Optogenetic stimulation of vagal nerves for enhanced glucose-stimulated insulin secretion and β cell proliferation.

The enhancement of insulin secretion and of the proliferation of pancreatic β cells are promising therapeutic options for diabetes. Signals from the vagal nerve regulate both processes, yet the effectiveness of stimulating the nerve is unclear, owing to a lack of techniques for doing it so selectively and prolongedly. Here we report two optogenetic methods for vagal-nerve stimulation that led to enhanced glucose-stimulated insulin secretion and to β cell proliferation in mice expressing choline acetyltransferase-channelrhodopsin 2.

Relationship between nailfold capillaroscopy parameters and the severity of diabetic retinopathy.

Purpose: To determine whether non-invasive measurements of the nailfold capillaries (NCs) are associated with the presence and severity of diabetic retinopathy (DR) in patients with type 2 diabetes.

Methods: Eighty-three eyes of 83 patients with type 2 diabetes were enrolled. Sixty-three age-matched non-diabetic subjects served as controls.

Phagocytosis by macrophages promotes pancreatic β cell mass reduction after parturition in mice.

Elucidating the mechanism(s) modulating appropriate tissue size is a critical biological issue. Pancreatic β cells increase during pregnancy via cellular proliferation, but how β cells promptly decrease to the original amount after parturition remains unclear. Herein, we demonstrate the role and mechanism of macrophage accumulation in this process.

A case of fulminant type 1 diabetes and protein C deficiency complicated by deep vein thrombosis.

A 25-year-old man was diagnosed with diabetic ketoacidosis (DKA) at the onset of fulminant type 1 diabetes. After acute-phase DKA treatment including placement of a central venous catheter, a massive deep vein thrombosis (DVT) and pulmonary embolism (PE) were detected on hospital day 15. His protein C (PC) activity and antigen levels were low even 33 days after completing the DKA treatment, indicating partial type I PC deficiency.

A highly sensitive strategy for monitoring real-time proliferation of targeted cell types in vivo.

Cell proliferation processes play pivotal roles in timely adaptation to many biological situations. Herein, we establish a highly sensitive and simple strategy by which time-series showing the proliferation of a targeted cell type can be quantitatively monitored in vivo in the same individuals. We generate mice expressing a secreted type of luciferase only in cells producing Cre under the control of the Ki67 promoter.

Inter-organ insulin-leptin signal crosstalk from the liver enhances survival during food shortages.

Crosstalk among organs/tissues is important for regulating systemic metabolism. Here, we demonstrate inter-organ crosstalk between hepatic insulin and hypothalamic leptin actions, which maintains survival during food shortages. In inducible liver insulin receptor knockout mice, body weight is increased with hyperphagia and decreased energy expenditure, accompanied by increased circulating leptin receptor (LepR) and decreased hypothalamic leptin actions.

Insulin-like growth factor-1 levels are associated with high comorbidity of metabolic disorders in obese subjects; a Japanese single-center, retrospective-study.

Insulin like growth factor-1 (IGF-1) plays important roles in metabolic functions, especially in adulthood. Additionally, obese subjects are reportedly predisposed to having low absolute IGF-1 levels. However, the prevalence and clinical characteristics of obese subjects with low IGF-1 levels are unknown.

Roles of FoxM1-driven basal β-cell proliferation in maintenance of β-cell mass and glucose tolerance during adulthood.

Aims/introduction: Whether basal β-cell proliferation during adulthood is involved in maintaining sufficient β-cell mass, and if so, the molecular mechanism(s) underlying basal β-cell proliferation remain unclear. FoxM1 is a critical transcription factor which is known to play roles in 'adaptive' β-cell proliferation, which facilitates rapid increases in β-cell mass in response to increased insulin demands. Therefore, herein we focused on the roles of β-cell FoxM1 in 'basal' β-cell proliferation under normal conditions and in the maintenance of sufficient β-cell mass as well as glucose homeostasis during adulthood.

Type 1 Diabetes Mellitus Associated with Nivolumab after Second SARS-CoV-2 Vaccination, Japan.

Recently, along with increasing use of immune checkpoint inhibitors such as nivolumab, the incidence of immune-related adverse events, including type 1 diabetes mellitus, has become a serious problem. We report a patient who had immune checkpoint inhibitor‒associated type 1 diabetes mellitus that developed after a second mRNA-based SARS-CoV-2 vaccination.

Two cases with fulminant type 1 diabetes that developed long after cessation of immune checkpoint inhibitor treatment.

Various immune-related adverse events (irAEs), including fulminant type 1 diabetes (FT1D), are known to be associated with immune checkpoint inhibitors (ICIs). We experienced two lung adenocarcinoma cases who developed fulminant type 1 diabetes long after discontinuation of ICI therapies. One, a 74-year-old male, received nivolumab and developed fulminant type 1 diabetes 44 days after the last infusion.

Continuous glucose monitoring in patients with remission of type 2 diabetes after laparoscopic sleeve gastrectomy without or with duodenojejunal bypass.

Bariatric surgery is associated with a high remission rate of type 2 diabetes mellitus. However, it is unclear whether patients showing remission of diabetes actually have normal blood glucose levels throughout the day. We therefore performed continuous glucose monitoring (CGM) in 15 ambulatory patients showing remission of diabetes after laparoscopic sleeve gastrectomy (LSG) without or with duodenojejunal bypass (DJB) at the time of diabetic remission (12.

Inhibition of Plasminogen Activator Inhibitor-1 Activation Suppresses High Fat Diet-Induced Weight Gain Alleviation of Hypothalamic Leptin Resistance.

Leptin resistance is an important mechanism underlying the development and maintenance of obesity and is thus regarded as a promising target of obesity treatment. Plasminogen activator inhibitor 1 (PAI-1), a physiological inhibitor of tissue-type and urokinase-type plasminogen activators, is produced at high levels in adipose tissue, especially in states of obesity, and is considered to primarily be involved in thrombosis. PAI-1 may also have roles in inter-organ tissue communications regulating body weight, because PAI-1 knockout mice reportedly exhibit resistance to high fat diet (HFD)-induced obesity.

Vascular resistance of carotid and vertebral arteries is associated with retinal microcirculation measured by laser speckle flowgraphy in patients with type 2 diabetes mellitus.

Aims: Evaluation of the retinal microcirculation is key to understanding retinal vasculopathies, such as diabetic retinopathy. Laser speckle flowgraphy (LSFG) has recently enabled us to directly evaluate the vascular resistance in both retinal vessels and capillaries, non-invasively. We therefore assessed whether retinal vessel blood flow and/or the capillary microcirculation are associated with blood flow in the cervical arteries in diabetic patients without severe retinopathy.

Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation.

The liver possesses a high regenerative capacity. Liver regeneration is a compensatory response overcoming disturbances of whole-body homeostasis provoked by organ defects. Here we show that a vagus-macrophage-hepatocyte link regulates acute liver regeneration after liver injury and that this system is critical for promoting survival.

Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers.

Background/objective: Insulin signals, via the regulation of key enzyme expression, both suppress gluconeogenesis and enhance lipid synthesis in the liver. Animal studies have revealed insulin signaling favoring gluconeogenesis suppression to be selectively impaired in steatotic livers. However, whether, and if so how, such selective insulin resistance occurs in human steatotic livers remains unknown.

Serum cystatin C level is associated with carotid arterial wall elasticity in subjects with type 2 diabetes mellitus: A potential marker of early-stage atherosclerosis.

Aims: Detection of early-stage atherosclerosis in type 2 diabetes mellitus (T2DM) patients is important for preventing cardiovascular disease. A phased tracking method for evaluating arterial wall elasticity sensitively detects early-stage atherosclerosis. However, biochemical markers for early-stage atherosclerosis have yet to be established.

Olfactory receptors are expressed in pancreatic β-cells and promote glucose-stimulated insulin secretion.

Olfactory receptors (ORs) mediate olfactory chemo-sensation in OR neurons. Herein, we have demonstrated that the OR chemo-sensing machinery functions in pancreatic β-cells and modulates insulin secretion. First, we found several OR isoforms, including OLFR15 and OLFR821, to be expressed in pancreatic islets and a β-cell line, MIN6.

Neuronal signals regulate obesity induced β-cell proliferation by FoxM1 dependent mechanism.

Under insulin-resistant conditions such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. A liver-brain-pancreas neuronal relay plays an important role in this process. Here, we show the molecular mechanism underlying this compensatory β-cell proliferation.

Activation of the Hypoxia Inducible Factor 1α Subunit Pathway in Steatotic Liver Contributes to Formation of Cholesterol Gallstones.

Background & Aims: Hypoxia-inducible factor 1α subunit (HIF1A) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with nonalcoholic fatty liver disease (NAFLD). NAFLD increases the risk for cholesterol gallstone disease by unclear mechanisms. We studied the relationship between HIF1A and gallstone formation associated with liver steatosis.

MicroRNAs 106b and 222 Improve Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes via Pancreatic β-Cell Proliferation.

Major symptoms of diabetes mellitus manifest, once pancreatic β-cell numbers have become inadequate. Although natural regeneration of β-cells after injury is very limited, bone marrow (BM) transplantation (BMT) promotes their regeneration through undetermined mechanism(s) involving inter-cellular (BM cell-to-β-cell) crosstalk. We found that two microRNAs (miRNAs) contribute to BMT-induced β-cell regeneration.

Lipoprotein Lipase Deficiency (R243H) in a Type 2 Diabetes Patient with Multiple Arterial Aneurysms.

Lipoprotein lipase (LPL) deficiency is a rare monogenic disorder that manifests as severe hypertriglyceridemia. Whether or not LPL deficiency accelerates the development of atherosclerosis remains controversial. We herein report a 66-year-old woman who was homozygous for the R243H LPL mutation.

Dapagliflozin, a Sodium-Glucose Co-Transporter 2 Inhibitor, Acutely Reduces Energy Expenditure in BAT via Neural Signals in Mice.

Selective sodium glucose cotransporter-2 inhibitor (SGLT2i) treatment promotes urinary glucose excretion, thereby reducing blood glucose as well as body weight. However, only limited body weight reductions are achieved with SGLT2i treatment. Hyperphagia is reportedly one of the causes of this limited weight loss.

Simultaneous copy number losses within multiple subtelomeric regions in early-onset type 2 diabetes mellitus.

Genetic factors play very important roles in the onset and progression of type 2 diabetes mellitus (T2DM). However, the genetic factors correlating with T2DM onset have not as yet been fully clarified. We previously found that copy number losses in the subtelomeric region on chromosome 4p16.