Diabetes Mellitus Flashcards
Diagnosis of diabetes mellitus (Physical examination)
What signs (during physical examination) may propose a diagnosis of DM?
Physical examination at diagnosis
Evidence of weight loss and dehydration may be present, and the breath may smell of ketones.
Older people may present with established complications. Occasionally, there will be physical signs of an illness causing secondary diabetes (see Boxes 23.4 and 23.5).
People with severe insulin resistance may have acanthosis nigricans, which is characterized by blackish pigmentation at the nape of the neck and in the axillae (see Fig. 22.37).
Hypertension is present in 50% of people with type 2 diabetes and in a higher proportion of people of African and Caribbean ethnicity.
Diagnosis of diabetes mellitus (Diagnosis and investigations)
Which laboratory measurements are utilized?
What is glycated hemoglobin?
What values are required in each measurements to diagnose DM?
Diagnosis with and without symptoms
What other diagnositc criterias are there and what are they described as?
Values required to define someone wih impaired fasting glucose
Once considered, diabetes is easy to diagnose. This may be by a laboratory measurement of fasting plasma glucose (FPG), random glucose or a 2-hour plasma glucose after a 75-g oral glucose tolerance test (OGTT).
The use of glycated haemoglobin (HbA1c; also called A1c in the USA) was introduced as an alternative method in 2011. HbA1c is an integrated measure of an individual’s prevailing blood glucose concentration over several weeks and is also used to guide treatment decisions.
Diabetes can be diagnosed if the fasting plasma glucose is higher than or equal to 7.0 mmol/L (126 mg/dL) or the random or 2-hour glucose tolerance test plasma glucose is more than or equal to 11.1 mmol/L (200 mg/dL) or the HbA1c is higher than or equal to 48 mmol/mol (6.5%).
When overt symptoms are present, only one biochemical test is needed but in the absence of clear symptoms, two abnormal glucose or HbA1c tests are required (Boxes 23.7 and 23.8).
Fasting, 2-hour glucose and HbA1c identify slightly different populations of people with diabetes; that is, someone may be diagnosed by one criteria but not another. However, with time, people will eventually cross the diagnostic threshold for the other tests.
The diagnostic criteria recognize two further categories of abnormal glucose concentrations: impaired fasting glycaemia (IFG) and impaired glucose tolerance (IGT). Collectively these have been described as ‘pre-diabetes’ but this is not strictly accurate because the majority will never develop diabetes.
Neither IFG nor IGT are clinical entities in their own right but they identify people who are at high risk of diabetes and cardiovascular disease.
Individuals with IGT have a similar risk of cardiovascular disease as those with frank diabetes, but do not develop microvascular complications.
Impaired fasting glucose (IFG) only overlaps with IGT to a limited extent, and the associated risks of cardiovascular disease and future diabetes are not directly comparable.
Impaired glucose tolerance can only be diagnosed with a glucose tolerance test (see Box 23.8) and is complicated by poor reproducibility of the key 2-hour value in this test. Impaired fasting glucose is defined as a fasting plasma glucose between 6.1 and 6.9 mmol/L (110–126 mg/dL) and has the practical advantage that it avoids the need for a glucose tolerance test.
The ADA definition of IFG differs slightly from the WHO criteria in that the ADA threshold is 100 mg/dL (5.6 mmol/L).
Glycosuria cannot be used to diagnose diabetes, but requires further investigation.
It is commoner in older people, who have an altered renal threshold for glucose. It may also occur in familial renal glycosuria, which is a monogenic disorder affecting function of the sodium–glucose co-transporter (SGLT2) and found in about 1 : 400 of the population.
Differential diagnosis of 1st and 2nd type of DM
What measurements can help determine the type of diabetes?
What is present when type 1 DM is diagnoed but disappears with time?
Other investigations
No further tests are needed to diagnose diabetes, but measurement
of C-peptide and islet auto-antibodies can help determine the type
of diabetes.
C-peptide can be measured in blood or urine; it is often
present when type 1 diabetes is diagnosed but disappears with time
and is a more useful investigation in people with a duration of diabetes
longer than 5 years.
Other routine investigations include urine
testing for protein, a full blood count, urea and electrolytes, liver
biochemistry and random lipids. The latter test is useful to exclude
associated hyperlipidaemia and, if elevated, should be repeated as
a fasting measurement after diabetes has been brought under control.
Investigations of secondary causes of diabetes or associated
autoimmune disease may be appropriate (see Box 23.4).
Treatment of type 1 (and 2) DM
What should the diet consist of?
In order to optimize glycaemic control, people need to…
Glycaemic index
Diet plays a key role in the management and clinical care of all
people with diabetes. However, there has been a lot of controversy
about what constitutes an ideal or optimal diet for a person with, or
at risk of, diabetes. Previous guidance focused on the ideal macronutrient
composition of the diet, but the latest guidance highlights
the role of certain foods and dietary patterns. In common with the
general population, people should be encouraged to eat more vegetables, fruits, wholegrains, fish, nuts and pulses while reducing the
consumption of red and processed meat, refined carbohydrates
and sugar-sweetened beverages. As no one diet is effective in managing
diabetes, it is important to adopt an individualized approach
taking into consideration the person’s personal and cultural preferences.
Box 23.10 summarizes the latest Diabetes UK dietary recommendations
for people with diabetes.
One exception to the food-based recommendations concerns
carbohydrate intake, which is important for people using intensive
insulin regimens, particularly those with type 1 diabetes. In people
without diabetes, the amount of insulin produced after eating
is dependent on the carbohydrate consumed. In order to optimize
glycaemic control, people need to match their insulin dose to the
carbohydrate in the meal and so it is important to teach people how
to ‘carbohydrate count’. Several books and apps are available to
help with this process.
The peak blood glucose after a meal varies with the type of carbohydrate.
For example, the glucose profile after eating pasta is
much flatter than that seen after eating the same amount of carbohydrate
as a sugary drink because pasta has a lower ‘glycaemic
index’. Foods with a low glycaemic index are encouraged to prevent
rapid swings in plasma glucose.
Treatment of type 2 (and 1) DM
What is a treatment option for people with severe obesity?
Benefits of physical activity
Physical activity - People with diabetes should be advised to…
Importance of weight loss in type 2 diabetes
For many years, it was thought that type 2 diabetes was an incurable
progressive condition; however, the latest evidence challenges
this view. People who can be supported to lose 10–15 kg of body
weight through lifestyle, pharmacological or surgical treatment can
enter remission.
Bariatric or metabolic surgery (see p. 1252) is a treatment option for people with severe obesity. The National Institute for Health and Care Excellence (NICE) recommends consideration of surgery in those with a body mass index (BMI) higher than 40 kg/m2, or in those with a BMI of more than 35 kg/m2 and co-morbidities, such as diabetes. In the USA, the Food and Drug Administration (FDA)-recommended BMI thresholds are lower. The most common operations are gastric bypass and sleeve gastrectomy. These operations lead to a mean weight loss of approximately 30% and diabetes remission in up to 70% of people, depending on the duration of diabetes. Surgery also improves quality of life and reduces cardiovascular disease and mortality. The operative mortality is low (1 in 1000) but there are long-term consequences for nutrition, bone health and suicide.
Physical activity
No treatment for diabetes is complete without exercise as physical
activity has profound benefits, including improved fitness, reduced
insulin requirement and better glycaemic control, lower cardiovascular risk and greater life expectancy.
The maxim that some exercise is better than no exercise and more exercise is better than some exercise applies. People with diabetes should be advised to take at least 150 minutes of aerobic exercise and resistance training per week spread over a minimum of 3 days. Prior to exercise, however, it is important to ascertain whether the individual has either macrovascular or microvascular complications as these may be exacerbated by unaccustomed activity.
People with type 1 diabetes should be advised that physical
activity can reduce the insulin requirement and lead to unstable glucose
levels during and immediately after exercise and a later risk of
severe hypoglycaemia.
Tobacco smoking
Smoking can adversely affect glucose management as well as
increasing the risk of a number of medical conditions and so healthcare
professionals should support people who smoke to quit.
Basic groups of oral drugs in therapy of DM (1/3)
Biguanides
MoA
Clinical use
Sulphonylureas
MoA
Clinical use
Biguanides: metformin
Metformin is currently the only available biguanide.
The precise mechanism of action of metformin remains unclear but
may involve the activation of the enzyme adenosine monophosphate
(AMP) kinase, which regulates cellular energy metabolism.
Metformin reduces the rate of gluconeogenesis, and hence hepatic
glucose output, and increases insulin sensitivity. It does not affect
insulin secretion, does not induce hypoglycaemia and does not predispose
to weight gain. In addition to its effects on glucose, it may
also suppress appetite and stabilize weight.
Metformin is the best-validated treatment for type 2 diabetes and appears as the first-line pharmacological agent in all type 2 diabetes guidelines.
Metformin may be given in combination with all other oral diabetes treatments as well as GLP-1 receptor agonists or insulin. Metformin has been used alongside insulin in people with type 1 diabetes but only with limited efficacy.
Sulphonylureas
Sulphonylureas act on the β cell to induce insulin secretion. They are ineffective in people without a functional β-cell mass and therefore have no effect in people with type 1 diabetes. Sulphonylureas bind to the sulphonylurea receptor on the β-cell membrane, which closes ATP-sensitive potassium channels and blocks potassium efflux. The resulting depolarization promotes calcium influx and stimulates insulin release.
Most clinical guidelines recommend that sulphonylureas can be used as an alternative first-line agent where metformin is contraindicated or not tolerated. Although this is more effective than many other oral agents in the short term (1–3 years), the sulphonylurea effect wears off as the β-cell mass declines. Sulphonylureas can also be used in combination with other oral antidiabetes agents or basal insulin, although it is usually stopped when the individual requires short-acting insulin at mealtimes.
Basic groups of oral drugs in therapy of DM (2/3)
Meglitinides or post-prandial insulin releasers
What are Meglitinides?
MoA of Meglitinides
Thiazolidinediones or ‘Glitazones’
Which drug is the only available thiazolidinedione in many countries?
MoA of Thiazolidinediones
Dipeptidyl peptidase-4 inhibitors or ‘Gliptins’
MoA
Meglitinides or post-prandial insulin releasers
Meglitinides are short-acting agents that promote insulin secretion in response to meals.
Like sulphonylureas, meglitinides act by closing the K+-ATP
channel in the β cells (see Fig. 23.4). They are rapidly metabolized
and have a short duration of action of less than 3 hours.
Thiazolidinediones or ‘Glitazones’
In many countries, pioglitazone is the only available thiazolidinedione.
Thiazolidinediones reduce insulin resistance by interaction with peroxisome proliferator-activated receptor-gamma (PPAR-γ), a nuclear receptor that regulates large numbers of genes, including those involved in lipid metabolism and insulin action.
Dipeptidyl peptidase-4 inhibitors or ‘Gliptins’
Dipeptidyl peptidase-4 (DPP4) inhibitors have been used since 2006
and are one of two classes of drug that improve glycaemic control
by enhancing the incretin effect.
These drugs inhibit the enzyme DPP4, which prevents the rapid
inactivation of glucagon-like peptide-1 (GLP-1), which in turn increases insulin secretion and reduces glucagon secretion.
DPP-4 inhibitors are most effective in the early stages of type 2 diabetes, when insulin secretion is relatively preserved, and are currently recommended for second-line use in combination with metformin or a sulphonylurea. Although they only have relatively modest effects on glucose lowering, they are included in most type 2 diabetes treatment algorithms because they are well tolerated. DPP-4 inhibitors do not promote weight gain, have a low risk of hypoglycaemia and can be used safely in people with renal impairment.
Basic groups of oral drugs in therapy of DM (3/3)
Sodium-glucose transporter 2 inhibitors (‘flozins’)
MoA
Alpha-glucosidase inhibitors
MoA
Sodium-glucose transporter 2 inhibitors (‘flozins’)
SGLT2 inhibitors have been available since 2011 (see Box 23.14). In
addition to their effects on blood glucose, they lower body weight,
improve renal dysfunction and reduce the risk of atherosclerotic
cardiovascular events and heart failure.
SGLT2 inhibitors lower the renal threshold for glucose, consequently
increasing urinary glucose excretion.
The glucose lowering effect is dependent on good renal function but the
renoprotective benefits are seen in people with lower eGFR. This
is leading to an expansion of their use in people with reduced eGFR.
Alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors, such as acarbose, are designer drugs
that reduce carbohydrate absorption after a meal.
Alpha-glucosidase inhibitors prevent α-glucosidase, the last enzyme involved in carbohydrate digestion, from breaking down disaccharides to monosaccharides. This slows the absorption of glucose after a meal and lowers post-prandial glucose.
Other oral therapies
Quick-release bromocriptine
Abnormal circadian rhythm is associated with the development
of insulin resistance, obesity and diabetes. When administered
at daybreak, quick-release bromocriptine appears to reset
hypothalamic dopamine circadian rhythms. It lowers HbA1c by
5–8 mmol/mol (0.5–0.7%) either as monotherapy or in combination
with other antidiabetes medications. The drug is well tolerated.
Colesevelam
Colesevelam is a bile acid-binding resin that lowers cholesterol, and
can reduce blood glucose concentrations by an unknown gastrointestinal
mechanism.
Short-acting insulins
Soluble human insulin is… (Characteristics)
Absorption is delayed because…
Names of Short-acting insulin analogues
Short-acting insulin characteristics
Soluble human insulin is absorbed slowly, reaching a peak 60–90
minutes after subcutaneous injection. Its action tends to persist
after meals, predisposing to hypoglycaemia.
Absorption is delayed because soluble insulin forms stable hexamers (six insulin molecules around a zinc core), which need to dissociate to monomers or dimers before it can enter the circulation.
This delay is inconvenient for people with diabetes because
the insulin should be injected 20–30 minutes prior to a meal,
which often is not feasible. Short-acting insulin analogues
(insulin lispro, insulin aspart and insulin glulisine) have been
engineered that dissociate more rapidly following injection without
altering the biological effect (see Fig. 23.2). These insulin
analogues enter and disappear from the circulation more rapidly
than soluble insulin. A newer formulation of insulin aspart has
been developed that dissociates and enters the circulation even
more rapidly.
The use of short-acting insulin analogues in people with type 1
diabetes reduces total and nocturnal hypoglycaemic episodes and
improves glycaemic control as judged by postprandial glucose concentrations and HbA1c. The benefits in people with type 2 diabetes
are more modest but short-acting insulin analogues seem to provide
better control of HbA1c and postprandial glucose than soluble
human insulin.
Intermediate and longer-acting insulins
The action of human insulin can be prolonged by the addition of
zinc or protamine. The most widely used form is NPH (neutral protamine
Hagedorn) or isophane insulin but its use is hampered by variability from one injection to another, the need to re-suspend the insulin prior to injection and a peak action, which generally occurs in the middle of the night.
Long-acting analogues have been developed to delay absorption and prolong the duration of action (see Fig. 23.2). Insulin glargine is soluble in the vial as a slightly acidic (pH 4) solution but precipitates at subcutaneous pH, thus prolonging its duration of action. A concentrated formulation of insulin glargine is now available with a longer and flatter duration of action than the standard preparation.
Insulin detemir and insulin degludec have a fatty acid ‘tail’ that binds to serum albumin; the slow dissociation from the bound state prolongs the duration of action. In the case of insulin degludec, it forms long multihexamer chains at the site of injection, which only dissociate very slowly. Long-acting insulin analogues reduce hypoglycaemia for people with both type 1 diabetes and type 2 diabetes, particularly at night.
As insulin analogues are more expensive than NPH insulin, in the
case of type 2 diabetes NICE recommends that insulin analogues
are reserved for people who do not respond well to NPH insulin.
The European Association of the Study of Diabetes and American
Diabetes Association consensus report on the management of type
2 diabetes notes the benefits of insulin analogues but highlights that
the way in which insulin is used has a greater impact on the effectiveness
and adverse effects of insulin than differences between
insulin formulations.
