Diabetes Mellitus - The impact of complications, action and management

 

What is diabetes? 

Diabetes Mellitus, more simply called diabetes, is a serious, long-term (or ‘chronic’) condition that occurs when there are raised levels of glucose in a person’s blood because their body cannot produce any or enough of the hormone insulin or cannot effectively use the insulin it produces. Insulin is a hormone produced in the pancreas; it is required to transport glucose from the bloodstream into the body’s cells where it is used as energy. The lack, or ineffectiveness, of insulin in a person with diabetes means that glucose remains circulating in the blood. Over time, the resulting high levels of glucose in the blood (known as hyperglycaemia) causes damage to many tissues in the body, leading to the development of disabling and life-threatening health complications. There are three main types of diabetes:

 

 

There are also other less common types of diabetes such as: Monogenic diabetes and secondary diabetes.

Modified diagnostic criteria for diabetes

Insulin is an essential hormone produced in the pancreas. It allows glucose from the bloodstream to enter the body’s cells where that glucose is converted into energy. Insulin is also essential for the metabolism of protein and fat. A lack of insulin, or the inability of cells to respond to it, leads to high levels of blood glucose (hyperglycaemia), which is the clinical indicator of diabetes. The threshold levels for the diagnosis of diabetes can be found in this picture.

 

Insulin deficit, if left unchecked over the long term, can cause damage to many of the body’s organs, leading to disabling and life-threatening health complications such as cardiovascular diseases (CVD), nerve damage (neuropathy), kidney damage (nephropathy) and eye disease (leading to retinopathy, visual loss and even blindness). However, if appropriate management of diabetes is achieved, these serious complications can be delayed or prevented altogether.

Type 1 diabetes

Type 1 diabetes is caused by an autoimmune reaction in which the body’s immune system attacks the insulin-producing beta cells of the pancreas. As a result, the body produces very little or no insulin. The causes of this destructive process are not fully understood but a likely explanation is that the combination of genetic susceptibility (conferred by many genes) and an environmental trigger, such as a viral infection, initiate the autoimmune reaction. Toxins or some dietary factors have also been implicated. The condition can develop at any age, although type 1 diabetes occurs most frequently in children and young people. Type 1 diabetes is one of the most common chronic diseases in childhood, although type 2 diabetes is also seen in older children and is on the increase due to childhood overweight and obesity becoming more common. 

Symptoms of type 1 diabetes: The most common symptoms of type 1 diabetes include:

• Abnormal and excessive thirst and a dry mouth
• Extreme hunger
• Frequent and abundant urination
• Bedwetting
• Sudden weight loss
• Blurred vision
• Lack of energy and extreme tiredness

People with type 1 diabetes need daily insulin injections to maintain a glucose level in the appropriate range. Without insulin, they would not survive. However, with appropriate daily insulin treatment, regular blood glucose monitoring, education, and support, they can live healthy lives and delay or prevent many of the complications associated with diabetes. 

 

Following a structured self-management plan – comprising insulin use, blood glucose monitoring, physical activity, and a healthy diet – is especially difficult in early childhood as well as in adolescence. 

 

In many countries, especially in economically disadvantaged families, access to insulin and selfcare tools, including structured diabetes education, can be limited. This may lead to severe disability and early death because of harmful substances known as ‘ketones’ building up in the body (diabetic ketoacidosis, DKA). 

 

Living with type 1 diabetes remains a challenge for a child and the whole family, even in countries with access to multiple daily injections or an insulin pump, glucose monitoring, structured diabetes education and expert medical care. Besides the acute complications of hypoglycaemia (abnormally low blood glucose) and DKA, poor metabolic control may lead to poor growth and the early onset of circulatory (or ‘vascular’) complications.   

 

The typical symptoms of type 1 diabetes are listed in this picture. The classic clinical picture of excessive thirst (polydipsia), frequent urination (polyuria) and weight loss may however not be present, and the diagnosis may be delayed or even missed entirely. Even in countries with universal health coverage (UHC), diagnosis of type 1 diabetes may be delayed until the first hospital admission for DKA, sometimes with fatal results. 

 

Type 1 diabetes is diagnosed by an elevated blood glucose concentration in the presence of some or, rarely, all the symptoms. However, diagnosing the type of diabetes is sometimes difficult and additional testing may be required to distinguish between type 1 and type 2 diabetes or other forms of diabetes, particularly the so-called ‘monogenic’ types. 

 

The incidence of type 1 diabetes is increasing worldwide, but there is considerable variation by country with some regions of the world having much higher incidence than others. The reasons for this are unclear but the rapid increase over time must be due to non-genetic, probably environmental, and perhaps lifestyle related changes, such as rapid weight gain and/or inappropriate feeding in infancy. The decreasing incidence of infections in western countries (the ‘hygiene hypothesis’) has also been suggested as a risk factor for the condition.

Type 2 diabetes

In type 2 diabetes, hyperglycaemia is the result, initially, of the inability of the body’s cells to respond fully to insulin, a situation termed ‘insulin resistance’. During the state of insulin resistance, the hormone is ineffective and, in due course, prompts an increase in insulin production. Over time, inadequate production of insulin can develop because of failure of the pancreatic beta cells to keep up with demand. Type 2 diabetes is most seen in older adults but is increasingly seen in children and younger adults owing to rising levels of obesity, physical inactivity, and inappropriate diet. 

Symptoms of type 2 diabetes: The symptoms of type 2 diabetes are similar to those of type 1 diabetes and include:

• Excessive thirst and a dry mouth
• Frequent and abundant urination
• Lack of energy, extreme tiredness
• Sexual issues
• Blurred vision
• Tingling or numbness in hands and feet
• Recurrent fungal infections in the skin and
• Slow-healing wounds

These symptoms can be mild or absent and so people with type 2 diabetes may live several years with the condition before being diagnosed.

Type 2 diabetes may present with symptoms like those of type 1 diabetes but, in general, the presentation of type 2 diabetes is much less dramatic, and the condition may be completely symptom-less. Also, the exact time of the onset of type 2 diabetes is usually impossible to determine. As a result, there is often a long pre-diagnostic period and as many as one-third to one-half of people with type 2 diabetes in the population may be undiagnosed. When unrecognized for a prolonged time, complications such as retinopathy or a lower-limb ulcer that fails to heal may be present at diagnosis. The causes of type 2 diabetes are not completely understood but there is a strong link with overweight and obesity, and increasing age, as well as with ethnicity and family history. As with type 1 diabetes, type 2 diabetes results from a combination of multi-gene predisposition and environmental triggers.

The cornerstone of type 2 diabetes management is the promotion of a lifestyle that includes a healthy diet, regular physical activity, smoking cessation, and maintenance of a healthy body weight. As a contribution to improving the management of type 2 diabetes, in 2017 IDF issued the IDF Clinical Practice Recommendations for Managing Type 2 Diabetes in Primary Care. If attempts to change lifestyle are not sufficient to control blood glucose levels, oral medication is usually initiated with metformin as the first-line medicine. If treatment with a single antidiabetic medication is not sufficient, a range of combination therapy options are now available (e.g., sulphonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) analogues). When oral medications are unable to control hyperglycaemia to recommended levels, insulin injections may be necessary.

Beyond the control of raised glucose levels, it is vital to manage blood pressure and blood lipid levels and to assess metabolic control on a regular basis (at least annually). This will enable screening for the development of renal complications, retinopathy, neuropathy, peripheral arterial disease, and foot ulceration. With regular check-ups and effective lifestyle management – and medication as needed – people with type 2 diabetes can lead long and healthy lives. 

Globally, the prevalence of type 2 diabetes is high and rising across all regions. This rise is driven by population aging, economic development and increasing urbanization leading to more sedentary lifestyles and greater consumption of unhealthy foods linked with obesity. However, the beneficial results of early detection, more effective treatment and the resulting longer survival are also contributing to the rise in prevalence. 

As previously mentioned, type 2 diabetes has also become a concern in children and young people because of an increasing prevalence of obesity. Unfortunately, population-based studies in this area are scarce and there is a large variety in methods and general quality of published observations. Nevertheless, it is clear that type 2 diabetes is particularly prevalent in some groups such as Pima, Navajo, and Canadian First Nation people and those of Asian and Afro-American descent. In these groups, and among American-Hispanic, Japanese, and Chinese children, type 2 diabetes appears to be on the increase, whereas no increase is seen in non-Hispanic white children, which probably reflects varying genetic susceptibility. Females are more commonly affected by type 2 diabetes in all groups.

Gestational diabetes

According to WHO and the International Federation of Gynaecology and Obstetrics (FIGO), hyperglycaemia in pregnancy (HIP) can be classified as either gestational diabetes mellitus (GDM) or diabetes in pregnancy (DIP). 

Women with slightly elevated blood glucose levels are classified as having gestational diabetes, which tends to occur from the 24th week of pregnancy, whilst women with substantially elevated blood glucose levels are classified as having diabetes mellitus in pregnancy. Previously unknown diabetes should be detected as early as possible in the pregnancy. 

Women with hyperglycaemia during pregnancy can control their blood glucose levels through a healthy diet, gentle exercise, and blood glucose monitoring. In some cases, insulin or oral medication may also be prescribed.

Gestational diabetes mellitus is diagnosed for the first-time during pregnancy and may occur anytime during pregnancy (most likely after 24 weeks). Diabetes in pregnancy applies to pregnant women who have previously known diabetes or have hyperglycaemia that was first diagnosed during pregnancy and meets WHO criteria of diabetes in the non-pregnant state. Diabetes in pregnancy may also occur at any time during pregnancy, including the first trimester. It has been estimated that most (75 to 90%) cases of hyperglycaemia in pregnancy are gestational diabetes mellitus.

Gestational diabetes normally disappears after birth. However, women who have been previously diagnosed are at higher risk of developing gestational diabetes in subsequent pregnancies and type 2 diabetes later in life.

Nevertheless, this risk can be halved through lifestyle and pharmacological interventions. Babies born to mothers with gestational diabetes also have a higher risk of developing type 2 diabetes in their teens or early adulthood.

An OGTT (two-hour oral glucose tolerance test) is recommended for the screening of gestational diabetes mellitus between the 24th and 28th week of pregnancy, but for high-risk women the screening should be conducted earlier in pregnancy. The diagnostic criteria for gestational diabetes mellitus vary and remain controversial, complicating the comparison of research data.

Besides those women with hyperglycaemia early in pregnancy, gestational diabetes mellitus arises in women with insufficient insulin secretory capacity to overcome the diminished action of insulin (insulin resistance) due to hormone production by the placenta. Risk factors for gestational diabetes mellitus include older age, overweight and obesity, previous gestational diabetes mellitus, excessive weight gain during pregnancy, a family history of diabetes, polycystic ovary syndrome, habitual smoking and a history of stillbirth or giving birth to an infant with a congenital abnormality. Gestational diabetes mellitus is more common in some ethnic groups.

Gestational diabetes mellitus usually exists as a transient disorder during pregnancy and resolves once the pregnancy ends. However, pregnant women with hyperglycaemia are at higher risk of developing gestational diabetes mellitus in subsequent pregnancies. In addition, the relative risk of developing type 2 diabetes is particularly high at 3 to 6 years after gestational diabetes mellitus and at less than 40 years of age. The increased risks remain markedly elevated thereafter. Considering the high risk of early onset type 2 diabetes and the fact that early onset type 2 diabetes predisposes to high Cardiovascular disease risk, any lifestyle intervention should be started within three years after the index pregnancy to achieve the maximum benefit for the prevention of diabetes. Babies born to mothers with gestational diabetes mellitus also have a higher lifetime risk of obesity and developing type 2 diabetes themselves.

Women with hyperglycaemia detected during pregnancy are at greater risk of adverse pregnancy outcomes. These include high blood pressure and a large baby for gestational age (termed ‘macrosomia’), which can make a normal birth difficult and hazardous, with the baby more prone to fractures and nerve damage. Identification of hyperglycaemia in pregnancy combined with good control of blood glucose during pregnancy can reduce these risks. Women of child-bearing age who are known to have diabetes prior to pregnancy should receive pre-conception advice, higher dose folic acid treatment, medication review, intensive diabetes management and a planned approach to pregnancy. All women who have hyperglycaemia in pregnancy – be it gestational diabetes mellitus, previously undiagnosed hyperglycaemia in pregnancy or existing and known diabetes – require optimal antenatal care and appropriate assistance in postnatal management. Women with hyperglycaemia during pregnancy may be able to control their blood glucose levels through a healthy diet, moderate exercise, and blood glucose monitoring. Interaction with healthcare professionals is important to support their self-management and to identify when medical (e.g., prescription of insulin or oral medications) or obstetric intervention is needed.

Impaired glucose tolerance and impaired fasting glucose

People with raised blood glucose levels that are high enough to be diagnosed as diabetes are considered to have impaired glucose tolerance (IGT), and/or impaired fasting glucose (IFG). These conditions are often described as pre-diabetes as they represent a high risk of transiting to diabetes. 

Impaired glucose tolerance is diagnosed following a glucose tolerance test. This involves measuring the blood glucose concentration two hours after a drink containing 75g of glucose. In impaired glucose tolerance, the glucose level is higher than normal, but not high enough to make a diagnosis of diabetes (which means between 7.8 and 11.1mmol/l (140 to 200 mg/dl)).  

Impaired fasting glucose is diagnosed when the fasting glucose level is higher than normal, but not high enough to make a diagnosis of diabetes (between 6.1 and 7 mmol/l (110 and 125 mg/dl)). Raised levels of HbA1c in the non-diabetic range can also be used to identify people at risk of developing type 2 diabetes. 

People with intermediate hyperglycaemia are at increased risk of developing type 2 diabetes. This shares many characteristics with type 2 diabetes, and is associated with advancing age and the body’s inability to use the insulin it produces. Not everyone with intermediate hyperglycaemia goes on to develop type 2 diabetes; lifestyle interventions – healthy diet and physical activity – can work to prevent the progression to diabetes.

Diagnostic criteria for diabetes

The American Diabetes Association (ADA) inclusion of HbA1c as part of the diagnostic criteria of diabetes and pre-diabetes. The World Health Organization (WHO) supports the use of HbA1c >6.5% for diabetes diagnosis but not for intermediate hyperglycaemia, on the grounds that quality assured HbA1c measurement is not available on a global scale. Currently, WHO and IDF recommend two-hour oral glucose tolerance test (OGTT) for the detection of IGT and IFG. However, there is accumulating evidence for the use of one-hour OGTT as a more sensitive method capable of identifying intermediate hyperglycaemia at an earlier time point.  

For type 1 diabetes, in the presence of symptoms (example - polyuria, polydipsia and unexplained weight loss) the diagnosis can be made without OGTT if the following are present: a random venous plasma glucose concentration ≥ 11.1 mmol/l or a fasting plasma glucose concentration ≥ 7.0 mmol/l (whole blood ≥ 6.1 mmol/l or HbA1c ≥ 6.5%).

Other types of diabetes

The recently published WHO report on the classification of diabetes mellitus lists a number of ‘other specific types’ [of diabetes] including monogenic diabetes and what was once termed ‘secondary diabetes’.

 

Monogenic diabetes, as the name implies, results from a single gene rather than the contributions of multiple genes and environmental factors as seen in type 1 and type 2 diabetes. Monogenic diabetes is much less common and represents 1.5–2% of all cases, though this may well be an underestimate. It is often misdiagnosed as either type 1 or type 2 diabetes. These monogenic forms present a broad spectrum, from neonatal diabetes mellitus (sometimes called ‘monogenic diabetes of infancy’), maturity onset diabetes of the young (MODY) and rare diabetes associated syndromic diseases. Although rare, these can serve as ‘human knockout models’ providing insight into diabetes pathogenesis. From a clinical perspective, the exact diagnosis of the monogenic forms of diabetes is important because in some instances therapy can be tailored to the specific genetic defect. Further distinction between the fourteen different sub-types of MODY leads not only to differences in clinical management but different predictions of complication risk. In recent years, with the accumulation of whole genome genetic studies, an increasing number of monogenic forms of diabetes is being discovered, thus the true prevalence of these types may be underestimated.

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