Ketonuria in pregnancy--with special reference to calorie-restricted food intake in obese diabetics.

Early morning ketonuria, as judged by Ketostix testing, occurred in 19% of urine samples from insulin-independent diabetic pregnant women eating 1000 calorie diets, in 14% from diabetics on higher calorie diets, and in 7% of urines from nondiabetic pregnant women. Ketostix test was never found to be positive in blood, even when it was 2+ in urine samples, and acetoacetate levels were always below 1 mmol/L. Enzymatic estimations of acetoacetate (AA) and beta-hydroxybutyrate (BB) in urine and plasma samples revealed (1) no significant differences in range or mean between the groups receiving different restricted diets or full diets, the highest value observed for plasma AA being 0.34 mmol/L; (2) that Ketostix became positive at a concentration of AA above 1 mmol/L and that such a value in urine corresponded to plasma levels of between 0.06 and 0.1 mmol/L, i.e., double the normal; and (3) a 50-100-fold increase in urine AA when blood levels exceeded 0.08 mmol/L. Neonates born to diabetic mothers with ketonuria had no fetal distress or asphyxia neonatorum. The lowest Apgar score at 5 min was 8; 80% of neonates had a score of 10. Hence, positive Ketostix tests in urine samples do not indicate toxic levels in the blood, and a 1000 calorie diet for obese pregnant diabetics appears to be safe as regards neonatal outcome.

The histocompatibility (HLA) antigen distribution in diabetes in southern African Blacks (Xhosa).

The frequency distributions of HLA antigens in 25 juvenile-onset diabetics (JOD) and 56 maturity-onset diabetics (MOD) belonging to a southern African black tribe (Xhosa) were compared with those of 153 non-diabetic Xhosa blacks. Unlike the findings in white JODs, there was no increase of B8 or B15 nor a reduced frequency of B7 but an apparently, significantly increased frequency of Bw35 and A2 in both Xhosa JODs and Xhosa MODs respectively. This is the first ethnic group in which an HLA antigen marker has been found for MOD. Furthermore, these findings suggest that diabetes, both JOD and MOD, in white people is a different genetic disease from the diabetes among the Xhosa tribe.

Immunoreactive glucagon responses to intravenous tolbutamide in chronic pancreatitis.

The effects of tolbutamide infusion (1 gm. over forty minutes) on plasma pancreatic glucagon-like immunoreactivity (PGLI), serum insulin, and blood glucose were studied in six patients with chronic pancreatitis and six matched controls.asal PGLI levels were significantly higher in the patients, despite higher fasting glucose concentrations. Tolbutamide infusion had no significant effect on mean PGLI levels in controls but was associated with significant elevation in pancreatitis patients, despite higher circulating glucose levels in the latter. The data suggest that chronic calcific pancreatitis patients hypersecrete immunoreactive glucagon, possibly from a nonpancreatic source and that this immunocreactive material may be stimulated by sulfonylureas.

The inexhaustible beta cell.

Repeated intensive pancreatic beta-cell stimulation was carried out in 42 subjects, comprising 22 normal controls, 10 mild to "severe" maturity-onset diabetics, and 10 chronic pancreatitis patients. Each subject received 75 gm. oral glucose twice and 1 mg. glucagon plus 0.5 gm. tolbutamide intravenously three times at short intervals. Each of the three combined stimuli caused almost equivalent marked spikes of insulin release in all experimental groups. The total calculated output of insulin was equivalent to the total daily insulin output in normal subjects. Pancreatitics and those with severe diabetes (fasting blood sugar greater than 120 mg./100 ml.) had qualitatively similar but a quantitatively smaller response. Those with mild diabetes were similar to the normal subjects but had an exaggerated response to the second oral glucose dose, suggesting overactivity of the enteroinsular axis. Despite the inordinate insulin levels, hypoglycemia did not occur.

The effect of dietary fiber on glucose and hormone responses to a mixed meal in normal subjects and in diabetic subjects with and without autonomic neuropathy.

We investigated the effects of fiber on responses of blood glucose, serum insulin, gastric inhibitory polypeptide (GIP), and immunoreactive pancreatic glucagon (IRG) to ingestion of mixed meal with and without added fiber (5 g guar and 5 g pectin) in 12 normal, healthy subjects and in 12 age-, sex-, and weight-matched non-insulin-dependent, maturity-onset diabetic subjects (NIDDM). Fiber markedly enhanced glucose tolerance in the normal subjects without a change in insulin or GIP but with a significant reduction in glucagon responses. Fiber also markedly improved glucose tolerance in the NIDDMs without changing insulin or GIP but with a significant reduction in the glucagon responses. The NIDDMs were divided into two groups of six subjects, with and without autonomic neuropathy (AN). In NIDDMs without AN, glucose tolerance was improved by fiber without a change in insulin, IRG, or GIP. In diabetic subjects with AN, glucose tolerance was not improved, although glucagon levels were lowered and insulin and GIP responses were unchanged. It appears, therefore, that fiber improves glucose tolerance by altering factors other than insulin. It seems also that autonomic nervous supply to the gastrointestinal tract is important in mediating the effect.

Insulin responses to crude cholecystokinin-pancreozymin in normal subjects, in patients with chronic pancreatitis and patients with mild maturity onset diabetes.

The effects of repeated injections of 75 U crude cholecystolinin-pancreozymin (CCK-PZ) at increasing plateau glucose concentrations achieved by glucose infusion were studied in 15 controls, 8 chronic pancreatitics and 8 mild maturity onset diabetics. In control subjects CCK-PZ alone caused minor insulin release but proportinally greater secretion with increasing blood glucose concentrations. Chronic pancreatitis patients who had normal responses to intravenous glucose responded normally to the CCK-PZ but at significantly higher plateau glucose levels. Diabetics had no response to IV glucose boluses of 5 g or 10 g, but with glucose infusions of 250-500 mg/min had almost normal insulin responses to CCK-PZ. The responses to CCK-PZ plus glucose were greater than either stimulus alone, indicating an interaction between these and the beta cell. These studies suggest that the gut homone-receptor in the beta cell is intact in maturity onset diabetes and chronic pancreatitis, whether the glucose receptor is normal or defective. The peptide-responsible in the crude CCK-PZ is not secretin, glucagon or gut glucagon, but may be gastric inhibitory polypeptide (GIP) since pure CCK-PZ has no insuli releasing properties.

Inhibition of exaggerated gastrointestinal glucagon responses in chronic pancreatitis by somatostatin.

Oral glucose administration caused an exaggerated release of cross-reacting gastrointestinal glucagon-like immunoreactivity (GLI) and a slight early rise in immunoreactive glucagon (IRG) concentration in patients with chronic pancreatitis, who have impaired insulin release. Intravenous administration of 200 microgram of somatostatin, followed by infusion of 200 microgram over 2 1/2 h, abolished the GLI and insulin responses, but did not change glucose tolerance. This contrasts with the relatively minor effects of somatostatin on GLI responses in control subjects where the clear deterioration in glucose tolerance may relate to inhibition of insulin release.

Sulfonylureas and platelet function.

The platelets of many patients with diabetes mellitus are abnormally sensitive to the effects of aggregatory agents in vitro. It has been proposed that this abnormal platelet function may play a role in the pathogenesis of vascular disease in diabetic subjects. We have investigated the effects of six weeks of treatment with the sulfonylurea agents gliclazide and glyburide on platelet aggregation in 10 noninsulin-dependent diabetic subjects. During treatment with diet alone, the platelets of these patients were abnormally sensitive to aggregation in response to 1 microM of adenosine diphosphate, as compared with those in normal controls. Treatment with both drugs normalized ADP-induced aggregation in these patients. Treatment with glyburide significantly reduced aggregation in response to 10 microM of epinephrine and collagen at 750 microgram/ml. The alteration in platelet function did not correlate with the improvement in plasma glucose concentration, thus suggesting that this may be an effect of the drug. Although one must be cautious in extrapolating these in vitro findings to the clinical situation, this alteration in platelet aggregatory function may be of importance in the prevention of vascular disease in diabetic subjects.

Selective inhibition of arachidonate 5-lipoxygenase by novel acetohydroxamic acids: biochemical assessment in vitro and ex vivo.

1. The chemically novel acetohydroxamic acids, BW A4C, BW A137C and BW A797C, are potent inhibitors of the synthesis of leukotriene B4 (LTB4) from arachidonic acid by human leucocyte homogenates: the concentrations required for 50% inhibition (IC50) were 0.1 microM, 0.8 microM and 0.5 microM respectively. Inhibition was less at higher concentrations of arachidonic acid. 2. These compounds also inhibited the synthesis of [14C]-5-HETE from [14C]-arachidonic acid and the calcium-dependent synthesis of LTB4 from 5-HPETE. This, therefore, suggests that they inhibit 5-lipoxygenase and LTA4 synthase. 3. Concentrations of acetohydroxamic acids required to inhibit metabolism of arachidonic acid by cyclo-oxygenase, 12-lipoxygenase and 15-lipoxygenase were 10 to 100 times higher than those required to inhibit 5-lipoxygenase. 4. The compounds were potent inhibitors of LTB4 synthesis induced by the ionophore, A23187, in human intact leucocytes. This inhibition was reversed by washing the cells. They were also potent, selective inhibitors of LTB4 synthesis induced by A23187 in whole rat blood: binding to rat plasma proteins did not greatly reduce the effectiveness of the compounds. 5. The effects of the acetohydroxamic acids, administered either intravenously or orally to rats, on the synthesis of LTB4, and thromboxane B2 (TXB2) in A23187-stimulated blood ex vivo was studied. The three compounds caused dose-dependent inhibition of the synthesis of LTB4 but not TXB2. Inhibition of LTB4 synthesis persisted for up to 6 h after a single oral dose of 50 mg kg-1. 6. The plasma concentrations of unchanged compound determined by h.p.l.c. correlated with the inhibition of LTB4 synthesis ex vivo.

The effects of a novel series of selective inhibitors of arachidonate 5-lipoxygenase on anaphylactic and inflammatory responses.

In conclusion, we have described a novel series of acetohydroxamic acids that are potent and selective inhibitors of arachidonate 5-lipoxygenase in vitro and in vivo. In addition, we have shown that these compounds attenuate "leukotriene-dependent" anaphylactic bronchospasm, the accumulation of inflammatory leukocytes, and the development of fever in experimental models. It now remains to be determined if these compounds have any therapeutic value in man.

The management of non-insulin-dependent diabetes during pregnancy.

We propose a rational regimen for management of non-insulin-dependent pregnant diabetics (NIDD), using appropriately constituted calorie-restricted diets with the oral agents metformin and glibenclamide as may be necessary, with rapid recourse to insulin if the latter do not produce excellent control of blood glucose. Using this regimen between June 1974 and December 1983 we have managed 423 new diabetics (ND, diagnosed during pregnancy) with a perinatal mortality (PNM) of 14 per 1000 and 268 established diabetics (known diabetics, KD) with a PNM of 70/1000 (57/1000 since 1978). A further 80 NIDDs were 'untreated', i.e., not seen by us until near term; these suffered a PNM of 313/1000. Side-effects of the drugs have been few and mild, they are not teratogenic; 'starvation ketosis' does not occur; neonatal hypoglycaemia is preventable by using continuous insulin infusion during delivery. We suggest that the regimen outlined here is acceptable to the patients, is safe, gives excellent results and furthermore teaches the diabetic mother proper dietary control and combats lifelong obesity. It should be useful especially in developing countries in which pregnant, overweight NIDDs are common. Precise control of the blood glucose is essential.