[Recent advances in type 2 diabetes mellitus]. / Neue Entwicklungen beim Typ-2-Diabetes.

Currently, the oral glucose tolerance test remains the "gold standard" for diagnosing type 2 diabetes, HbA (1c) being of subordinate value because of its limited diagnostic sensitivity. Fully evaluated risk scores and questionnaires are helpful in determining individual type 2 diabetes risk profiles and may prove valuable tools in preventing this type of diabetes. Genetic studies support our current understanding of the pathophysiology of type 2 diabetes. In the near future genetic data may become useful in optimizing individual preventative and therapeutic strategies. Recent data suggest that it is reasonable to adjust therapeutic aims on the specific situation of individual patients for achieving optimal results. The present therapeutic armamentarium for the treatment of type 2 diabetes has been rapidly extended over the recent years. To deal with this situation, pharmacovigilance is an essential tool to ensure drug safety and improve existing therapeutic standards.

Alcohol consumption and other psycho-social conditions as important factors in the development of diabetic foot ulcers.

AIMS: To characterize bio-psycho-social factors, particularly mental disorders and self-harm behaviour, associated with the development of diabetic foot ulcers. METHODS: Two groups of diabetic patients with and without foot ulcers (n=47 in each group) with similar sex, age and diabetes duration were assessed for mental disorders using the Composite International Diagnostic Interview. Self-harm behaviour, quality of life, depressive symptoms and self-compassion were rated using different standard questionnaires. RESULTS: Patients from the ulcer group visited their practitioners and/or psychotherapists less frequently in the last 12 months than patients in the control group 0 vs. 13%; P=0.026). The ulcer group patients had a history of increased alcohol consumption (43 vs. 19%; P=0.025), lower levels of education (8 vs. 10 grades; P=0.014) and income (1190 vs. 1535 €/month; P=0.039). Additionally, they were less likely to be diagnosed with anxiety disorders (11 vs. 32%; P=0.022). No significant differences in glycated haemoglobin, body mass index, smoking and direct self-harm behaviour were identified. CONCLUSIONS: Patients with foot ulcers tend to exhibit lower health-conscious behaviour, particularly higher lifetime alcohol consumption, lower utilization of medical services and less general anxiety. Practitioners should be aware of these behaviours, since early detection of diabetes patients at psycho-social risk and consecutive psychological intervention may be an effective preventive strategy in avoiding the development of foot ulcers.

Heparin-induced Extracorporal LDL precipitation (H.E.L.P) in diabetic foot syndrome - preventive and regenerative potential?

Peripheral arterial disease is more aggressive in concomitant diabetes posing an increased risk for critical limb ischemia and subsequent limb loss. The majority of therapies available are not effective to prevent amputation in patients with severe disease. The current observational study reports the effect of the heparin-induced extracorporal LDL-precipitation (H.E.L.P.) as a novel therapeutic approach in patients with severe diabetic foot syndrome. Seventeen diabetic patients with septic foot lesions recruited from the diabetic outpatient clinic underwent H.E.L.P. apheresis regularly until fibrinogen levels were stabilized at 3 g/l or infection was controllable as evidenced by alleviation of necrosis. Patients were subsequently followed up for 2 to 73 months. Fibrinogen levels were reduced by 68% after H.E.L.P. treatment. No severe complications were noted. Necrosis could be confined in sixteen patients. Minor amputations were indicated in twelve patients. Three patients underwent major amputations of the lower limb and two patients received surgical reconstruction. In conclusion, H.E.L.P. apheresis may offer an alternative therapeutic option to diabetic patients with critically ischemic feet and appears to have a beneficial major/minor amputation ratio.

Influence of treatment with acarbose or glibenclamide on insulin sensitivity in type 2 diabetic patients.

AIM: The aim of our double-blind, placebo-controlled study was to compare the effect of acarbose and glibenclamide on the insulin sensitivity in type 2 diabetes. METHODS: We investigated 77 patients (mean age 58.7 years, mean BMI 27.3 kg/m2), treated by diet alone for at least 4 weeks. The subjects were randomized into three treatment groups for 16 weeks: 100 mg t.i.d. acarbose (n = 25) or 1 mg t.i.d. glibenclamide (n = 27) or one t.i.d. placebo (n = 25). Before and after therapy, the levels of fasting plasma glucose, glycosylated haemoglobin, fasting insulin, plasma glucose and insulin 1 h after a standardized breakfast were measured and insulin sensitivity determined by euglycaemic hyperinsulinaemic clamp test. RESULTS: After the treatment period, BMI in the acarbose and placebo group decreased significantly, whereas in the glibenclamide group a significant increase was observed. Fasting plasma glucose was only significant reduced under glibenclamide. The postprandial glucose decreased significantly after acarbose (13.8 vs. 11.4 mmol/l, p < 0.05) and glibenclamide treatment (14.6 vs. 11.4 mmol/l, p < 0.05) and was unchanged under placebo (13.8 vs. 13.7 mmol/l). The fasting insulin levels remained unchanged in all three groups, whereas postprandial insulin values increased significantly under glibenclamide. Neither acarbose nor glibenclamide significantly changed insulin sensitivity [acarbose: glucose disposal rate before treatment 2.3 mg/kg body weight/min/insulin, after treatment 3.2; glibenclamide 2.2 vs. 2.1; placebo 2.6 vs. 3.0]. CONCLUSIONS: Our results show a more substantial improvement of glucose control under glibenclamide than under acarbose which, however, was not associated with an increase of insulin sensitivity.

Cessation of insulin infusion at night-time during CSII-therapy: comparison of regular human insulin and insulin lispro.

Development of hyperglycemia with subsequent ketoacidosis is one of the potential risks of a sudden cessation of insulin delivery during continuous insulin infusion therapy with insulin pumps in patients with IDDM. To evaluate differences in the development of ketoacidosis after a sudden pump stoppage between regular human insulin and insulin lispro, we performed an open label randomized crossover investigation with 7 patients (6 male/1 female, mean age (SD: 40.9 +/- 12.9 years). At 10 p.m., 4 hours after a light dinner with a preprandial injection of the corresponding insulin, the catheter was pulled out of the skin. During the observation period, blood glucose (every hour), pH-values and base excess values (every two hours) were measured until 7 a.m. One patient, in the insulin lispro treatment arm, discontinued because early interruption criteria were met after 7 hours. With insulin lispro, the metabolic changes developed 1.5 to 2 hours earlier than with regular human insulin (after 3 hours: difference in base excess (BE) mean +/- SD: regular human insulin: -0.41 +/- 1.04 mmol/l; insulin lispro: -1.69 +/- 0.83 mmol/l, p < 0.05; blood glucose: regular human insulin: 4.93 +/- 2.87 mmol/l, insulin lispro: 8.97 +/- 3.48, p < 0.05; pH values: regular human insulin: 7.38 +/- 0.02, insulin lispro: 7.36 +/- 0.02, n.s.). In general, metabolic deterioration tended to be more pronounced with insulin lispro than with regular human insulin (deltaBE after 7 h: regular human insulin: -2.39 +/- 1.30 mmol/l; insulin lispro: -3.27 +/- 2.43 mmol/l, n.s.). In conclusion, if patients want to be treated with insulin lispro in an insulin pump, they have to be well-educated about the pharmacokinetic properties of the insulin analogue and about the possibility that ketoacidotic deterioration after an interruption of the insulin delivery may occur earlier in comparison to regular human insulin. It is anyway recommendable to perform a pump stop test when starting CSII-treatment in patients with diabetes mellitus.

Hepatic function in a family with a nonsense mutation (R154X) in the hepatocyte nuclear factor-4alpha/MODY1 gene.

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic disorder characterized by autosomal dominant inheritance, onset usually before 25 yr of age, and abnormal pancreatic beta-cell function. Mutations in the hepatocyte nuclear factor(HNF)-4alpha/MODY1, glucokinase/MODY2, and HNF-1alpha/MODY3 genes can cause this form of diabetes. In contrast to the glucokinase and HNF-1alpha genes, mutations in the HNF-4alpha gene are a relatively uncommon cause of MODY, and our understanding of the MODY1 form of diabetes is based on studies of only a single family, the R-W pedigree. Here we report the identification of a second family with MODY1 and the first in which there has been a detailed characterization of hepatic function. The affected members of this family, Dresden-11, have inherited a nonsense mutation, R154X, in the HNF-4alpha gene, and are predicted to have reduced levels of this transcription factor in the tissues in which it is expressed, including pancreatic islets, liver, kidney, and intestine. Subjects with the R154X mutation exhibited a diminished insulin secretory response to oral glucose. HNF-4alpha plays a central role in tissue-specific regulation of gene expression in the liver, including the control of synthesis of proteins involved in cholesterol and lipoprotein metabolism and the coagulation cascade. Subjects with the R154X mutation, however, showed no abnormalities in lipid metabolism or coagulation except for a paradoxical 3.3-fold increase in serum lipoprotein(a) levels, nor was there any evidence of renal dysfunction in these subjects. The results suggest that MODY1 is primarily a disorder of beta-cell function.

An approach for identifying simple sequence repeat DNA polymorphisms near cloned cDNAs and genes. Linkage studies of the islet amyloid polypeptide/amylin and liver glycogen synthase genes and NIDDM.

Genetic factors contribute to the development of NIDDM, and genes involved in regulating pancreatic beta-cell function and insulin's effects on glucose metabolism are good candidates for being NIDDM susceptibility loci. However, testing candidate genes for linkage to NIDDM depends on the identification of highly informative DNA polymorphisms in or near the candidate locus. Here we describe an approach for identifying highly polymorphic markers near candidate genes that utilizes the emerging physical map of the human genome. A sequence-tagged site from the candidate gene is used to screen the Centre d'Etude du Polymorphisme Humain megabase-insert yeast artificial chromosome library, which contains information on the physical localization of >3,000 genetically mapped simple sequence repeat DNA polymorphisms. Thus, identification of a yeast artificial chromosome containing the candidate locus will in many instances also identify a physically linked simple sequence repeat DNA polymorphism that can be used as a marker for the candidate gene in linkage studies. We have used this approach to identify a marker for the islet amyloid polypeptide gene on chromosome 12. The physical mapping of this gene to a yeast artificial chromosome showed that it was in the same yeast artificial chromosome as the gene encoding liver glycogen synthase, another possible NIDDM susceptibility gene. Affected sib pair studies using a simple sequence repeat DNA polymorphism physically linked to the islet amyloid polypeptide and liver glycogen synthase genes showed no evidence for linkage with NIDDM, indicating that they are not major genes contributing to NIDDM susceptibility.