Recessive mutations in IER3IP1 (immediate early response 3 interacting protein 1) cause a syndrome of microcephaly, epilepsy, and permanent neonatal diabetes (MEDS). IER3IP1 encodes an endoplasmic reticulum (ER) membrane protein, which is crucial for brain development; however, the role of IER3IP1 in β cells remains unknown. We have generated two mouse models with either constitutive or inducible IER3IP1 deletion in β cells, named IER3IP1-βKO and IER3IP1-iβKO, respectively. We found that IER3IP1-βKO causes severe early-onset, insulin-deficient diabetes. Functional studies revealed a markedly dilated β-cell ER along with increased proinsulin misfolding and elevated expression of the ER chaperones, including PDI, ERO1, BiP, and P58IPK. Islet transcriptome analysis confirmed by qRT-PCR revealed decreased expression of genes associated with β-cell maturation, cell cycle, and antiapoptotic genes, accompanied by increased expression of antiproliferation genes. Indeed, multiple independent approaches further demonstrated that IER3IP1-βKO impaired β-cell maturation and proliferation, along with increased condensation of β-cell nuclear chromatin. Inducible β-cell IER3IP1 deletion in adult (8-wk-old) mice induced a similar diabetic phenotype, suggesting that IER3IP1 is also critical for function and survival even after β-cell early development. Importantly, IER3IP1 was decreased in β cells of patients with type 2 diabetes (T2D), suggesting an association of IER3IP1 deficiency with β-cell dysfunction in the more-common form of diabetes. These data not only uncover a critical role of IER3IP1 in β cells but also provide insight into molecular basis of diabetes caused by IER3IP1 mutations.

Rationale: Ectopic insulinomas are extremely rare and challenging to diagnose for clinicians. Precise preoperative localization is essential to successful treatment. Patient concerns: A 23-year-old man presented with a 1-year history of recurrent hypoglycemia. Diagnosis: Examinations in the local hospital did not reveal any pancreatic lesion. After admission, a fasting test and a 5-hour oral glucose tolerance test (OGTT) suggested a diagnosis of endogenous hyperinsulinemic hypoglycemia. Enhanced volume perfusion computed tomography (VPCT) revealed 2 nodules in the tail of the pancreas, a nodule in the gastric antrum, and a nodule in the hilum of the spleen. To differentiate which nodule was responsible for hypoglycemia, we performed 68 Ga-Exendin-4 PET/CT and 68 Ga-DOTATATE PET/CT which helped to make a conclusive diagnosis that the lesion in the gastric antrum was an ectopic insulinoma. Interventions: The patient was cured with minimally invasive laparoscopic resection of the tumor. Outcomes: The symptoms were relieved and the blood glucose level remained normal after surgery. Conclusions: This case shows that 68 Gallium-exendin-4 PET/CT is useful for precise localization and thereby successful treatment of insulinoma, especially for occult insulinomas and those derived from an ectopic pancreas.

Objective: Progressive beta cell dysfunction is a hallmark of type 2 diabetes (T2D). Increasing evidence indicates that over-stimulating proinsulin synthesis causes proinsulin misfolding and impairs insulin maturation and storage in db/db mice. However, defective insulin maturation in patients with T2D remains unknown. Methods: We examined intra-islet and intra-cellular distributions of proinsulin and insulin and proinsulin to insulin ratio in the islets of patients with T2D. The expression of transcription factor NKX6.1 and dedifferentiation marker ALDH1A3, as well as glucagon were detected by immunofluorescence. Results: We identified a novel subgroup of beta cells expressing only proinsulin but not insulin. Importantly, significantly increased proinsulin positive and insulin negative (PI+/INS-) cells were evident in T2D, and this increase was strongly correlated with levels of Hemoglobin A1C (HbA1c) in T2D and prediabetes. The percentages of beta cells expressing prohormone convertase 1/3 and carboxypeptidase E were not reduced. Indeed, while proinsulin displayed higher degree of co-localization with the Golgi markers GM130/TGN46 in control beta cells, it appeared to be more diffused within the cytoplasm and less co-localized with GM130/TGN46 in PI+/INS- cells. Furthermore, the key functional transcription factor NKX6.1 markedly decreased in the islets of T2D, especially in the cells with PI+/INS-. The decreased NKX6.1+/PI+/INS+ was strongly correlated with levels of HbA1c in T2D. Almost all PI+/INS- cells showed absence of NKX6.1. Moreover, the percentages of PI+/INS- cells expressing ALDH1A3 were elevated along with an increased acquisition of glucagon immunostaining. Conclusion: Our data demonstrates defective insulin maturation in patients with T2D.

Preproinsulin (PPI) translocation across the membrane of the endoplasmic reticulum (ER) is the first and critical step of insulin biosynthesis. Inefficient PPI translocation caused by signal peptide (SP) mutations can lead to β-cell failure and diabetes. However, the effect of proinsulin domain on the efficiency of PPI translocation remains unknown. With whole exome sequencing, we identified a novel INS nonsense mutation resulting in an early termination at the 46th residue of PPI (PPI-R46X) in two unrelated patients with early-onset diabetes. We examined biological behaviors of the mutant and compared them to that of an established neonatal diabetes causing mutant PPI-C96Y. Although both mutants were retained in the cells, unlike C96Y, R46X did not induce ER stress or form abnormal disulfide-linked proinsulin complexes. More importantly, R46X did not interact with co-expressed wild-type (WT) proinsulin in the ER, and did not impair proinsulin-WT folding, trafficking, and insulin production. Metabolic labeling experiments established that, despite with an intact SP, R46X failed to be efficiently translocated into the ER, suggesting that proinsulin domain downstream of SP plays an important unrecognized role in PPI translocation across the ER membrane. The study not only expends the list of INS mutations associated with diabetes, but also provides genetic and biological evidence underlying the regulation mechanism of PPI translocation.

Aims/Introduction To investigate the association of subtle alterations in thyroid function with presarcopenia among patients with type 2 diabetes mellitus. Materials and Methods A total of 1,865 adult patients with type 2 diabetes mellitus were enrolled in this cross‐sectional study, excluding patients with overt thyroid dysfunction. Skeletal muscle mass measured by dual energy X‐ray absorptiometry was used to assess presarcopenia. Logistic regression models were used to estimate the effects of thyroid hormones on presarcopenia, and subgroup analyses were carried out in different strata of age, sex and body mass index, respectively. Results Compared with the euthyroid group (Euthy), the subclinical hyperthyroidism group had an increased odds of presarcopenia (multivariate‐adjusted odds ratio 1.99, 95% confidence interval 1.09–3.63), but the subclinical hypothyroidism group did not (P > 0.05). In the subclinical hyperthyroidism group, age and body mass index <24 kg/m2 were independent risk factors for presarcopenia. In the overall Euthy group, an increased odds of presarcopenia was correlated with the elevated free thyroxine : free triiodothyronine ratio (all P for trend <0.05), whereas not with increment in free triiodothyronine level (P for trend >0.05). Additionally, in Euthy subgroup analyses stratified by middle‐age, sex and body mass index, a similar association was noted (all P for trend <0.05), but not in the older‐aged patients (P for trend >0.05). Conclusions Subclinical hyperthyroidism was an independent risk factor for presarcopenia in patients with type 2 diabetes mellitus, but subclinical hypothyroidism was not. In the Euthy group with type 2 diabetes mellitus, a high free thyroxine : free triiodothyronine ratio was a good index of presarcopenia in addition to older age.