Bo Hellman, 19 June 1930–4 December 2023

Photo credit: photograph of Bo at home in Uppsala taken by his son Jarl Hellman.

On an early December morning in 2023, Bo Hellman, the grand old man of Swedish experimental diabetes research, passed away at the age of 93. Bo was a dedicated scientist who made many important discoveries throughout his remarkable 70 year career. Science was both his profession and his passion, and it remained a topic of discussion even from his hospital bed, just a week before his passing.

Born in Mariestad in 1930, Bo studied medicine at Uppsala University and became an MD in 1958. In parallel, he began a scientific career and published his first article in 1953. In his thesis, awarded in 1959, Bo applied stereological methods to pancreas sections to determine the number, total volume and size distribution of islets in the rat and human [1] pancreas. Together with his first student, Claes Hellerström, Bo developed a silver impregnation technique that could separate ‘alpha cells’ into two distinct populations [2], α₁ and α₂ (delta and alpha cells according to current terminology). Administration of glucagon induced nuclear atrophy selectively in α₂ cells, supporting the hypothesis that these cells produce glucagon [3]. Subsequently, Bo demonstrated that α₁ cells produce a local inhibitory factor [4]; however, it was some time before other scientists identified this factor as somatostatin.

Early in his career, Bo suspected that beta cell metabolism might be important for insulin secretion and he therefore began studying the activity of different islet enzymes using histochemical techniques. His first steps into biochemistry were taken in 1961 when he studied the metabolism of ¹⁴C-labelled glucose in Brockmann bodies [5], the more easily accessible fish islets. In 1966, Bo was appointed professor of histology at Umeå University and was among the pioneers who developed preclinical medicine at this new university. Bo stayed in Umeå for 10 years, a golden period dominated by studies of insulin secretion mechanisms using radiotracer and biochemical techniques.

In contrast to the view that beta cells are freely permeable to glucose, Bo and his co-workers showed that glucose uptake is mediated by a stereospecific transporter, but that uptake is not rate limiting for glucose metabolism [6]. This group studied glucose metabolism using different techniques, measuring glycolytic and oxidative degradation, as well as potential signal metabolites. Thus, the role of cAMP as an amplifier rather than an initiator of insulin secretion was defined [7]. Bo and his co-workers also had a great impact on the understanding of the diverse mechanisms by which amino acids affect insulin secretion through their uptake and/or metabolism. Subsequent studies of sulfonylurea uptake showed that these compounds bind reversibly to the beta cell membrane, indicating the existence of a receptor [8]; this was confirmed with the discovery of the K_ATP channel-associated sulfonylurea receptor 12 years later.

In 1976, Bo was appointed professor at his old department in Uppsala. From this point on, he focused his research on the role of Ca²⁺ in insulin secretion, initially by measuring uptake and efflux of ⁴⁵Ca and, later, with the advent of fluorescent indicators, by directly recording cytoplasmic Ca²⁺ concentrations ([Ca²⁺]_i). This led to the important discovery that glucose stimulates Ca²⁺ sequestration in the endoplasmic reticulum (ER), a physiological mechanism creating conditions for Ca²⁺ mobilisation from this organelle in response to, for example, neurotransmitters [9]. Bo and his co-workers subsequently showed that ER Ca²⁺ uptake is associated with initial lowering of [Ca²⁺]_i [10], which results in a paradoxical temporary inhibition of insulin release and probably contributes to poor initial first-phase insulin secretion in individuals with type 2 diabetes [11]. The introduction of the Ca²⁺ indicator Fura-2 revolutionised this field and enabled single-cell [Ca²⁺]_i measurements. One day, the PhD student Eva Grapengiesser drew attention to an exciting experiment showing a glucose-stimulated beta cell with huge slow [Ca²⁺]_i oscillations, a discovery [12] that had a great impact on future research in Bo’s and others’ laboratories. These oscillations depended on Ca²⁺ influx into the rhythmically depolarised beta cells, a phenomenon linked to ATP oscillations affecting K_ATP channel activity [13]. Using imaging technology it was discovered that the glucose-induced [Ca²⁺]_i oscillations spread in waves between beta cells situated in small clusters [14], thus explaining why entire islets show synchronised oscillations. By collecting superfusion medium from an islet under the microscope, the glucose-induced [Ca²⁺]_i oscillations were found to coincide with pulsatile insulin release [15].

Gap junctions explain how [Ca²⁺]_i waves spread in clusters, but Bo and his co-workers sometimes observed synchronisation between beta cells lacking cell–cell contacts. They reported how physically separated beta cells showed simultaneous [Ca²⁺]_i spikes due to intracellular Ca²⁺ mobilisation [16], a phenomenon explained by the activation of purinergic receptors on neighbouring beta cells by ATP released together with insulin [17]. They also found that ATP contributes to the synchronisation of the slow [Ca²⁺]_i oscillations between islets [18]. A further study showing that purinergic receptor blockade prevented insulin pulsatility in the perfused rat pancreas supported the idea that neural ATP release is probably involved in islet synchronisation in vivo [19].

Subsequent islet studies revealed that not only insulin secretion but also glucagon and somatostatin secretion are pulsatile [20]. The somatostatin pulses were slightly phase-shifted in relation to those of insulin, whereas glucagon was released in opposite phase. As stimulated glucagon secretion at low glucose concentrations was non-pulsatile, it was assumed that the pulses at high glucose concentrations were generated by paracrine inhibition by delta and beta cells [21].

In 2012, Bo and his co-workers reported that the first glucagon response to an elevation in glucose concentrations is a temporary stimulation that coincides with the previously found paradoxical inhibition of insulin secretion [22]. During Bo’s final years, he again focused on the mechanisms underlying this inhibition. Although K_ATP channels are central to the generation of glucose-induced [Ca²⁺]_i oscillations, Bo discovered that similar [Ca²⁺]_i oscillations can be generated when these channels are blocked with sulfonylurea, and particularly in the presence of somatostatin [23]. These oscillations are generated by repolarisation of the plasma membrane with lowering of [Ca²⁺]_i from an elevated level rather than depolarisation with elevation of [Ca²⁺]_i from the basal level. The underlying mechanism and whether it could reveal a potential drug target for the treatment of type 2 diabetes were open questions that occupied Bo and his wife Eva Grapengiesser during the COVID-19 pandemic when restrictions meant that they were unable to visit the laboratory.

Bo published more than 400 articles and received several prestigious prizes, including the EASD’s Minkowski Prize in 1969. He was vice-president of the EASD from 1970 to 1973 and honorary secretary from 1973 to 1976, and was made a lifetime honorary member of the organisation in 2014. Bo was an utterly inspiring, encouraging and devoted scientist who enthusiastically supported his co-workers. As a supervisor of PhD students and postdoctoral researchers, Bo has left his mark both nationally and internationally. Many of his former students and postdoctoral researchers have become full professors who continue in the field of experimental diabetes research at universities worldwide, including the four Minkowski/Claude Bernard laureates Inge-Bert Täljedal, the late Claes Hellerström, Åke Lernmark and Patrik Rorsman. Indeed, much of the current research in this field has its roots in Bo’s laboratory. A pioneer in diabetes research has passed away, but his legacy will live on for a long time.