A PNPLA3 Polymorphism Confers Lower Susceptibility to Incident Diabetes Mellitus in Subjects With Nonalcoholic Fatty Liver Disease.

BACKGROUND AND AIMS: We investigated the association between the patatin-like phospholipase domain-containing-3 (PNPLA3) rs738409 genotype and the risk of diabetes mellitus (DM) using a biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) cohort and a longitudinal observational cohort. METHODS: Associations between genotypes and the prevalence of DM were evaluated with stratification according to the histological severity of NAFLD in the Boramae cohort (n = 706). A longitudinal cohort consisting of nondiabetic individuals with ≥2 health checkups was then selected to investigate the risk of incident DM according to the genotype (the GENIE cohort; n = 4998). RESULTS: Among subjects with NAFLD in the Boramae cohort, the G allele was independently associated with a lower prevalence of DM in both NAFL (odds ratio [OR] per 1 allele, 0.66; 95% confidence interval [CI], 0.46-0.97) and nonalcoholic steatohepatitis (OR per 1 allele, 0.59; 95% CI, 0.38-0.92). This result was replicated in the longitudinal GENIE cohort. The G allele was associated with a lower risk of incident DM during the median follow-up of 60 months in subjects with NAFLD (hazard ratio, 0.65; 95% CI, 0.45-0.93). In contrast, G allele carriers without NAFLD showed higher odds for DM in the context of the Boramae cohort (OR, 2.44; 95% CI, 1.00-5.95). CONCLUSIONS: These findings clarify conflicting results regarding the association between the PNPLA3 rs738409 genotype and the risk of DM, demonstrating a clear difference between subjects with and without NAFLD; this difference might be explained by the low metabolic risk in genetic NAFLD.

Muscle strength, an independent determinant of glycemic control in older adults with long-standing type 2 diabetes: a prospective cohort study.

BACKGROUND: Although the proportion of older patients with type 2 diabetes mellitus (T2DM) has increased, few studies have reported the factors affecting glucose levels in older patients with long-standing T2DM. This study assessed the determinants of glycemic control in older adults with T2DM of a duration of ≥10 years, including muscle mass, muscle quality, and ß-cell function. METHODS: This was a prospective study of older patients aged ≥60 years with a T2DM duration of ≥10 years. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index, handgrip strength (HGS), and body composition through bioelectrical impedance analysis were assessed. The primary outcome was a composite of: (i) increment of glycated hemoglobin (HbA1c) from the baseline ≥0.6% and (ii) HbA1c ≥ 9% at any time point during the follow-up period. To find the predicting determinants of the outcome, we performed the Cox proportional hazard analysis. RESULTS: Among 100 patients (mean age, 64.0 ± 8.6 years; median duration of diabetes, 20 [interquartile range (IQR), 17-23] years; median HbA1c at baseline, 7.1 [IQR, 6.7-7.4] %), the primary outcome was observed in 40 (40.0%) patients during 4.0 (IQR 2.3-5.0) years of follow-up. A Cox proportional hazards model adjusted for age, sex, baseline HbA1c, obesity, duration of DM and anti-diabetic medication at baseline showed that low HGS and insulin resistance at the baseline were independent determinants of the primary outcome (hazard ratio [HR] = 2.23 [95% confidence interval (CI), 1.06-4.72] and 2.39 [95% CI, 1.18-4.83], respectively). Sex stratification confirmed that HGS and muscle mass were independent determinants of the primary outcome only in women (HR per quartile, 0.58 [95% CI, 0.37-0.93] and 0.46 [95% CI, 0.25-0.85], respectively). `. CONCLUSIONS: Low HGS and insulin resistance were independent risk factors for aggravated glycemic control among older patients with long standing T2DM.

Glucolipotoxicity Suppressed Autophagy and Insulin Contents in Human Islets, and Attenuation of PERK Activity Enhanced Them in an ATG7-Dependent Manner.

BACKGRUOUND: Administration of pancreatic endoplasmic reticulum kinase inhibitor (PERKi) improved insulin secretion and hyperglycemia in obese diabetic mice. In this study, autophagic balance was studied whether to mediate it. METHODS: Human islets were isolated from living patients without diabetes. PERKi GSK2606414 effects were evaluated in the islets under glucolipotoxicity by palmitate. Islet insulin contents and secretion were measured. Autophagic flux was assessed by microtubule associated protein 1 light chain 3 (LC3) conversion, a red fluorescent protein (RFP)-green fluorescent protein (GFP)- LC3 tandem assay, and P62 levels. For mechanical analyses, autophagy was suppressed using 3-methyladenine in mouse islets. Small interfering RNA for an autophagy-related gene autophagy related 7 (Atg7) was transfected to interfere autophagy. RESULTS: PERKi administration to mice decreased diabetes-induced P62 levels in the islets. Glucolipotoxicity significantly increased PERK phosphorylation by 70% and decreased insulin contents by 50% in human islets, and addition of PERKi (40 to 80 nM) recovered both. PERKi also enhanced glucose-stimulated insulin secretion (6-fold). PERKi up-regulated LC3 conversion suppressed by glucolipotoxicity, and down-regulated P62 contents without changes in P62 transcription, indicating enhanced autophagic flux. Increased autophagosome-lysosome fusion by PERKi was visualized in mouse islets, where PERKi enhanced ATG7 bound to LC3. Suppression of Atg7 eliminated PERKi-induced insulin contents and secretion. CONCLUSION: This study provided functional changes of human islets with regard to autophagy under glucolipotoxicity, and suggested modulation of autophagy as an anti-diabetic mechanism of PERKi.

Association between hypotension during pancreatectomy and development of postoperative diabetes.

CONTEXT: With advancements in long-term survival after pancreatectomy, post-pancreatectomy diabetes has become a concern, and the risk factors are not established yet. Pancreatic islets are susceptible to ischemic damage, though there is a lack of clinical evidence regarding glycemic deterioration. OBJECTIVE: To investigate association between hypotension during pancreatectomy and development of post-pancreatectomy diabetes. DESIGN: In this retrospective, longitudinal cohort study, we enrolled patients without diabetes who underwent distal pancreatectomy or pancreaticoduodenectomy between January 2005 and December 2018, from two referral hospitals in Korea. MAIN OUTCOME MEASURES: Intraoperative hypotension [IOH] was defined as a 20% or greater reduction in systolic blood-pressure. The primary and secondary outcomes were incident diabetes and postoperative Homeostatic Model Assessment [HOMA] indices. RESULTS: We enrolled 1,129 patients (average age, 59 years; 49% men; 35% distal pancreatectomy). IOH occurred in 83% (median duration, 25 minutes; interquartile range [IQR], 5-65). During a median follow-up of 3.9 years, diabetes developed in 284 patients (25%). The cumulative incidence of diabetes was proportional to increases in the duration and depth of IOH (P < 0.001). For the median duration in an IOH when compared to a reference time of 0 minute, the hazard ratio [HR] was 1.48 (95% CI, 1.14-1.92). The effect was pronounced with distal pancreatectomy compared to pancreaticoduodenectomy. Furthermore, the duration of IOH was inversely correlated with 1-year HOMA beta-cell function (P < 0.002), but not with HOMA insulin resistance. CONCLUSIONS: These results support the hypothesis that IOH during pancreatectomy may elevate risk of diabetes by inducing beta cell insufficiency.

Partial Deletion of Perk Improved High-Fat Diet-Induced Glucose Intolerance in Mice.

Although pancreatic endoplasmic reticulum kinase (PERK) is indispensable to beta cells, low-dose PERK inhibitor improved glucose- stimulated insulin secretion (GSIS) and hyperglycemia in diabetic mice. Current study examined if partial deletion of Perk (Perk+/-) recapitulated the effects of PERK inhibitor, on the contrary to the complete deletion. Perk+/- mice and wild-type controls were fed with a high-fat diet (HFD) for 23 weeks. Glucose tolerance was evaluated along with serum insulin levels and islet morphology. Perk+/- mice on normal chow were comparable to wild-type mice in various metabolic features. HFD-induced obesity was not influenced by Perk reduction; however, HFD-induced glucose intolerance was significantly improved since 15-week HFD. HFD-induced compromises in GSIS were relieved by Perk reduction, accompanied by reductions in phosphorylated PERK and activating transcription factor 4 (ATF4) in the islets. Meanwhile, HFD-induced islet expansion was not significantly affected. In summary, partial deletion of Perk improved glucose tolerance and GSIS impaired by diet-induced obesity, without changes in body weights or islet mass.

Endoplasmic Reticulum Stress and Dysregulated Autophagy in Human Pancreatic Beta Cells.

Pancreatic beta cell homeostasis is crucial for the synthesis and secretion of insulin; disruption of homeostasis causes diabetes, and is a treatment target. Adaptation to endoplasmic reticulum (ER) stress through the unfolded protein response (UPR) and adequate regulation of autophagy, which are closely linked, play essential roles in this homeostasis. In diabetes, the UPR and autophagy are dysregulated, which leads to beta cell failure and death. Various studies have explored methods to preserve pancreatic beta cell function and mass by relieving ER stress and regulating autophagic activity. To promote clinical translation of these research results to potential therapeutics for diabetes, we summarize the current knowledge on ER stress and autophagy in human insulin-secreting cells.

Hyperglycemic Hemichorea: A Case Series.

Hemichorea has been reported in subjects with hyperglycemia and the recurrent was rarely reported. We identified clinical presentation and course of hypeglycemic hemichorea in six cases, one of whom experienced recurrence. Mean age was 77.2 years and five were women. Duration of diabetes was 1-35 years. Initial HbA1c levels were 9.3%-13% and most patients had poor compliance. Five patients undertook brain magnetic resonance imaging and high signal intensities of basal ganglia was observed in T1-weighted images. All patients were treated with insulin, and four patients were treated with dopamine-receptor blockers. Mean duration of hemichorea was 69 days. One patient's hemichorea was recurred after 2 months from the time when the first event was resolved and then finally diagnosed with vasculitis. The prognosis of hyperglycaemic hemichoerea seemed to be good. However, we should consider other cause such as vasculitis when the symptom was recurred after adequate glycaemic control.