Fig. 1

Mice with reduced insulin gene dosage have reduced fasting insulin levels and body weight. A Schematic describing a mouse model designed to test the role of insulin on HFD-accelerated PDAC initiation. On the background of Ptf1a^CreER-induced Kras^G12D pancreatic cancer model (PK), we compared experimental mice with 1 null allele of Ins2 and control mice with 2 null alleles of Ins2, all in the absence of Ins1 (Ins1^-/-) to prevent compensation. B Three-week-old PK-Ins1^-/-;Ins2^+/+ control and PK-Ins1^-/-;Ins2^+/- experimental mice were weaned to a high-fat diet (HFD) and were injected for 3 consecutive days with tamoxifen (TM) beginning at 4 weeks. After repeated physiological measures over the course of a year, the mice were euthanized at 57 weeks of age for histological analysis and scRNA-seq. C–D Fasting insulin levels in male and female PK-Ins1^-/-;Ins2^+/+ and PK-Ins1^-/-;Ins2^+/- mice measured over 1 year (n = 18–29). E–F Fasting glucose levels in male and female PK-Ins1^-/-;Ins2^+/+ and PK-Ins1^-/-;Ins2^+/- mice measured over 1 year (n = 18–29). G–H Body weight in male and female PK-Ins1^-/-;Ins2^+/+ and PK-Ins1^-/-;Ins2^+/- mice measured over 1 year (n = 18–29). I–J Glucose-stimulated insulin release in 52-week-old male and female mice (n = 17–30). K–L Blood glucose response to intraperitoneal delivery of an insulin analog in 52-week-old male and female PK-Ins1^-/-;Ins2^+/+ and PK-Ins1^-/-;Ins2^+/- mice (n = 10–29). M–N Blood glucose response to intraperitoneal delivery of glucose in 52-week-old male and female PK-Ins1^-/-;Ins2^+/+ and PK-Ins1^-/-;Ins2^+/- mice (n = 16–29). *p < 0.05 and **p < 0.01. Values are shown as mean ± SEM