The snack is critical for the blood glucose profile during treatment with regular insulin preprandially

OBJECTIVES: To evaluate how a snack influences the blood glucose profile during treatment with preprandial regular human insulin. DESIGN: In a randomized study a mid-morning snack either was or was not served. Insulin was given 30 min before the usual breakfast of the patients. Plasma free insulin and blood glucose were repeatedly determined for 5 h. SETTING: Outpatient clinic at a university hospital. SUBJECTS: Twenty patients with type 1 diabetes treated with multiple injections of regular insulin (Actrapid) and eight non-diabetic subjects. INTERVENTIONS: A mid-morning snack either was or was not served 2 h after the usual morning insulin injection. MAIN OUTCOME MEASURES: A difference in the blood glucose profile after a mid-morning snack. RESULTS: With a snack there was no difference in blood glucose fasting and at 12.30 h, whilst without a snack there was a decrease of almost 4 mmol L-1, several patients experienced low blood glucose and three had hypoglycaemia. An extended peak of free insulin was reached 30 min after the insulin injection with a slow decrease to the fasting level after 5 h. After the insulin injection a significant decrease in blood glucose occurred within 30-45 min. CONCLUSIONS: A snack 2 h after the insulin injection results in a smoother blood glucose profile and reduces the risk of hypoglycaemia in patients with type 1 diabetes treated with preprandial regular human insulin. Furthermore, the recommended interval of 30 min between insulin injection and a meal may be too long.     

Low vitamin E status is a potential risk factor for insulin-dependent diabetes mellitus

Objectives. To study the association of vitamin E status with occurrence of insulin-dependent diabetes mellitus (IDDM). Design. A case–control study nested within a 21-year follow-up study. Subjects. Nineteen incident IDDM patients with an average age of 28 years and three individually matched controls per patient. Main outcome measure. Serum concentrations of alpha-tocopherol. Results. Serum alpha-tocopherol concentration at the baseline examination was inversely associated with IDDM occurring 4–14 years later. The cholesterol-adjusted relative risk of IDDM between the highest and lowest thirds of the vitamin concentration was 0.12 (95% confidence interval = 0.02– 0.85). Conclusions. The finding corroborates the hypothesis of a protective effect of vitamin E against development of IDDM. Because of the relatively old age of the patients in the present population, further epidemiological studies on the topic are warranted.     

Screening for coeliac disease among Egyptian children

Introduction

To screen for coeliac disease in Egyptian children with non-endocrinal short stature, refractory iron deficiency anaemia and type 1 diabetes. Also, to evaluate the sensitivity and specificity of different serological tests for diagnosis of coeliac disease (CD).

Material and methods

The study included 292 patients with clinical risk of CD. Testing for coeliac antibodies was performed, together with upper gastrointestinal endoscopy and small intestinal biopsy.

Results

Eleven patients (44%) among 25 patients with refractory iron deficiency anaemia, 23 patients (34.3%) among 67 patients with non-endocrinal short stature, and 6 patients (3%) among 200 patients with type I diabetes mellitus were diagnosed by jejunal biopsy as having coeliac disease. AGA (IgG) had the highest sensitivity for diagnosing CD (80.0%) followed by the TTG (72.7%) antibody, while ARA had the highest specificity (95.9%) followed by anti-EMA (94.7%).

Conclusions

Coeliac disease is more common in Egyptian children with refractory iron deficiency anaemia, non-endocrinal short stature and type 1 diabetes than was previously thought; therefore it is mandatory to screen such patients for CD. Serological tests showed fairly good sensitivity and specificity for the diagnosis; however, intestinal biopsy remains the cornerstone for definitive diagnosis of patients with immunological reaction to gluten.     

Synergistic effect of deoxyspergualin (DSP) and cyclosporin A (CsA) in the prevention of spontaneous autoimmune diabetes in BB rats

Dose-dependent side effects are frequently observed with immunosuppressive drugs of potential relevance for the immunotherapy of insulin-dependent diabetes mellitus (IDDM), such as CsA and DSP. If CsA and DSP acted synergistically in vivo, their combined use would allow using each compound at lower doses than those required when each drug is given in monotherapy. Consequently, dose-dependent side effects could be reduced and the therapeutic activity maintained or even enforced. Toward this end we studied the effects of combined treatment with CsA and DSP on the course of IDDM in the diabetes-prone (DP)-BB rat. The results show that two ‘low’ doses of CsA (2mg/kg) and DSP (1mg/kg) that are clinically ineffective in suppressing IDDM development in BB rats when administered alone under a prolonged prophylactic regimen (30–105 days old), may successfully prevent, but not cure, the disease when given contemporaneously under the same experimental conditions. The combined treatment was well tolerated, and no side effects were noticed. These data suggest that the combined use of CsA and DSP may deserve consideration for its possible application in the prevention/treatment of human IDDM and other autoimmune diseases.     

Different contribution of HLA-DR and -DQ genes in susceptibility and resistance to Insulin-dependent diabetes mellitus (IDDM)

Abstract: Previous studies have indicated that certain alleles of HLA-DR and -DQ genes were strongly associated with susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM), and the role of DQ molecule in IDDM has been suggested. To further clarify the association of DQ alleles with IDDM, we determined the nucleotide sequences of full-length cDNA from 13 DQA1 alleles and 14 DQB1 alleles. The sequencing analysis revealed sequence polymorphisms outside the hypervariable region of DQ genes. We then analyzed the DQA1 and DQB1 polymorphisms along with that of DRB genes in 86 B-lymphoblastoid cell lines (B-LCLs) from various ethnic groups and in healthy unrelated Japanese and Norwegian individuals. The allelic and haplotypic distributions in each population revealed the characteristic haplotypic formation in the HLA class II region. HLA genes in 139 Japanese and 100 Norwegian IDDM patients were analyzed. DQB1*0301 was negatively associated with IDDM in both ethnic groups, irrespective of associated DRB1 and DQA1 alleles. In DQB1*0302 positive populations, which represented a positive association with IDDM in both ethnic groups, DRB1*0401, *0404, *0802 haplotypes increased in the patients, whereas DRB1*0406 haplotype decreased. Considering about the hierarchy in DRB1 alleles with IDDM susceptibility (DRB1*0401>*0404>*0403 in Norwegian and DRB1*0802>*0403>*0406 in Japanese), the genetic predisposition to IDDM is suggested to be defined by the combination of DR-associated susceptibility and DQ-associated susceptibility and by the DQ-associated resistance which is a dominant genetic trait.     

HLA-D and -DR antigens in genetic analysis of insulin dependent diabetes mellitus

Summary Three groups of patients with insulin-dependent diabetes mellitus, ascertained by different procedures, were investigated for HLA-A, B, C and D antigens (n=164), and a subset (n=93) for HLA-DR. Both HLA-D/DR3 and D/DR4 were strongly positively associated and D/DR2 was negatively associated with insulin-dependent diabetes. HLA-DR4 was found to be a better marker for insulin-dependent diabetes than Dw4. The HLA-B associations (B8, B15 and B18) were clearly secondary to the increases of HLA-D/DR3 and D/DR 4. The HLA associations did not differ between familial and isolated cases indicating that these two groups may well have a common genetic background. Based on analysis of HLA-haplotype sharing in affected sibling pairs, a simple dominant model of inheritance could be ruled out, and a simple recessive model was found unlikely. The relative risks for the HLA-Dw3,4 and HLA-DR3,4 phenotype were 21.2 and 44.4 respectively and exceeded those of both the HLA-Dw3 and HLA-DR3 (5.6 and 4.3) as well as the HLA-Dw4 and DR4 (10.1 and 10.5) phenotypes. This argues against an intermediate genetic model but further studies are needed to clarify whether there is more than one susceptibility gene for insulin-dependent diabetes mellitus within the HLA-system. Note. A list with detailed data on all patients is available from the authors on request.     

The unique nucleotide sequence of the A beta gene in the NOD mouse is shared with its nondiabetic sister strains, the ILI and the CTS mouse

It is generally held that one of the recessive genes controlling diabetes in the NOD mouse is linked to the major histocompatibility complex (MHC). Unique substitution of Asp57 with Ser in the A beta chain is considered to make the A beta gene the MHC-linked susceptibility gene. We therefore analysed the nucleotide sequences of the A beta second exon in ILI, CTS, and NON mice, which are nondiabetic inbred strains but are derived from the same Jcl-ICR mice as the NOD mouse. The DNA sequence analyses revealed that the A beta second exon sequences in the ILI and CTS mice, but not in the NON mouse, are identical to that of the NOD mouse. Possible roles of Ser57 of the A beta chain in the nondiabetic sister strains are discussed.     

Functional and morphological effects of interleukin-1β on the perfused rat pancreas

Summary We recently reported a potentiating effect of recombinant human interleukin-1 on glucose-stimulated insulin release from the isolated perfused pancreas. With the aim of determining whether the stimulatory effect of recombinant interleukin-1 on the B cell in the intact gland was modulated by varying the concentration, time of exposure to recombinant interleukin-1 or B-cell activity, and to elucidate a possible mechanism of action, we measured in the perfused rat pancreas the release of insulin, glucagon and/or prostaglandin E₂ according to the following three different protocols: (1) perfusion with 20 ng/ml of recombinant interleukin-1 for 92 min at 5 and 20 mmol/1 D-glucose (2) perfusion with varying concentrations of recombinant interleukin-1 ranging from 0.1×10^–3 ng/ml to 100 ng/ml at 5 and 20 mmol/l D-glucose (3) perfusion with 20 ng/ml of recombinant interleukin-1 at 5,11 or 20 mmol/l D-glucose. Furthermore, in a separate set of experiments we examined the influence of the cytokine on the morphology of the endocrine pancreas. Interleukin-1 stimulated insulin secretion at 11 and 20 mmol/l D-glucose and potentiated first as well as second phase insulin release in a dose-dependent fashion, with decreasing effect at higher concentrations. Glucagon secretion was also stimulated by recombinant interleukin-1, irrespective of increasing glucose (5, 11, 20 mmol/l) and insulin concentrations. The potentiating effect of recombinant interleukin-1 on insulin secretion was evident even after discontinued perfusion with the cytokine, suggesting a priming effect on B-cell function. Furthermore, we did not observe any relation between the recombinant interleukin-1 mediated insulin and glucagon release and prostaglandin E₂. Electron microscopy of the pancreata perfused with recombinant interleukin-1 revealed significant B cell and to a lesser extent A-cell lysis as well as induction of cell protrusions (blebs) in B cells only, accompanied by peripheral degranulation and rearrangement of rough endoplasmatic reticulum. We suggest that in addition to a paracrine effect of locally produced interleukin-1 systemic interleukin-1 may have an endocrine effect on A- and B-cell function and viability. Interleukin-1 should be considered to be a physiological modulator of insulin and glucagon secretion e.g. during the acute phase response, but also as a pathogenetic factor in Type 1 (insulin-dependent) diabetes mellitus.     

A trial of nicotinamide in newly diagnosed patients with Type 1 (insulin-dependent) diabetes mellitus

Summary Various agents have been tried in subjects with newly diagnosed Type 1 (insulin-dependent) diabetes mellitus in an attempt to preserve Beta-cell function. In this double-blind study, nicotinamide or placebo were given for one year to 35 children and adolescents with newly-diagnosed Type 1 diabetes. All subjects were within six weeks of diagnosis and were between the ages of 6 and 18 years. Nicotinamide, a poly-(ADP-ribose) synthetase inhibitor, was given in a dose of 100 mg/year of age up to a maximum of 1.5 g/day. There were no initial differences between the 17 control and the 18 test subjects in relation to mean age, sex distribution, or severity at onset. Mean insulin dosages and HbA₁ values were similar for the two groups during the year of study. Fasting and glucagon-stimulated C-peptide levels were similar for the control and nicotinamide treated groups at the beginning and after 4 and 12 months. There were no differences in remission rates between the two groups. Nicotinamide, at this dosage, does not preserve residual insulin secretion in subjects with newly diagnosed Type 1 diabetes.