One form of maturity-onset diabetes of the young, Type 3 (MODY3), results from mutations in the gene coding for hepatocyte nuclear factor-1alpha (HNF-1alpha), a transcription factor first described in the liver. MODY3 is characterized by a defective glucose-stimulated insulin secretion. Earlier observations of glycosuria with normal blood glucose levels in some MODY families suggest an additional renal manifestation of the respective genetic defect. We measured the renal threshold for glucose in five diabetic carriers of a missense mutation (Arg 272 His) in HNF-1alpha and, for comparison, in eight Type 1 diabetic patients, applying a non-invasive protocol of frequent parallel blood and urine sampling during a slow shift in blood glucose levels. We found that the mean renal threshold for glucose was lowered in the HNF-1alpha diabetic patients compared to those with Type 1 diabetes (6.5 +/- 0.9 mmol l(-1) vs 10.7 +/- 0.5 mmol l(-1); p < 0.01). This lowered glucose threshold might be an indication of an extra-pancreatic effect of HNF-1alpha gene mutations in humans. Defects in HNF-1alpha may lead to an altered tubular glucose reabsorption, possibly due to decreased expression of the renal glucose transporter proteins involved in reabsorption of glucose from the urine.

We have recently shown that mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF)-1alpha are the cause of one form of maturity-onset diabetes of the young (MODY3). Here, we report the exon-intron organization and partial sequence of the human HNF-1alpha gene. In addition, we have screened the ten exons and flanking introns of this gene for mutations in a group of 25 unrelated white subjects from Germany who presented with NIDDM before 35 years of age and had a first-degree relative with NIDDM. Mutations were identified in nine of these individuals, suggesting that mutations in the HNF-1alpha gene are a common cause of diabetes in German subjects with early-onset NIDDM and a family history of diabetes. Thus, screening for mutations in this gene may be indicated in subjects with early-onset NIDDM. Interestingly, three of the nine mutations occurred at the same site in exon 4 with insertion of a C in a polyC tract, centered around codon 290 (designated Pro291fsinsC), thereby resulting in a frameshift during translation and premature termination. Analyses of linked DNA polymorphisms in the HNF-1alpha gene indicated that the Pro291fsinsC mutation was present on a different haplotype in each subject, implying that the polyC tract represents a mutational hot spot. We have also identified the mutation in the HNF-1alpha gene in the Jutland pedigree, one of the original MODY pedigrees reported in the literature, as being a T-->G substitution in codon 241, resulting in the replacement of a conserved Cys by Gly (C241G). The information on the sequence of the HNF-1alpha gene and its promoter region will facilitate the search for mutations in other subjects and studies of the role of the gene in determining normal beta-cell functions.

Isolated pancreatic rat islets incubated in vitro were used as a bioassay system for investigating the influence of human insulin antibodies on insulin secretion. Serum samples with different titres of insulin antibodies were obtained from juvenile diabetics after various periods of insulin therapy. The insulin secretion of isolated islets is enhanced by insulin antibodies and positively correlated to the measured antibody titres in serum.In agreement with Cahill (1973) and Block et al. (1973) we are of the opinion that the initial remission phase may play an important role in the prognosis of diabetes mellitus. This period is characterized by a recovered stabilization of diabetes due to an improved insulin secretion (Blaim 8c KielanowskaStunieka 1971;Menzel et al. 1972;Block et al. 1973). After different time periods the functional capacity of B-cells is exhausted and a more or less severe juvenile diabetes results. At present some possibilities for the final impairment of B-cell function are under discussion. Firstly it seems possible that the pathogenetic process continues to disturb the B-cells. Secondly the B-cell exhaustion could also be influenced by immunological reactions (cellu¬ lar and humoral) against exogenous insulin. Even if there is no strong cor¬ relation between the insulin-antibody titres and the termination of the initial remission phase, it is remarkable that under the commonly used insulin

Certain RIS existed in 11 insulin-dependent diabetics, 12 were without any RIS (uncertain RIS in 10 patients). Glucose tolerance and daily glycemia differed significantly among the two groups. However, all diabetics were far from euglycemia, (3.3-9.3 mmol/l): Fasting plasma glucose 12.0 +/- 0.9 (certain RIS), 15.0 +/- 0.8 (no RIS), 13.9 +/- 1.8 (uncertain RIS). Serum magnesium was significantly lower in all diabetics, both before and during the test. There was no change during the OGTT-glucagon-test and no difference among the three groups of insulin-dependent diabetics. So, we conclude that a small RIS in our longterm insulin-dependent diabetics has no influence on the behaviour of serum magnesium. But, magnesium depletion can influence coronary blood flow, blood clotting, and atherogenesis. Therefore, it should be necessary to pay more attention to the hypomagnesemia in insulin-dependent diabetics.

Two types of insulin pens MADI and MD, were connected to subcutaneous catheters. These "catheter-pens" were used like hand-driven insulin pumps. Results after 1 year of treatment in 30 type 1 diabetics (HCP-negative; age at onset of diabetes 16.5 +/- 1.7 years; duration of diabetes 18.5 +/- 1.6 years, on multiple insulin injections before catheter-pen application): 1. better quality of life (reduction of frequency of needle pricks, more flexibility, inconspicuous application of insulin in public); 2. daily insulin--increased number of "injections" (4.2 +/- 0.1 vs 5.8 +/- 0.1, p less than 0.01), reduction of units per kg BW (0.70 +/- 0.02 vs 0.60 +/- 0.01, p less than 0.01), reduction of intermediate-acting insulin (14.1 +/- 1.3 vs 9.2 +/- 1.2 U/d, p less than 0.05); 3. no change of HbA1 (10.8 +/- 0.8 vs 10.2 +/- 0.2%, normal range 7.7 to 8.4%), mean blood glucose (MBG) in stress situation (8.4 +/- 0.4 vs 7.7 +/- 0.3 mmol/l), serum cholesterol and body weight, both within normal range; 4. improvement (p less than 0.05) of serum triglycerides, serum HDL-cholesterol, ratio of apolipoprotein A1/B; 5. rare skin reactions at the needle site. Conclusion. Catheter-pens offer a very convenient alternative for insulin administration in intensified conventional insulin treatment with multiple injections in type 1 diabetics.