Investigating the pathogenesis of problematic hypoglycaemia

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In order to investigate counterregulatory mechanisms, it is important to produce hypogly-caemia in a controlled laboratory setting where physiological and cognitive responses can be measured accurately and reproducibly. Two variables can be measured: the ability to counterregulate, in which the subject's ability to arrest a falling glucose is determined; and the elements of the counterregulatory responses themselves, in which the hypoglycaemic challenge is strictly controlled by the investigator, in order to compare the responses to that particular hypoglycaemia in different settings. The former is best assessed by exposure to an unopposed hypoglycaemic agent; in the latter, the hypoglycaemic agent is applied but the rate and magnitude of the response is modified by monitored application of exogenous glucose. In comparing the response to hypoglycaemia between conditions (for example, if it is necessary to compare the effects of different clinical situations or treatments on hypoglycaemia), some attempt must be made to achieve a reproducible stimulus. A hypoglycaemic challenge can vary in timing, magnitude, rate of fall and method of induction.

For a successful study, it is important that all aspects of planning are considered, from logistics and location to selection of appropriate subjects, instructions to the subjects and, of course, decisions regarding the study protocol. It is important to ensure there are enough personnel. Tasks include clinical care of the subject; frequent blood sampling and care of intravenous lines; timely centrifugation and processing of blood samples, with rapid readout of glucose concentrations; frequent appropriate adjustment of glucose infusion rates; collection of physiological data; symptom scores; and cognitive function. The study should be carried out in a spacious, quiet and, ideally, temperature controlled environment, with all equipment in close proximity (Figure 5.3). Safety of the subject and of the researchers

Cognitive function testing

Pulse and BP monitoring

Hot box

Glucose infusion pump

Figure 5.3 Subject in position during experimental induction of hypoglycaemia. In this example, the subject is undergoing a stepped hypoglycaemic clamp.

Cognitive function testing

Pulse and BP monitoring

Hot box

Glucose infusion pump

Figure 5.3 Subject in position during experimental induction of hypoglycaemia. In this example, the subject is undergoing a stepped hypoglycaemic clamp.

is of paramount importance. Strict aseptic technique, wearing of disposable gloves and safe disposal of sharps are essential ground rules. Subjects need to be carefully observed both during and after an induced hypoglycaemic challenge. Blood glucose should always be restored to normal and the subject fed after a study, and observation should be continued, including blood glucose monitoring, until the investigator is sure that normoglycaemia is being maintained spontaneously.

It is important to avoid carrying out hypoglycaemia studies on people with ischaemic heart disease, epilepsy, hypertension, untreated hypothyroidism, hypoadrenalism or unstable diabetic retinopathy. It is crucial not to carry out studies on women of childbearing age if radioisotopes or potentially teratogenic or fetotoxic drugs are to be used, because of the potential risk to any future fetus.

For comparative studies, subjects should be age and gender matched, as there are important differences in counterregulatory responses between sexes and age groups (Matyka et al. 1997; Davis et al. 2000). Mixing genders and ages will at the very least increase the variance of the measures made and may obscure differences resulting from other factors. If groups are of mixed gender in a cross sectional study, the gender distribution must be matched. Vigorous exercise and caffeine should be avoided prior to the study as they can also affect counterregulatory responses (Debrah et al. 1996; Sandoval et al. 2006). Subjects should be studied in the same position (lying or standing) as there is a greater perception of hypoglycaemic symptoms in the standing position than in the lying position (Hirsch et al. 1991). It is usual to study subjects in the fasting or post-absorptive state. This allows a steady-state baseline. In the fed state, symptoms of hypoglycaemia are decreased, but counterregulatory hormone responses are increased (Porcellati et al. 2003). Furthermore, there are diurnal rhythms in many counterregulatory hormones - such as cortisol and growth hormone - which may affect both insulin sensitivity and counter-regulatory responses. It is important that comparator studies are done at the same time of day to avoid such confounders. With fasting subjects, this will usually be in the morning.

For subjects with diabetes, it is often necessary to achieve near-normoglycaemia prior to study. Otherwise, the magnitude of the hypoglycaemic challenge may vary enormously, with some subjects falling to hypoglycaemia from significant hyperglycaemia, and others starting with a near-normoglycaemic blood glucose concentration. Based on evidence that exposure to hypoglycaemia during the night will reduce counterregulatory responses to hypoglycaemia next day, it is also very important to avoid such asymptomatic hypoglycaemia the night before study. The gold standard is to admit the patient to an observation bed the evening before the study, omit the usual evening intermediate-acting or long-acting subcutaneous insulin and control blood glucose overnight with a monitored low dose intravenous insulin infusion, given as a sliding scale. Unlike clinical sliding scales, this will be run unopposed (i.e. without a simultaneous glucose infusion) to maintain the fasting state. Blood (or plasma) glucose is measured every 30-60 minutes at the bedside and the rate of the insulin infusion adjusted to maintain near-normoglycaemia. If the blood is sampled from an intravenous cannula by an experienced operator, the subject at least can usually get some sleep!

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