Pancreatic β‐cell imaging in humans: fiction or option?

Diabetes mellitus is a growing worldwide epidemic disease, currently affecting 1 in 12 adults. Treatment of disease complications typically consumes ～10% of healthcare budgets in developed societies. Whilst immune‐mediated destruction of insulin‐secreting pancreatic β cells is responsible for Type 1 diabetes, both the loss and dysfunction of these cells underly the more prevalent Type 2 diabetes. The establishment of robust drug development programmes aimed at β‐cell restoration is still hampered by the absence of means to measure β‐cell mass prospectively in vivo, an approach which would provide new opportunities for understanding disease mechanisms and ultimately assigning personalized treatments. In the present review, we describe the progress towards this goal achieved by the Innovative Medicines Initiative in Diabetes, a collaborative public–private consortium supported by the European Commission and by dedicated resources of pharmaceutical companies. We compare several of the available imaging methods and molecular targets and provide suggestions as to the likeliest to lead to tractable approaches. Furthermore, we discuss the simultaneous development of animal models that can be used to measure subtle changes in β‐cell mass, a prerequisite for validating the clinical potential of the different imaging tracers.     

Sickle‐cell haemoglobin polymerization: is it the primary pathogenic event of sickle‐cell anaemia?

Sickle cell anaemia is associated with a mutant haemoglobin, HbS, which forms polymers in the red blood cells of patients. The primary role of the HbS polymerization for the pathophysiology has been questioned: observations in patients and model organisms contradict deterministic scenarios of sickling crises triggered by polymerization. However, results with knock-out sickle-cell mice, which were cured by delaying HbS polymerization, reconfirm polymerization's primary role. To reconcile the contradictory observations, this article reviews recent findings on two steps in polymerization: homogeneous nucleation of fibres, and their growth. The fibre growth is faster by far than for any other protein ordered structure. This is due to a negligible free-energy barrier for incorporation into a fibre, determined by an entropy gain, stemming from the release of water molecules structured around HbS. The kinetics of fibre nucleation have shown that the formation of the polymer nucleus is preceded by a metastable droplet of a dense liquid. The properties of the dense liquid are sensitive functions of solution composition, including components in micro- and nanomolar amounts. This mechanism allows low-concentration solution components to strongly affect the nucleation kinetics, accounting for the high variability of the disease. These insights can potentially be utilized for control of HbS polymerization and treatment of the disease.     

Noninvasive diagnosis of esophageal varices: is it feasible?

The possibility of identifying cirrhotic patients with esophageal varices by noninvasive means is attractive, because it would allow for the restriction of the performance of screening endoscopy to patients at high risk of having varices. Over the years, several studies addressing this issue have been performed with little success. The recently proposed platelet count/spleen diameter ratio appears to be the best noninvasive predictor of esophageal varices developed so far. However, the available evidence is not yet sufficient to allow for the modification of the current policy of screening cirrhotic patients by endoscopy at the time of diagnosis to detect varices.     

αα‐Crosslinked Hemoglobin: Was Failure Predicted by Preclinical Testing?

In 1998, Baxter Healthcare announced that it was abandoning its product, diaspirin-crosslinked hemoglobin (DCLHb), the first 'blood substitute' to complete all phases of human trials. The company announced that the phase III (pivotal) trials in humans had resulted in an unexpectedly high survival in a group of patients serving as controls for those who received their product in a trauma setting. It is not possible to quantitate the time, efforts and money that were expended in the course of developing this product, from 1985 to 1998. It is rumored that the giant healthcare company had expended more than a half billion dollars on this product, not to mention the investment in the same product by the US Army, the National Institutes of Health and many independent university-based scientists. The disappointment was profound and far-reaching. Although the threat of HIV transmission by banked blood has all but disappeared in the developed world, still the bulk of the world's population faces blood shortages, which this product and its future generations might have helped alleviate. Only Baxter and the Food and Drug Administration may forever know key elements of the history of development of this product. However, because the US Army decided to make its version of the product widely available to scientists, there is a substantial published record, contributed to by both Baxter and independent scientists. Examination of this record leads to the conclusion that there is no single reason for failure. However, it shows that the characteristic hemodynamic response caused by alphaalphaHb increased vascular resistance, and probably eliminates its potential as a red cell substitute. Newer solutions that overcome this limitation should fare better in clinical development when this problem is overcome.     

Can β‐cells be derived from exocrine pancreas?

A major goal of research aiming at improving islet cell replacement therapy is to find the most suitable progenitor cell type from which functional beta-cells can be generated in large numbers. Many possibilities have been raised, including beta-cells themselves, embryonic or adult stem cells and reprogramming of other cell types. Some of these progenitor types may be active or reside in a dormant state in adults in vivo, while others can be rather considered to be products of tissue engineering in vitro. Starting from the available pancreas organs from cadaveric donors, an attractive possibility is to reprogram acinar exocrine cells into beta-cells. Indeed, acinar cells isolated from adult rats display a pronounced plasticity in culture. After an initial step of dedifferentiation, they can be redirected to the beta-cell phenotype by adding agonists of the JAK2/STAT3 signalling pathway to the medium (epidermal growth factor and leukaemia inhibitory factor). The acinar cells that undergo exocrine-to-endocrine transdifferentiation first need to re-express neurogenin-3 and then need to escape inhibition by Notch signalling. The insulin-expressing cells that are generated in this way are glucose-regulated and can normalize glycaemia after transplantation into diabetic immunocompromised mice. It will now be important to translate these findings to human cells.     

Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: Is the addition of subcutaneous interferon‐α‐2b beneficial?

Aim:  We previously reported the benefits of hepatic arterial infusion chemotherapy (HAIC) using cisplatin (CDDP), 5-fluorouracil (5-FU) [low-dose FP], and leucovorin/isovorin for advanced hepatocellular carcinoma (HCC). In this study, we investigated the efficacy of combination therapy with HAIC and subcutaneous interferon (IFN)- α-2b in patients with advanced HCC.
Methods:  Of the 48 patients, 31 received low-dose FP with leucovorin/isovorin (HAIC group) and 17 received combination therapy comprising low-dose FP with isovorin and subcutaneous IFN-α-2b (combination group). Prognostic factors were evaluated by univariate and multivariate analyses of the patient and the disease characteristics.
Results:  There were no significant differences in the response rate (patients with complete or partial response/all patients; P  = 0.736) and survival ( P  = 0.399) between both groups. Univariate analysis revealed that IFN therapy was not a significant prognostic factor. Multivariate analysis showed 3 variables, namely, Child–Pugh score ( P  = 0.010), α-fetoprotein level ( P  = 0.0047), and additional therapy ( P  = 0.002), to be significant prognostic factors.
Conclusions:  We considered that combination therapy with HAIC and subcutaneous interferon (IFN)-α-2b was not beneficial for advanced HCC.     

Programmed disorders of β‐cell development and function as one cause for type 2 diabetes? The GK rat paradigm

Now that the reduction in beta-mass has been clearly established in humans with type 2 diabetes mellitus (T2DM) 1-4, the debate focuses on the possible mechanisms responsible for decreased beta-cell number and impaired beta-cell function and their multifactorial etiology. Appropriate inbred rodent models are essential tools for identification of genes and environmental factors that increase the risk of abnormal beta-cell function and of T2DM. The information available in the Goto-Kakizaki (GK) rat, one of the best characterized animal models of spontaneous T2DM, are reviewed in such a perspective. We propose that the defective beta-cell mass and function in the GK model reflect the complex interactions of three pathogenic players: (1) several independent loci containing genes causing impaired insulin secretion; (2) gestational metabolic impairment inducing a programming of endocrine pancreas (decreased beta-cell neogenesis) which is transmitted to the next generation; and (3) secondary (acquired) loss of beta-cell differentiation due to chronic exposure to hyperglycemia (glucotoxicity). An important message is that the 'heritable' determinants of T2DM are not simply dependant on genetic factors, but probably involve transgenerational epigenetic responses.     

How important is stimulation of α‐adrenoceptors for melatonin production in rat pineal glands?

The objective of this study was to determine the role of alpha-adrenoceptors in melatonin production by rat pineal gland. Pineal glands were isolated from adult male rats and maintained in organ baths. The perfusate was sampled every 5 min, stored, and later assayed for melatonin. Exposure to norepinephrine (10 microM) or the beta-adrenoceptor agonist orciprenaline (2-10 microM) increased the glands' production of melatonin. The time courses of melatonin production in response to these agonists were unaffected by the rats' pretreatment in vivo with the alpha-adrenoceptor antagonist prazosin (2 mg/kg i.p., three times). Rats that had had their superior cervical ganglia removed were primed with either orciprenaline (2 mg/kg i.p) or both orciprenaline and phenylephrine (1 mg/kg i.p) 1 hr before decapitation. Exposure of the pineal glands from these rats to orciprenaline evoked melatonin release that was similar in each group. These results lend weight to the suggestion that the marked potentiation by alpha-adrenoceptor agonists of the stimulation of cAMP and N-acetyltransferase (NAT) by beta-adrenoceptor agonists, demonstrated most readily in cultured glands or dispersed rat pinealocytes, does not carry over into significant augmentation of melatonin production in intact pineal glands.     

Is the β thalassaemia trait of clinical importance?

Although the beta thalassaemia trait affects millions of people worldwide, there have been no controlled studies to determine whether it is associated with any clinical disability or abnormal physical signs. To address this question, 402 individuals were studied: 217 with beta thalassaemia trait, of whom 154 were aware of the diagnosis and 63 were unaware until after the completion of the study; 89 normal controls; and 96 controls with mild hypochromic anaemia. There was a significant increase in symptoms ascribable to anaemia and episodes of pyrexia in those with the beta thalassaemia trait that were not influenced by prior knowledge that they had this condition. There was no difference in physical findings, notably splenomegaly, between those with beta thalassaemia trait and either control group.     

Human biliary β‐glucuronidase activity before and after relief of bile duct obstruction: Is it the major role in the formation of pigment gallstones?

BACKGROUND AND AIMS: The bacterial beta-glucuronidase (bBG) can deconjugate conjugated bilirubin to form calcium bilirubinate gallstone. Yet, the role of the human biliary beta-glucuronidase (hBG) in the pathogenesis of pigment gallstone formation still remains unsolved. METHODS: Hepatic bile was collected from bile-duct-obstructed patients on the day of, and 3 days after, biliary drainage. Patients were divided into pigment-stone (PS) group (n = 34) and stone-free (SF) group (n = 29). All patients of the PS group had the complication of cholangitis. The concentrations of bile contents and the activities of bBG and hBG were measured. RESULTS: The activities of hBG and bBG in bile obtained on the day of biliary drainage were higher in the PS group than in the SF group (activities corrected for bile salt concentration: hBG 128.7 +/- 340.0 vs 13.1 +/- 25.0 U/mmol; bBG 12.5 +/- 22.2 vs 4.6 +/- 7.7 U/mmol, P < 0.05). This difference disappeared after biliary drainage. The changes of enzyme activity in the bile of the SF group were unremarkable before and after biliary drainage. The mean concentrations of bile pigments and free calcium in the PS group were lower than those in the SF group. CONCLUSIONS: An increase in the activity of hBG may be a secondary response, developed after bile duct inflammation because it was elevated only when the bile duct obstruction was associated with infection.