The suggestion of an increase in the number of sudden deaths of young people with Type 1 diabetes in the UK has been investigated. It was suggested that such deaths were due to hypoglycaemia and related to the increasing use of human insulin. In total we were notified of 50 deaths of people with Type 1 diabetes under age 50 years in the UK in 1989 which our informants (relatives, physicians, and pathologists) considered sudden and unexpected. An autopsy had been done in all cases and we supplemented this with detailed clinical information from relatives and case records. Of the 50 cases we excluded five with a definite cause of death, 11 suicides or self-poisonings, six cases of ketoacidosis, and four in which there was insufficient information about the circumstances of death to drawn any conclusions. Of the other 24 cases, two patients had been found with irreversible hypoglycaemic brain damage and died after a period of artificial ventilation. The most puzzling group were 22, aged 12-43 years, most of whom had gone to bed in apparently good health and been found dead in the morning. Nineteen of the 22 were sleeping alone at the time of death and 20 were found lying in an undisturbed bed. Most had uncomplicated diabetes and in none were anatomical lesions found at autopsy. There are major difficulties in diagnosing hypoglycaemia post-mortem, but the timing of death and other circumstantial evidence suggests that hypoglycaemia or a hypoglycaemia-associated event was responsible. All patients were taking human insulin at the time of death but most had been changed from animal insulin between 6 months and 2 years earlier and there was nothing to implicate the species of insulin as a factor in these deaths.

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Gastric emptying is a significant determinant of the blood glucose response after an oral carbohydrate load [1] due to the key role this process plays in regulating the rate of nutrient delivery to the small intestine. Gastric emptying may therefore be a previously under-recognized contributor to variations in glycaemic control in diabetes mellitus. Faster rates of gastric emptying have been reported not only in rat models of insulin-dependent diabetes mellitus (IDDM) [2,3] but also in patients with IDDM [4,5] and recent studies suggest that modulation of gastric emptying could be used to improve glycaemic control in patients with diabetes [6].Amylin is a 37 amino acid polypeptide co-secreted with insulin by pancreatic beta cells, in response to nutrient stimuli. It circulates at concentrations of 5±30 pmol/l in normal subjects. IDDM patients are not only insulin deficient but also amylin deficient [7,8]. Amylin concentrations in IDDM patients range from the lower end of the normal range to undetectable and do not increase in response to a glucose load. The peptide pramlintide is a stable trisub- Diabetologia (1998) 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 mg pramlintide) subcutaneously. At 0 min they ate a standard meal consisting of a pancake, labelled with 99m Tc, 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 111 In. 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]

No abstract

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 micrograms/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.