In patients with type 11 diabetes the morbidity and mortality attributable to macrovascular complications is increased by two to four times and the microvascular complications is severalfold greater than in an unmatched nondiabetic population. In addition to hyperglycemia, diabetic type 11 patients are characterised by a variety of abnormalities such as obesity, hyperlipidemia, hypertension, insulin resistence, and diabetic retinopathy. In Sweden for example insulin is currently used 3.7 times more frequently per 1000 inhabitants than in neighbouring Finland, although the incidence of diabetes in Sweden is only 70% that of in Finland.

The beneficial effects of insulin treatment for type 11 diabetic patients include: - Reduces fasting and postprandial hyperglycemia - Reduces gluconeogenesis and heptic glucose production - Enhances insulin secretion in response to a mixed meal or glucose stimulus - Improves oxidative and nonoxidative glucose disposal - Induces antiatherogenic changes in serum lipid and lipoproteins

The adverse effects are however: - Risk of hypoglycemia and severe hypoglycemia - Increases body weight, primarily fat mass - Hunger - Sodium and fluid retention - Hyperinsulinemia

Hyperinsulinemia could be an innocent bystander with respect insulin treatment of diabetic patients. (6,9)

Hypoglycemia Unawareness

Hypoglycemia Unawareness in IDDM is a disturbing area in the treatment and management of IDDM in which a threefold increase in incidence has been seen in the UK in the last decade. Syndromes include severe iatrogenic hypoglycaemia and pathogenesis is unknown but is multi factorial creating a vicious circle. Many patients suffer 1-2 episodes of hypoglycemia per week and in a year 10-25% of patients suffer one severe disabling episode of hypoglycemia resulting in coma or seizure which can result in disturbing neurological activity including in some instances leading to aggression and possibly violence. 4% of deaths of IDDM patients are from hypoglycaemia. Physiological and behavioural defences against hyperinsulinemia sometimes occur. Behavioural changes of neuroglycopenia (glucose deprivation) include seizures, coma and the ultimate result of prolonged neuroglycopenia is death. Patients with cervical chord transections (interrupt brain to sympathochromaffin neural outflow) do not recognise hypoglycaemia. Thresholds in patients vary from 3.8mM to 2.8mM glucose. 7% of patients have reported hypoglycaemia unawareness and up to 16% of patients have reported partial unawareness. It is believed there is a need to deliver insulin in a more physiological fashion in order to avoid the problems of hypoglycemia. (7)

Insulin Regimes and Strategies for IDDM

Insulin regimens and strategies for IDDM have been based upon insulin research over the last 80 years resulting in improved purity, an availability of human insulin, the development of insulin analogues uning recombinant DNA technology to improve pharmacokinetics. Despite these advances however attempts at physiological insulin replacement for IDDM continue to be disappointing.

Numerous variables affect insulin absorption and as a consequence may cause circulating insulinemia. Variables which affect absorption include site of injection, depth of injection, insulin species, insulin mixtures, insulin dose, exercise and local heat. The rate of insulin absorption decreases progressively when comparing abdomen to arm to leg. These differences can be large and it has been shown that I125 labeled regular insulin disappears 86% faster from the abdomen than from the leg. If an attempt is made to maintain consistency in nutrient intake in relationship to insulin dose for a specific meal it appears evident that the site of insulin injection be consistent. This is contrary to the traditional advice given to patients several years ago to avoid lipodystrophy. The depth of insulin injection and ambient temperature can affect insulin absorption. This may mean that if a patient is used to the temperate climate of the UK then take a summer vacation in the Mediterranean then hypoglycemia may occur one to three hours after intake of morning insulin as experienced in the form of hypoglycemia unawareness by the author. The effect of exercise on subcutaneous insulin absorption has been well documented in animal and human studies and if insulin is injected into a limb, and that limb is exercised, marked acceleration in insulin absorption can occur. A typical example can be if insulin is injected into the leg, then grass is cut using a motor lawnmower, in a reasonable sized garden, glucose level elevated to say 15.5mM by carbohydrate intake prior to exercise, can reduce to as low as 4.2mM after exercise which is dangerously close to the threshold level for some patients.

The pharmacokinetics of insulin absorption are influenced by the insulin species, the dose, and the interaction of various modified insulin preparations. Human insulin is absorbed more rapidly than animal insulins, however when considering basal insulin requirements, beef and pork insulins have a longer duration of action and for most purposes can be considered peakless when compared with human insulin. Many reports have indicated an increased frequency of hypoglycemia unawareness with human insulin when patients are switched from beef/pork insulins.

The most significant and well documented risk of intensive insulin therapy is the increased frequency and risk of severe hypoglycemia resulting in confusion, coma and seizure leading in some instances to violence. Insulin treatment depends on patients motivation, benefits, self management, goals of therapy, social support and financial implications. In this state of severe hypoglycemia a patient is likely to require immediate assistance from family, friends, collegues, and in some instances a doctor or the emergency services. There is an urgent need in the UK to provide information and training to members of the public, family, friends and collegues of diabetics, diabetic clinic staff and clinicians, GPs and the emergency services to address the problem. (5)

Physiological Responses to Hypoglycemia

Physiological responses to hypoglycemia depends upon the availability of glucose as a fuel for cerebral metabolism. Blood glucose must be maintained above a critical level to preserve adequate brain function. To deny the brain of glucose leads to loss of neurologica and motor control. This can lead to a change in P300 responses and cerebral function change.

Since 1987 there has been an issue of public concern with the loss of awareness of hypoglycaemia in human insulin treated patients as changes to the brain function occur during hypoglycaemia. This issue appears not to have been correctly addressed by the NHS in the UK since its discovery. (8)