I. A. Macdonald

Protection by lactate of cerebral function during hypoglycaemia

Severe hypoglycaemia with brain dysfunction limits intensified therapy in patients with insulin-dependent diabetes mellitus, despite evidence that such therapy reduces the risk of chronic complications of the disease. We have investigated the effect of infusing lactate (a potential non-glucose fuel for brain metabolism) on protective, symptomatic neurohumoral responses and on brain function during hypoglycaemia in seven healthy men. Elevation of lactate (within a physiological range) substantially diminished catecholamines, growth hormone, cortisol, and symptomatic responses to hypoglycaemia and lowered the glucose level at which these responses began. Glucagon responses were unaffected. Lactate was also associated with a significant lowering of the glucose level at which brain function deteriorated, suggesting that brain function was protected during the hypoglycaemia. The defect in counter-regulation is similar to that seen in hypoglycaemia-prone diabetic patients. Initiation of the protective responses to hypoglycaemia (except glucagon) can be delayed by supporting metabolism with an alternative metabolic fuel. Cerebral cortical dysfunction of severe hypoglycaemia is also delayed. Our demonstration that higher brain function can be protected during hypoglycaemia may have therapeutic potential.

Altered ventricular repolarization during hypoglycaemia in patients with diabetes

There is circumstantial evidence implicating hypoglycaemia in the sudden overnight death of young patients with insulin‐dependent (Type 1) diabetes mellitus (IDDM), the mechanism of which is unknown. We have investigated the effects of hypoglycaemia on the electrocardiogram in 15 patients with diabetes (8 with IDDM and 7 with NIDDM) using a high resolution computer‐based system. Patients were randomized to either 2u2009h of euglycaemia or hypoglycaemia (at around 3u2009mmol l−1 ) during the afternoon, using hyperinsulinaemic glucose clamps, the two visits separated by a period of at least 4 weeks. Corrected QT interval (QTc), plasma potassium, and adrenaline were measured at baseline and at 0, 60, and 120u2009min. The degree of QTc lengthening (from baseline) during clamped hypoglycaemia was greater compared to the euglycaemic control period in patients with IDDM (median{range} at 60 min, 156{8 to 258 } vs 6{−3 to 28} ms, p <0.02) and NIDDM (120 min, 128{16 to 166} vs 4{ −3 to 169} ms, p <0.05). The fall in plasma potassium was greater during clamped hypoglycaemia compared to euglycaemia in those with NIDDM ( p <0.03) but not with those with IDDM ( p >0.06). The rise in plasma adrenaline was greater during clamped hypoglycaemia in both groups (IDDM p <0.02, NIDDM p <0.02) and there was a strong relationship between the rise in adrenaline and increase in QTc ( r = 0.73, p <0.0001).These data demonstrate alteration of ventricular repolarization with lengthening of the QT interval during hypoglycaemia and suggest a possible mechanism by which hypoglycaemia could cause ventricular arrhythmias.

Arterial, arterialized venous, venous and capillary blood glucose measurements in normal man during hyperinsulinaemic euglycaemia and hypoglycaemia

SummaryThe purpose of this study was to evaluate the effectiveness of the warm-air box method on the arterialization of venous blood during euglycaemia and hypoglycaemia. Six healthy male volunteers were studied using an i.v. infusion of insulin (144 mU·kg−1·h−1). Arterial blood glucose was clamped at the baseline level for the first 30 min and subsequently reduced to 3.2 and to 2.5 mmol/l for 20 min. At each stage, including prior to insulin infusion, arterial, arterialized venous (heating the hand in a warm-air box set to 55–60°C), venous and capillary blood samples were taken simultaneously for analyses of blood glucose and oxygen saturation (not for capillary blood). The oxygen saturations in arterialized blood were approximately 3% below the arterial values. The arterial-arterialized difference of blood glucose was about 0.1 mmol/l (the 95% confidence interval: from −0.19 to 0.41 mmol/l), which tended to correlate with the difference in oxygen saturations between the arterial and arterialized blood samples (r=0.25, p=0.08). During the test the forearm venous blood oxygen saturation increased by 9% and the arteriovenous difference in blood glucose ranged from 0.2 to 0.5 mmol/l which correlated significantly with the difference in oxygen saturations (r=0.48, p<0.001). Capillary glucose was similar to the arterialized value. Rectal temperature was stable during the experiment. We conclude that the heated hand technique using the warm-air box sufficiently arterializes venous blood so that the glucose measurement in the arterialized blood provides a reasonable estimate of the arterial value and that the venous blood from the contralateral forearm is also markedly arterialized, probably reflecting a vasodilator effect of heating.

Infusion of pramlintide, a human amylin analogue, delays gastric emptying in men with IDDM

Summary Pramlintide, a human amylin analogue, reduces hyperglycaemia after meals in patients with insulin-dependent diabetes mellitus (IDDM). We investigated whether this was due to delayed gastric emptying. Eight men with uncomplicated IDDM were studied twice in a randomised, double-blind crossover design. Euglycaemia was maintained overnight by intravenous infusion of glucose and/or insulin and the following morning a 5-h infusion of pramlintide 25 μg/h or placebo was started at 08.00 hours. At 08.30 hours the patients injected their normal morning insulin dose subcutaneously and 30 min later ate a meal (600 kcal, 50 % carbohydrate) of which the solid component was labelled with Technetium-99 m and the liquid with Indium-111 to quantify gastric emptying. Gamma-scintigraphic images were obtained every 20 min for the next 4 h. Insulin and glucose were infused as necessary to maintain blood glucose levels within 3 mmol/l of the pre-meal value. Compared to placebo, pramlintide significantly delayed emptying of both liquid (median lag time 69 vs 7.5 min) and solid (median lag time 150 vs 44.5 min) components of the meal. Pramlintide delayed gastric emptying so much that t50 values could not be calculated for solid or liquid. Amylin agonists such as pramlintide may, therefore, be of value in improving glycaemic control in IDDM by modifying gastric emptying. [Diabetologia (1997) 40: 82–88]

The effect of single doses of pramlintide on gastric emptying of two meals in men with IDDM.

Summary In a previous study we have shown that an intravenous infusion of pramlintide (an analogue of human amylin) delayed gastric emptying, but the dose of pramlintide was supraphysiological in relation to the amylin response to food in non-diabetic subjects. The purpose of this study was to examine the dose response relationship of subcutaneous injections of pramlintide on gastric emptying and to determine whether administration of the drug before one meal has an impact on the subsequent meal. Eleven men with insulin-dependent diabetes mellitus were studied in a double-blind, randomised, four-way crossover design. None had autonomic neuropathy. Euglycaemia was maintained overnight before the study day. At −30 min the patients self-injected their usual morning insulin and at −15 min they injected the study drug (either placebo or 30, 60 or 90 μg pramlintide) subcutaneously. At 0 min they ate a standard meal consisting of a pancake, labelled with 99mTc, and a milkshake containing 3-ortho-methylglucose (3-OMG). Gastric emptying images were obtained for the next 8 h. At 240 min the subjects ate a similar meal, but on this occasion the pancake was labelled with 111In. All three doses of pramlintide delayed emptying of the solid component of the first meal (p < 0.004) with no significant difference between the drug doses. There were no differences between placebo and pramlintide after the second meal. All three doses of pramlintide resulted in a prolongation in the time to peak plasma 3-OMG level (p < 0.0001) after the first meal but there was no difference after the second meal. [Diabetologia (1998) 41: 577–583]

Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with Type 1 (insulin-dependent) diabetes

SummaryBoth hypoglycaemia and alcohol consumption affect cognitive function but it is unclear whether moderate drinking alters awareness of hypoglycaemia. We have examined this in a single blind randomised hyperinsulinaemic clamp study in eight non-diabetic subjects and seven Type 1 (insulin-dependent) diabetic patients. After 30 min of euglycaemia (blood glucose 4.5 mmol/l) subjects drank either 0.75 g/kg ethanol or a placebo drink after which blood glucose was lowered to 2.5 mmol/l for 40 min. Awareness of hypoglycaemia, reaction time and physiological responses were measured before and after ethanol. At a blood glucose concentration of 4.5 mmol/l, ethanol (producing peak blood levels of 20–25 mmol/l) caused a transient increase in systolic blood pressure (p<0.05), a sustained increase in heart rate (p<0.01) and a slowing of reaction time in both normal subjects and diabetic patients. During hypoglycaemia in both groups, the slowing of reaction time and increase in sweating were more marked after ethanol than placebo (both p<0.05), while the increase in finger tremor (p<0.05) was blunted after ethanol, in both groups. Counter regulatory hormone secretion was not affected by ethanol. Despite increases in symptoms during hypoglycaemia, only 2 of 15 individuals “felt hypoglycaemic” after ethanol compared to 11 out of 15 after placebo. We conclude that after moderate drinking non-diabetic subjects and Type 1 diabetic patients are less aware of hypoglycaemia despite exaggerated physiological changes.

Lack of preservation of higher brain function during hypoglycaemia in patients with intensively-treated IDDM

SummarySevere hypoglycaemia with cognitive dysfunction is 3 times more common in intensively, rather than conventionally, treated insulin-dependent diabetes mellitus (IDDM). To investigate the effect of diabetes control on higher brain function during acute hypoglycaemia, we studied one of the earliest detectable changes in cognitive function, i.e. the four-choice reaction time, and symptomatic and hormonal responses during euglycaemic and hypoglycaemic clamping in human subjects. There were no changes in symptoms or counterregulatory hormones and four-choice reaction time was stable during 220 min of euglycaemic insulin clamping in five men with IDDM, with a coefficient of variation of less than 2.2% (1% for accuracy) for the cognitive function test. During stepped hypoglycaemic clamping however, hormonal responses and subjective awareness of hypoglycaemia occurred in all groups but started at much lower blood glucose concentrations in eight intensively-treated diabetic subjects (Group 1) than in ten conventionally-treated (Group 2) or in eight non-diabetic subjects (Group 3). For example, for adrenaline, plasma glucose thresholds were 2.7±0.2 vs 3.4±0.2 and 3.2±0.1 mmol/l, respectively, p<0.05, Group 1 vs Groups 2 or 3 and for subjective awareness of hypoglycaemia 2.3±0.2 vs 3.0±0.1 and 3.2±0.1 mmol/l, p ≤ 0.003), as in previous studies. In contrast, deterioration in reaction time occurred at 3.2±0.3, 3.2±0.2 and 3.0+0.2 mmol/l, respectively (p=NS), thus occurring at higher glucose levels than subjective awareness in the intensively-treated subjects only. The altered hierarchy of responses to hypoglycaemia in well-controlled intensively-treated diabetes explains the increased risk of severe hypoglycaemia without warning seen in such patients.

Gender differences in counterregulation to hypoglycaemia

SummaryTo investigate the effect of gender on catecholamine responses to hypoglycaemia, single-step euglycaemic-hypoglycaemic clamps have been performed in 14 healthy men and 17 women. Adrenaline responses were 44% lower in females (p<0.01) and noradrenaline 17% lower (p=0.08). In response to low-dose intravenous insulin infusion (0.3 mU · kg−1 · min−1), plasma glucose fall and counter-regulation in seven men and seven women had a different course (p<0.001), with different glucose kinetics. In men, endogenous glucose output recovered quickly to levels that exceeded basal; in women suppression of endogenous glucose output was more prolonged, without rates ever exceeding basal (p<0.05). Peripheral glucose uptake was stimulated in men only. The hormones of acute glucose counter-regulation (catecholamines and glucagon) did not differ between the sexes during this challenge, the catecholamine response in the women being supported by the continuous fall in plasma glucose. These results suggest that: 1) catecholamine responses to moderately controlled hypoglycaemia are diminished in women, and 2) Peripheral insulin sensitivity in men is enhanced over that of women but hepatic sensitivity to insulin may be greater in women.

The measurement of cognitive function during acute hypoglycaemia : Experimental limitations and their effect on the study of hypoglycaemia unawareness

The risk of hypoglycaemia and the resulting impairment in brain function are major factors preventing those with diabetes achieving normoglycaemia. The need to define these risks more precisely has prompted an increasing research effort to identify which aspects of cerebral function are particularly vulnerable and at which glucose level. Much of the evidence is inconsistent, reflecting not only the wide range of methods for measuring cognitive function and inducing hypoglycaemia, but also the inherent variability of the response. Nevertheless, the data suggest that those mental activities which are relatively undemanding are often unaffected at all levels of experimental hypoglycaemia while the performance of more complex tasks deteriorates at glucose concentrations of around 3u2009mmolu2009l−1. The relative imprecision of cognitive testing is reflected in the debate which surrounds the pathogenesis of hypoglycaemia unawareness. There is some evidence that the glycaemic threshold for autonomic activation and symptoms can vary while the threshold for cognitive impairment is fixed. This has led to the hypothesis that hypoglycaemia unawareness arises when the autonomic response develops at a blood glucose below that for impaired cognition, thus preventing patients from recognizing or responding to their usual symptoms. However, contradictory data suggest that the threshold for cognitive impairment can alter in line with the autonomic response, a conclusion which fails to fit either the above hypothesis or the clinical description of hypoglycaemia unawareness. These differences may be methodological or relate to the relative imprecision of measurements of cognitive function. Resolution of these discrepancies may have to await the development of advanced technology such as high resolution MRI or PET scanning. In the meantime, progress could be made if all groups agreed on a limited range of cognitive function tests and used them in a standardized manner.

Gastric emptying in diabetes.

Gastric emptying abnormalities are common in diabetic patients but correlate poorly with gastrointestinal symptoms. Poor diabetic control is more likely to lead to gastrointestinal complications of diabetes and the converse is also true. Gastric emptying may be a previously under‐recognized contributor to variations in glycaemic control in diabetes. There is evidence for both accelerated and delayed gastric emptying. More rapid gastric emptying would result in higher postprandial glucose levels and, therefore, pharmacological means to delay the rate of gastric emptying may be a new approach to slowing postprandial nutrient absorption and improving diabetic control. Hyperglycaemia reduces the rate of gastric emptying in both Type 1 (insulin‐dependent) and Type 2 (non‐insulin‐dependent) diabetic patients. The exact mechanisms responsible for the inhibitory action of hyperglycaemia on gastric emptying are unknown. There is insufficient data on the effect of hypoglycaemia on gastric emptying but one study has reported more rapid gastric emptying.