The integrated incretin effect is reduced by both glucose intolerance and obesity in Japanese subjects.

Introduction: Incretin-based drugs are extensively utilized in the treatment of type 2 diabetes (T2D), with remarkable clinical efficacy. These drugs were developed based on findings that the incretin effect is reduced in T2D. The incretin effect in East Asians, whose pancreatic ß-cell function is more vulnerable than that in Caucasians, however, has not been fully examined. In this study, we investigated the effects of incretin in Japanese subjects. Methods: A total of 28 Japanese subjects (14 with normal glucose tolerance [NGT], 6 with impaired glucose tolerance, and 8 with T2D) were enrolled. Isoglycemic oral (75 g glucose tolerance test) and intravenous glucose were administered. The numerical incretin effect and gastrointestinally-mediated glucose disposal (GIGD) were calculated by measuring the plasma glucose and entero-pancreatic hormone concentrations. Results and discussion: The difference in the numerical incretin effect among the groups was relatively small. The numerical incretin effect significantly negatively correlated with the body mass index (BMI). GIGD was significantly lower in participants with T2D than in those with NGT, and significantly negatively correlated with the area under the curve (AUC)-glucose, BMI, and AUC-glucagon. Incretin concentrations did not differ significantly among the groups. We demonstrate that in Japanese subjects, obesity has a greater effect than glucose tolerance on the numerical incretin effect, whereas GIGD is diminished in individuals with both glucose intolerance and obesity. These findings indicate variances as well as commonalities between East Asians and Caucasians in the manifestation of incretin effects on pancreatic ß-cell function and the integrated capacity to handle glucose.

Effects of dipeptidyl peptidase-4 inhibition in vivo: Dipeptidyl peptidase-4 inhibitor/gut microbiome crosstalk suggests novel therapeutic options for diabetes management.

Wang et al. report that clinical dipeptidyl peptidase-4 (DPP-4) inhibitors show little effect on microbial DPP-4 produced by Bacteroides genus. Furthermore, oral administration of microbial DPP-4 to high-fat diet-fed mice was found to reduce plasma active glucagon-like peptide-1 levels through an increase in extraluminal intestinal tissular DPP-4 activity, resulting in reduced glucose-induced insulin levels and exacerbated glucose tolerance.

Intestinal Morphology and Glucose Transporter Gene Expression under a Chronic Intake of High Sucrose.

Sucrose is a disaccharide that is degraded into fructose and glucose in the small intestine. High-sucrose and high-fructose diets have been reported, using two-dimensional imaging, to alter the intestinal morphology and the expression of genes associated with sugar transport, such as sodium glucose co-transporter 1 (SGLT1), glucose transporter 2 (GLUT2), and glucose transporter 5 (GLUT5). However, it remains unclear how high-fructose and high-sucrose diets affect the expression of sugar transporters and the intestinal morphology in the whole intestine. We investigate the influence of a chronic high-sucrose diet on the expression of the genes associated with sugar transport as well as its effects on the intestinal morphology using 3D imaging. High sucrose was found to increase GLUT2 and GLUT5 mRNA levels without significant changes in the intestinal morphology using 3D imaging. On the other hand, the delay in sucrose absorption by an α-glucosidase inhibitor significantly improved the intestinal morphology and the expression levels of SGLT1, GLUT2, and GLUT5 mRNA in the distal small intestine to levels similar to those in the proximal small intestine, thereby improving glycemic control after both glucose and sucrose loading. These results reveal the effects of chronic high-sugar exposure on glucose absorption and changes in the intestinal morphology.

A Case Report of Diabetes in a Patient with Glycogen Storage Disease Type 1a.

Glycogen storage disease type 1a (GSD-1a) is a rare congenital disease. Recently, life expectancy with GSD-1a has been improved by its early diagnosis and management. Complications of diabetes with GSD-1a are extremely rare. The optimal treatment for glucose control using this disease combination remains unclear. The existence of GSD-1a and diabetes can cause both hypoglycemia and hyperglycemia, making glucose control especially problematic. In the present report, α-glucosidase inhibitor (α-GI) and dipeptidyl peptidase-4 (DPP-4) inhibitors improved hyperglycemia without symptoms of hypoglycemia in a patient with diabetes and GSD-1a using intermittent continuous glucose monitoring (isCGM).

Favorable effect of CD26/DPP-4 inhibitors on postoperative outcomes after lung transplantation: A propensity-weighted analysis.

BACKGROUND: We have shown the efficacy of CD26/dipeptidyl peptidase 4 (CD26/DPP-4) inhibitors, antidiabetic agents, in allograft protection after experimental lung transplantation (LTx). We aimed to elucidate whether CD26/DPP-4 inhibitors effectively improve postoperative outcomes after clinical LTx. METHODS: We retrospectively reviewed the records of patients undergoing LTx at our institution between 2010 and 2021 and extracted records of patients with diabetes mellitus (DM) at 6 months post-LTx. The patient characteristics and postoperative outcomes were analyzed. We established 6 months post-LTx as the landmark point for predicting overall survival (OS) and chronic lung allograft dysfunction (CLAD)-free survival. Hazard ratios were estimated by Cox regression after propensity score weighting, using CD26/DPP-4 inhibitor treatment up to 6 months post-LTx as the exposure variable. We evaluated CLAD samples pathologically, including for CD26/DPP-4 immunohistochemistry. RESULTS: Of 102 LTx patients with DM, 29 and 73 were treated with and without CD26/DPP-4 inhibitors, respectively. Based on propensity score adjustment using standardized mortality ratio weighting, the 5-year OS rates were 77.0% and 44.3%, and the 5-year CLAD-free survival rates 77.8% and 49.1%, in patients treated with and without CD26/DPP-4 inhibitors, respectively. The hazard ratio for CD26/DPP-4 inhibitor use was 0.34 (95% confidence interval (CI) 0.14-0.82, p = 0.017) for OS and 0.47 (95% CI 0.22-1.01, p = 0.054) for CLAD-free survival. We detected CD26/DPP-4 expression in the CLAD grafts of patients without CD26/DPP-4 inhibitors. CONCLUSIONS: Analysis using propensity score weighting showed that CD26/DPP-4 inhibitors positively affected the postoperative prognosis of LTx patients with DM.

Correction: A consensus statement from the Japan Diabetes Society (JDS): a proposed algorithm for pharmacotherapy in people with type 2 diabetes.

[This corrects the article DOI: 10.1007/s13340-022-00605-x.].

Prediction-based prompt levothyroxine replacement to prevent a hypothyroid state after immune-related adverse events involving the thyroid gland.

Immune checkpoint inhibitors (ICIs) are used for various malignancies, although they frequently cause immune-related adverse events involving the thyroid gland (thyroid irAEs). We conducted a retrospective cohort study to elucidate thyroid function outcomes. Fifty of 639 patients who received PD-1 blockade therapy met criteria and were divided into the following groups: thyrotoxicosis with subsequent hypothyroidism (Toxic-Hypo, n = 21); thyrotoxicosis without subsequent hypothyroidism (Toxic, n = 9); and hypothyroidism without prior thyrotoxicosis (Hypo, n = 20). The Toxic-Hypo group developed thyroid irAEs earlier than the Toxic group (26 vs. 91 days; p < 0.001), and had higher serum free T4 levels (3.210 vs. 1.880 ng/dL; p = 0.011). In addition, positive anti-thyroglobulin antibodies (TgAbs) at thyroid irAE onset were more common in the Toxic-Hypo group (93.3%) than in the Toxic group (0.0%; p = 0.005) and Hypo group (44.4%; p = 0.007). The Toxic-Hypo group developed severe hypothyroidism and required larger levothyroxine (LT4) doses than the Hypo group (75 vs. 25 µg/day; p = 0.007). We predicted that patients with positive TgAbs who developed severe thyrotoxicosis within 4 weeks after the first ICI administration would develop subsequent hypothyroidism. We treated 4 such patients with prompt LT4 replacement, characterized by LT4 initiation after thyrotoxicosis improvement and quick dose titration. Their euthyroid state was successfully maintained, in contrast with patients receiving conventional replacement. In conclusion, rapid-onset severe thyrotoxicosis in patients with TgAbs correlated with a high likelihood of subsequent hypothyroidism. Accordingly, prompt LT4 replacement is suggested to prevent a severely hypothyroid state.

Effects of nutrient metabolism on pancreatic ß-cell mass and function: Recent findings.

This article summarizes recent findings on the effects of nutrients on pancreatic ß-cell mass and function. Further studies are expected to facilitate the prevention of the onset and treatment of diabetes by nutritional therapy.

Impact of the angiotensin receptor-neprilysin inhibitor in clinical diabetes management: Potential benefits and pitfalls.

The possible mechanism of increased urinary C-peptide due to neprilysin inhibitors is investigated. Neprilysin inhibition blocks degradation of natriuretic peptides, and elicits a natriuretic and antihypertensive effect. Neprilysin inhibition might similarly block degradation of C-peptides in the kidney and thus increase the urinary C-peptide level.

Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding.

Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics' ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) - brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways.

Inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-fat diet feeding.

G protein-coupled receptor (GPR) 120 is expressed in enteroendocrine cells secreting glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP), and cholecystokinin (CCK). Although GPR120 signaling in adipose tissue and macrophages has been reported to ameliorate obesity and insulin resistance in a high long-chain triglyceride (LCT) diet, intestine-specific roles of GPR120 are unclear. To clarify the metabolic effect of GPR120 in the intestine, we generated intestine-specific GPR120-knockout (GPR120int-/-) mice. In comparison with floxed GPR120 (WT) mice, GPR120int-/- mice exhibited reduced GIP secretion and CCK action without change of insulin, GLP-1, or peptide YY (PYY) secretion after a single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed a mild reduction of body weight and substantial amelioration of insulin resistance and fatty liver. Moreover, liver and white adipose tissue (WAT) of GPR120int-/-mice exhibited increased Akt phosphorylation and reduced gene expression of suppressor of cytokine signaling (SOCS) 3, which inhibits insulin signaling. In addition, gene expression of inflammatory cytokines in WAT and lipogenic molecules in liver were reduced in GPR120int-/- mice. These findings suggest that inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-LCT diet feeding.NEW & NOTEWORTHY We generated novel intestine-specific GPR120-knockout (GPR120int-/-) mice and investigated the metabolic effect of GPR120 in the intestine. GPR120int-/- mice exhibited a reduction of GIP secretion and CCK action after a single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed mild improvement in obesity and marked amelioration of insulin resistance and hepatic steatosis. Our results indicate an important role of intestinal GPR120 on insulin resistance and hepatic steatosis.

Efficacy of antihyperglycemic therapies on cardiovascular and heart failure outcomes: an updated meta-analysis and meta-regression analysis of 35 randomized cardiovascular outcome trials.

BACKGROUND: Effects of antihyperglycemic therapies on cardiovascular and heart failure (HF) risks have varied widely across cardiovascular outcome trials (CVOTs), and underlying factors remain incompletely understood. We aimed to determine the relationships of glycated hemoglobin (HbA1c) or bodyweight changes with these outcomes in all CVOTs of antihyperglycemic therapies. METHODS: We searched PubMed and EMBASE up to 25 January 2023 for all randomized controlled CVOTs of antihyperglycemic therapies reporting both major adverse cardiovascular events (MACE) and HF outcomes in patients with type 2 diabetes or prediabetes. We performed meta-regression analyses following random-effects meta-analyses to evaluate the effects of HbA1c or bodyweight reductions on each outcome. RESULTS: Thirty-five trials comprising 256,524 patients were included. Overall, antihyperglycemic therapies reduced MACE by 9% [risk ratio (RR): 0.91; 95% confidence interval (CI) 0.88-0.94; P < 0.001; I2 = 36.5%]. In meta-regression, every 1% greater reduction in HbA1c was associated with a 14% reduction in the RR of MACE (95% CI 4-24; P = 0.010), whereas bodyweight change was not associated with the RR of MACE. The magnitude of the reduction in MACE risk associated with HbA1c reduction was greater in trials with a higher baseline prevalence of atherosclerotic cardiovascular disease. On the other hand, antihyperglycemic therapies showed no overall significant effect on HF (RR: 0.95; 95% CI 0.87-1.04; P = 0.28; I2 = 75.9%). In a subgroup analysis based on intervention type, sodium-glucose cotransporter-2 inhibitors (SGLT2i) conferred the greatest HF risk reduction (RR: 0.68; 95% CI 0.62-0.75; P < 0.001; I2 = 0.0%). In meta-regression, every 1 kg bodyweight reduction, but not HbA1c reduction, was found to reduce the RR of HF by 7% (95% CI 4-10; P < 0.001); however, significant residual heterogeneity (P < 0.001) was observed, and SGLT2i reduced HF more than could be explained by HbA1c or bodyweight reductions. CONCLUSIONS: Antihyperglycemic therapies reduce MACE in an HbA1c-dependent manner. These findings indicate that HbA1c can be a useful marker of MACE risk reduction across a wide range of antihyperglycemic therapies, including drugs with pleiotropic effects. In contrast, HF is reduced not in an HbA1c-dependent but in a bodyweight-dependent manner. Notably, SGLT2i have shown class-specific benefits for HF beyond HbA1c or bodyweight reductions.

Residue-Selective C-H Sulfenylation Enabled by Acid-Activated S-Acetamidomethyl Cysteine Sulfoxide with Application to One-Pot Stapling and Lipidation Sequence.

A tyrosine (Tyr)- or tryptophan (Trp)-selective metal-free C-H sulfenylation reaction using an acid-activated S-acetamidomethyl cysteine (Cys) sulfoxide, Cys(Acm)(O), has been achieved. The dually protonated intermediate produced from Cys(Acm)(O) under acidic conditions allows the sulfenylation of Tyr. Significantly, the reaction in the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf) mainly affords a Cys-Tyr-linked peptide even in the presence of Trp residues. In contrast, a Cys-Trp-linked peptide was selectively obtained from the reaction in the presence of guanidine hydrochloride (Gn ⋅ HCl) under acidic conditions. Established Tyr- and Trp-selective sulfenylation methods were used in the Cys-Tyr stapling and Trp lipidation of glucagon-like peptides 1 in a one-pot/stepwise manner. Investigation of the mechanism showed that orbital- and charge-controlled reactions are responsible for the Trp and Tyr selectivity, respectively.

An analysis of intestinal morphology and incretin-producing cells using tissue optical clearing and 3-D imaging.

Tissue optical clearing permits detailed evaluation of organ three-dimensional (3-D) structure as well as that of individual cells by tissue staining and autofluorescence. In this study, we evaluated intestinal morphology, intestinal epithelial cells (IECs), and enteroendocrine cells, such as incretin-producing cells, in reporter mice by intestinal 3-D imaging. 3-D intestinal imaging of reporter mice using optical tissue clearing enabled us to evaluate both detailed intestinal morphologies and cell numbers, villus length and crypt depth in the same samples. In disease mouse model of lipopolysaccharide (LPS)-injected mice, the results of 3-D imaging using tissue optical clearing in this study was consistent with those of 2-D imaging in previous reports and could added the new data of intestinal morphology. In analysis of incretin-producing cells of reporter mice, we could elucidate the number, the percentage, and the localization of incretin-producing cells in intestine and the difference of those between L cells and K cells. Thus, we established a novel method of intestinal analysis using tissue optical clearing and 3-D imaging. 3-D evaluation of intestine enabled us to clarify not only detailed intestinal morphology but also the precise number and localization of IECs and incretin-producing cells in the same samples.

Sodium-Glucose Cotransporter 2 Inhibitors and New-onset Type 2 Diabetes in Adults With Prediabetes: Systematic Review and Meta-analysis of Randomized Controlled Trials.

CONTEXT: The preventive effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors for new-onset diabetes was investigated in secondary analyses of several randomized controlled trials (RCTs). However, the results were inconsistent. OBJECTIVE: This work aimed to synthesize available evidence and evaluate whether SGLT2 inhibitors are effective in preventing new-onset diabetes. METHODS: In this systematic review and meta-analysis of RCTs, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched through February 11, 2022. Two independent authors screened the search results and extracted summary data from eligible RCTs (including original and post hoc analyses) comparing SGLT2 inhibitors and placebo for the risk of new-onset diabetes among adults with prediabetes. Meta-analysis was conducted using random-effects models to calculate risk ratios and 95% CIs. RESULTS: We included 4 RCTs with 5655 participants who had prediabetes. Based on the random-effects meta-analysis, SGLT2 inhibitors were significantly associated with a lower risk of new-onset diabetes (relative risk, 0.79; 95% CI, 0.68-0.93). The relative risks of new-onset diabetes in dapagliflozin and empagliflozin were 0.68 (95% CI, 0.52-0.89) and 0.87 (95% CI, 0.72-1.04), respectively (P-for-heterogeneity = .14). The frequency of severe hypoglycemia was not elevated in the SGLT2 inhibitors group compared to the placebo group. CONCLUSION: In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of new-onset type 2 diabetes among adults with prediabetes and heart failure or chronic kidney disease. These findings indicate the potential usefulness of SGLT2 inhibitors in preventing diabetes among high-risk populations with prediabetes.

Noninvasive Evaluation of GIP Effects on ß-Cell Mass Under High-Fat Diet.

Pancreatic ß-cell mass (BCM) has an importance in the pathophysiology of diabetes mellitus. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging has emerged as a promising tool for BCM evaluation. While glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is known to be involved in high-fat diet (HFD)-induced obesity, the effect of GIP on BCM is still controversial. In this study, we investigated indium 111 (111In)-labeled exendin-4 derivative ([Lys12(111In-BnDTPA-Ahx)]exendin-4) single-photon emission computed tomography/computed tomography (SPECT/CT) as a tool for evaluation of longitudinal BCM changes in HFD-induced obese mice, at the same time we also investigated the effects of GIP on BCM in response to HFD using GIP-knockout (GIP-/-) mice. 111In-exendin-4 SPECT/CT was able to distinguish control-fat diet (CFD)-fed mice from HFD-fed mice and the pancreatic uptake values replicated the BCM measured by conventional histological methods. Furthermore, BCM expansions in HFD-fed mice were demonstrated by time-course changes of the pancreatic uptake values. Additionally, 111In-exendin-4 SPECT/CT demonstrated the distinct changes in BCM between HFD-fed GIP-/- (GIP-/-+HFD) and wild-type (WT+HFD) mice; the pancreatic uptake values of GIP-/-+HFD mice became significantly lower than those of WT+HFD mice. The different changes in the pancreatic uptake values between the two groups preceded those in fat accumulation and insulin resistance. Taken together with the finding of increased ß-cell apoptosis in GIP-/-+HFD mice compared with WT+HFD mice, these data indicated that GIP has preferable effects on BCM under HFD. Therefore, 111In-exendin-4 SPECT/CT can be useful for evaluating increasing BCM and the role of GIP in BCM changes under HFD conditions.

S-Protected Cysteine Sulfoxide-Enabled Tryptophan-Selective Modification with Application to Peptide Lipidation.

Lipidation of peptides is a promising means of modification that can improve the therapeutic character of biologically active peptides. Here, a novel lipidation protocol for peptides is described. The C-H sulfenylation of indole in peptides using S-p-methoxybenzyl cysteine sulfoxide under acidic conditions in the presence of ammonium chloride, anisole, and triisopropylsilane enables late-stage tryptophan-selective peptide lipidation. This developed protocol has been used successfully for the lipidation of glucagon-like peptides. Oral glucose tolerance tests in wild-type mice indicated that the resulting lipidated peptides stimulate insulin secretion and exhibit a more long-lasting blood-glucose-lowering effect than a parent nonlipidated peptide.