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As a consequence of the global epidemic of obesity, the incidence of type 2 diabetes (T2D) is increasing worldwide. T2D is characterized by hyperglycaemia, hyperinsulinaemia and a reduced insulin response in muscular and fatty tissue. Over time, an increased insulin demand leads to cellular fatigue and death of the insulin-producing b-cells. In response, the patients with T2D become insulin-dependent and subjected to the boundaries of lifelong insulin treatment. Preservation of b-cell insulin secretion and a sufficient b-cell mass is thus a corner stone in optimal T2D treatment.Physiologically, b-cell function and survival are closely related to zinc homeostasis. Zinc is essential for the primary functions of b-cells; insulin biosynthesis, insulin storage and insulin secretion and zinc are co-secreted with insulin in response to glucose stimulation. Hypozincaemia accompanied by hyperzincuria is often present in patients with diabetes [1]. On the other hand, fluctuations in extracellular zinc levels can become toxic for b-cells if high concentrations arise locally during stress or increased insulin secretion [2].Regulation of cellular-free zinc homeostasis is orchestrated by two categories of zinc-carrying proteins; the zinc-buffering metallothioneins (MTs) and the zinc transporters also known as Zinc Transporters (ZnTs) and Zrt-and Irt-like proteins (ZIPs). The ZnTs are responsible for Zn 2+ efflux from the cytoplasm to the extracellular matrix and into intracellular organelles like insulin-containing vesicles, whereas the ZIPs transport Zn 2+ in the opposite direction [3]. MTs tightly regulate the intracellular level of free zinc, and the levels of MTs are relatively high in the pancreas [3,4], suggesting that MTs are involved in the normal function of the gland. New studies link dysregulation or dysfunction of zinc-transporting proteins with impaired insulin processing and impaired glucose metabolism [4,6]. Furthermore, polymorphisms in genes encoding for isoforms of MTs have been related to the development of type 2 diabetes and to the extent of diabetic complications [7]. Transgenic mice, with b-cell-specific over-expression of MT-2 display, significantly reduced b-cell death, and the mice have a better preservation of insulin production when exposed to bcell toxic Streptozotocin [8] . Moreover, a specific neuroprotective role has been postulated for extracellular MT [9]. Here, we suggest that increasing MT levels by means of exogenous Zn 7 -MT-2A will be beneficial for b-cell function by contributing to an optimal zinc supply and regulation, testing this hypothesis in the glucose-sensitive, insulin-producing INS-1E b-cell culture. MethodsCell culture. INS-1E (rat), originally kindly provided by Prof. C.B. Wollheim, Switzerland, was employed in this study. The INS-1E cells are cultured in a CO 2 atmosphere in complete RPMI 1640 supplemented with 11 mM glucose, 10% (v/v) heat-inactivated foetal bovine serum, 50 lM b-mercaptoethanol, 2 mM L-Glutamine, 100 U/ ml penicillin and 100 lg/ml streptomycin as previous...

PurposeHaemophilus in uenzae is a common cause of mucosal infections that warrants accurate surveillance.We aimed to assess the prevalence of the species in clinical specimens, and characterise population structure and resistance to aminopenicillins by whole genome sequencing. MethodsWe assessed the point prevalence by entering the database records of one day in Denmark, and examined the genome sequences of nationwide, collected isolates from the same day. ResultsThe prevalence of H. in uenzae in clinical samples on the 10 th of January 2018 was 1.78 per 100,000 person-days (all samples), and 2.47 per 1,000 hospital bed-days (hospital samples). Of 2,009 bacteria deemed clinically relevant and collected in a concerted action by the Danish departments of clinical microbiology, 62 (3.1%) were H. in uenzae. All 62 isolates belonged to phylogenetic group I and were unencapsulated. Three strains from separate Danish regions had identical core genome sequences, but a small number of intergenic mutations testi ed to circulating clones, rather than individual cases of patient-to-patient transmission. The TEM-1 β-lactamase gene was present in 24 strains, while 13 strains were genetically categorised as ampicillin-resistant due to substitutions in penicillin-binding protein 3; shared patterns of amino acid substitutions in unrelated strains indicated putative lateral transfer of chromosomal resistance. ConclusionsCirculating clones of H. in uenzae are frequent, and host factors, rather than direct transmission of epidemic strains, may be the primary cause of infection. The bleak presence of ampicillin resistance revealed by sequencing of point prevalence strains underscores the necessity for close examination of testing methods.

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PurposeHaemophilus influenzae is a common cause of mucosal infections that warrants accurate surveillance. We aimed to assess the prevalence of the species in clinical specimens, and characterise population structure and resistance to aminopenicillins by whole genome sequencing.MethodsWe assessed the point prevalence by entering the database records of one day in Denmark, and examined the genome sequences of nationwide, collected isolates from the same day. ResultsThe prevalence of H. influenzae in clinical samples on the 10th of January 2018 was 1.78 per 100,000 person-days (all samples), and 2.47 per 1,000 hospital bed-days (hospital samples). Of 2,009 bacteria deemed clinically relevant and collected in a concerted action by the Danish departments of clinical microbiology, 62 (3.1%) were H. influenzae. All 62 isolates belonged to phylogenetic group I and were unencapsulated. Three strains from separate Danish regions had identical core genome sequences, but a small number of intergenic mutations testified to circulating clones, rather than individual cases of patient-to-patient transmission. The TEM-1 β-lactamase gene was present in 24 strains, while 13 strains were genetically categorised as ampicillin-resistant due to substitutions in penicillin-binding protein 3; shared patterns of amino acid substitutions in unrelated strains indicated putative lateral transfer of chromosomal resistance. ConclusionsCirculating clones of H. influenzae are frequent, and host factors, rather than direct transmission of epidemic strains, may be the primary cause of infection. The bleak presence of ampicillin resistance revealed by sequencing of point prevalence strains underscores the necessity for close examination of testing methods.