Glucokinase and ATP-sensitive potassium (KATP) channels in pancreatic β-cells control insulin secretion in response to glucose stimulation to maintain glucose homeostasis. It is well established that loss-of-function (LOF) variants in GCK, which encodes glucokinase, are diabetogenic, whereas LOF variants in KATP channel genes lead to congenital hyperinsulinism (HI) and hypoglycemia. However, how the co-occurrence of […]
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Whey Protein Ingestion Stimulates Glucagon Secretion and Raises Blood Glucose Levels in Adults With Type 1 Diabetes
This study characterized the dose effect of whey protein isolate (WPI) ingestion on glucagon secretion, glycemia, and the underlying mechanisms in adults with type 1 diabetes. Twelve insulin pump–treated adults with type 1 diabetes (mean ± SD age 47.3 ± 16.4 years; BMI 26.1 ± 3.8 kg/m2) and six adults without diabetes (age 36.2 ± […]
Read MoreIslet Autotransplant Recipients Have Elevated Proinsulin–to–C-Peptide Ratios Supporting Metabolic Stress as a Cause of Islet Attrition
Attrition of islet function is observed over time following total pancreatectomy with islet autotransplantation (TPIAT). Metabolic stress on a suboptimal islet mass is a suspected, but unconfirmed, contributor. We measured proinsulin–to–C-peptide (PI:C) ratios as an indicator of β-cell stress in TPIAT recipients >5 years post-TPIAT. Individuals ≥16 years old with TPIAT 5–20 years prior underwent […]
Read MoreMicroRNAs in Islet Biology and Diabetes: Progress, Gaps, and Opportunities
MicroRNAs (miRNAs) are small RNAs that posttranscriptionally repress gene expression of their target mRNAs. miRNA discovery dates to 1993, when Ambros and Ruvkun identified them in nematodes. More than two decades later, their pioneering research was recognized with the Nobel Prize in Medicine, a fitting acknowledgment of the profound impact these tiny molecules exert on […]
Read MoreLysosomal Ion Channel TRPML1 Contributes to Neuropathic Pain Associated With Diabetic Peripheral Neuropathy in Mice
Neuropathic pain associated with diabetic peripheral neuropathy (DPN) is a common and hard-to-treat complication of diabetes. Ion channels of plasma membrane are major mechanisms and targets for DPN pain. This study explores the role of a major lysosomal ion channel, TRPML1, in DPN pain. Mouse models of DPN pain and TRPML1 knockout were combined with […]
Read MoreNeuroligin-3: A Novel Exercise-Induced Secreted Factor Enhancing Insulin Sensitivity in Obese Insulin-Resistant Mice
The salutary effects of physical exercise in mitigating metabolic disorders, particularly type 2 diabetes, are well recognized. Several studies have demonstrated that endurance training boosts the production of exercise-induced myokines, which are pivotal for interorgan communication enhancing insulin sensitivity. However, several challenges, including an incomplete understanding of underlying molecular mechanisms, hinder their therapeutic application. Here, […]
Read MoreGut-Derived GLP-1 Released by Rare Sugar d -Allulose Cooperates With Insulin to Activate Left-Sided Vagal Afferents and Enhance Insulin Sensitivity
Glucagon-like peptide 1 receptor agonists (GLP-1RAs) ameliorate hyperglycemia by directly stimulating insulin secretion from the pancreas. In contrast, the physiological role of short-lived endogenous GLP-1 remains unclear largely because of its limited access to pancreatic β-cells. Here, we used d-allulose, a nonmetabolizable noncaloric rare sugar, as a GLP-1 secretagogue. We show that d-allulose–induced intestinal GLP-1 […]
Read MoreCHD4 and NKX2.2 Cooperate to Regulate β-Cell Function by Repressing Non–β-Cell Gene Programs
NKX2.2 is a transcription factor that regulates pancreatic islet β-cell identity and function; however, cofactor proteins that modulate the functional activity of NKX2.2 in β-cells are relatively unexplored. An unbiased proteomics screen identified chromodomain helicase DNA-binding protein 4 (CHD4) as an NKX2.2 interacting partner. CHD4 is a nucleosome remodeler that directs the appropriate differentiation, maturation […]
Read MoreThe Glucagonotropic Effect of GIP Is Negated During Insulin-Induced Hypoglycemia in Type 1 Diabetes: A Randomized, Placebo-Controlled, Crossover Study
Glucose-dependent insulinotropic polypeptide (GIP[1–42]) increases glucagon levels in the presence of normal-to-low plasma glucose concentrations in individuals with type 1 diabetes (T1D), suggesting its potential use as a safeguard against hypoglycemia. We investigated the dose-dependent effects of exogenous full-length GIP[1–42] and its truncated variant GIP[1–30]NH2 on glucagon concentrations during insulin-induced hypoglycemia in individuals with T1D. […]
Read MoreEstrogen Mediates Capacity for Hyperplastic Adipose Expansion and Preserves Adipose Progenitor Cell Availability in Subcutaneous Depots of Female Mice
Female protection against cardiometabolic disease wanes after menopause, concomitant with a transition toward the male-like pattern of visceral adiposity. Since recruitment of adipose progenitor cells (APCs) to support adipose expansion is depot-specific and thought to maintain metabolic homeostasis, sex differences in the capacity for APC differentiation were explored as a mechanism underlying female cardiometabolic protection. […]
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