MOLECULAR AND METABOLIC MEDICINE UPDATE April 2006 volume 2 number 3

EDITORIAL
Prof. Michael Pepper
MBChB, PhD, MD
NetCare Molecular Medicine Institute,
Unitas Hospital
Prof. Tessa van der Merwe
MBChB, FCP(SA), PhD, Reg.Endo.
Netcare Bariatric Centres of Excellence

The basic defect in patients with diabetes is a decrease in the ability of insulin to induce cells of the body to remove glucose from the blood. Whether this is due to a decrease in the amount of insulin produced (e.g. Type I Diabetes) or an insensitivity of the body’s cells to normal amounts of insulin (Type II Diabetes), the result is the same, namely the presence of hyperglycemia.

The classic symptoms of hyperglycemia are polyphagia, polyuria and polydipsia. Other symptoms include visual disturbances, fatigue, weight loss, poor wound healing, dry mouth and dry or itchy skin, impotence and recurrent infections such as vaginal thrush, groin rash and external ear infections. Prediabetes occurs when blood glucose levels are higher than normal but not high enough to qualify for a diagnosis of diabetes. In order to determine whether a patient has pre-diabetes or diabetes, a Fasting Plasma Glucose (FPG) test or an Oral Glucose Tolerance Test (OGTT) should be performed. The FPG is easier, faster, and less expensive to perform. However, in borderline patients, especially those at risk, a 75g OGTT is indicated.

In the first article by Dr. Marietjie Meyer, criteria for the detection and interpretation of hyperglycemia are presented.

In the second article, the current and future applications of stem cell therapy are outlined. Stem cell therapy is currently practiced in several centers in South Africa in the form of bone marrow transplantation. However, in many parts of the world, several other potential applications are being assessed in pre-clinical and early clinical trials. One of the most mediatized, although still experimental, is the use of bone marrow-derived stem cells for myocardial infarction, the objective of which is to salvage injured myocardium and improve myocardial function. NetCare has recently established a cell-therapy company, NetCell Therapeutics. Application of the exciting promise of stem cell technology requires realism and a firm scientific foundation. These are the cornerstones of NetCell Therapeutics’ business.

For more information, visit http://www.ampath.co.za
or contact:
Prof. Michael Pepper
Tel: 012-677-8504 Secretary: 012-677-8503
E-mail: mpepper@doctors.netcare.co.za

DETECTION OF HYPERGLYCEMIA
Dr. Marietjie Meyer
MBChB, MMed(Chem. Path)
Drs Du Buisson and Partners Inc.,
AMPATH National Laboratory Service
  • Screening for hyperglycemia in high-risk individuals is highly recommended
     
  • A FPG is essential as a screening tool
     
  • A diagnostic OGTT may be indicated at a FPG > 5.6 mmol/l (> 100 mg/dl)
Introduction

The diagnosis of Diabetes Mellitus depends solely on the demonstration of hyperglycemia. This is especially true for the diagnosis of type 2 DM. It is problematic that hyperglycemia may be a relatively late development in the course of type 2 DM – delaying the diagnosis and underestimating the prevalence of DM in the population. Complications of DM are present in more than 30% of patients at clinical diagnosis and the onset of type 2 DM probably occurs at least 4 to 7 years before diagnosis. Screening of high-risk individuals is now recommended.

Criteria for testing for DM in Asymptomatic, Undiagnosed Individuals*

Persons without risk factors for DM should be tested at age 45 yr and retested at 3-yr intervals. Testing MOLECULAR AND METABOLIC MEDICINE UPDATE June 2006. Volume 2, number 3 should be considered at a younger age or carried out more frequently in people who:
  • are overweight or obese (BMI > 25 kg/m2)
  • have a family history of DM
  • are members of a high risk ethnic population
  • are sedentary
  • have hypertension or dyslipidemia
  • have a history of polycystic ovarian syndrome
  • on previous testing had impaired glucose tolerance (IGT) or impaired fasting glucose (IFG)
  • have delivered a baby weighing ≥ 4 kg or have been diagnosed with gestational DM

*The oral glucose tolerance test (OGTT) or fasting plasma glucose (FPG) may be used to diagnose DM; however, in clinical settings the morning FPG test is preferred because of ease of determination, convenience, acceptability to patients, and lower cost.

Fasting plasma glucose

It is important to perform the fasting glucose test in the morning (i.e. before 9 a.m.) since the glucose level decreases after this time and may give a false negative result.

What is a normal fasting glucose level?

A FPG of < 5.6 mmol/L is defined as “normal”.

However, studies have shown that mid- and high-“normal” FPG levels are associated with lipid abnormalities that are similar to those found in IFG and IGT:

  • FPG of 4.9 – 5.3 mmol/L Triglyceride level is higher and HDL level lower than when FPG is < 4.9 mmol/L
  • FPG of 5.3 – 5.6 mmol/L Significantly higher triglyceride level, lower HDL level and reduced LDL particle size than when FPG is < 4.9 mmol/L. The same lipid abnormalities are seen in the Metabolic Syndrome.

Oral Glucose Tolerance Test

The 75g OGTT is more sensitive than FPG. It is recommended by the International Diabetes Federation (IDF) for high risk asymptomatic patients as well as previously undiagnosed patients with a FPG > 5.6 mmol/l (> 100 mg/dl) and < 7.0 mmol/l (<126 mg/dl) with symptoms suggestive of diabetes (metabolic syndrome, overt complications). The World Health Organization (WHO) further suggests that an OGTT should be performed in the elderly, as well as in certain high risk ethnic groups (e.g. Aians). The OGTT more accurately identifies patients at risk for developing complications of DM than a FPG, especially in morbidly obese patients. It is however important to note that the OGTT is affected by a large number of factors that result in poor reproducibility.

Factors other than DM that may influence the OGTT

  • Patient preparation:
    Duration of fast (10 to 16 hours)
    Prior carbohydrate intake (at least 150g of carbohydrates / day)
    Medications (thiazides, oral contraceptives, corticosteroids)
    Trauma
    Intercurrent illness
    Age
    Activity (unrestricted activity; patient should be ambulatory)
    Weight
     
  • Administration of glucose:
    Form of glucose (anhydrous or monohydrate)
    Quantity of glucose ingested (75g)
    Volume in which administered (300ml water)
    Rate of ingestion (5 minutes)
     
  • During the test:
    Posture (should be seated)
    Anxiety (increases glucose levels)
    Caffeine (increases glucose levels)
    Smoking (nicotine opposes insulin)
    Activity (no activity during test)
    Time of day (early morning)

Criteria for the diagnosis of DM*
Diabetes Mellitus
Any one of the following is diagnostic: #
1. FPG ≥ 7.0 mmol/L
2. Classic symptoms of DM and casual plasma
glucose ≥ 11.1 mmol/L
3. 2-hour post load plasma glucose ≥ 11.1 mmol/L
during the OGTT
#: should be repeated on a different day

Impaired Fasting Glucose
FPG 5.6 – 6.9 mmol/L

Impaired Glucose Tolerance
Two criteria must be met:
1. FPG 5.6 – 6.9 mmol/L
2. 2-hour OGTT plasma glucose 7.8 – 11.0 mmol/L *American Diabetes Association (ADA) criteria (1997)

For more information, visit http://www.ampath.co.za
or contact:
Marietjie Meyer on 082 808 9309
E-mail: meyerm@ampath.co.za


STEM CELL THERAPY
Prof. Michael Pepper
MBChB, PhD, MD
NetCare Molecular Medicine Institute,
Unitas Hospital
  • Cell-based therapy relies on the use of human cells to replace lost or diseased tissue
  • The concept is readily grasped, and has high intrinsic appeal
  • It may involve adult or embryonic stem cells, and may be autologous or allogeneic
  • The discipline remains under intense scrutiny from various regulatory authorities

Cell-based therapy is set to become an important new treatment modality as well as a complement to existing forms of therapy for a variety of human diseases.

Stem cells are defined as undifferentiated cells capable of self-renewal that can differentiate into more than one specialized cell type (referred to as plasticity) when exposed to appropriate chemical cues. One way of broadly looking at stem cell technology is to consider the sources of stem cells, and their applications.

With regard to sources, two types are recognized: adult stem cells and embryonic stem (ES) cells. Adult stem cells are found in bone marrow, peripheral blood and umbilical cord blood. Other “non-traditional” sources of adult stem cells include adipose tissue, neural tissue, skeletal muscle, skin, liver and olfactory epithelium.

ES cells are derived from early human embryos. Much of the legal and ethical controversy surrounding stem cells is related to ES cells. To date, ES cells have not produced successes resulting in routine clinical application in human patients.

The routine clinical application of stem cell therapy is currently limited to bone marrow transplantation, the objective of which is to replace hematopoietic stem cells. Major indications include leukemia, lymphoma, anemia (Fanconi’s, aplastic), multiple myeloma and immune deficiency.

Other potential applications of adult stem cells include myocardial regeneration (myocardial ischemia and cardiomyopathy), nervous tissue regeneration (spinal cord injury, cerebral palsy, Parkinson’s disease, Alzheimer’s idsease), skin regeneration, generation of insulin-producing betacells, corneal and retinal reconstruction, and others.

Currently there is no alternative to bone marrow transplantation for the replacement of hematopoietic stem cells in cancer patients. This procedure restores stem cells that have been destroyed by high doses of chemotherapy and/or radiation therapy. Currently, the most common source of stem cells for this application is peripheral blood, in which the stem cell count is markedly increased after GCSF/ Neupogen stimulation. Stem cells are purified from the peripheral blood in a procedure called elutriaton, currently performed in South Africa by the South African National Blood Service. Prior to the implementation of this procedure, stem cells were mainly obtained from bone marrow. Bone marrow transplantation may be autologous or allogeneic. The success of the latter relies on finding a matching donor, and even after a successful bone marrow transplantation, rejection occurs in a significant percentage of cases. In addition, the transplant itself may reject the host in so-called graft-versushost disease.

Umbilical cord blood is a rich source of hematopoietic stem cells and has to date been used to treat a number of hematological diseases. Umbilical cord blood stem cells are an excellent alternative to peripheral blood and bone marrow, with no risk of rejection if autologous. Research has shown that there is a 1 in 4 chance of a new-born’s stem cells being able to be used for a sibling and a 1 in 8 chance for a parent. To date, the majority of cord blood transplantations have taken place with stem cells having been sourced from siblings. Other advantages of cord blood stem cells include less stringent requirements for tissue compatibility, and a very much lower incidence of graft-versus-host disease. It goes without saying that all parents would like to use as many opportunities as possible to ensure the future health of their children. Storing cord blood stem cells provides a unique opportunity to recall autologous stem cells should the need arise.

Several unresolved issues remain regarding the use of stem cells in other settings. These include:
1. Identification of the chemical signals that are required to induce differentiation into a defined cell type.

2. Stem cells in tissues are often present in very small numbers. Accessibility is often a problem, and they need to be clearly identified before purification strategies can be devised.

The field of stem cell research has evolved rapidly over the past decade, and many reports have raised hopes that tissue repair by stem cell transplantation could be within reach in the near future. However, how this will translate into routine clinical therapy remains to be determined.

Recommended reading
Ballen KK. New trends in umbilical cord blood transplantation. Blood. 2005 May; 105(10): 3786-3792.

Korbling M, Estrov Z. Adult stem cells for tissue repair - a new therapeutic concept? N Engl J Med. 2003 Aug 7; 349(6): 570-582.

Lakshmipathy U, Verfaillie C. Stem cell plasticity. Blood Rev. 2005 Jan; 19(1): 29-38.

Mayhall EA, Paffett-Lugassy N, Zon LI. The clinical potential of stem cells. Curr Opin Cell Biol. 2004 Dec; 16(6): 713-720.

Okie S. Stem-cell research - signposts and roadblocks. N Engl J Med. 2005 Jul 7; 353(1): 1-5.

For more information visit http://www.netcells.co.za
or contact:
Kim Long: 082-776-1688
E-mail: kim.long@netcare.co.za

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