Overview of diabetes

Nicholas Tentolouris

What is the definition of diabetes mellitus?

Diabetes mellitus (DM) is a group of metabolic disturbances, characterized mainly by hyperglycaemia, and finally resulting in the appearance of various complications (macro- and micro-angiopathy, etc.). These complications relate basically to the heart, the vessels, the eyes, the kidneys and the nervous system. Hyperglycaemia is a result of defects in the secretion or action of insulin, or both.

How many types of DM exist?

According to the latest classification, there are four main types of DM (Table 1.1).

Type 1 diabetes mellitus is characterized by an absolute lack of insulin, and survival of persons affected by this type of DM is dependent on the exogenous administration of insulin. This form of the disease is divided into autoimmune and idiopathic DM (Type 1A and 1B, respectively; see also Chapter 2). In Type 1A, there is an autoimmune destruction of the b-cells and auto-antibodies are detected in the serum. In Type 1B, the exact mechanism of b-cell destruction is unknown and auto-antibodies are not detected in the serum; this is why this type of DM is called idiopathic. Type 1B is a relatively rare disturbance, mainly encountered in persons of African and Asian descent. Patients with idiopathic Type 1 DM have severe insulinopenia and so frequently develop diabetic

Diabetes in Clinical Practice: Questions and Answers from Case Studies. Nicholas Katsilambros et al. © 2006 John Wiley & Sons, Ltd. ISBN: 0-470-03522-6

Table 1.1. Classification of diabetes mellitus

I. Type 1. Destruction of p-cells, which means total lack of insulin

II. Type 2. Includes the whole spectrum of combinations from mainly insulin resistance with relative lack of insulin to mainly impaired secretion of insulin accompanied by a lesser degree of insulin resistance

III. Other specific Types of diabetes mellitus (see Table 1.2)

IV. Gestational diabetes mellitus ketoacidosis. Also, this type of DM is not associated with the major histocompatibility complex antigens.

Type 2 diabetes mellitus comprises a heterogeneous group of metabolic disorders, characterized by either a defect in the secretion or a defect in the action of insulin, in proportions that vary from person to person (or even within the same person) during the course of the disease, depending on its duration. It is accepted today that, in the majority of cases, Type 2 DM is manifested when both secretion and insulin disturbances are present.

With the expected future recognition of specific disturbances in the secretion or action of insulin, it is expected that the category of Type 2 DM is going to shrink, and cases that are now characterized as Type 2 are going to be shifted to the group of other specific types of diabetes (a list of which appears in Table 1.2).

Gestational diabetes comprises those cases in which the disease appears for the first time during pregnancy (usually after the 28th week of pregnancy).

What is the frequency of DM?

Diabetes mellitus frequency, both Type 1 and Type 2, varies from country to country. In western countries, it is estimated that DM affects, on average, 6-8 percent of the adult population. Type 2 DM is, however, very frequent in persons over 60 years old (frequency around 20 percent) of both sexes. Type 2 comprises 85-90 percent of cases of Caucasians and 95 percent of other races. Type 2 DM frequency is increasing worldwide, but the biggest increase is seen in the developing countries.

Overview of diabetes 3 Table 1.2. Other specific Types of diabetes mellitus

A. Genetic defects of beta-cell function

1. Chromosome 12, Hepatocyte Nuclear Factor (HNF)-1-alpha (MODY 3)

2. Chromosome 7, glucokinase (MODY 2)

3. Chromosome 20, HNF-4-alpha (MODY 1)

4. Chromosome 13, insulin promoter factor (IPF)-1 (MODY 4)

6. Chromosome 2, NeuroD1 (MODY 6)

7. Mitochondrial DNA

8. Others

B. Genetic defects in insulin action

1. Type A insulin resistance

2. Leprechaunism

3. Rabson-Mendenhall syndrome

4. Lipoatrophic diabetes

5. Others

C. Diseases of the exocrine pancreas

1. Pancreatitis

2. Trauma (pancreatectomy)

3. Neoplasia

4. Cystic fibrosis

5. Haemochromatosis

6. Fibrocalculous pancreatopathy

7. Others

D. Endocrinopathies

1. Acromegaly

2. Cushing's syndrome

3. Glucagonoma

4. Pheochromocytoma

5. Hyperthyroidism

6. Somatostatinoma

7. Aldosteronoma

8. Others

E. Drug- or chemical-induced

1. Vacor

2. Pentamidine

3. Nicotinic acid

4. Glucocorticoids

5. Thyroid hormone

6. Diazoxide

7. Beta adrenergic agonists

8. Thiazides

9. Phenytoin

10. Interferon alpha

11. Others

F. Infections

1 Congenital rubella

2 Cytomegalovirus

3 Others

G. Uncommon forms of immune-mediated diabetes

1. 'Stiff-man' syndrome

2. Anti-insulin receptor antibodies

3. Others

H. Other genetic syndromes sometimes associated with diabetes

1. Down's syndrome

2. Klinefelter's syndrome

3. Turner's syndrome

4. Wolfram's syndrome

5. Friedreich's ataxia

6. Huntington's chorea

7. Lawrence-Moon-Biedl syndrome

8. Myotonic dystrophy

9. Porphyria

10. Prader-Willi syndrome

11. Others

For example, in India, prevalence of Type 2 DM in 1972 was 2.3 percent whereas in the year 2000, it was 12.1 percent (a five-fold increase). It is estimated that the number of people suffering from DM by the year 2025 will have doubled worldwide. Therefore, DM is correctly referred to as a disease with epidemic proportions.

Type 1 DM incidence is also showing an incremental tendency, with an increase of 3 percent between 1960 and 1996 in many countries. For example, the incidence of Type 1 DM in Greece during the last decade was ten cases of the disease for every 100000 people. This frequency is around five times higher in northern European countries and in the island of Sardinia. A preponderance of males are affected, especially when disease onset happens during puberty.

CASE STUDY 1

A 52 year old man was diagnosed with DM 15 days ago. The patient reports a history of high dose corticosteroid ingestion (methylprednisolone) ten years ago, for a period of six months, due to glomerulonephritis (minimal change disease). During that time he had developed DM, which was treated with a combination of insulin and pills, but the diabetes subsequently disappeared after discontinuation of corticosteroid therapy. Plasma glucose levels during the last few years had been normal (fasting plasma glucose < 100 mg/dl [5.5 mmol/L]), but were found to be elevated recently. One year ago the patient was diagnosed with hypertension, for which he was prescribed a small dose of diuretics (hydrochlorthiazide 12.5 mg/day). What type of DM does this patient have?

According to the history, this patient had steroid-induced DM ten years ago, which subsided after discontinuation of steroids. This happens in about 50 percent of patients developing steroid-induced DM; in the rest, DM persists after termination of steroids. Chronic administration of thiazide diuretics is known to cause a small increase in blood glucose levels; a significant increase, however, is extremely rare. In the majority of cases, these patients already have Type 2 DM, and diuretic administration simply exacerbates the already existent hyperglycaemia.

This case shows that DM can be the final result of the effect of various factors. For example, a woman with DM diagnosed for the first time during pregnancy has Type 2 DM, unless she has pre-existent Type 1.

Reference to the above cases is made in order to emphasize the fact that, regardless of the pathogenetic mechanism, for the patient and his treating physician it is more important to treat the metabolic disturbance than strictly classify the disease into Type 2 or one of the 'other specific types of diabetes'. Of course, the attempt to categorize the type of DM will help in the correct, rational use of therapy (pills, insulin or combination of the two).

CASE STUDY 2

A patient who has had Type 2 DM for seven years receives full dose combination oral antidiabetic therapy (sulfonylurea and metformin) and has had poor glycaemic control for the previous five months (mean fasting blood glucose 170 mg/dl [9.4 mmol/L], HbA1c = 8 percent), despite adequate dietetic advice. The patient had had good glycaemic control with this therapeutic regimen for the previous six years. He also reports a weight loss of around 5 kg (11 lb) during the last five months. What will you recommend to the patient?

Since the patient has been in poor glycaemic control for a relatively long time, it is most likely a secondary failure of antidiabetic treatment. The United Kingdom Prospective Diabetes Study (UKPDS, 1998) showed that up to 70 percent of Type 2 DM patients with a known duration of DM of 7-8 year will require insulin to achieve good glycaemic control. Also, the unexplained weight loss is an indication of lack of insulin.

In the present case, it is obvious that the patient needs insulin for good diabetic control. If we want to be more accurate, we can do a glucagon stimulation test to evaluate more objectively the insulin secretory ability of the pancreas.

What are the indications for performing a glucagon test?

The glucagon test evaluates the ability of the pancreatic b-cells to secrete insulin. During the test, the fasting serum C-peptide concentration is measured at baseline and six minutes after the intravenous administration of 1 mg glucagon. Measurement of the C-peptide concentration is preferred to measurement of the insulin levels. It should be noted that C-peptide and insulin are secreted in equimolar quantities from the pancreas. Although, a proportion of around 40-60 percent of insulin is metabolized during the first pass from the liver, C-peptide is not metabolized and is slowly excreted. Thus, C-peptide level is, in comparison to insulin level, a more reliable index of insulin secretion.

The indications for performing a glucagon test are as follows:

1. the differential diagnosis of Type 1 from other types of DM in some clinically indiscernible cases;

2. the evaluation of residual insulin secretion from the pancreas in some pancreatic diseases due to various causes (pancreatectomy, trauma, chronic pancreatitis);

3. as a criterion for initiation of insulin therapy in people with longstanding Type 2 DM when they do not respond to oral antidiabetic therapy.

The test is performed in the morning, in a fasting state of at least eight hours, without previous administration of insulin or oral antidiabetic medicines. It should also be noted that glucagon should be stored in the refrigerator (maintenance temperature of 4°C) until it is used.

How are the results interpreted?

When serum C-peptide concentrations are very low (< 0.06 ng/ml), this is compatible with lack of insulin and an indication of Type 1 DM presence. C-peptide concentrations at the 6th minute after glucagon administration are better able to discern people with adequate residual ability for insulin secretion (positive for C-peptide) than those with inadequate secretion (negative for C-peptide). The normal values for serum C-peptide levels six minutes after 1 mg of glucagon injection are 3.03-12.12 ng/ml in non-diabetic and in Type 2 diabetic persons, but < 1.81 ng/ml in C-peptide negative (insulin-dependent) persons (patients with Type 1 DM). A C-peptide increment of less than 1.06 ng/ ml from the baseline value after injection of glucagon predicts with great accuracy a failure of oral antidiabetic medicines and need for insulin initiation.

What are the contraindications and the side effects of a glucagon test?

Glucagon can produce 'a crisis' in people with pheochromocytoma and can even be used as a diagnostic tool for the presence of the disease. Thus, the test is contraindicated in people with pheochromocytoma.

Side effects of glucagon administration include allergic reactions (rarely anaphylactic reactions), nausea, vomiting, dizziness, headache and increase of blood glucose levels (due to glycogenolysis and gluco-neogenesis in the liver).

CASE STUDY 3

A 42 year old man comes to the office with the probable diagnosis of 'diabetes mellitus'. Recent biochemistry results show a fasting plasma glucose level of 120mg/dl (6.7 mmol/L). He denies polyuria, polydipsia or weight loss. His family history is positive for Type 2 DM in his mother, diagnosed at the age of 54 years. The patient's height is 1.74 m (5 ft, 8.5 in) and his weight 95 kg (209.5 lb). Does this patient have DM?

According to the diagnostic criteria for diabetes mellitus of the American Diabetes Association (ADA) in 1997 and the World Health Organization (WHO) in 1999, this patient does not fulfil the criteria for the diagnosis of DM. There are three criteria for diagnosing DM:

1. Fasting plasma glucose level > 126 mg/dl (7.0 mmol/L). Fasting means abstinence from calorie intake for at least eight hours.

2. Random plasma glucose level > 200 mg/dl (11.1 mmol/L) with simultaneous presence of symptoms compatible with DM (i.e., polyuria, polydipsia and unexplained weight loss). Random plasma glucose level means that measurement of plasma level is done at any time during the day, irrespective of food intake.

3. Plasma glucose level > 200 mg/dl (11.1 mmol/L) two hours after oral administration of 75 g glucose.

When one of the above criteria is positive, it should be verified with one of the others on a different day.

According to the above results, does this patient have a disturbance of glucose metabolism?

According to the latest classification of disturbances of glucose metabolism, the above patient has impaired fasting glucose (IFG). The previous classification of glucose metabolism disturbances (made by WHO in 1985) did not include this entity. Normal fasting plasma glucose values are 70-109 mg/dl (3.9-6.0 mmol/L). This upper limit of normal values is basically arbitrary, but is a level above which a loss of the first phase of insulin secretion, during the intravenous administration of glucose, is observed. Furthermore, values above 109mg/dl (6.0 mmol/L) are associated with an increase in the risk of micro- and mainly macro-vascular complications. The category of impaired fasting glucose (fasting glucose 110-125 mg/dl [6.1-6.9 mmol/L]) was established in order to include those glucose values that, although not fulfilling the criteria for diabetes diagnosis (fasting glucose >126 mg/dl [>7.0 mmol/L]), are not entirely normal.

In 2003, the American Diabetes Association proposed a level of 100 mg/dl (5.6 mmol/L) as an upper limit of normal for fasting plasma glucose. The reason for this decrease was that the level of 100 mg/dl is better associated with the future appearance of DM than the level of 110 mg/dl (6.1 mmol/L).

Impaired fasting glucose and impaired glucose tolerance are potentially reversible conditions that are associated with the risk of developing Type 2 DM in the future and, as mentioned above, with the risk for cardiovascular events. Impaired fasting glucose and impaired glucose tolerance are collectively called 'pre-diabetes'.

The disturbances of glucose metabolism are shown in Table 1.3.

Table 1.3. Criteria for diagnosis of diabetes mellitus and impaired glucose control

Fasting plasma glucose

<100 mg/dl

Normal

(5.6 mmol/L)

Fasting plasma glucose

100-125 mg/dl

Impaired Fasting

(5.6-6.9 mmol/L)

Glucose (IFG)

Fasting plasma glucose

> 126 mg/dl

Diabetes mellitus

(7.0 mmol/L)

Plasma glucose 2 hrs after

<140 mg/dl

Normal glucose

75 g glucose

(7.8 mmol/L)

tolerance

Plasma glucose 2 hrs after

140-199 mg/dl

Impaired Glucose

75 g glucose

(7.8-11.0 mmol/L)

Tolerance (IGT)

Plasma glucose 2 hrs after

> 200 mg/dl

Diabetes mellitus

75 g glucose

(11.1 mmol/L)

The above values are valid for USA. In Europe normal fasting plasma glucose is considered to be a value <110 mg/dl (6.1 mmol/L) and impaired fasting glucose 110-125 mg/dl (6.1-6.9 mmol/L).

The above values are valid for USA. In Europe normal fasting plasma glucose is considered to be a value <110 mg/dl (6.1 mmol/L) and impaired fasting glucose 110-125 mg/dl (6.1-6.9 mmol/L).

What will you recommend to the patient?

This is a slightly obese person (body mass index: 31.38 kg/m2). Additionally, he has a positive family history of diabetes (first degree relative with Type 2 DM). Therefore, he has two risk factors for development of Type 2 DM. Several studies have shown that, in obese persons, fasting plasma glucose values are often normal, even though the two hour glucose value during an oral glucose tolerance test is abnormal (above the level for diagnosis of DM: > 200 mg/dl). Therefore, the repeat of fasting glucose measurement in this patient (even though it is an easier, quicker, cheaper, and more widely accepted test by the examinees, with a higher reproducibility than the oral glucose tolerance test) is probably not the most appropriate test in this case. Measurement of a random glucose level is also not indicated, since there are no symptoms compatible with DM. Thus, in order to exclude DM or coexistence of impaired glucose tolerance in this patient, an oral glucose tolerance test (OGTT) is indicated.

CASE STUDY 4

A 48 year old woman comes to the office because she is worried she might be suffering from DM. The reason for her worries is that her father was diagnosed with Type 2 DM at the age of 55 years and died from an acute myocardial infarction at 74. Her cousin has also suffers from Type 2 DM (for ten years) and recently started treatment with insulin injections. A chemistry profile a year ago showed a fasting plasma glucose level of 96 mg/dl (5.3 mmol/L). She has two children: the first child was born 3.6 kg (7.9 lb) and the second 4.5 kg (9.9 lb). She does not report any diabetic symptoms. Her weight is 77.8 kg (171.5 lb) and her height 1.67 m (5 ft, 5.7 in). What will you recommend to the patient?

The patient has three risk factors for developing Type 2 DM: i) she is overweight (body mass index: 27.9 kg/m2); ii) she has a positive family history of Type 2 DM (one first degree relative with Type 2 DM); and iii) she most likely had gestational DM in one of her pregnancies (a neonate's birth weight of > 4 kg is considered to be evidence of macrosomia, most likely due to gestational DM).

According to the recommendations of international scientific organizations, pre-symptomatic screening for Type 2 DM is indicated in all persons over 45 years of age, especially if they have a high body mass index (> 25 kg/m2). If the results do not show presence of DM, the

Table 1.4. Risk factors for development of Type 2 diabetes mellitus

• Increased body weight (body mass index > 25 Kg/m2)

• Family history of Type 2 diabetes

• Sedentary lifestyle

• History of gestational diabetes or child birth weighing > 4 kg

• Dyslipidaemia (HDL-cholesterol < 35 mg/dl [0.9 mmol/L] or/and fasting triglycerides > 250 mg/dl [2.8 mmol/L])

Polycystic ovary syndrome

• History of impaired fasting glucose or impaired glucose tolerance

• History of atherosclerotic disease

• People of certain ethnic groups (African Americans, Hispanics, Asians, Pima Indians, inhabitants of certain Pacific islands)

screening test should be repeated every three years. The three year interval is set because even if DM is to manifest in the meantime, it is not expected to cause any complications. It is advised, however, that people above 45 years of age who have at least one of the risk factors mentioned in Table 1.4, are screened more frequently. Also, overweight persons (BMI> 25 kg/m2), of lower age (<45 years) with one additional risk factor from those mentioned in Table 1.4, should be screened for Type 2 DM as for persons aged > 45 years. For all these reasons, therefore, the woman in question should be screened for DM.

The bigger the number of risk factors present, the higher the risk of developing Type 2 DM.

Which method will you choose for diagnosis?

The patient does not have symptoms of DM, so it is not indicated to measure plasma glucose in a random sample of blood. The easiest way, for reasons analysed in the previous case, is to measure fasting plasma glucose level. A different approach would be to perform an oral glucose tolerance test. This is preferred to the measurement of fasting plasma glucose level as a screening test for DM, according to the recommendations of the World Health Organization. A drawback of the method is its poor reproducibility, whereas an advantage is its slightly higher sensitivity compared to fasting plasma glucose in diagnosing DM.

How do you perform an oral glucose tolerance test (OGTT)?

In order to get correct results from an oral glucose tolerance test it is essential that the patient has a proper preparation. The test is performed early in the morning after an overnight fast of 8-14 hours, although drinking water is permitted. In addition, it is essential that for the three days prior to the test the patient does not abstain from carbohydrates (he or she should consume at least 150 g of carbohydrates daily). The evening before the test the patient should eat supper with an overage quantity of carbohydrates (30-50 g).

During the test the patient should remain in the office, seated. Smoking cigarettes, drinking coffee or other beverages (even those that do not contain calories) is not allowed in the morning before or during the test.

After drawing blood for measuring fasting plasma glucose, the adult patient receives, within five minutes, 75 g anhydrous glucose, diluted in 230-250 ml of water. This quantity of anhydrous glucose corresponds to 82.5 g of monohydric glucose. In children, 1.75 g of anhydrous glucose per kg of body weight is given, with a maximum quantity of 75 g. The quantity of anhydrous glucose given for diagnosing gestational diabetes can be different (see Chapter 10). The OGTT starts from the moment the glucose is consumed. A blood sample is drawn two hours after the glucose load.

The blood samples drawn should be quickly centrifuged. If centrifuga-tion is not going to be performed within 60 minutes of the blood being drawn, the blood should be stored in a test tube with an inhibitor of glycolysis (usually sodium fluoride, 2.5 mg per ml of blood). It should be noted that glycolysis is slowed but not completely abolished by the addition of glycolysis inhibitors. The measurement of plasma glucose concentration should also be performed without delay, preferably with an enzymatic method (hexokinase or glucose oxidase method). Measurement of blood glucose concentrations during an OGTT with portable glucose meters (using capillary or venous blood) is not acceptable, since these meters do not have the required accuracy.

The interpretation of the results of the OGTT is shown in Table 1.3.

An oral glucose tolerance test was performed on the patient. The results were as follows: fasting plasma glucose level of 98 mg/dl (5.4 mmol/L); plasma glucose level two hours after glucose load of 130 mg/dl (7.2 mmol/L). What will your instructions to the patient be?

The patient is not suffering from DM nor does she have a disturbance in glucose metabolism (according to the criteria of Table 1.3). Since she is at increased risk of developing DM in the future, however, she should be advised to repeat a screening test for DM in 1-3 years. Since, additionally, there is ample evidence that development of Type 2 DM can be prevented or postponed with the application of lifestyle changes, we would recommend that this woman try and lose some of her excess body weight, and increase her physical activity and proper nutrition. Prevention of Type 2 DM is analysed in Chapter 30.

CASE STUDY 5

A 70 year old man, diagnosed with Type 2 DM two months ago, comes to the office for a follow-up visit. His blood sugar levels are high, both fasting and after meals (250-350 mg/dl [13.9-19.4 mmol/L]). The patient was started initially on treatment with gliclazide (40 mg twice a day), which was gradually increased on a weekly basis. For the last 15 days, he has received the maximum dose of 320 mg/day. His weight is 68 kg (149.9 lb) and his height 1.78 m (5 ft, 10 in). The patient had not had a ketoacedotic coma at diagnosis, although before the diagnosis he had noticed significant weight loss accompanied by symptoms compatible with DM (polyuria, polydipsia), which continue despite nutritional treatment. There is no family history of DM. How will you treat this patient?

The patient in question is not overweight (BMI: 21.46 kg/m2) and does not have a family history of Type 2 DM (for conditions that usually accompany Type 2 DM, see Table 1.5). Appearance of diabetes at an older age is not a reliable criterion for diagnosing Type 2 DM. In the present case we have to consider the possibility of Type 1 DM, which appears at an older age. One such form of DM is LADA (Latent Autoimmune Diabetes in Adults). This Type of DM accounts for about 10 percent of new cases of DM in northern European countries, although it is rarer in the south. It is generally known that in up to 25 percent of patients with Type 1 DM, diagnosis of the disease is made after the age of 35 years. LADA is characterized by a slower autoimmune destruction of the b-cells compared to younger persons and so its clinical presentation is not very noticeable. It is often mistaken initially for Type 2 DM. There are, however, some differences from Type 2 DM that help in the differential diagnosis: i) in LADA there is no family history of Type 2 DM, although there may be first degree relatives with Type 1 DM;

Table 1.5. Main differences between Type 1 and Type 2 diabetes

Age at presentation

Weight Ketoacidosis

Type 1

Mainly <40 years (peak = 12th year)

Thin persons, as a rule there is weight loss at presentation

Type 2

As a rule overweight or obese persons

May be present Is seen rarely and under special conditions

Need for insulin administration

Insulin is necessary for survival

Insulin is not necessary for survival

Comments

10% of older people have Type 1 diabetes (LADA).

20% of diabetic children in some countries have Type 2 diabetes.

The number of people with Type 1 diabetes who are obese at the time of diagnosis increases.

Weight loss may more rarely happen at the time of diagnosis in Type 2 diabetes as well.

Ketoacidosis may be the presenting symptom in Type 1 diabetes.

It is rare in Type 2 diabetes and occurs during a serious infection, trauma, surgery or acute myocardial infarction.

During the 'honeymoon phase' in a person with Type 1 diabetes, insulin administration may not be necessary or insulin needs may be very small.

Insulin may be the only effective treatment for controlling persons with

(continued)

Table 1.5. (Continued)

Type 1

Type 2

Comments

Type 2 diabetes who have long

standing diabetes.

Ability of insulin

Absent

Adequate

Some patients with Type 1 diabetes

secretion from

may have some ability of insulin

p-cells

secretion at the time of diagnosis of the disease.

In some patients with Type 2 diabetes and long duration of the disease, the ability of insulin secretion may be seriously decreased.

Auto-antibodies

Positive

Negative

Falsely positive and falsely negative results can occur in both Types of diabetes.

ii) affected persons are lean at diagnosis of DM, whereas persons with Type 2 diabetes are in the majority of cases (80 percent) overweight or obese; iii) these patients do not respond well to oral antidiabetic treatment and quickly require insulin to control their blood sugar; iv) it is more common in northern European countries; v) determination of auto-antibodies against components of the pancreatic islets and b-cells, which characteristically appear in Type 1 DM, is positive in these patients. The major differences between Type 1 and Type 2 DM are shown in Table 1.5.

In the present case, based on the medical history and clinical picture, it seems likely that this is DM of the LADA Type and insulin therapy should be recommended. Diagnosis could be confirmed with determination of specific auto-antibodies in the patient's serum and a glucagon stimulation test (which will show low levels of serum C-peptide and small response of after injection of 1 mg glucagon). If auto-antibodies are negative, it may be the case that it is Type 2 DM with primary failure of oral antidiabetic medicines, or Type 1 DM without auto-antibodies (idiopathic). In either case insulin therapy is indicated.

CASE STUDY 6

A 54 year old woman comes to the clinic for evaluation of possible DM. She was referred by an ophthalmologist, because during fundoscopy for a glaucoma check-up, microaneurysms and haemorrhages were found in the retina. The patient is asymptomatic, without any significant medical history. Her mother had Type 2 DM, diagnosed at the age of 76. Can diabetic complications precede the clinical presentation and diagnosis of the disease?

The United Kingdom Prospective Diabetes Study (UKPDS, 1990) showed that at the time of diagnosis a significant proportion of the patients already had microvascular complications. Retinopathy was especially common (25 percent), although peripheral neuropathy (7 percent) and nephropathy (3 percent) were less common. In some cases, maculopathy, a condition that threatens vision, was also present. Erectile dysfunction was common as well (20 percent). Rarely, there can be neurotrophic ulcers in the soles due to severe diabetic peripheral neuropathy. This happens because the disease can be present for many years without being detected. In population studies it has been shown that for every ten cases of diagnosed diabetes, another five cases are undiagnosed.

Regarding macrovascular complications, UKPDS (1990) showed that up to 40 percent of patients at the time of diagnosis had one such complication (stroke, coronary artery disease or peripheral vascular disease). Hypertension was also especially common (40 percent), in both sexes.

How does Type 2 DM manifest?

In about half of patients there are the classic symptoms of DM (polyuria, polydipsia, rarely weight loss) in a mild form, whereas a proportion of up to 20 percent presents with characteristic infections (especially fungal infections of the genital tract). In 30 percent of the cases, diagnosis of Type 2 DM is made accidentally during examinations for various other reasons (check-up or pre-operative evaluation, examinations for insurance, etc.). Visual disturbances are also common, even when there are no lesions in the retina. These are due to accumulation of glucose and water in the lens owing to the hyperglycaemia. Some patients develop muscular cramps in the lower extremities, burning sensation in the soles and the toes, or hyperalgesia. In a small proportion of patients, especially of older age, the first manifestation of Type 2 DM can be hyperglycaemic hyperosmolar coma, due more frequently to a concomitant infection. As already mentioned, in a non-negligible percentage of patients, diagnosis of DM can happen after the manifestation of one of its complications.

How does Type 1 DM manifest?

In typical cases, Type 1 DM presents with sudden weight loss (in the order of 1-2 kg/week) accompanied by intense polyphagia, polydipsia and polyuria, especially during the night, in persons aged < 30 years old. Usually there is concomitant generalized feelings of fatigue, weakness, sleepiness and significant loss of muscular mass. Visual disturbances as well as skin infections (fungal infections of the genital organs, staphylococcal skin infections, etc.) are also common. Physical examination can reveal evidence of dehydration, muscular atrophy, especially in the thigh area, and acetone breathing, when there is concomitant ketosis.

If diagnosis is delayed, the patient displays deterioration of the symptoms and signs of severe dehydration, while the increase of ketone bodies in the blood causes anorexia, nausea, vomiting, diffuse abdominal pains (which can mimic acute abdomen) and muscle cramps. In a small proportion of patients, especially in very young children, the presenting feature can be a ketoacidotic coma.

Contrary to Type 2 DM, the characteristic microvascular complications of the disease are not present at the time of diagnosis of Type 1 DM.

CASE STUDY 7

A 67 year old patient with Type 2 DM for six years, treated with sulfonylureas and metformin, comes to the clinic for a scheduled follow-up visit. His fasting blood sugar levels in the morning are 130-170 mg/dl (7.2-9.4 mmol/L), before lunch 130-150 mg/dl (7.2-8.3 mmol/L) and before dinner 120-160 mg/dl (6.7-8.9 mmol/L). His post-prandial levels (two hours after a meal) range between 140-200 mg/dl (7.8-11.1 mmol/L). His HbA1c is 7.6 percent. Is his blood sugar control adequate?

This patient's blood sugar control is inadequate. Glycaemic control goals in both types of DM are shown in Table 1.6.

We emphasize that glycaemic control goals should be individualized. In persons living alone, it may be dangerous to attempt very strict control, because a serious hypoglycaemic episode can be fatal. In persons with hypoglycaemia unawareness or frequent hypoglycaemic episodes, as

Table 1.6. Goals of glycaemic control in diabetes

American

International

American College

Diabetes

Diabetes

of Clinical

Association

Federation

Endocrinologists

HbA1c

<7%

<6.5%

<6.5%

Pre-prandial

90-130 mg/dl

<100 mg/dl

<110 mg/dl

glucose level

(5.0-7.2 mmol/L)

(5.6 mmol/L)

(6.1 mmol/L)

Post-prandial

<180 mg/dl

<135 mg/dl

<140 mg/dl

glucose level

(10.0 mmol/L)

(7.5 mmol/L)

(7.8 mmol/L)

Post-prandial measurements should be performed 1-2 hours after meal. The American Diabetes Association recommends an effort for a further decrease of the proposed post-prandial blood glucose levels when pre-prandial glucose levels are normal but HBA1c values are high.

Post-prandial measurements should be performed 1-2 hours after meal. The American Diabetes Association recommends an effort for a further decrease of the proposed post-prandial blood glucose levels when pre-prandial glucose levels are normal but HBA1c values are high.

well as in children, it is preferable to allow higher glucose values. Also, in people with a short life expectancy, the goal is to eliminate hypergly-caemia symptoms. However, in DM during pregnancy we should try to achieve normal HbA1c values individually, whenever possible, since most studies have shown a linear correlation between HbA1c values and frequency of microvascular complications. Of course, the penalty for such a strict control is frequent hypoglycaemias, and especially serious instances in people with Type 1 DM. In the Diabetes Control and Complications Trial (DCCT, 1993), the frequency of all hypoglycaemic episodes was three times higher in the group with intensive insulin treatment, whereas the frequency of serious hypoglycaemias was five times higher when HbA1c values were < 6 percent, compared with persons who had HbA1c values > 8 percent. In the UKPDS (1990) study, people with better glycaemic control had double the frequency of serious hypoglycaemic episodes. There are now newer insulin analogues with pharmacokinetic properties that help in reaching the goals of glycaemic control with a lower risk of hypoglycaemias.

Why must the patient have good glycaemic control?

In both Types of DM, good glycaemic control protects from microvas-cular complications. In the DCCT (1993) study of Type 1 diabetics, it was shown that during a follow-up period of six and a half years the frequency of appearance and evolution of microvascular complications could be reduced by up to 76 percent in the group with good, compared to those with not so good, glycaemic control. Specifically, better control (HbA1c values 7.1 versus 9.0 percent) resulted in a decreasd risk of:

• microalbuminuria by 39 percent

• proteinuria by 54 percent

• neuropathy by 60 percent

• development of retinopathy by 76 percent

• deterioration of retinopathy by 54 percent

• major cardiovascular events by 42 percent.

Additionally, better glycaemic control was associated with a decrease in the levels of total cholesterol, LDL-cholesterol and triglycerides and an increase in HDL-cholesterol. Also, the intima-media thickness of the carotid arteries, an index of premature atherosclerosis, was significantly lower in persons with better glycaemic control. Cardiovascular events (myocardial infarctions, strokes, peripheral vascular disease) were not significantly lowered in this study (p = 0.08), but this was due to the small number of events (40 events in the conventional treatment group versus 23 events in the group with intensive insulin treatment) since participants in the study were young persons without macrovascular complications.

In persons with Type 2 DM, the UKPDS and other smaller studies as well, showed that in a period of ten years better glycaemic control (HbA1c values 7.0 percent versus 7.9 percent) resulted in a decreased risk of:

• all DM-related events by 12 percent

• microvascular complications by 25 percent

cataract surgeries by 24 percent

• retinopathy by 21 percent

• microalbuminuria by 33 percent

• myocardial infarction by 16 percent.

Decrease in the risk for myocardial infarction in the UKPDS was borderline (p = 0.052). Although there is no proof from large studies that improvement in glycaemic control decreases the risk of cardiovascular events (which are very common in people with Type 2 DM), it seems that in order to decrease that risk an optimal control of blood sugar is needed in addition to aggressive treatment of the other concomitant risk factors (hypertension, obesity, dyslipidaemia, smoking).

How feasible is the achievement and attainment of the proposed glycaemic control goals in DM?

All long-term studies in DM (DCCT and UKPDS) have shown that although achievement of glycaemic goals is relatively easy, long-term attainment of the glycaemic control in normal levels is extremely difficult. In the DCCT (1993) study, in which, it should be emphasized, there was provision of full and continuous support of the patients, only about 5 percent of patients managed to retain HbA1c values < 6 percent over the whole length of the study. Variations of HbA1c values in the intensive insulin treated group were between 6.5 and 8 percent during the 10-year follow-up. Also, in the intensively treated group, both fasting glucose levels and post-prandial ones had great deviations from desirable targets.

A steadily continuous deterioration of blood sugar levels and HbA1c values was observed in Type 2 DM, such that a frequent escalation of the therapeutic regimen was necessitated, in order to retain mean HbA1c values at an acceptable level. HbA1c values in the groups that followed an intensive versus conventional therapeutic regimen, per 5-year periods, were as follows: 0-5 years 6.6 versus 7.4 percent; 5-10 years 7.5 versus 8.4 percent; and 10-15 years: 8.1 versus 8.7 percent.

Data from various studies have shown that a small proportion of diabetics achieve values of HbA1c < 7 percent, (around 37 percent) while only 7 percent of them had achieved the total of all therapeutic diabetic goals (HbA1c < 7 percent, blood pressure < 130/80 mmHg and total cholesterol < 200 mg/dl [5.17 mmol/L]).

Further reading

American Diabetes Association (1997) Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20, 1183-97.

Expert Committee on the Diagnosis of Diabetes Mellitus (2003) Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26, 3160-67. Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med, 329, 977-86.

Katsilambros, N. and Aliferis, K., Darviri, C., Tsapogas, P., Alexiou, Z., Tritos, N., Arvanitis, M. (1993) Evidence for an increase in the prevalence of known diabetes in a sample of an urban population in Greece. Diabet Med, 10, 87-90. Katsilambros, N., Hatzakis, A., Perdicaris, G., Pefanis, A., Touloumi, G. (1991) Total and cause-specific mortality in a population based cohort of diabetes in Greece. Diabete Metab, 17, 410-14. Katsilambros, N. and Tentolouris, N. (2003) Type 2 diabetes: an overview, in Textbook of Diabetes, 3rd edn (eds J. Pickup and G. Williams Blackwell Science Ltd, Oxford), 4, pp. 1-19. Pinkney, J. (2003) Clinical research methods in diabetes, in Textbook of Diabetes, 3rd edn, (eds) J. Pickup and G. Williams Blackwell Science Ltd, Oxford, 35, pp. 1-20.

Sacks, D.B., Bruns, D.E., Goldstein, D.E., Maclaren, N.K., McDonald, J.M., Parrott, M. (2002) Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Clinical Chemistry, 48,436-72.

UKPDS Study Group. UK Prospective Diabetes Study 6 (1990) Complications in newly diagnosed Type 2 diabetic patients and their association with different clinical and biochemical risk factors. Diabetes Research, 13, 1-11.

UKPDS Study Group (1998) Intensive blood glucose control with sulfonylurea or insulin compared with conventional treatment and risk of complications in patients with Type 2 diabetes (UKPDS 33). Lancet, 352, 837-53.

World Health Organization (1999) Definition, Diagnosis and Classification of Diabetes Mellitus and its Complications: Report of WHO Consultation. Part 1: Diagnosis and Classification of Diabetes Mellitus. Geneva, World Health Orgnization.

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