Paracrine interactions between pancreatic islet cells have been proposed as a mechanism to regulate hormone secretion and glucose homeostasis. Here, we demonstrate the importance of proglucagon-derived peptides (PGDPs) for α to β cell communication and control of insulin secretion. Signaling through this system occurs through both the glucagon-like peptide receptor (Glp1r) and glucagon receptor (Gcgr). Loss of PGDPs, or blockade of their receptors, decreases insulin secretion in response to both metabolic and nonmetabolic stimulation of mouse and human islets. This effect is due to reduced β cell cAMP and affects the quantity but not dynamics of insulin release, indicating that PGDPs dictate the magnitude of insulin output in an isolated islet. In healthy mice, additional factors that stimulate cAMP can compensate for loss of PGDP signaling; however, input from α cells is essential to maintain glucose tolerance during the metabolic stress induced by high-fat feeding. These findings demonstrate an essential role for α cell regulation of β cells, raising the possibility that abnormal paracrine signaling contributes to impaired insulin secretion in diabetes. Moreover, these findings support reconsideration of the role for α cells in postprandial glucose control.

No abstract

Glucose-dependent insulinotropic polypeptide (GIP) communicates nutrient intake from the gut to islets, enabling optimal levels of insulin secretion via the GIP receptor (GIPR) on β cells. The GIPR is also expressed in α cells, and GIP stimulates glucagon secretion; however, the role of this action in the postprandial state is unknown. Here, we demonstrate that GIP potentiates amino acid–stimulated glucagon secretion, documenting a similar nutrient-dependent action to that described in β cells. Moreover, we demonstrate that GIP activity in α cells contributes to insulin secretion by invoking paracrine α to β cell communication. Last, specific loss of GIPR activity in α cells prevents glucagon secretion in response to a meal stimulus, limiting insulin secretion and driving glucose intolerance. Together, these data uncover an important axis by which GIPR activity in α cells is necessary to coordinate the optimal level of both glucagon and insulin secretion to maintain postprandial homeostasis.

Glucagon is classically described as a counterregulatory hormone that plays an essential role in the protection against hypoglycemia. In addition to its role in the regulation of glucose metabolism, glucagon has been described to promote ketosis in the fasted state. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) are a new class of glucose-lowering drugs that act primarily in the kidney, but some reports have described direct effects of SGLT2i on α-cells to stimulate glucagon secretion. Interestingly, SGLT2 inhibition also results in increased endogenous glucose production and ketone production, features common to glucagon action. Here, we directly test the ketogenic role of glucagon in mice, demonstrating that neither fasting- nor SGLT2i-induced ketosis is altered by interruption of glucagon signaling. Moreover, any effect of glucagon to stimulate ketogenesis is severely limited by its insulinotropic actions. Collectively, our data suggest that fasting-associated ketosis and the ketogenic effects of SGLT2 inhibitors occur almost entirely independent of glucagon.

Our aim was to develop and validate a method for separate quantitation of 25‐hydroxyvitamin D2 (25OHD2) and 25‐hydroxyvitamin D3 (25OHD3) and its epimer (epi‐25OHD3), with complete chromatographic resolution of 25OHD3 and epi‐25OHD3. Serum (100 uL) was diluted with internal standards (d3‐25OHD2 and d6‐25OHD3) and extracted with hexanes. The organic layer was evaporated, reconstituted and injected onto a Kinetex PFP column (2.1 × 100 mm × 1.7 um) using an Accela UHPLC system coupled with a triple quadrupole Vantage mass spectrometer. All analytes were isocratically eluted with 72% MeOH/H2O flowing at 0.4 mL/min within 14 min. The mass spectrometer was set in positive APCI mode and two SRM transitions (quantitation and confirmation ions) were monitored for each analyte. Calibration was performed in 4% albumin‐PBS and verified with NIST standard reference materials. Inter‐assay precision was < 10% when concentrations were > 12.5 nmol/L. Method bias was < 5%. Limits of detection were 2 to 5 nmol/L. The method showed excellent performance in proficiency testing programs. Convenience samples from blood donors (n=36) and pregnant women (n=35) showed median values (nmol/L) for 25OHD2, 25OHD3, and epi‐25OHD3 of 0.3, 43, 0.7 and 1.8, 88, 4, respectively. This method is accurate, precise, robust and suitable for the assessment of vitamin D status in populations.