Effect of sulphonylurea on insulin secretion and glucose control in insulin-treated diabetics.
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Biomedical subjects
Publications and source records attributed to R C Turner.
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Previous studies have shown that vessels from diabetics produce less prostacyclin in vitro than those from normal controls. To determine whether this decreased production is related to complications elective biopsy of a superficial forearm vein was performed on 12 insulin-dependent male diabetics, six with nil or minimal and six with proliferative retinopathy, and seven male controls. Vein segments from the diabetics and controls produced similar amounts of prostacyclin in vitro (medians 0.11 and 0.19 ng/mg tissue respectively), but the segments from the diabetics with nil or minimal retinopathy produced less than those from the diabetics with proliferative retinopathy (medians 0.09 and 0.18 ng/mg respectively). Preoperative plasma immunoreactive concentrations of 6-keto-prostaglandin F1 alpha were not significantly different between the controls and the diabetics (medians 101 and 116 pg/ml respectively). In a separate study, however, 11 diabetics with duration of disease of over 10 years and nil or minimal retinopathy had significantly lower concentrations than a matched group of 16 with background or proliferative retinopathy (medians 79 and 121 pg/ml respectively). These results do not support an association between reduced prostacyclin production and diabetic retinopathy.
The molecular and macroscopic changes occurring during the polymerization of poly(methyl methacrylate) (PMMA) bone cement have been investigated. Electron paramagnetic resonance (EPR) spectroscopy was used to monitor free-radical generation and this was compared to temperature changes occurring in the cement for various ratios of polymer powder to liquid monomer (P/L ratio) used in the sample preparation. Both the concentration and the characteristic growth time of the free radicals associated with the polymerization of the bone cement depended on the P/L ratio used. Larger P/L ratio resulted in shorter characteristic growth time for the free radicals as well as a shorter time for the occurrence of the peak sample temperature. Smaller P/L ratios gave smaller maximum concentrations of free radicals and larger peak temperatures. These results are explained on the basis of (1) more initiators present at higher P/L ratios resulting in faster polymerization and (2) less initiators and more monomers present at smaller P/L ratios resulting in fewer radicals but more exothermic reactions. The free radicals present in the bone cement due to the manufacturer's sterilization process were found to be proportional to the fraction of powder used in the preparation, indicating negligible monomer loss during sample mixing.
The relative efficacy of two twice-daily insulin regimens using highly purified insulins, once daily Ultratard with twice daily Actrapid (ultralente/soluble) and twice daily Actrapid with twice daily Retard (soluble/isophane), has been studied in 12 diabetics in a cross-over study. Control was optimised as an out-patient, and assessed by in-patient 24 hour profiles. Similar day-time glucose control was achieved, but the mean overnight plasma glucose concentrations were more steady on ultralente/soluble (0100, 0300, 0500, 0700, 0800 h values 5.6, 5.3, 5.8, 7.8, 10.4 mmol/l) than on soluble/isophane (4.3, 3.4, 5.2, 7.5, 12.2 mmol/l). The minimum overnight plasma glucose concentrations were lower (p less than 0.05) on soluble/isophane (mean 2.8 mmol/l) than on ultralente/soluble (mean 4.8 mmol/l), associated with higher (p less than 0.05) nocturnal free plasma insulin levels after the evening soluble/isophane injection. The plasma glucose rise between 0700 and 0800 h was greater (p less than 0.05) on soluble/isophane than on ultralente/soluble. The morning insulin injection should probably be taken immediately on rising, to prevent the pre-breakfast plasma glucose rise. The ultralente/soluble combination gave similar day-time plasma glucose control to soluble/isophane with less nocturnal hypoglycaemia.
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The 'basal' plasma glucose, defined as the stable overnight concentration, has been assessed as an index of diabetes control by comparison with plasma glucose measurements during 24-h profiles in diet-treated maturity-onset diabetic patients and normal subjects. The basal plasma glucose correlated with the total (r=0.98) and incremental (r=0.86) glucose areas, as well as the 24-h M value (r=0.90). In mild diabetes the basal value was more abnormal than the incremental glucose area after meals, since 3 h after meals 'reactive hypoglycaemia' lowered the plasma glucose to less than the basal value. Thus diabetics with a raised basal glucose up to 8 mmol/l can have a normal 3-h post-prandial value. A raised basal plasma glucose provides similar diagnostic information to conventional oral glucose tolerance tests and provides an apposite measure of diabetes control. Diabetics who come up to a clinic, or who exercise whilst fasting, have fasting plasma glucose and insulin concentrations slightly higher than their overnight 'basal' levels, whereas there is little change in normal subjects. This higher 'stressed fasting' plasma glucose needs to be taken into account when assessing fasting plasma glucose values.
Metabolic turnover of fibrinogen and plasminogen were studied in thirty insulin-treated diabetics and ten non-diabetic controls. 131-iodine labelled fibrinogen and 125-iodine labelled plasminogen were injected intravenously and the plasma clearance of the two proteins measured simultaneously over a period of 8 days. The diabetics were selected to represent three grades of severity of diabetic retinopathy assessed by ophthalmoscopy and fluorescein angiography; ten patients had no significant retinopathy, ten background and ten proliferative retinopathy. Subjects were matched as closely as possible for body weight, age and duration of diabetes. Plasma fibrinogen concentrations were higher in diabetics (3.24 g/l) than controls (2.65 g/l; P less than 0.025); the patients with the severest retinopathy had the highest fibrinogen concentrations (3.75 g/l). As a direct consequence of the elevation of plasma fibrinogen the catabolic rate was higher in diabetics (20.9 mg kg-1 day-1) than controls (14.0 mg kg-1 day-1; P less than 0.025) and higher in patients with background retinopathy (24.1 mg kg-1 day-1) and proliferative retinopathy (22.4 mg kg-1 day-1) than diabetics without retinopathy (16.3 mg kg-1 day-1; P = 0.05). Fibrin(ogen) degradation products were detectable in all diabetics but in only one-third of controls. Plasminogen metabolism was normal in all groups of diabetics. It is concluded that fibrinogen metabolism is increased in diabetes and bears a relationship to diabetic retinopathy but is not accompanied by significant alterations of plasminogen metabolism.
Three newborn infants are reported who developed severe non-ketotic hypoglycaemia (blood glucose less than 1.1 mmol/l; 19.8 mg/100 ml) within 6 hours of birth. All had inappropriately raised plasma insulin concentrations for the level of glycaemia, and required high rates of glucose infusion (less than 15 mg glucose/kg per minute) to prevent symptoms of hypoglycaemia. Medical treatment (hydrocortisone, diazoxide, chlorothiazide, phenytoin, propranolol, and depot glucagon) was ineffective in preventing hypoglycaemia and all 3 infants were subjected to partial and then total pancreatectomy. The pathological features of nesidioblastosis are reported from quantitative immunohistochemical studies on the pancreata. These results together with those from metabolic and endocrine studies performed on the 3 infants during the investigation of the cause of the hypoglycaemia and during the preoperative and postoperative period are presented in detail in order to define a practical approach to the management of this difficult clinical problem in the neonate.
The basal plasma insulin and glucose concentrations of 12 diet-treated maturity-onset diabetics were measured at minute intervals for 2 h. Brief, irregular oscillations (mean period 8.8 min) in plasma insulin were superimposed on longer term fluctuations (greater than 30 min). Time series analysis demonstrated a synchronous plasma glucose oscillation (mean amplitude 0.03 mmol/L) associated with short insulin cycles. The glucose changes seen in diabetic subjects were similar to the short plasma insulin cycles (less than 10 min) observed in normal subjects. In contrast, the longer plasma insulin cycles (greater than 10 min) of normal subjects were associated with a plasma glucose oscillation that rose before the end of the cycle. The demonstration of insulin oscillations independent of preceding plasma glucose changes in both normal and diabetic subjects suggests a pancreatic oscillating mechanism of "pacemaker". The associated glucose changes may reflect the entrainment, by the insulin cycles, of glucose production or utilization.
Control of diabetes in a group of 82 insulin-treated diabetics was assessed by in-patient 24-hour plasma glucose profiles and haemoglobin A1 (HbA1) estimation. Thirty-two of these patients (39 per cent) had hypoglycaemia (plasma glucose less than or equal to 2 mmol/l) which was rarely associated with symptoms. Twenty-seven (61 per cent) of 44 patients who took a series of out-patient pre-prandial capillary blood samples over a three-day period had hypoglycaemia. Conventional measurements of diabetic control including fasting plasma glucose and HbA1, were lower in patients with hypoglycaemia than in those without. Rebound hyperglycaemia following hypoglycaemia was not seen and its absence was not due to diabetic autonomic neuropathy. Cortisol/creatinine ratios in early morning urine samples were similar in patients with and without nocturnal hypoglycaemia, consistent with the absence or rebound hyperglycaemia. Diabetic retinopathy was less prevalent in patients with hypoglycaemia, possibly reflecting better long-term diabetic control in this group. HbA1 concentration reflects overall blood glucose control in diabetes but near-normal levels must be interpreted with caution since they may be associated with recurrent hypoglycaemia.
Twenty-four-hour metabolic profiles were performed twice in each of 15 diabetic children, once when they were receiving single daily injections of insulin (Monotard plus Actrapid) and once on a twice-daily regimen (Semitard plus Actrapid). Before the study control was optimised at home on each regimen. There were no differences in overall 24-hour diabetic control on the two regimens as measured by mean blood glucose concentration, area under the blood glucose curve, M value, and 24-hour urinary glucose excretion. Hyperglycaemia after breakfast occurred on both regimens. Significant differences were noted before breakfast, when blood glucose and ketone concentrations were lower and plasma free insulin higher on the single-injection regimen, and after supper and during the night, when blood glucose values were lower on the two-injection regimen and associated with a rise in plasma free insulin after the evening injection. Once-daily injections provided insufficient circulating insulin after the evening meal, while twice-daily injections did not last through the night. Plasma C peptide, indicating residual endogenous insulin secretion, was just detectable in two children but easily detectable in four children, whose 24-hour diabetic control was significantly better than that in the remaining 11 children.Conclusions about the superiority of one insulin regimen over another must be based on specific differences in diabetic control. Both regimens studied achieved adequate control, and though neither provided physiological control specific modifications to the regimens could help to produce more normal profiles.
1. Adult male hooded rats which were offered a mixed, high energy diet for 90 days were hyperphagic and became significantly obese compared to chow-fed control rats. Fasting plasma insulin and glucose levels were initially elevated in the experimental rats, but later in the 90 day period were similar to control levels. 2. When the high energy foods were withdrawn after 90 days and just chow was available, the obese rats maintained the elevated body weights. The obese rats were initially hypophagic, but chow intakes rapidly reached control levels. Plasma insulin and glucose levels were similar in both groups, suggesting that the persisting obesity may not be associated with altered insulin resistance. 3. Five weeks after withdrawal of the 'fattening' diet, half of the experimental rats were offered restricted access to chow for 27 days to reduce their weights to control levels. When the rats were again given free access to chow, they returned to the previously elevated weight. 4. Eighteen weeks after withdrawal of the 'fattening' diet, the experimental rats had significantly elevated body weights and fat stores. The elevated body weight was not simply due to increased growth because, although the experimental rats had slightly more lean body mass than the control rats, the increase in fat was not related to body size.
15 metabolic profiles were performed on 10 diabetic children who were on once-daily injections of insulin. Blood and urine glucose concentrations were high throughout much of the day and night, and were associated with abnormal levels of blood ketones, lactate, and pyruvate. The plasma free-insulin profiles gave a characteristic pattern for each type of insulin. The investigation gives valuable information for the clinical management of such children.
In order to determine the feasibility of using electron paramagnetic resonance (EPR) to monitor the molecular processes occurring in polymethylmethacrylate (PMMA) bone cement, a preliminary study has been conducted on the bone cement in vitro. It has been found that a sufficient concentration of free radicals is generated in the bone cement during the polymerization process so that both the polymerization and the curing can be monitored by EPR. The results of these measurements on both radiolucent and radiopaque Surgical SimplexR P bone cement are presented. It has also been found that free radicals are present in the radiopaque bone cement powder as received from the manufacturer. These radicals which apparently are produced in the radiation sterilization process have been found to be unaffected by the polymerization/curing process and to be stable for temperatures below about 100 degrees C. It has clearly been shown that EPR can used to monitor the molecular processes of bone cement in vitro. It is hoped that this technique can be utilized to monitor the in vivo ageing process of bone cement used to fix orthopedic implants.
In a study of whether oscillations in plasma glucose and insulin occur in human beings, plasma samples were taken at one-minute intervals from 10 normal subjects for periods lasting between one and two hours. In five subjects the basal plasma insulin concentrations cycled regularly, with a mean period of 13 minutes and mean amplitude of 1.6 mU per liter (11.5 pmol per liter). A concurrent plasma glucose cycle was demonstrated, with a mean amplitude (after averaging to minimize random error) of 0.05 mmol per liter (1 mg per decliter). The average plasma glucose cycle was two minutes in advance of the plasma insulin. In the subjects with less regular plasma insulin cycles, a similar plasma glucose rise was demonstrated two minutes before the insulin rise. These phase relations are compatible with the presence of a negative-feedback loop between the liver and pancreatic beta cells that regulates both basal plasma insulin and glucose concentrations, although the cyclic beta-cell secretion could be independent of plasma glucose.
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