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Artificial pancreas systems should be designed considering different patient profiles, which is challenging from a control theory perspective. In this paper, a flexible-hybrid dual-hormone control algorithm for an artificial pancreas is proposed. The algorithm handles announced/unannounced meals by means of a non-interacting feedforward scheme that safely incorporates prandial boluses. Also, a coordination strategy is employed to distribute the counter-regulatory actions, which can be delivered as a continuous glucagon infusion via an automated pump, as an oral rescue carbohydrate recommendation, or as a rescue glucagon dose recommendation to be administrated through a glucagon pen. The different configurations of the proposed controller were evaluated in silico using a 14-day virtual scenario with random meal intakes and exercise sessions, achieving above 80% time-in-range and low time spent in hypoglycemia. [ABSTRACT FROM AUTHOR]

Neonatal hypoglycemia (NH) is broadly defined as a low plasma glucose concentration that elicits hypoglycemia-induced impaired brain function. To date, no universally accepted threshold (reference range) for plasma glucose levels in newborns has been published, as data consistently indicate that neurologic responses to hypoglycemia differ at various plasma glucose concentrations. Infants at risk for NH include infants of diabetic mothers, small or large for gestational age, and premature infants. Common manifestations include jitteriness, poor feeding, irritability, and encephalopathy. Neurodevelopmental morbidities associated with NH include cognitive and motor delays, cerebral palsy, vision and hearing impairment, and poor school performance. This article offers a timely discussion of the state of the science of NH and recommendations for neonatal providers focused on early identification and disease prevention. [ABSTRACT FROM AUTHOR]

The role of co-agonists of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) in chronic kidney disease (CKD) remains unclear. Herein we found that GLP-1R and GCGR expression levels were lower in the kidneys of mice with CKD compared to healthy mice and were correlated with disease severity. Interestingly, GLP-1R or GCGR knockdown aggravated the progression of kidney injury in both diabetic db/db mice and non-diabetic mice undergoing unilateral ureteral obstruction (UUO). Based on the importance of GLP-1R and GCGR in CKD, we reported a novel monomeric peptide, 1907-B, with dual-agonism on both GLP-1R and GCGR. The data confirmed that 1907-B had a longer half-life than long-acting semaglutide in rats or cynomolgus monkeys (∼2–3 fold) and exhibited better therapeutic contribution to CKD than best-in-class monoagonists, semaglutide, or glucagon, in db/db mice and UUO mice. Various lock-of-function models, including selective pharmacological activation and genetic knockdown, confirmed that 1907-B's effects on ameliorating diabetic nephropathy in db/db mice, as well as inhibiting kidney fibrosis in UUO mice, were mediated through GLP-1 and glucagon signaling. These findings highlight that 1907-B, a novel GLP-1R and GCGR co-agonist, exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment. 1907-B, as a highly potent ultralong-acting GLP-1 and glucagon co-agonist, exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study aimed to elucidate the possible effects of the acute/long-term infusion of glucagon in the brain as the regulatory role on the endocrine secretions of the pancreas. MATERIALS AND METHODS: Ninety male Wistar albino rats were divided as Control, artificial Cerebrospinal Fluid (aCSF) (120 min), Glucagon (120 min), pancreatic denervation (PD)+aCSF (120 min), PD+Glucagon (120 min), aCSF (7 days), Glucagon (7 days), PD+aCSF (7 days) and PD+Glucagon (7 days). Glucagon and solvent (aCSF) were administered after pancreatic denervation (PD) by Hamilton syringe and osmotic mini pump (1 µg/10 µl/min) in the third ventricle of the brain. RESULTS: Acute intracerebroventricular (icv) administration of glucagon resulted in an elevation of glucagon levels and a concurrent reduction in blood glucose levels. Furthermore, in both the PD+aCSF (7 days) and PD+Glucagon (7 days) groups, there was a notable decrease in propiomelanocortin (POMC) and agouti-related protein (AgRP). Significant changes were observed in feed consumption and body weight, as well as pancreatic glucagon levels, with a simultaneous decrease in insulin levels in the PD (7 days), Glucagon (7 days), and PD+Glucagon (7 days) groups. These alterations were statistically significant when compared to the control group (p<0.05). CONCLUSIONS: The research outcomes established that pancreas-secreted glucagon functions as a neurohormone within the brain, activating central pathways linked to blood glucose regulation. The presence of glucagon led to a decrease in POMC levels. Surprisingly, this reduction in POMC resulted in the suppression of AgRP. Contrary to expectations, the suppression of AgRP led to an increase in food intake rather than a decrease. As already highlighted in the results section, it was emphasized that POMC may play a more significant role than AgRP in influencing feeding behavior. [ABSTRACT FROM AUTHOR]

Zinc ion can play critical role in glycemic control in diabetes mellitus (DM), contributing to both insulin synthesis and secretion. In this study, we aimed to investigate the level of zinc in diabetic patients and its association with glycemic parameters, insulin, and glucagon level. Methods: 112 individuals (59 cases of type 2DM and 53 non-diabetic controls) were included in this study. Biochemical parameters (FBG, 2hpp, HbA1C), and zinc level in the serum were measured using colorimetric assays. Insulin and glucagon were measured by ELISA method. HOMA-IR, HOMA-B, reciprocal HOMA-B, and Quicki indices were calculated using appropriate formula. For further analysis, patients were divided into two groups: high (>135.5 μg/dl) and low (<135.5 μg/dl) zinc. Glucagon suppression was considered yes if 2hpp glucagon < fasting glucagon. Results: Our results showed that serum Zn level in type 2 DM patients was lower than control (P value=0.02). Patients with lower Zn had higher fasting insulin (P value=0.006) and higher β-cell activity index (HOMA-B, p value=0.02), however fasting glucagon and parameters of hyperglycemia (FBG, 2hpp, Hba1C) were not different. Moreover, insulin sensitivity and resistance indices (Quicki, HOMA-IR,1/HOMA-IR) showed non-significantly improved status in high Zn group. We found non-significant association between glucagon suppression and Zn level in both genders (N = 39, p value = 0.07), however, it was significant in males (N = 14, p value = 0.02). Conclusion: Altogether, our results indicated reduced serum Zn in type 2DM can exacerbate hyperinsulinemia and glucagon suppression (only significant in the male), highlighting its importance in type 2DM control. • Serum Zn level in type2 DM patients was lower than the control group (0.02). • Type 2 diabetes patient with lower zinc level have hyper-insulinemia. • Glucagon suppression response is significantly disturbed in male patients with lower zinc. [ABSTRACT FROM AUTHOR]

The pancreas is a mixed exocrine and endocrine gland which plays an essential role in our body's digestive system and nutrient metabolism. The exocrine pancreas secretes digestive enzymes for the breakdown of carbohydrates, proteins and lipids. The roles of these enzymes as biomarkers for cellular damage in pancreatitis are further discussed in this article. The endocrine function is involved in the regulation of appetite, glucose homeostasis and gastrointestinal secretions. We will explore the highly coordinated feedback mechanisms of the secretion of these pancreatic hormones and their effects on effector organs such as muscles and adipose tissues. [ABSTRACT FROM AUTHOR]

Blood glucose concentrations are required to be maintained within a narrow therapeutic range in order to ensure the normal functioning of the body. This is accomplished through a complex, interactive, finely coordinated neuro-endocrine regulatory process. Hormonal control through the opposing actions of insulin and glucagon secreted by the islet cells of the pancreas serve as the primary response mechanism to avert post-prandial hyperglycaemia and fasting hypoglycaemia. In addition to this basic response, a range of endocrine mediators concurrently intervene, to enable the fine modulation of the process through a range of insulin-dependent and insulin-independent processes, which ultimately achieve glycaemic control by influencing tissue glucose uptake, glycolysis, glycogenesis, glycogenolysis and gluconeogenesis. More recent evidence supports a central, predominantly hypothalamic role initiated through nutrient (glucose, fatty acid) and hormonal (insulin, leptin, glucagon-like peptide-1) stimuli that influences glucose regulation by direct or indirect effects on skeletal muscle glucose uptake, islet cell insulin/glucagon secretion and hepatic glucose production. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Melatonin regulates the mammalian circadian rhythm and plays metabolic functions such as glucose homeostasis. Both melatonin receptors (MTNR1A and MTNR1B, encoded by the MTNR1A and MTNR1B genes, respectively) are expressed in pancreatic beta cells and mediate the glucometabolic roles of melatonin as well as insulin secretion. The MTNR1B gene is a well-known genetic risk factor in type 2 diabetes (T2D); however, little is known about the involvement of the MTNR1A gene in here T2D. We aimed to investigate whether MTNR1A is linked to and/or associated with familial T2D. SUBJECTS AND METHODS: We genotyped 14 single nucleotide polymorphisms within the MTNR1A gene in 212 peninsular Italian families with T2D. We performed parametric linkage and linkage disequilibrium analyses to investigate the role of MTNR1A variants in conferring T2D risk. We considered variants statistically significant if conferring linkage or linkage disequilibrium with p < 0.05. RESULTS: We found 3 novel variants (rs62350392, rs2119883, and rs13147179) significantly linked to and/or associated with T2D in multigenerational Italian families. CONCLUSIONS: This is the first study to report MTNR1A as a novel risk gene in T2D. Functional studies are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Amino acids powerfully release glucagon but their contribution to postprandial hyperglucagonemia in type 2 diabetes remains unclear. Exogenously applied GIP stimulates, while GLP-1 inhibits, glucagon secretion in humans. However, their role in mixed meals is unclear, which we therefore characterized. In three experiments, participants with type 2 diabetes and obese controls randomly received different loads of sugars and/or proteins. In the first experiment, participants ingested the rapidly cleaved saccharose (SAC) or slowly cleaved isomaltulose (ISO) which is known to elicit opposite profiles of GIP and GLP-1 secretion. In the second one participants received test meals which contained saccharose or isomaltulose in combination with milk protein. The third set of participants underwent randomized oral protein tests with whey protein or casein. Incretins, glucagon, C-peptide, and insulin were profiled by specific immunological assays. 50 g of the sugars alone suppressed glucagon in controls but slightly less in type 2 diabetes patients. Participants with type 2 diabetes showed excessive glucagon responses within 15 min and lasting over 3 h, while the obese controls showed small initial and delayed greater glucagon responses to mixed meals. The release of GIP was significantly faster and greater with SAC compared to ISO, while GLP-1 showed an inverse pattern. The glucagon responses to whey or casein were only moderately increased in type 2 diabetes patients without a left shift of the dose response curve. The rapid hypersecretion of glucagon after mixed meals in type 2 diabetes patients compared to controls is unaffected by endogenous incretins. The defective suppression of glucagon by glucose combined with hypersecretion to protein is required for the exaggerated response. NCT03806920, NCT02219295, NCT04564391. [ABSTRACT FROM AUTHOR]

Glucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained under contexts that allow the defence of lean mass. We investigate the metabolic effects of the long-acting glucagon receptor agonist, G108, when administered to obese mice at low-doses, and with dietary protein supplementation. Dietary protein supplementation can only fully defend lean mass at a low dose of G108 that is sub-anorectic and does not reduce fat mass. However, in this context, G108 is still highly effective at improving glucose tolerance and reducing liver fat in obese mice. Mechanistically, liver RNA-Seq analysis reveals that dietary protein supplementation defends anabolic processes in low-dose G108-treated mice, and its effects on treatment-relevant glucose and lipid pathways are preserved. Glucagon-mediated energy expenditure and weight loss may be mechanistically coupled to hypoaminocidemia and lean mass loss. However, our data suggest that glucagon can treat MAFLD at doses which allow full defence of lean mass given sufficient dietary protein intake. Therefore, proportionate glucagon therapy may be safe and effective in targeting hepatocytes and improving in glycaemia and liver fat. Low dose glucagon agonism stimulates amino acid catabolism and lipid metabolism in liver. A high protein diet prevents the consequences of hypoaminoacidemia without affecting beneficial effects on MAFLD. [Display omitted] • Glucagon analogue, G108, improves metabolic parameters independent of weight loss. • Dietary protein supplementation fully defends lean mass at low doses of G108. • The metabolic benefits of G108 are not affected by dietary protein supplementation. • Liver RNA-seq analysis provides mechanistic insight in to G108-action. [ABSTRACT FROM AUTHOR]

The evolution of glucagon has seen the transition from an impurity in the preparation of insulin to the development of glucagon receptor agonists for use in type 1 diabetes. In type 2 diabetes, glucagon receptor antagonists have been explored to reduce glycemia thought to be induced by hyperglucagonemia. However, the catabolic actions of glucagon are currently being leveraged to target the rise in obesity that paralleled that of diabetes, bringing the pharmacology of glucagon full circle. During this evolution, the physiological importance of glucagon advanced beyond the control of hepatic glucose production, incorporating critical roles for glucagon to regulate both lipid and amino acid metabolism. Thus, it is unsurprising that the study of glucagon has left several paradoxes that make it difficult to distill this hormone down to a simplified action. Here, we describe the history of glucagon from the past to the present and suggest some direction to the future of this field. Glucagon has important endocrine functions in metabolism. However, the physiological and pharmacological properties of this hormone remain unclear and debated. Therapeutically, ongoing efforts include both agonism and antagonism this system, highlighting our incomplete understanding of glucagon's actions. Here, Capozzi et al. review the past, present, and future of glucagon biology. [ABSTRACT FROM AUTHOR]

Peptide dual agonists toward both glucagon-like peptide 1 receptor (GLP-1R) and glucagon receptor (GCGR) are emerging as novel therapeutics for the treatment of type 2 diabetes mellitus (T2DM) patients with obesity. Our previous work identified a Xenopus GLP-1-based dual GLP-1R/GCGR agonist termed xGLP/GCG-13, which showed decent hypoglycemic and body weight lowering activity. However, the clinical utility of xGLP/GCG-13 is limited due to its short in vivo half-life. Inspired by the fact that O -GlcNAcylation of intracellular proteins leads to increased stability of secreted proteins, we rationally designed a panel of O -GlcNAcylated xGLP/GCG-13 analogs as potential long-acting GLP-1R/ GCGR dual agonists. One of the synthesized glycopeptides 1f was found to be equipotent to xGLP/GCG-13 in cell-based receptor activation assays. As expected, O -GlcNAcylation effectively improved the stability of xGLP/GCG-13 in vivo. Importantly, chronic administration of 1f potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, and normalized lipid metabolism and adiposity in both db/db and diet induced obesity (DIO) mice models. These results supported the hypothesis that glycosylation is a useful strategy for improving the in vivo stability of GLP-1-based peptides and promoted the development of dual GLP-1R/GCGR agonists as antidiabetic/antiobesity drugs. [ABSTRACT FROM AUTHOR]

The glucagon stimulation test (GST) is used for the simultaneous assessment of central adrenal insufficiency (CAI) and growth hormone deficiency. The new Roche cortisol II (C II) assay was recently introduced, confounding interpretation of the GST. The performance of the GST in diagnosing central adrenal insufficiency (CAI), utilising the C II assay, was therefore compared with that of the overnight metyrapone test (ONMTPT). A diagnostic accuracy study was performed by retrospectively analysing folders and laboratory records of 25 children and adolescents investigated for hypopituitarism with the GST and the ONMTPT between September 2016 and December 2019. The peak serum cortisol (C) of the GST, the post-metyrapone serum 11-deoxycortisol and adrenocorticotropin levels of the ONMTPT were recorded. Diagnostic performance of the GST at a previously suggested cut-off of 374 nmol/L was evaluated. Seventeen boys and 8 girls, aged 1.7–16.3 years (median 7.3 years) were identified. The sensitivity of the post-GST C-level at 374 nmol/L was 0.40 (95% confidence interval [CI] 0.17–0.69), specificity 0.64 (95% CI 0.39–0.84), positive predictive value 0.44 (95% CI 0.19–0.73), negative predictive value 0.60 (95% CI 0.36–0.80), accuracy 0.54 (95% CI 0.35–0.72), positive likelihood ratio (+LR) 0.93 (95% CI 0.49–1.77) and negative LR 1.12 (95% CI 0.40–3.15). The area under the receiver of operating characteristics (ROC) curve was 0.379 (95% CI 0.142–0.615). This study suggests that the GST at any C II cut-off cannot replace the ONMTPT as a diagnostic test for CAI in children. Findings should be confirmed in a larger study. [ABSTRACT FROM AUTHOR]

Proglucagon-derived peptides (PGDPs) secreted by the gut and pancreas play a major role in metabolism. We measured concentrations of five PGDPs in response to per os (PO) or intravenous (IV) glucose or lipid intake and a mixed meal test (MMT) consumed by subjects with normal weight, overweight or obesity. GLP-1, oxyntomodulin and glicentin (gut-secreted PGDPs) and glucagon and MPGF (pancreas-secreted PGDPs) were assessed in: (a) 32 subjects receiving PO or IV glucose, lipids or water over 6 h, (b) 33 subjects with normal weight, overweight or obesity who consumed a MMT. (a) GLP-1, oxyntomodulin, glicentin and glucagon levels increase more profoundly and persistently after lipids PO (2.5 g/kg) than glucose PO (2.5 g/kg) or IV lipids (Intralipid/Liposyn II 20% at 0.35 ml/kg/h and Intralipid/Liposyn II 20% at 0.83 ml/kg/h for 6 h) or IV glucose (10% glucose at 3.6 ml/kg/h for 6 h). Oxyntomodulin and glicentin increased more than GLP-1 in response to lipids PO. MPGF levels decrease in response to glucose PO or IV indicating a shift towards preferential production of gut-secreted peptides. (b) Fasting and postprandial areas under the curve (AUCs) after MMT of GLP-1, MPGF and glucagon levels correlated positively with BMI. The fasting levels of glucagon and MPGF were elevated in obesity and remained elevated after the MMT. Circulating levels of PGDPs are differentially regulated by body weight, the type of macronutrients administered and the respective route of administration. Mechanistic studies are needed to define the exact mechanisms underlying this regulation. Study 1 has the NCT01520454 and the NCT04888325 number in ClinicalTrials.gov. Study 2 has the number NCT01495754 in ClinicalTrials.gov. [ABSTRACT FROM AUTHOR]