Medicine for Africa - Medical Information Service

 

IABETES ELLITUS

 
   

 

Definition:

Diabetes mellitus (DM), also just called diabetes, is a syndrome of disturbed sugar metabolism, which is usually a combined disorder, derived from a combination of hereditary, environmental and life-style causes, resulting in an abnormally high blood sugar (glucose) level – ‘hyperglycemia’. 

Glucose levels are controlled by a hormone, called insulin, which is being secreted by the pancreas – more specifically, by the so-called beta-cells which are located in the islets of Langerhans within the pancreas. 

The two most common forms of diabetes are Diabetes type 1 – the ‘juvenile type’ of diabetes, and Diabetes type 2 – the ‘adult type’ of diabetes.

Type 1 diabetes, also called the ‘juvenile type of diabetes mellitus’, or the ‘insulin-dependent type of DM’ (IDDM), is characterized by the more or less complete absence of insulin production by the beta of the pancreas – thus making it more or less impossible for the person to digest certain sugars or any glucose-containing food products.  The main cause of this absence of beta cells is thought to be a T-cell (from the body’s own immune system) mediated immune attack upon this group of cells.  This type of diabetes starts in early childhood and there is currently no preventive measurement available to stop the onset of the syndrome in disease-prone individuals.  Type 1 diabetes consists of about 10% of the overall diabetic patient population, although in some countries it occurs in a higher percentage as compared to the overall prevalence of diabetes mellitus.

Type 2 diabetes, formerly called the ‘adult onset type of diabetes’, or ‘non-insulin-dependent DM’ (NIDDM), is the direct result of a diminished response of the body’s own metabolism to insulin, caused by either insufficient secretion of the hormone upon need, or an inappropriate action by the pancreas upon the (often overwhelming) intake of glucose/sugar by the individual, well exceeding his/her body’s capabilities to properly digest this ‘sweet onslaught’ to its system.

There are a number of different theories that imply the development of type 2 diabetes.  These include central obesity (fat deposits that are concentrated around the waist/belly, with little overall subcutaneous fat deposits), which is known to predispose patients for developing resistance to the actions of insulin.  Abdominally located fat deposits are particularly ‘active’ in secreting hormones such as adipokines (also called adipocytokines, which are a group of cytokines – cell-to-cell signaling proteins – that are secreted by adipose tissue), which are thought to impair the body’s glucose tolerance.  

Both type 1 and type 2 diabetes result in hyperglycemia – an increase in the blood glucose (sugar) levels to often unsustainable levels, resulting in various severe and sometimes life-threatening symptoms (see below).

Obesity is present in at least 55% of patients who are diagnosed with type 2 diabetes, making overweight the most prevalent and most important risk factor for the development of diabetes mellitus.

Other factors that may result in an increased prevalence of diabetes include a family history of DM, and advanced age (20% of elderly patients in North America have diabetes type 2).  Within the last 15 to 20 years, type 2 diabetes has become more and more prevalent (present) in children and adolescents, most likely associated with the increased prevalence of childhood obesity in developed countries.

Gestational diabetes – the occurrence of diabetes during pregnancy – resembles type 2 DM in a number of aspects, including a combination of inappropriate insulin secretion and responsiveness upon needs and demands.  This type of diabetes occurs in about 2% to 5% of all pregnancies (in developed countries), and may improve or completely disappear after delivery.   While gestational diabetes can be treated successfully under careful medical supervision, 20% to 50% of all affected women will develop type 2 DM some time later in life.

Untreated gestational diabetes may cause harm to the unborn child and the mother alike.  Typical DM associated risks to the newborn include a well above (increased) average birth weight (macrosomia), congenital (born with) anomalies of the cardiac and central nervous system (CNS), and skeletal malformations.  Secondary syndromes may include the respiratory distress syndrome (due to inhibition of fetal surfactant production), and hyperbilirubinemia (increase in blood bilirubin levels, resulting from excessive red blood cell destruction). 

Diabetic ketoacidosis – DKA, is an acute and dangerous complication of DM and considered a medical emergency!  Lack – severe lack of insulin causes the liver to process fat into ketone bodies in order to use them for ‘fuel’ to run the body’s normal metabolism.  While intermittent or occasional production of ketones is physiological (normal), sustained production of ketone bodies over an extended period of time can result in serious negative consequences such as a decreased blood pH level due to an increase in blood ketone levels, leading to DKA.  Late stage DKA can severely impair the consciousness of the patient, cause hypotension (low blood pressure) and shock, ending in death. 

Hypoglycemia – an abnormally low blood glucose level is an acute complication of various DM treatments.  Iatrogenic (self-inflicted as a result of medical treatment) hypoglycemia typically results from the interplay of relative or absolute insulin excess and compromised glucose counter regulation in type 1 and advanced type 2 DM.

Metabolic Syndrome – also called syndrome X – develops in association with insulin-resistant diabetes type 2, and results in hypertension (increased blood pressure), increased levels of lipids and LDL (low density lipoprotein) cholesterol in blood, with concurrent decreased levels of HDL (high density lipoproteins [the good cholesterol]) cholesterol, and elevated triglycerides levels.  Central obesity with a pronounced ‘belly’ and abnormal blood clotting symptoms, as well as a relatively high rate of concomitant cardiovascular disease processes are also associated with the metabolic syndrome.

The so-called pre-diabetes is a condition that is related to diabetes – while the blood glucose level is higher than physiologically normal, it is not quite high enough to call it ‘diabetes’ as yet (see ‘Diagnosis’).

Pre-diabetes does increase the subsequent development of full-blown diabetes type 2, and also increases the chance of developing heart disease and/or stroke.  This condition can often be reversed by just adhering to a (modest) weight loss regimen and increased physical activity, which can at least delay the onset of diabetes type 2, if not prevent it entirely.    

          Epidemiology of Diabetes mellitus

The World Health Organization, WHO, reported in 2000 that more than 170 million people worldwide are suffering from diabetes – 2.8% of the world’s population.  However, this number is increasing daily, resulting in an estimated doubling of diabetic patients by the year 2030. 

While diabetes (especially type 2) is currently more prevalent in developed countries than in developing countries, the greatest increase in future prevalence is expected to occur in developing countries of Africa and Asia, where the largest numbers of DM patients will be found in the year 2030.  This increase will largely be due to increased urbanization and the changes in life style of the population, including the adoption of ‘Western-style’ eating habits and changes in their diet. 

          Historic Review

The word ‘diabetes’ is derived from the Greek, meaning ‘one that straddles’, or specifically, ‘a compass siphon’ – whereas ‘siphon’ gave rise to the name ‘diabetes’, describing the excessive amount of [sweet] urine that is discharged in the context of the disease.

Avicenna (980-1037 in Persia) described a detailed account of diabetes mellitus, detailing a primary and secondary form of the disease.  He not only described the diabetic gangrene, he also came up with the first treatment schedule for diabetes – a mixture of lupine, fenugreek and zedoary seeds, resulting in a considerable reduction of sugar excretion.  The basic principles of his therapy are still prescribed today.  He was also the first to describe diabetes insipidus in a detailed manner.

It was only in late 19th century that the role of the pancreas has been identified with the development of diabetes.  Finally, in 1910, Sir Edward A. Sharpey-Schafer, an English physiologist, identified the one single chemical compound that appeared to be lacking in diabetes as the substance, he called ‘insulin’, derived from the Latin, meaning insula or island, referring to the physiological areas of its production – the islets of Langerhans.

Finally, the distinction between diabetes type 1 and type 2 was made by Sir Harold Himsworth in 1936.
 
The first group of drugs for treating diabetes, the sulfonylureas, were identified in 1942, followed by the biguanide-group of drugs in the late 1950s.

In 1980, the first human insulin was developed by isolating genetically-altered bacteria to produce large quantities of [human] insulin.

          Diabetes insipidus

Diabetes insipidus (DI) should not be confused with DM.  While they do share some signs and symptoms, such as excessive thirst and urination, they are indeed unrelated. 

DI is caused by a deficiency of a hormone called ‘antidiuretic hormone’ – ADH, also known as vasopressin.  The deficiency is secondary to the destruction of the posterior part (the back part) of the pituitary gland (also called hypophysis), which is a pea-sized endocrine gland, located near the bottom of the hypothalamus at the base of the brain – ‘central DI’.
 
In addition, DI can also be caused by an insensitivity of the kidneys to the influence of ADH – ‘nephrogenic DI’, due to a variety of chronic disorders of the kidneys; or it can be caused iatrogenically (self-inflicted) by various drugs and drug interactions.

 

Symptoms:

Both diabetes type 1 and type 2 cause high blood glucose levels, called ‘hyperglycemia’, ultimately causing damage to the eyes (diabetic retinopathy – a leading cause of blindness), the kidneys (ending in kidney failure), the nervous system (diabetic neuropathy) and the blood vessels. 

The classic triad of diabetes symptoms includes:

  • Polyuria – frequent urination – with subsequent dehydration;
  • Polydipsia – increased thirst;
  • Polyphagia – increased appetite – with subsequent weight gains.

These symptoms may develop fairly rapidly (over weeks or months) in type 1 diabetes in children; however, in type 2 diabetes, the adult form, they develop much more slowly (‘insidiously’) and may be very subtle for a long period of time.  While type 1 diabetes is often associated with weight loss, type 2 diabetes typically presents with weight increases.

Acute complications may include:

  • Hyperglycemia (see above);
  • Hypoglycemia;
  • Ketoacidosis;
  • Non-ketotic hyperosmolar coma.

Hypoglycemia – abnormally low blood glucose levels – a medical emergency, can occur in patients with diabetes, usually the result of taking too much diabetes medication or an insulin injection that is too high for the current needs.  Hypoglycemia typically presents itself with headaches, dizziness, poor concentration, sweating and tremors of the hands – fainting and experiencing a seizure are not uncommon.

Diabetic ketoacidosis (plasma glucose levels above 300 mg/dl [15 mmol/l]) is another medical emergency, caused by uncontrolled hyperglycemia (excessive blood glucose levels), due to the absolute or relative lack of insulin (insufficient insulin injections).  Clinically, diabetic ketoacidosis can cause severe renal (kidney) damage, with subsequent diabetic syndromes as described above.

Hyperosmolar hyperglycemic (non-ketotic) syndrome reveals extremely high blood glucose levels, which the body tries to eliminate via the urine, resulting in severe dehydration with subsequent seizures, coma and death.  Typically, this occurs in patients with type 2 diabetes, who cannot control their glucose levels appropriately, or suffer extraordinary stress or injury, or take other interfering medications, such as steroids.

Chronic complications may include:

  • Cardiovascular disease;
  • Microvascular damage – impotence and poor wound healing (gangrene, amputations);
  • Chronic renal failure – dialysis;
  • Retinal damage with subsequent blindness;
  • Nerve damage – loss of sensation or pain;
  • Increased blood pressure, and
  • Liver damage, due to non-alcoholic steatohepatitis.

Cardiovascular disease – chronic diabetes, i.e. chronic increase of blood glucose levels, leads to angiopathy (damage of blood vessels – ‘intermittent claudicatio’) by ‘opening up’ the vessels’ endothelial cells and taking up more than normal amounts of glucose.  This uptake produces more than normal surface glycoproteins along the vessels’ basement membrane, resulting in both a thicker and weaker membrane as the disease progresses.  These changes are termed ‘microvascular diabetic disease’, if small blood vessels are damaged, or ‘macrovascular disease’, if large arteries are affected. 

Diabetes also accelerates the development of atherosclerosis (hardening of the arteries due to fatty deposits within the vessels’ walls) due to increased or high cholesterol and triglyceride levels.  This can cause hypertension and result in the development of a thrombus (blood clot) with subsequent heart attack, stroke or peripheral vascular disease (diminished blood circulation in/to the arms and legs). Furthermore, DM causes an overall higher sensitivity in attracting infectious diseases which may also become more dangerous/difficult to treat in the diabetic patient as compared to the general population.

Diabetic retinopathy – is a major cause of vision loss and blindness in diabetic patients, resulting from macular edema and subsequent degeneration, and vascular damage to the small blood vessels (microinfarctions) in the retina (typical ‘cotton wool’ appearance of the retina).

Diabetic nephropathy is probably the best known damaging result of diabetes, when chronic renal failure finally requires dialysis!  Blood glucose levels of more than 200 mg/dl (10 mmol/l), accompanied by discomfort and frequent urination, can often lead to severe dehydration.
 
Diabetic cardiomyopathy, and diabetic neuropathy cause various severe damages to the heart and nervous system, respectively.  The former leading to diastolic dysfunctions, while the latter can cause abnormal and/or decreased sensations in a typical ‘glove and stocking’ distribution, starting with the feet (‘diabetic foot’).

Diabetic foot – a classic sign of advanced diabetes, is the result of a combination of neuropathy and advanced arterial disease, causing skin ulcers and associated infections, and finally resulting in necrosis and gangrene of individual toes at first, spreading upwards if not aggressively treated with medication and/or local surgery (amputation).

Diabetic encephalopathy – the increased incidence of dementia with an associated decline of cognitive perception is thought to be the result of alterations in the vascular supply to the brain as well as altered interactions of insulin within the brain itself.

Other symptoms associated with type 1 diabetes include:

  • Diabetic ketoacidosis – coma (see above);
  • Acetone smell of the breath;
  • Rapid, deep breathing, called ‘Kussmaul breathing’;
  • Nausea and vomiting;
  • Abdominal pain;
  • Altered states of consciousness (e.g. hostility, mania, confusion lethargy).

Other symptoms associated with type 2 diabetes include:

  • Frequent urination;
  • Excessive thirst;
  • Extreme appetite/hunger;
  • Increased fatigue;
  • Unexplainable weight loss;
  • Blurred vision;
  • Irritability.


 
Diagnosis:

Diabetes mellitus characteristically shows a persistent high blood glucose level (hyperglycemia), which can be diagnosed by one of the following:

  • Fasting (in the morning, before eating anything) plasma glucose level of 126 mg/dl (7.0 mmol/l) or higher;
  • Glucose tolerance test, GTT – 75 g oral glucose load, draw blood two hours later – plasma glucose levels of 200 mg/dl (11.1.mmol/l) or higher indicates diabetes;
  • Random plasma glucose levels of or above 200 mg/dl (11.1 mmol/l).

If any one of the above tests is positive in the absence of clinical symptoms of diabetes (see above), it should be confirmed by performing one of the other test methods on another day.

Two fasting glucose measurements of above 126 mg/dl (7.0 mmol/l) at two different occasions are currently considered to be diagnostic for diabetes mellitus.

Diabetes is often detected when a person suffers one of the diabetes-related problems, such as a heart attack or stroke, poor wound healing or the classical foot ulcer, neuropathy or retinopathy (certain vision/eye problems), or when delivering a baby with macrosomia (excessive birth weight – ‘big-baby’ syndrome) or hypoglycemia.

Patients with fasting glucose levels of between 110 and 125 mg/dl are considered to have ‘impaired fasting glycemia’; while patients with a GTT of 140 mg/dl or more are said to have ‘impaired glucose tolerance’.  Both are pre-diabetic states, with the latter one being a major risk factor for developing into full-blown diabetes mellitus and cardiovascular disease.

Diabetic ketoacidosis (DKA), a medical emergency, will present itself with extreme plasma glucose levels; urine analysis also reveals significant levels of ketone bodies in the urine (acidic urine, decreased pH value), even prior to the development of overt DKA symptoms.  DKA is much more common in diabetes type 1 than in type 2.

‘Glycosylated hemoglobin’ or HbA1c of 6% or more is considered abnormal.  Since in persistently elevated levels of glucose, the glucose binds to hemoglobin, testing HbA1c levels are used to track the effectiveness of the treatment over a longer period of time.  Diabetic patients with HbA1c of less than 7% are considered to be under glycemic control, and thus have a significantly lower risk of developing diabetes related complications, including diabetic nephropathy or retinopathy.


Treatment:

Diabetes type 1:

Patients usually require daily insulin injections for life, in order to sustain life.

New ways of delivering insulin, aside from the old-style subcutaneous injections, several times a day, include an insulin pump, which allows a 24 hour continuous infusion of insulin at preset levels, including the provision of a bolus injection at or around meal times.  There is also an inhaled version of insulin, although the producer has discontinued this version in late 2007 for business-related reasons.  Another type of pump that can be inserted subcutaneously, measures the current blood glucose level and provides the necessary insulin in a timely manner (closed-loop insulin pump), has been developed, but is not yet commercially available.

At this point in time, there is no alternative treatment to regular and repeated insulin injections for patients with type 1 diabetes.   A major part of an effective therapy schedule consists of adequate patient training, stressing the need for keeping an appropriate weight, exercise schedule and performing regular testing of glucose levels and dosing of insulin injections.   

Type 1 diabetes cannot be treated with any of the antidiabetic drugs that are used for, and can be effective in treating type 2 diabetes.

Currently available types of insulin include:

  • Regular insulin;
  • NPH insulin (‘Neutral Protamine Hagedorn’, a porcine form of insulin);
  • Beef insulin (not available anymore in the USA);
  • Synthetic insulin analogs, which are divided into:
    • ‘fast acting’ insulin analogs – Insulin lispro, insulin aspart, insulin glulisine; and
    • ‘long lasting’ insulin analogs – Insulin glargine, insulin detemir.

The option of a transplant as a combined kidney-pancreas transplant requires extensive immuno-suppressive treatment and is not considered an optimal therapy; the transplantation of exogenous beta cells has been performed in mice and humans, but is still far from becoming an effective and acceptable way of treatment.

And finally, stem cell research, which can permit the regrowth of beta cells within the islets of Langerhans, has been performed in mice, and a first trial in 2007 with type 1 diabetic patients showed that the majority of patients did not require any insulin injections for a prolonged period of time.  However, these therapies are still in early stages of development, and local and/or national resistance to stem cell research may further delay the development of this kind of effective treatment.

Diabetes type 2:

Can usually be controlled by adhering to an appropriate diet (low in fat, cholesterol and simple sugars), losing weight if overweight, doing regular exercise, and oral medications.  However, more than 50% of patients with type 2 diabetes may also require insulin at some point during their illness, in order to control their blood glucose levels.

In pre-diabetic stages or early and ‘low-grade’ diabetes, weight loss, proper diet and increased physical activities can often result in long-term and very satisfactory glucose control.  If these measures fail to keep the blood glucose level within an acceptable range, the next step is treatment with one or more antidiabetic drugs (oral hypoglycemics).

Several groups of oral antidiabetic drugs are available which act in different ways:

  • To increase the insulin output by the beta cells of the pancreas by sensitizing them to the action of glucose – ‘sulfonylureas’, such as the first generation drugs chlorpropamide, tolbutamide and carbutamide, or the second generation drugs glipizide, glibenclamide, glibomuride, glimepiride, and others; these drugs can also inhibit glucagon secretion and sensitize target tissues to the action of insulin.
  • To increase/potentiate the sensitivity (response) of cells to the action/effects of insulin – ‘thiazolidinediones’, also called glitazones, include drugs such as rosiglitazone, troglitazone and pioglitazone; these drugs also reduce the glucose production in the liver.
  • To decrease the hepatic glucose production from amino acids and lipids (gluconeogenesis), and the amount of glucose released from the liver – ‘biguanide class’, the only available drug is metformin (Glucophage®); this drug also increases the glucose uptake and utilization by tissues (especially muscle tissues), and decreases the intestinal absorption of glucose.
  • To delay/reduce the absorption of carbohydrates from the intestinal tract – ‘alpha-glucosidase inhibitors’, such as acarbose, miglitol and emiglitate.


At some point in time, oral medication will fail due to continuous impairment of beta cell insulin secretion; now, it will be necessary to start insulin therapy in order to maintain normal or acceptable blood glucose levels.

Another, albeit still somewhat controversial therapy, consists of ‘gastric bypass surgery’ – the surgery is intended to bypass the absorption of glucose in the duodenum and the proximal jejunum (the first and second part, respectively, of the [three parts of the] small intestine) by surgically removing these sections of the small intestine.  This kind of approach may become a standard treatment, especially in morbidly obese patients (diabetics with excessive overweight), provided that the medical specialists are also available.  While the exact mechanism of its success is still under research, it is believed that the proximal segments of the small intestine are dysfunctional in performing their physiological duties in type 2 diabetic patients. 

Hypoglycemia:

Hypoglycemia can usually be treated very easily by drinking a glass of (orange) juice or other sugary drinks or eating sugary food.

In severe cases, an intravenous (i.v.) infusion of dextrose or an injection of glucagon, a hormone that counteracts the effects of insulin, can be administered.  The glucagon injection is usually done in case of an emergency situation, while the i.v. dextrose infusion is the preferred way of treating hospitalized patients.

In summary – patients with diabetes (both type 1 and type 2) should never underestimate the importance of a proper diet and regular exercise.  While these two functions do not treat diabetes, they can prevent or delay its development, and this kind of healthy lifestyle is certainly a mainstay in any treatment schedule for controlling any form and extent of diabetes.


 
Prevention:

Diabetes type 1 is known to depend on a genetic predisposition, based on specific HLA types (Human Leukocyte Antigen), in particular on types HLA-DR3 and HLA-DR4; a possible, yet unknown environmental trigger (infection?); or an uncontrolled autoimmune response that attacks and destroys the beta cells within the islets of Langerhans in the pancreas.

Breastfeeding has been shown to decrease the risk of diabetes in later life!

Vitamin D in doses of 2,000 IU, given to children early in life, appears to be associated with a reduced risk of developing type 1 diabetes.  Similarly, Vitamin B3 (niacin) given to children with or without antibodies to beta cell proteins, has been shown to be related to a significantly reduced risk of developing type 1 diabetes.

The risk of developing diabetes type 2 can often be reduced by adjusting changes in one’s diet and increasing overall physical activities.  Interestingly, moderate alcohol consumption appears to have some kind of preventive effect towards the development of diabetes, while heavy consumption of alcohol clearly increases the damage to the body’s system considerably.

 

                                                   

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