R.D.G. Leslie

HÆMOGLOBIN A1 IN DIABETIC PREGNANCY

Abstract Serum-haemoglobin A 1 (HbA 1 ) did not alter in normal pregnancy but in pregnant diabetic patients HbA 1 was raised in the first trimester, falling as the pregnancy progressed, presumably because of better diabetic control. Post partum, when the control was relaxed, HbA 1 increased. In diabetics at 36 weeks gestation HbA 1 correlated with the fasting blood-glucose 4 weeks previously. 3 out of 5 pregnant diabetics whose HbA 1 was greater on presentation than that of well-controlled diabetics gave birth to children with fatal congenital abnormalities. No abnormalities were detected in children born of mothers with an HbA 1 level within the range for well-controlled diabetes.

SENSITIVITY TO ENKEPHALIN AS A CAUSE OF NON-INSULIN DEPENDENT DIABETES

Non-insulin-dependent diabetes is associated with facial flushing after alcohol in patients on chlorpropamide (chlorpropamide alcohol flushing, C.P.A.F.) especially when there is a family history of diabetes. C.P.A.F. in three subjects (two diabetics, one non-diabetic) was blocked by the specific opiate antagonist naloxone. In nine subjects (six diabetics) C.P.A.F. was reproduced by the enkephalin analogue with opiate-like activity [D-Ala2, MePhe4, Met (O)-ol] enkephalin (DAMME). C.P.A.F. thus may be due to increased sensitivity to endogenous opiates. DAMME and other substances with opiate-like activity, such as morphine and beta-endorphin, affect carbohydrate metabolism and insulin secretion. Increased sensitivity to endogenous opiates such as enkephalin may thus give rise to non-insulin-dependent diabetes associated with C.P.A.F.

Increased proinsulin levels as an early indicator of B-cell dysfunction in non-diabetic twins of type 1 (insulin-dependent) diabetic patients.

SummaryGlucose tolerance and insulin secretion were studied in two groups of non-diabetic identical twins of recently-diagnosed Type 1 (insulin-dependent) diabetic patients: (1) a group of 5 twins with islet cell antibodies, and (2) a group of 6 twins without. Despite similar fasting glucose, insulin and C-peptide concentrations both groups of twins had significantly higher fasting proinsulin concentrations than the control group (p<0.05). The twins with complement-fixing islet cell antibodies had reduced glucose tolerance and clearance, whilst the twins without islet cell antibodies did not. Neither group of twins showed any abnormality in insulin, C-peptide or proinsulin response to oral or intravenous glucose. We conclude that increased fasting proinsulin levels precede abnormalities of insulin secretion, and are an early indication of minor B-cell damage in these twins irrespective of their risk of developing diabetes.

PATHOGENESIS OF INSULIN-DEPENDENT DIABETES: A ROLE FOR ACTIVATED T LYMPHOCYTES

Expression of HLA DR antigens on T lymphocytes indicates that these cells are actively involved in an immune response. Raised levels of activated T lymphocytes were found in 14 of 15 recently diagnosed but in only 7 of 28 long-standing insulin-dependent diabetics. 9 of the recently diagnosed patients retested 6 months later still had high levels of activated T lymphocytes. Even long-standing insulin-dependent diabetics had significantly higher levels of activated T lymphocytes than non-insulin-dependent diabetics and healthy controls. 5 of 7 unaffected co-twins of recently diagnosed insulin-dependent diabetics had high levels of activated T cells; this increase persisted in 2 retested 6 months later, when mildly impaired glucose tolerance had developed. These results confirm that there is an active cellular immune reaction in newly diagnosed insulin-dependent diabetics which may precede the disease and persist for at least 6 months after its appearance.

Evidence that the reduced number of natural killer cells in Type 1 (insulin-dependent) diabetes may be genetically determined

SummaryViruses may cause Type 1 (insulin-dependent) diabetes. We wondered whether the number and function of natural killer cells, which are important in anti-viral defense, are disturbed in diabetic patients. We studied 16 recently diagnosed Type 1 diabetic patients, 18 Type 1 diabetic patients diagnosed more than 15 years previously, 18 Type 2 (non-insulin-dependent) diabetic patients and 23 control subjects. We determined the number of natural killer cells (expressed as log10%) using anti-Leu 11 monoclonal antibody and the function (in log10 lytic units) concurrently using a 51Cr release assay with K 562 as target cells. We found that the number of natural killer cells was reduced in Type 1 diabetes (1.01±0.04) as compared with Type 2 diabetic patients (1.16±0.04, p=0.004) and normal control subjects (1.16±0.04, p=0.006). To establish whether the reduced natural killer cell number is genetically determined we studied 19 identical twin pairs discordant for Type 1 diabetes; we found that even the non-diabetic co-twins had a reduced natural killer cell number (0.93±0.05, p= 0.0006) as compared with normal control subjects. Natural killer cell function was similar in all groups while natural killer activity per cell was significantly increased in the recently diagnosed diabetic patients (1.63±0.07) as compared with long-standing diabetic patients (1.26±0.26, p= 0.03) and controls subjects (1.36±0.07, p= 0.006). In conclusion the reduced number of natural killer cells in Type 1 diabetes appears to be genetically determined while their activity at diagnosis is increased.

Impaired glucose tolerance precedes but does not predict insulin-dependent diabetes mellitus: a study of identical twins

SummaryNon-diabetic identical twins of insulin-dependent diabetic patients were studied within five years of the diagnosis of their index twin in order to determine whether changes in intermediary metabolism precede the onset of insulin-dependent diabetes mellitus. Two studies were performed: a cross-sectional study of 12 non-diabetic twins and a prospective study of a separate group of 41 non-diabetic twins. Ofthe 12 twins tested in the cross-sectional study six developed insulin-dependent diabetes and six did not; the six who developed diabetes were given an oral glucose load a mean of 10 months before diagnosis; they then had normal fasting blood glucose levels but worse glucose tolerance than control subjects (120 min post-load (mean±SD) blood glucose 8.5±3.5 vs 4.9±0.9 mmol/l respectively, p<0.05). However, blood lactate, pyruvate, alanine, glycerol, 3-hydroxybutyrate and serum insulin levels were similar. In contrast, the six twins in this cross-sectional study who did not develop diabetes and are now unlikely to do so, as a group, had no significant changes compared with the control subjects though one had impaired glucose tolerance. To determine the predictive value of impaired glucose tolerance a separate group of 41 non-diabetic twins was studied prospectively for 8 to 22 years having a total of 147 glucose tolerance tests in this period; in this group six developed diabetes. Eight of the 41 had impaired glucose tolerance; impaired glucose tolerance was found in four of the six who developed diabetes as compared with only four of the 35 who did not (p<0.01). Impaired glucose tolerance in these non-diabetic identical twins had a positive predictive value of33% for developing diabetes. The four twins with impaired glucose tolerance who remain nondiabetic now have normal glucose tolerance. We conclude that impaired glucose tolerance may precede the onset of insulin-dependent diabetes mellitus by many months but the change does not specifically predict the disease even in identical twins of diabetic patients. These observations are consistent with the possibility that in some twins the disease process can occur yet remit without leading to diabetes.

Effect of Initiation of Insulin Therapy on T‐lymphocyte Activation in Type 1 Diabetes

Levels of activated T‐lymphocytes are characteristically increased in recently diagnosed patients with Type 1 diabetes and remain elevated up to 6 months after diagnosis. To determine whether insulin treatment has a role in initiating or maintaining this activation 12 patients were studied at diagnosis and again 1,5, and 70 days after the start of insulin therapy. Levels of activated T‐lymphocytes were found to be elevated at diagnosis (9.7 ± 1.6 % (± SD)) before insulin treatment compared with normal control subjects (4.2 ± 1.1 %; p < 0.001). One day after starting insulin therapy, the level of activated T‐lymphocytes had not changed but by day 5 it had fallen significantly (7.6 ± 1.9 %; p < 0.05) compared with pre‐treatment levels. By day 70, activated T‐lymphocytes were returning towards the high levels found before treatment. Investigation of the phenotype of the activated T‐lymphocytes showed that there was an increase in the percentage of activated cells expressing the CD8 (suppressor/cytotoxic) phenotype at 70 days compared with pre‐treatment values (p < 0.02). These results show that elevated levels of activated T‐lymphocytes found in recently diagnosed Type 1 diabetes are not a result of insulin treatment. Treatment may, however, have a role in maintaining T‐lymphocyte activation and modifying the distribution of functional subsets of the activated cells.