Johan Tolö

At birth, blood glucose levels drop sharply before rising to normoglycemic adult levels. This is accompanied by functional maturation of pancreatic β-cells and the acquisition of glucose-responsive insulin secretion. Although transcriptional programs have been well characterized, the metabolic adjustments that enhance insulin secretion in neonatal β-cells remain poorly understood. Neonatal islets exhibit a high rate of basal insulin secretion, and elevating glucose to high concentrations produces little additional stimulation (unlike adult islets). This study aimed to elucidate how neonatal pancreatic β-cells become glucose-responsive, using an in vitro protocol involving culture of neonatal islets at low glucose to emulate systemic hypoglycemia. Low-glucose exposure markedly improved glucose responsiveness of neonatal islets by selectively lowering insulin secretion at low glucose concentrations. Unlike adult β-cells, neonatal β-cells were depolarized and generated spontaneous action potentials at low glucose, resulting in elevated [Ca2+]i and a blunted response to high glucose. These changes were reversed by brief (1-2 hours) low-glucose culture, which was accompanied by increased KATP channel surface expression and activity. The effects of low-glucose incubation were mimicked by the AMPK agonist AICAR. These insights may inform strategies to restore glucose-regulated insulin secretion in type 2 diabetes.

Somatostatin, produced by pancreatic islet δ cells, is a key intra-islet paracrine factor that regulates the secretion of the glucoregulatory hormones insulin and glucagon from β cells and α cells, respectively. Here, we show that glutamate and glucagon released by α cells cooperatively activate neighbouring δ cells through AMPA and glucagon receptors, thereby enabling spatiotemporal feedback control of glucagon secretion. Crucially, prior hypoglycaemia enhances this mechanism by sensitizing δ cells to α cell-derived factors and inducing long-lasting structural and functional changes that facilitate δ cell and α cell paracrine interaction. This culminates in somatostatin hypersecretion that impairs counter-regulatory glucagon release. These hypoglycaemia-driven effects were emulated by chemogenetic activation of α cells or high concentrations of exogenous glucagon but prevented by inhibitors of glucagon receptors or the transcription factor CREB. This plasticity represents a key component of the islet’s ‘metabolic memory’, which, through impaired counter-regulatory glucagon secretion, increases the occurrence of recurrent hypoglycaemia that complicates the management of insulin-dependent diabetes.

The pancreatic islet hormones insulin, glucagon and somatostatin play a crucial role in maintaining normoglycaemia. Effective communication between beta, alpha, and delta cells is essential for glucose homeostasis and disruption of this intra-islet crosstalk is observed diabetes. Optogenetics is a great way to study pancreatic islets as it eliminates the need for drugs that might have off-target effects, while preserving islet architecture. We generated mouse models of optogenetics to interrogate the physiological and humoral response to electrical and paracrine stimulus in pancreatic islets. To better employ optogenetics on islets, we designed a box to illuminate the islets in batch incubations. Our innovative box is a useful tool for studying islets cell crosstalk in a drug-free, controlled environment and provides a new standard for investigating the dynamic interactions within islets.

Diabetes mellitus involves both insufficient insulin secretion and dysregulation of glucagon secretion¹. In healthy people, a fall in plasma glucose stimulates glucagon release and thereby increases counter-regulatory hepatic glucose production. This response is absent in many patients with type-1 diabetes (T1D)², which predisposes to severe hypoglycaemia that may be fatal and accounts for up to 10% of the mortality in patients with T1D³. In rats with chemically induced or autoimmune diabetes, counter-regulatory glucagon secretion can be restored by SSTR antagonists^4–7 but both the underlying cellular mechanism and whether it can be extended to humans remain unestablished. Here, we show that glucagon secretion is not stimulated by low glucose in isolated human islets from donors with T1D, a defect recapitulated in non-obese diabetic mice with T1D. This occurs because of hypersecretion of somatostatin, leading to aberrant paracrine inhibition of glucagon secretion. Normally, K_ATP channel-dependent hyperpolarization of β-cells at low glucose extends into the δ-cells through gap junctions, culminating in suppression of action potential firing and inhibition of somatostatin secretion. This ‘electric brake’ is lost following autoimmune destruction of the β-cells, resulting in impaired counter-regulation. This scenario accounts for the clinical observation that residual β-cell function correlates with reduced hypoglycaemia risk⁸.

The adult heart develops hypertrophy to reduce ventricular wall stress and maintain cardiac function in response to an increased workload. Although pathological hypertrophy generally progresses to heart failure, physiological hypertrophy may be cardioprotective. Cardiac-specific overexpression of the lipid-droplet protein perilipin 5 (Plin5) promotes cardiac hypertrophy, but it is unclear whether this response is beneficial. We analyzed RNA-sequencing data from human left ventricle and showed that cardiacPLIN5expression correlates with up-regulation of cardiac contraction–related processes. To investigate how elevated cardiac Plin5 levels affect cardiac contractility, we generated mice with cardiac-specific overexpression ofPlin5(MHC-Plin5mice). These mice displayed increased left ventricular mass and cardiomyocyte size but preserved heart function. Quantitative proteomics identified sarcoplasmic/endoplasmic reticulum Ca²⁺ATPase 2 (SERCA2) as a Plin5-interacting protein. In situ proximity ligation assay further confirmed the Plin5/SERCA2 interaction. Live imaging showed increases in intracellular Ca²⁺release during contraction, Ca²⁺removal during relaxation, and SERCA2 function in MHC-Plin5versus WT cardiomyocytes. These results identify a role of Plin5 in improving cardiac contractility through enhanced Ca²⁺signaling.

By restoring glucose-regulated insulin secretion, glucagon-like peptide-1–based (GLP-1–based) therapies are becoming increasingly important in diabetes care. Normally, the incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) jointly maintain normal blood glucose levels by stimulation of insulin secretion in pancreatic β cells. However, the reason why only GLP-1–based drugs are effective in improving insulin secretion after presentation of diabetes has not been resolved. ATP-sensitive K⁺ (K_ATP) channels play a crucial role in coupling the systemic metabolic status to β cell electrical activity for insulin secretion. Here, we have shown that persistent membrane depolarization of β cells due to genetic (β cell–specific Kcnj11^–/– mice) or pharmacological (long-term exposure to sulfonylureas) inhibition of the K_ATP channel led to a switch from Gs to Gq in a major amplifying pathway of insulin secretion. The switch determined the relative insulinotropic effectiveness of GLP-1 and GIP, as GLP-1 can activate both Gq and Gs, while GIP only activates Gs. The findings were corroborated in other models of persistent depolarization: a spontaneous diabetic KK-Ay mouse and nondiabetic human and mouse β cells of pancreatic islets chronically treated with high glucose. Thus, a Gs/Gq signaling switch in β cells exposed to chronic hyperglycemia underlies the differential insulinotropic potential of incretins in diabetes.