Effect of two starting insulin regimens in patients with type II diabetes not controlled on a combination of oral antihyperglycemic medications.

In an open-label, 24-week, parallel-group study, 135 patients inadequately controlled with oral antihyperglycemic medications (OAMs) were treated with maximally tolerated doses of metformin and glibenclamide for at least 8 weeks and then randomized to bedtime neutral protamine Hagedorn (NPH) insulin plus maximally tolerated dose of glibenclamide BID (glib/NPH group) or insulin lispro mix 50 (50% lispro, 50% insulin lispro protamine suspension [ILPS]) pre-breakfast and lispro mix 25 (25% lispro, 75% ILPS) pre-dinner (LM50/LM25 group) (both OAMs discontinued). The LM50/LM25 group had significantly lower 2-hour postprandial BG (both meals combined) compared with glib/NPH after 12 (11.70+/-3.40 mmol/L vs. 13.15+/-2.44 mmol/L, p=0.010) and 24 weeks (11.13+/-3.31 mmol/L vs. 14.46+/-2.93 mmol/L, p =0.0001). Both regimens significantly decreased HbA1c. The reduction was greater with LM50/LM25 (-1.31+/-2% vs. -0.5+/-1.6%; P=0.01). At endpoint, the overall hypoglycemia rate increased with LM50/LM25 and decreased with glib/NPH compared with baseline (0.22+/-0.9 vs. -0.08+/-0.72 episodes/patient/30 days; p =0.037). Treatment with LM50/LM25 compared with glib/NPH in patients with inadequate control on combined OAMs yielded better postprandial and overall glycemic control with a higher rate of hypoglycemia.

A comparison of insulin lispro Mix25 and human insulin 30/70 in the treatment of type 2 diabetes during Ramadan.

OBJECTIVE: To compare insulin lispro Mix25 and human insulin 30/70 with regard to their effect on morning and evening postprandial glucose (PPG) control, and on average daily blood-glucose (BG), in patients with Type 2 diabetes who wish to fast during Ramadan. METHOD: Insulin lispro Mix25 and human insulin 30/70 were compared in an open-label, multicenter, randomised, crossover study involving 151 patients. Each treatment period had a duration of 14 days during which the patients self-monitored their BG before and 2 h after the main meals on any 3 days within the last 5 days of each treatment period. RESULTS: The 2 h PPG excursion following the main evening meal after sunset was significantly lower with insulin lispro Mix25 (3.4+/-2.9 mmol/l) compared with human insulin 30/70 (4.0+/-3.2 mmol/l, P=0.007). The evening pre-meal fasting BG values were also lower with insulin lispro Mix25 (7.1+/-2.2 mmol/l) versus human insulin 30/70 (7.5+/-2.6 mmol/l, P=0.034). The average daily BG concentration was 9.5+/-2.4 mmol/l during treatment with insulin lispro Mix25 versus 10.1+/-2.5 mmol/l with human insulin 30/70 given in identical doses (P=0.004). CONCLUSION: When compared with human insulin 30/70, treatment of insulin-requiring Type 2 patients with insulin lispro Mix25 during Ramadan resulted in better average daily glycaemia, and better BG control before and after the evening meal. Insulin lispro Mix25 should be considered as a therapeutic option during Ramadan.

In vivo and in vitro permeability in coeliac disease.

BACKGROUND: An increased permeability to sugars is found in the intestine of untreated patients with coeliac disease after oral ingestion. AIM: To test whether in vitro permeability resembles in vivo permeability tests and whether an in vitro gliadin gluten challenge could be performed by an in vitro permeability test. METHODS: We measured in vivo (urinary excretion after sucrose-lactulose-mannitol ingestion) and in vitro permeability (by mini-Ussing chambers) in 25 healthy controls, 12 relatives of coeliac disease patients, 19 treated, eight partly treated and 16 untreated patients with coeliac disease. RESULTS: In vivo sugar permeability was increased in nearly all coeliac patients. Additionally, in vitro permeability to lactulose (P=0.0007), mannitol (P=0.004) and sucrose (P=0.042) was higher in untreated patients with coeliac disease. It correlated with in vivo permeability (sucrose tau=0.61, P=0.006; lactulose tau=0.41, P < 0.0001; mannitol tau=- 0.56, P=0.62) and was dependent on mucosal damage. An in vitro gliadin challenge over 24 h could not significantly change in vitro permeability in treated patients with coeliac disease. CONCLUSIONS: An in vitro permeability test capable of measuring elevated permeability in coeliac mucosa was described, but this test cannot replace oral gluten challenge by in vitro gliadin incubation.

In vitro production of endomysial antibodies in cultured duodenal mucosa from patients with celiac disease.

OBJECTIVE: Endomysial antibodies (EMAs) had been found recently after in vitro gluten challenge of duodenal mucosa from treated celiac patients. This was a promising result for diagnosis of potential/latent celiac disease. Therefore, we tested the usefulness of the production of EMAs of in vitro-challenged mucosa for diagnosis of celiac disease and determined the location of EMA production. METHODS: We investigated EMAs in the serum, in the supernatants of in vitro gliadin-challenged duodenal mucosa specimens in 68 patients, and in homogenized native duodenal and gastric specimens in seven patients. Twenty-one of the 68 patients served as nonceliac controls, 11 as candidates for potential celiac disease, 23 celiac patients were on glutenfree diet, and 13 were newly diagnosed. RESULTS: EMAs were just found in the supernatants of duodenal biopsies of those celiac patients who had demonstrable EMAs in serum, independent of gliadin challenge. In these patients EMAs were also found in homogenized native duodenal biopsies, but not in gastric biopsies. CONCLUSIONS: EMAs seem to be produced in the small bowel mucosa of celiac patients, but not in other tissues such as gastric mucosa. The production of EMAs could not be initiated under standard in vitro conditions and therefore, such as in vitro challenge cannot be used for diagnostic purposes.

Fat-soluble vitamins in patients with acute renal failure.

OBJECTIVE: Systematic investigations on the status of fat-soluble vitamins in patients with acute renal failure (ARF) are lacking and hence no recommendations for vitamin supply can be defined for these subjects. Thus we compared the status of fat-soluble vitamins, of transport molecules and some vitamin-dependent proteins in patients with ARF and healthy controls. SETTING: Nephrology unit of a university hospital. PATIENTS AND METHODS: Eight patients with ARF requiring hemodialysis therapy were investigated and 28 healthy volunteers served as controls. Plasma concentrations of retinol (vitamin A) and retinol-binding protein (RBP), 25-OH and 1,25-(OH)2 vitamin D3, of parathyroid hormone (PTH), of alpha-tocopherol (vitamin E) and of phylloquinone (vitamin K), osteocalcin and noncarboxylated osteocalcin, respectively, were measured and plasma lipoprotein fractions (as vitamin transport vehicle) were evaluated. RESULTS: Vitamin A levels were decreased (p < 0.001), but RBP levels were normal in ARF patients. Vitamin D3 metabolites 25-OH and 1,25-(OH)2 vitamin D3 plasma levels were profoundly depressed, and PTH was elevated (p < 0.001). Vitamin E plasma concentration was reduced (p < 0.001) but this cannot be accounted for by decreased LDL cholesterol or triglyceride levels. In contrast, vitamin K plasma level was rather elevated in ARF patients with a broad range of individual values. Blood coagulation was normal but total and carboxylated osteocalcin were decreased. No correlation of vitamin K concentrations and any of the plasma lipoprotein fractions could be identified. CONCLUSION: With the exception of vitamin K, profound deficiencies of fat-soluble vitamins develop in patients with ARF. Current recommendations for vitamin supplementation are inadequate and should be reevaluated for these patients.

Changes in gastrointestinal permeability in celiac disease.

Increased gastrointestinal permeability was found in celiac disease already 20 years ago. Originally a genetical defect was supposed leading to elevated permeability and later to celiac disease. However, patients under long-term gluten-free diet normalized their permeability tests. On the other side, unaffected relatives of patients with celiac disease showed high permeability but not different from patients with irritable bowel syndrome and with a tendency for normalization during follow-up. In active symptomatic celiac disease, permeability is elevated in the gastroduodenum - measured by sucrose test - as well as in the small intestine - measured by lactulose/mannitol ratio. The sensitivity in active celiac disease is high (near 100%), the specificity is low due to high permeability in many intestinal diseases as in acute infectious gastroenteritis, Crohn's disease, nonsteroidal anti-inflammatory drug treatment, etc. In contrast, lactulose/mannitol test permeability is much less sensitive in silent celiac disease without diarrhea (74%). The real importance of permeability disease is established by its use for follow-up of celiac patients under gluten-free diet whereas it is correlated to the degree of mucosal atrophy. In vitro tests also show increased lactulose mucosal to serosal flux in celiac disease, but not correlated to oral permeability test. In conclusion, lactulose/mannitol test is the only noninvasive functional test in celiac disease which has essential importance in active celiac disease and in follow-up under diet.

In vitro model of the pathogenesis of celiac disease.

The in vitro challenge of duodenal mucosa with gliadin is a useful model to reproduce the immunological features of celiac disease (CD) and allows the study of early pathogenetic events in this disease. With this model it was shown that antigens such as ICAM-1 and HLA-DR are upregulated as early as 1-2 h after gliadin challenge in patients with CD. After 24 h the lamina propria contained CD4+ T cells expressing the IL-2 receptor alpha-chain, which is a sign of activation. Intraepithelial lymphocytes increased in number and showed proliferative activity. After in vitro stimulation with gliadin, endomysial antibodies were found in the supernatant of the cultured mucosa from patients with CD following a gluten-free diet. This supported the notion that endomysial antibodies are at least in part produced locally. The model was also successfully used to identify toxic constituents of gliadin. Presently, organ culture is not commonly used for diagnostic purposes.

Impairment of citrate metabolism in acute hepatic failure.

AIMS: To compare the utilization of citrate employed as anticoagulant in patients with acute hepatic failure and subjects with normal liver function. PATIENTS AND METHODS: Three patients in acute hepatic failure and normal renal function were studied during therapeutic plasma exchange with citrate containing fresh frozen plasma. Six patients receiving immunapheresis or LDL-apheresis anticoagulated with citrate served as controls. Determinations of serum citrate concentrations, of ionized calcium and blood pH were performed before, during, and after the extracorporeal treatment. Total body clearance and elimination half life were calculated in a two compartment model. RESULTS: Preinfusion citrate levels were higher in the patients with acute hepatic failure than in the controls (n.s.). The citrate level rose to 1.73 +/- 0.2 mmol/l in the liver patients versus 0.99 +/- 0.1 mmol/l in the healthy subjects (p < 0.03). Total body clearance was markedly reduced in patients with acute hepatic failure (3.31 +/- 0.03 ml/kg/min) as compared with the controls (6.34 +/- 0.16 ml/kg/min) (p < 0.02), the elimination half life (t/2 k1e) was prolonged (49.7 +/- 5.4 vs. 32.9 +/- 1.02 min, p < 0.05). In the controls blood pH rose from 7.4 +/- 0.01 to 7.45 +/- 0.01 (p < 0.05) after citrate infusion, whereas in the liver patients no rise in pH was observed, again reflecting the impairment of citrate metabolism. Ionized calcium was lower in the patients with acute hepatic failure at the beginning (1.01 +/- 0.05 vs. 1.21 +/- 0.04 mmol/l, p < 0.05) and the end (0.68 +/- 0.02 vs. 0.93 +/- 0.04 mmol/l, p < 0.05) of the citrate infusion. CONCLUSIONS: Citrate metabolism is severely impaired and the plasmatic calcium stores are reduced in acute hepatic failure and, thus, the risk of adverse effects is high. Therapeutic infusions of citrate should be restricted in patients with acute hepatic failure and, if necessary, therapy should be closely monitored by repeated measurements of ionized calcium to avoid the development of potentially hazardous hypocalcemia.