Relation between breast-feeding and incidence rates of insulin-dependent diabetes mellitus. A hypothesis.

The variations in incidence rates of insulin-dependent diabetes mellitus (IDDM) in childhood within and between genetically very similar Scandinavian populations and the variations in incidence rates with time are difficult to explain. Epidemiological data show that the incidence of childhood IDDM may now be declining and suggest an inverse correlation between breast-feeding frequency and IDDM in childhood. Case-control data show that diabetic children were breast-fed for shorter periods of time than their healthy siblings and the population at large and that a smaller proportion of diabetic children were ever breast-fed.

Spontaneous in vitro immunoglobulin secretion at the diagnosis of insulin-dependent diabetes.

Blood mononuclear cells obtained from 17 newly diagnosed insulin-dependent diabetic (IDDM) patients treated with insulin for 5-7 days were assessed for the number of spontaneous and pokeweed mitogen (PWM)-stimulated immunoglobulin-secreting cells in a reverse haemolytic plaque assay. The spontaneous in vitro immunoglobulin secretion was evanescent and decreased in individual patients within 1-4 months of insulin treatment. Compared to matched controls, 53% (9/17) of the IDDM patients had an elevated spontaneous secretion of immunoglobulin, 41% (7/17) for IgG, 35% (6/17) for IgM, and 35% (6/17) for IgA.

DNA sequences flanking the insulin gene on chromosome 11 confer risk of atherosclerosis.

The allelic frequency of DNA restriction fragments of a large size class (U alleles) in the polymorphic region flanking the 5'-end of the human insulin gene on chromosome 11 was 2 X 5 times higher in a group of patients with extensive atherosclerosis than in subjects in whom atherosclerosis could not be demonstrated by coronary arteriography and careful clinical examination. The U alleles apparently do not confer risk of atherosclerosis through conventional risk factors such as body weight or blood pressure or levels of blood glucose, triglycerides, cholesterol, or lipoproteins.

Smoking habits and prevalence of clinical diabetic microangiopathy in insulin-dependent diabetics.

All patients having insulin-dependent diabetes with onset before 30 years of age and a duration of disease of 12-40 years who visited a diabetes centre within one year were registered. 97% (n = 668) answered a WHO questionnaire on cigarette smoking. The smoking habits were compared to the frequency of proliferative retinopathy and/or diabetic nephropathy (persistent proteinuria).

Comparison of six assays for glycosylated haemoglobin determination.

To examine which glycosylated haemoglobin A components and which assays are the most useful in assessing long-term control in diabetic patients we have compared glycosylated haemoglobin concentrations in normal subjects and diabetic patients measured by six different methods, three chromatographic, a colorimetric, an isoelectric focusing and an agar gel electrochromatographic method. Despite the fact that the correlation between methods was high and the precision calculated from intra-assay variations acceptable, several differences in results were found. Thus Isolab columns determined lower values than other chromatographic methods and the unstable aldimine fraction interfered in agar gel electrochromatography.

Analysis of islet cell antibodies on frozen sections of human pancreas.

The sensitivity and specificity of the assay for islet cell cytoplasmic antibodies in human serum were examined using cryostat sections from fresh frozen pancreas. The specificity of the assay was close to 100% while the sensitivity was 40%-98% depending on the pancreas used. Inter-observer variation was 12-27%.

Genetics of diabetes in Nauru: effects of foreign admixture, HLA antigens and the insulin-gene-linked polymorphism.

Genetic factors play a major role in predisposition to diabetes in the Micronesian population of Nauru. In people aged 60 years and older, 83% of full-blooded Nauruans were diabetic compared with 17% of those with ancestral foreign admixture, as detected by HLA typing. HLA distributions also showed a small increased risk for early onset of diabetes (less than 46 years) associated with HLA-Bw22 (Bw56).

DNA insertion sequences near the insulin gene are not associated with maturity-onset diabetes of young people.

The association between DNA insertion sequences located near the insulin gene and the dominantly inherited maturity-onset diabetes of young people was studied in a large family. The distribution of the restriction fragments was compatible with Mendelian segregation. However, no linkage was found between the DNA insertion sequences and this form of diabetes.

Possible association between DNA sequences flanking the insulin gene and atherosclerosis.

The proportion of subjects homozygous for DNA restriction fragments of a large size class (U alleles), in the polymorphic region flanking the 5' end of the insulin gene of chromosome 11, was higher in a group of non-insulin-dependent diabetic (NIDDM) patients than in normal controls. This finding confirms that the U allele is associated with at least one form of NIDDM. The U alleles were also found to be strongly associated with macroangiopathy in diabetic as well as in non-diabetic subjects.

Glycosylated haemoglobin and steady-state mean blood glucose concentration in Type 1 (insulin-dependent) diabetes.

Since glucose control and glycosylated haemoglobin varies asyncroneously, we have studied the steady-state relationship between these two factors. In Type 1 (insulin-dependent) diabetic patients with a constant haemoglobin A1c during the preceding 2 years, 15 ambulatory blood glucose profiles during a 5-week period showed a constant glucose level and provided a precise estimate of the mean blood glucose concentration. In addition, we studied 15 non-diabetic subjects who provided three glucose profiles and had one haemoglobin A1c determination performed.

Absence of H-2 genetic influence on streptozotocin-induced diabetes in mice.

Five daily injections of streptozotocin (40 mg/kg) produced a delayed but progressively increasing level of hyperglycaemia in long term studies with male Naval Medical Research Institute mice and C3D2F1 (DBA 2 J male x C3H/Tif female) F1 hybrid mice. The development of hyperglycaemia was paralleled by decreased amounts of pancreatic immunoreactive insulin as well as degranulation and necrosis of pancreatic B cells. Insulitis was found from days 9-25 after the first injection of streptozotocin.

DNA insertion sequences near the insulin gene affect glucose regulation.

There is restriction-fragment length polymorphism in the 5'-flanking region of the insulin gene on the short arm of chromosome 11 in man. The polymorphic DNA sequences in 53 members of a large family were analysed by means of the restriction endonuclease BglI. In this family, the BglI restriction fragments were found in four sizes--2.

Restriction fragment length polymorphism of the insulin gene in diabetes mellitus.

Variant DNA sequences flanking the human insulin gene were found in the Danish population using restriction endonucleases (restriction fragment length polymorphism). The frequencies of these DNA sequences were determined in 47 non-insulin-dependent diabetics and 93 control individuals. We report an association between a restriction fragment length polymorphism of the insulin gene and NIDDM.

The low dose streptozotocin murine model of type 1 (insulin-dependent) diabetes mellitus: studies in vivo and in vitro of the modulating effect of sex hormones.

The influence of sex on pancreatic islet B cell susceptibility to streptozotocin was studied in mice given multiple low doses of streptozotocin. Male C3 D2 F1 mice developed a steadily increasing blood glucose level after a lag period of about 3 weeks, in contrast to females who were resistant. Spleen cells from streptozotocin treated female animals produced hyperglycaemia in total body irradiated syngeneic female recipients, but only if the recipients were treated with testosterone.

Neutrophil and lymphocyte function in patients with diabetes mellitus.

Neutrophil granulocyte chemotaxis and intraneutrophilic and plasma levels of lysozyme as well as the number of T and B lymphocytes and lymphocyte transformation in vitro on stimulation with mitogens and microbial antigens were studied in four groups of patients with diabetes mellitus (DM). Twelve patients with insulin-dependent diabetes mellitus (IDDM) and ketoacidosis and 4 patients with non-insulin-dependent diabetes mellitus were studied at the time of diagnosis and before and after start of treatment. Ten patients with IDDM of less than 10 years' duration which had been difficult to regulate well and 10 patients with IDDM well regulated for more than 20 years were studied at their regular outpatient visits.

HLA and diabetes.

HLA studies have conclusively demonstrated that IDDM and non-IDDM are separate disease entities. A considerable part of the genetic susceptibility to IDDM is due to one or more HLA genes. The HLA-DR3 and -DR4 factors showing the strongest association with IDDM belong to the so-called DR antigens, which are believed to be the immune response determinants of man.

Synthesis of glycosylated haemoglobin in vivo.

The synthesis of glycosylated haemoglobins in vivo was measured during 24 h of controlled hyperglycaemia in seven insulin dependent diabetics. The mean blood glucose concentration was 22 mmol/l, while electrolytes and other metabolites were kept normal by infusion of 4-23 IU of insulin during hyperglycaemia. The study confirmed the velocity and magnitude of unstable HbAlc formation previously found in vitro.