Dr Lisa Landymore-Lim, a British chemist specializing in immunology and biomedical chemistry, became curious about the explosion of childhood illnesses such as asthma and diabetes, and carried out a pilot study of drug-prescribing among juvenile diabetics. In 1994, WDDTY published her initial findings. Here is her evidence for suggesting a link between the excessive use of antibiotics and diabetes.
Cases of chemicals and drugs causing temporary and permanent insulin-dependent diabetes (IDD) are well documented in the medical literature (Pharmacol Rev, 1970; 2: 485-518; J Rheumatol, 1987; 14: 732-5). Unfortunately, such cases don’t usually come to the attention of physicians, and most patients are completely unaware of these potential hazards.
Two of the best-known chemicals capable of damaging pancreatic beta cells-responsible for the production of insulin-are the antibiotic streptozocin (Zanosar®, also used in chemotherapy) and the chemical alloxan. These drugs are routinely used in animal experiments to study diabetes. Vacor, a rat poison, has also been reported to cause the disease.
There is a structural similarity between the chemicals streptozocin, alloxan and Vacor: in each, there is at least one oxygen atom joined by two bonds to a carbon atom (C=O), forming a carbonyl group, which is flanked on each side by a nitrogen (N) atom.
This is of interest because carbonyl groups and nitrogen atoms can be considered reactive species due to their excess of negative charge. This means that they are electron-rich and, thus, have an affinity for positively charged species such as zinc ions (Zn2+). Thus, they behave like magnets, attracting oppositely charged species.
Insulin is stored in the pancreas together with zinc. In fact, the pancreas has the highest concentration of zinc in the body, making it potentially a major target for chemical attack.
In addition, double-bonded oxygen groups are also potential sources for the formation of free radicals, those destructive agents that have been implicated in the onset of cancer.
Other chemicals known to be capable of producing diabetes in humans include the drugs dapsone, used in the treatment of leprosy, and pentamidine isethionate, an anti-protozoal agent used to treat pneumonia in AIDS patients.
However, dapsone and pentamidine bear little structural resemblance to streptozocin and alloxan, except that dapsone does contain electronegatively charged oxygen atoms that are double-bonded to sulphur (instead of carbon). Both drugs also have electronegative terminal amino (NH2) groups attached to, or in close proximity of, a benzene ring.
Nevertheless, comparison of daps-one and pentamidine with the drugs frusemide and chlorthiazide, diuretics reportedly associated with the onset of diabetes, also reveals structural similarities. In frusemide, once again we see the electronegative sulphonyl (S=O) group and a terminal amino (NH2) group, whereas chlorthiazide has two SO2 groups and a terminal NH2.
Such groups are not commonly found in drugs. In the American Hospital Formulary Service Drug Information database, which lists some 1000 drugs, less than 5 per cent have either an amino group or a carbon atom bound to a benzene ring.
Sulphonyl groups, however, are commonly found in thiazide diuretics and sulphonamide drugs. Alarmingly, in Australia, diuretics like hydrochlorthiazide (identical to chlorthiazide except for an additional hydrogen atom) are given to young women to treat premenstrual water retention.
Indeed, diuretics are among the top most frequently prescribed drugs in the West. If drugs such as thiazides are causing diabetes, then it comes as no surprise that the incidence of diabetes is increasing in adults.
There have also been reports that some antihypertensives (drugs prescribed to control high blood pressure) may also cause diabetes. One of these is the calcium channel-blocker nifedipine. Again, although the overall structure of this drug is not like any of the other drugs previously mentioned, it does contain several electronegative double-bonded oxygen groups, including an NO2 group bound to a benzene ring such as is found in Vacor rat poison. So, indeed, it is evident that nifedipine shares some structural similarity with chemicals known to cause diabetes.
To summarize, the chemicals and drugs currently known or suspected to be associated with a risk of diabetes appear to have a primary amine (NH2), a carbonyl (C=O) group close to a nitrogen or an oxygen atom, and S02 or NO2 groups. Primary amines and oxygen atoms bound to carbon, sulphur or nitrogen-all considered reactive species due to their negatively charged centres-will bind to zinc under the right conditions by a process known as ‘chelation’, a form of tight chemical attachment.
The pancreas, being a rich source of zinc, could therefore be a potential target for attack by zinc-seeking chemicals. Indeed, it has been suggested that chemicals that can cause diabetes may do so by interacting with zinc in the insulin-secreting beta cells of the pancreas (Mol Pharmacol, 1985; 27: 366-74).
This suggestion is supported by the fact that diabetes arising from chemical exposure is accompanied by a loss of detectable zinc from the pancreatic beta cells (Arch Exp Pathol Pharmakol, 1952; 216: 457-72), and that zinc injected into animals before exposure to a diabetes-causing chemical will protect the animals against developing the disease (Anat Record, 1951; 109: 377; Indian J Exp Biol, 1982; 20: 93-4). It has also been reported that penicillin interacts with zinc (J Pharm Pharmacol, 1966; 18: 729-38).
So, it is conceivable that a chemical such as penicillin circulating in the bloodstream could be attracted to the beta cells of the pancreas, which contain zinc. This could result in the displacement of insulin bound to zinc and chelation of penicillin to zinc, thereby changing the acidity within the cells as new, different bonds are formed. This, in turn, could cause the insulin-zinc aggregates to dissolve, leading to a marked increase in osmotic pressure and cellular rupture.
It is then possible that such chemical changes within the pancreatic beta cells might activate the body’s immune-defence system, resulting in the formation of antibodies directed against the beta cells in an attempt to bind and destroy them, as they are now seen as being foreign to the body.
This may account, at least in part, for the presence of islet-cell antibodies in the blood of many newly diagnosed diabetics. And if this is so, the agent that caused the diabetes would be the chemical that led to rupture of the pancreas cells, but not to the production of antibodies, as the cells of the pancreas have already been damaged.
This is an important distinction as, after the discovery of islet-cell anti-bodies, the current scientific thinking as to the origin of diabetes has centred on its being an autoimmune disorder, causing the body, for some unknown reason, to manufacture antibodies directed against pancreatic beta cells, damaging their ability to produce insulin. This scenario implies that it is the patient’s constitution (immune function) that is at fault.
However, if chemicals and drugs can cause diabetes, there is every likelihood that both IDD and NIDD-which in many Western countries today has reached epidemic proportions-are predominantly the result
of chemical exposure by way of prescription drugs.
Possible zinc-drug interaction
If it’s true that drugs, or the chemical byproducts formed in the body following their ingestion, have an affinity for zinc, then when they enter the bloodstream and pass through the pancreas, they will bind to the zinc in the islet cells of the pancreas. This could displace some-if not all-of the six insulin molecules that are temporarily bound to zinc in the pancreas.
Such an interaction could change the acidity of the cells, causing them to burst as the osmotic pressure within them becomes too great. The result would be irreversible damage to the cells that, in turn, could result in activation of the immune system as it detects a ‘deformed’ cell, which it would regard as ‘foreign’ (abnormal in form).
This would trigger the formation of antibodies, proteins that are directed against such ‘foreign’ (non-self) agents within the body, and explain why many newly diagnosed diabetics have islet-cell antibodies in their blood.
However, if this were the case, these islet-cell antibodies would simply be formed as a result of preexisting damage to the pancreas, but would not be the agents responsible for the destruction of the insulin-producing capacity of the pancreas-as is currently thought.
If chemicals such as drugs or their byproducts are not responsible for eliciting an immune response that results in the formation of antibodies, the unanswered question then remains: what is it that triggers the immune system to produce these antibodies?
On the other hand, if some chemicals are indeed capable of destroying the ability of pancreatic beta cells to secrete insulin, as is known to occur in those who have ingested the rat poison Vacor, then it
is conceivable that the damage may be gradual, with just a portion of the pancreas being destroyed with each chemical attack.
Also, it would appear to be logical to suppose that children who are exposed as fetuses and newborns to such an agent might become diabetic at a younger age than those exposed to the same agent as babies or children, and may require only one exposure to cause damage if it occurred in utero or soon after birth.
For example, if a fetus of 25 weeks has half of its insulin-producing cells already destroyed during its development, it would be unlikely to present any of the clinical symptoms currently associated with diabetes. However, after birth, the child may be expected to ‘run out’ of its insulin-producing capability at an earlier age than a baby that is exposed to the same amount of toxic chemical, but after birth. In the latter child, a smaller proportion of the pancreas would be affected as its exposure was later in its development. Damaged pancreatic cells, unlike liver cells, are not replaced as they lack any significant capacity for regrowth.
So, as the body weight of both these infants increases after birth, the one with the lower level of insulin-producing capability would be expected to exhibit signs of diabetes sooner, at an earlier age.
The drug penicillamine-which is also one of the breakdown products of penicillin-is an effective chelator of metal ions, including zinc, and is used in medicine as chelation therapy for the reduction of toxic levels of zinc salts. Also, although erythromycin was reported some 25 years ago as not binding to zinc, it is now known that it can be made to react in vitro [in the lab] in a one-to-one ratio (Brocades Pharma [now known as Yamanouchi Europe], a personal communication).
The probability of binding (chelation) between zinc and organic compounds-that is, compounds containing carbon, nitrogen and oxygen-is high. Such binding usually occurs between the negative-ion-
rich centres of either the oxygen or nitrogen groups of the chemical and the positively charged zinc (Zn2+) ion. In the case of insulin-zinc complexes found naturally in the pancreas, the binding is reversible, as it enables insulin to be stored until required.
Whatever the route of destruction of the pancreas’ ability to secrete insulin, it is worthwhile noting that some of the drugs that diabetic children are exposed to during fetal development are structurally similar to each other. For example, in the survey of diabetic children that I carried out, one child was exposed to Asacol (mesalamine) and another to paracetamol. The structure of Asacol is similar to para-aminophenol, a highly toxic chemical formed in the body in tiny quantities following paracetamol (acetamino-phen) breakdown.
What’s more, Asacol and penicillamine both have an amine (NH2) and a carboxyl (COOH) group.
A drug connection would also account for another mysterious feature of diabetes: that only the beta cells of the pancreas are destroyed. The alpha and delta cells of the pancreas, also located in the islets of Langerhans where the beta cells are, are not damaged in diabetes. It is only the zinc-containing beta cells that are damaged. This selective destruction may well be caused by chemicals with an affinity for zinc.
UK dispensing practices
When considering diabetic children in the same family, rather than heredity, the cause may be the family doctor.
If the family’s physician commonly prescribes antibiotics to babies and children, and if one accepts that antibiotics may be implicated in the onset of diabetes, then it would not be surprising to find more than one diabetic child in the same family.
The table shown in the box on page 7 shows the geographical variation in the incidence of diabetes in England among the under-15-year-old age group. East Anglia, a predominantly rural area, has the highest incidence, whereas the four Thames regions, areas of higher population density and pollution, have the lowest. The incidence in East Anglia is more than double that of the North West Thames region.
This pattern of a rural area having a higher incidence of diabetes than an urban region is also seen in Scotland. In the UK, doctors are allowed to dispense their own drugs for patients who are living more than a mile away from the closest pharmacy. Consequently, although few GPs in builtup areas dispense their own drugs, in rural areas, the proportion of dispensing practices can be rather high.
In one study comparing children living in the Cambridgeshire and Wessex Areas, the health authorities’ data showed that a high proportion of diabetic children lived in the countryside and not in the towns, despite the presumably higher population density of children in the latter.
In other words, if all children were at equal risk of diabetes irrespective of where they lived, the expectation would be to find more diabetic children in the urban areas.
Furthermore, it appears that some of the dispensing practices in the countryside were considerably more affluent-despite being supported by fewer GPs-compared with those in the outer-London areas. Indeed, some surgeries had recently been purpose-built, and at considerable cost. It was also noticeable that in some of these practices, antibiotics were apparently being liberally prescribed to babies and children. The small areas looked at were located in area health authorities with a high incidence of diabetes.
This raises the question of whether the proportion of dispensing doctors might be related to the incidence of diabetes in children. If drugs such as antibiotics were implicated in any way with the onset of diabetes, and if dispensing doctors prescribed them more liberally perhaps as a result of financial incentives, then it might be reasonable to expect to find a higher incidence of diabetes in country vs city children.
The North Western and Mersey regions, which both have a medium incidence of diabetes and yet a low number of dispensing doctors, are both, incidentally, regions with the highest number of prescriptions (excluding those dispensed by prescribing doctors) per person in England for 1981 and for 1990. They are also the regions with the greatest increase in the number of prescriptions per person in England between 1981 and 1990-an average increase of 25 per cent-compared with around 8.7 per cent for the four Thames regions over the same time period.
In addition, the NW Thames area [the Thames region with the lowest incidence of diabetes in under-15s during 1988] was also the region with the lowest number of prescriptions per person in 1981 and in 1990-5.6 and 5.9, respectively. By way of comparison, the SE Thames area (the Thames region with the highest incidence of diabetes) was the Thames region with the highest number of prescriptions per person for 1981 and 1990 (6.3 and 7.0, respectively).
Although these data do not include prescriptions issued by dispensing doctors, the percentage of dispensing doctors in both of these Thames regions is approximately the same. However, the SW Thames region,
which has a low percentage of dispensing doctors (6 per cent), but ranked second highest for incidence of diabetes of the four Thames regions (see box, page 7), was reported in
1985 to have the highest rate of induced births in England (23.9 per cent), compared with an average of 17.2 per cent for the other Thames regions (Francome C. Changing Childbirth: Interventions in Labour in England and Wales. London: Maternity Alliance, 1989).
Since dispensing doctors are more liberal in handing out drugs, then it might be expected that an area with a high proportion of dispensing doctors would also have a high incidence of disease-which is indeed the case here. Furthermore, regions with a higher number of prescriptions per person also had a higher incidence of diabetes.
The idea that drugs can cause diabetes is not new. What is novel is
the suggestion that there are drugs in common use that may be partly responsible for the epidemics currently seen in many industrialized countries today.
Dr Landymore-Lim is a chemist who specializes in immunology. Visit her website at http://www.atomichealth.co.uk.