion (genes encoding glucokinase and transcription factors are identified)

Question 38

Describe how ketosis-prone diabetes is a differential

Answer 38

Presents with unprovoked ketosis or ketoacidosis.[57]

Considered an ‘idiopathic diabetes’, as patients have no evidence of autoimmunity. Often misclassified as type 1 diabetes, as individuals have episodic ketoacidosis and exhibit varying degrees of insulin deficiency between episodes. However, a type 2 diabetes phenotype is common (obesity, insulin resistance, metabolic syndrome).[58]

Patients are usually from a minority ethnic group, and have a positive family history of diabetes.[58]

On discontinuation of insulin therapy, the period of near-normoglycaemic remission may last for a few months to several years. However, almost half will be insulin dependent 10 years after diagnosis.

Absent islet cell auto-antibodies.

C-peptide often low or undetectable during diabetic ketoacidosis; recovery may be used as reliable predictor of insulin discontinuation

Question 39

Describe how gestational diabetes is a differential

Answer 39

Only occurs during pregnancy.

Gestational diabetes is generally detected by screening during pregnancy. Based on the current evidence, the US Preventive Services Task Force recommends screening for gestational diabetes in asymptomatic pregnant women after 24 weeks of gestation.[59] One-step or 2-step screening strategies may be used.[2]

When overt hyperglycaemia occurs during pregnancy, it may be difficult to distinguish between undetected pre-existing type 2 diabetes and gestational diabetes.

Question 40

Describe the screening of T2DM

Answer 40

The US Preventive Services Task Force (USPSTF) now recommends screening for glucose status for adults aged 40 to 70 years who have body mass index (BMI) ≥25. Those with normal test results should be re-screened every 3 years. Those who have pre-diabetes should subsequently be screened annually for diabetes.[60]

The American Diabetes Association (ADA) has recommended routine screening of non-pregnant asymptomatic adults of any age with BMI ≥25 kg/m² (≥23 kg/m² for people from South Asia) plus one or more risk factors for diabetes. Those without risk factors should be screened starting at age 45 years. Risk factors for diabetes include family history of diabetes, overweight or obesity, sedentary lifestyle, high-risk ancestry, gestational diabetes, hypertension, dyslipidaemia (low HDL-cholesterol and/or elevated triglycerides), vascular disease, glucose intolerance, or polycystic ovary syndrome.[2]

Recommended screening tests include fasting plasma glucose (pre-diabetes if 5.6 to 6.9 mmol/L [100-125 mg/dL] once, in the absence of diabetes) and/or HbA1c (pre-diabetes if 39-46 mmol/mol [5.7% to 6.4%] once, in the absence of diabetes; diabetes if ≥48 mmol/mol [≥6.5%] twice). Oral 75 g glucose tolerance test is less commonly used in non-pregnant adults