Delayed-rectifier K⁺ currents (I_DR) in pancreatic β-cells are thought to contribute to action potential repolarization and thereby modulate insulin secretion. The voltage-gated K⁺ channel, K_V2.1, is expressed in β-cells, and the biophysical characteristics of heterologously expressed channels are similar to those of I_DR in rodent β-cells. A novel peptidyl inhibitor of K_V2.1/K_V2.2 channels, guangxitoxin (GxTX)-1 (half-maximal concentration ∼1 nmol/l), has been purified, characterized, and used to probe the contribution of these channels to β-cell physiology. In mouse β-cells, GxTX-1 inhibits 90% of I_DR and, as for K_V2.1, shifts the voltage dependence of channel activation to more depolarized potentials, a characteristic of gating-modifier peptides. GxTX-1 broadens the β-cell action potential, enhances glucose-stimulated intracellular calcium oscillations, and enhances insulin secretion from mouse pancreatic islets in a glucose-dependent manner. These data point to a mechanism for specific enhancement of glucose-dependent insulin secretion by applying blockers of the β-cell I_DR, which may provide advantages over currently used therapies for the treatment of type 2 diabetes.

Voltage‐gated potassium (Kv) currents of human pancreatic islet cells were studied by whole‐cell patch clamp recording. On average, 75% of the cells tested were identified as β‐cells by single cell, post‐recording RT‐PCR for insulin mRNA. In most cells, the dominant Kv current was a delayed rectifier. The delayed rectifier activated at potentials above −20 mV and had a V_½ for activation of −5.3 mV. Onset of inactivation was slow for a major component (τ= 3.2 s at +20 mV) observed in all cells; a smaller component (τ= 0.30 s) with an amplitude of ∼25% was seen in some cells. Recovery from inactivation had a τ of 2.5 s at −80 mV and steady‐state inactivation had a V_½ of −39 mV. In 12% of cells (21/182) a low‐threshold, transient Kv current (A‐current) was present. The A‐current activated at membrane potentials above −40 mV, inactivated with a time constant of 18.5 ms at −20 mV, and had a V_½ for steady‐state inactivation of −52 mV. TEA inhibited total Kv current with an IC₅₀= 0.54 mm and PAC, a disubstituted cyclohexyl Kv channel inhibitor, inhibited with an IC₅₀= 0.57 μm . The total Kv current was insensitive to margatoxin (100 nm), agitoxin‐2 (50 nm), kaliotoxin (50 nm) and ShK (50 nm). Hanatoxin (100 nm) inhibited total Kv current by 65% at +20 mV. Taken together, these data provide evidence of at least two distinct types of Kv channels in human pancreatic β‐cells and suggest that more than one type of Kv channel may be involved in the regulation of glucose‐dependent insulin secretion.

Polyamines contribute to several physiological and pathological processes, including cardiac hypertrophy in experimental animals. This involves an increase in ornithine decarboxylase (ODC) activity and intracellular polyamines associated with cyclic adenosine monophosphate (cAMP) increases. The aim of the study was to establish the role of these in the human heart in living patients. For this, polyamines (by high performance liquid chromatography) and the activity ofODCand N¹‐acetylpolyamine oxidases (APAO) were determined in the right atrial appendage of 17 patients undergoing extracorporeal circulation to correlate with clinical parameters. There existed enzymatic activity associated with the homeostasis of polyamines. Left atria size was positively associated withODC(r= 0.661,P= 0.027) and negatively withAPAO‐N¹‐acetylspermine (r= −0.769,P= 0.026), suggesting that increased levels of polyamines are associated with left atrial hemodynamic overload. Left ventricular ejection fraction (LVEF) and heart rate were positively associated with spermidine (r= 0.690,P= 0.003;r= 0.590,P= 0.021) and negatively with N¹‐acetylspermidine (r= −0.554,P= 0.032;r= −0.644,P= 0.018).LVEFwas negatively correlated withcAMPlevels (r= −0.835,P= 0.001) and withcAMP/ODC(r= −0.794,P= 0.011),cAMP/spermidine (r= −0.813,P= 0.001) andcAMP/spermine (r= −0.747,P= 0.003) ratios. AbnormalLVEFpatients showed decreasedODCactivity and spermidine, and increased N¹‐acetylspermidine, andcAMP. Spermine decreased in congestive heart failure patients. The trace amine isoamylamine negatively correlated with septal wall thickness (r= −0.634,P= 0.008) and was increased in cardiac heart failure. The results indicated that modifications in polyamine homeostasis might be associated with cardiac function and remodelling. IncreasedcAMPmight have a deleterious effect on function. Further studies should confirm these findings and the involvement of polyamines in different stages of heart failure.