Regulation Of Glucagon Secretion Research Articles

Sympathetic Innervation of Human Alpha Cells

Autonomic input is critical for the regulation of glucagon secretion to maintain blood glucose levels. Glucagon secretion is abnormal in patients with type 1 diabetes (T1D) and we hypothesize this results from dysfunctional sympathetic innervation of alpha-cells and may be present in at-risk autoantibody positive (AAb+) individuals. To characterize alpha-cell sympathetic innervation, pancreas tail samples were used from age-matched organ donors in three groups: controls (n=6), AAb+ (4), and T1D (4). Fresh frozen 40μm sections or 1-2 cm optically cleared samples were stained with markers for neuroendocrine cells (GCG, INS), total (NCAM)/ sympathetic nerves (tyrosine hydroxylase (TH)), and vascular smooth muscle cells (SMA) followed by confocal and Lightsheet imaging. To determine whether sympathetic fibers were decreased in AAb+ and/or T1D donors, TH+ fiber numbers were counted within islets and the percentage (%) of TH+ fibers/NCAM+ fibers determined. The TH+ fibers/islet were not significantly different between controls (1.5 ± 0.36, n=6), AAb+ (1.2 ± 0.27 (4)), and T1D (1.8 ± 0.57 (4)) donors (p = 0.07, ANOVA) with similar results for TH+ %. TH+ fibers were observed at alpha-cells in all donors. TH+ nerve densities were also similar between islets and exocrine regions between groups. Microarray analysis of single islet transcriptomes obtained using laser microdissection (n=120 islets, 13 control, 12 T1D) showed decreased expression of VMAT2 in insulin+ islets from T1D donors compared to control islets (p=0.047) while insulin- islets in T1D donors had significantly reduced VMAT2 levels compared to control islets (p<0.0001). These data indicate a potential direct mechanism by which the sympathetic nervous system may regulate alpha-cell glucagon secretion with dysregulation of a vesicular monoamine transporter that accumulates monoamines in synaptic vesicles in islets without beta-cells in T1D donors. Sympathetic innervation of alpha-cells could play a direct role in exacerbation of dysregulated glucagon secretion in T1D. Disclosure E.A. Butterworth: None. L.H. Nasif: None. K. Nasif: None. K.N. Carty: None. C.E. Mathews: None. M.A. Atkinson: Other Relationship; Self; Patent Issued. I.C. Gerling: None. M. Campbell-Thompson: None.

δ-cells and β-cells are electrically coupled and regulate α-cell activity via somatostatin.

Key points We used a mouse expressing a light‐sensitive ion channel in β‐cells to understand how α‐cell activity is regulated by β‐cells.Light activation of β‐cells triggered a suppression of α‐cell activity via gap junction‐dependent activation of δ‐cells.Mathematical modelling of human islets suggests that 23% of the inhibitory effect of glucose on glucagon secretion is mediated by β‐cells via gap junction‐dependent activation of δ‐cells/somatostatin secretion. Glucagon, the body's principal hyperglycaemic hormone, is released from α‐cells of the pancreatic islet. Secretion of this hormone is dysregulated in type 2 diabetes mellitus but the mechanisms controlling secretion are not well understood. Regulation of glucagon secretion by factors secreted by neighbouring β‐ and δ‐cells (paracrine regulation) have been proposed to be important. In this study, we explored the importance of paracrine regulation by using an optogenetic strategy. Specific light‐induced activation of β‐cells in mouse islets expressing the light‐gated channelrhodopsin‐2 resulted in stimulation of electrical activity in δ‐cells but suppression of α‐cell activity. Activation of the δ‐cells was rapid and sensitive to the gap junction inhibitor carbenoxolone, whereas the effect on electrical activity in α‐cells was blocked by CYN 154806, an antagonist of the somatostatin‐2 receptor. These observations indicate that optogenetic activation of the β‐cells propagates to the δ‐cells via gap junctions, and the consequential stimulation of somatostatin secretion inhibits α‐cell electrical activity by a paracrine mechanism. To explore whether this pathway is important for regulating α‐cell activity and glucagon secretion in human islets, we constructed computational models of human islets. These models had detailed architectures based on human islets and consisted of a collection of >500 α‐, β‐ and δ‐cells. Simulations of these models revealed that this gap junctional/paracrine mechanism accounts for up to 23% of the suppression of glucagon secretion by high glucose.

CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells

Glucagon is the main counterregulatory hormone in the body. Still, the mechanism involved in the regulation of glucagon secretion from pancreatic alpha cells remains elusive. Dysregulated glucagon secretion is common in patients with Cystic Fibrosis (CF) that develop CF related diabetes (CFRD). CF is caused by a mutation in the Cl− channel Cystic fibrosis transmembrane conductance regulator (CFTR), but whether CFTR is present in human alpha cells and regulate glucagon secretion has not been investigated in detail. Here, both human and mouse alpha cells showed CFTR protein expression, whereas CFTR was absent in somatostatin secreting delta cells. CFTR-current activity induced by cAMP was measured in single alpha cells. Glucagon secretion at different glucose levels and in the presence of forskolin was increased by CFTR-inhibition in human islets, whereas depolarization-induced glucagon secretion was unaffected. CFTR is suggested to mainly regulate the membrane potential through an intrinsic alpha cell effect, as supported by a mathematical model of alpha cell electrophysiology. In conclusion, CFTR channels are present in alpha cells and act as important negative regulators of cAMP-enhanced glucagon secretion through effects on alpha cell membrane potential. Our data support that loss-of-function mutations in CFTR contributes to dysregulated glucagon secretion in CFRD.

Reestablishment of Glucose Inhibition of Glucagon Secretion in Small Pseudoislets.

Misregulated hormone secretion from the islet of Langerhans is central to the pathophysiology of diabetes. Although insulin plays a key role in glucose regulation, the importance of glucagon is increasingly acknowledged. However, the mechanisms that regulate glucagon secretion from α-cells are still unclear. We used pseudoislets reconstituted from dispersed islet cells to study α-cells with and without various indirect effects from other islet cells. Dispersed islet cells secrete aberrant levels of glucagon and insulin at basal and elevated glucose levels. When cultured, murine islet cells reassociate to form pseudoislets, which recover normal glucose-regulated hormone secretion, and human islet cells follow a similar pattern. We created small (∼40-µm) pseudoislets using all of the islet cells or only some of the cell types, which allowed us to characterize novel aspects of regulated hormone secretion. The recovery of regulated glucagon secretion from α-cells in small pseudoislets depends upon the combined action of paracrine factors, such as insulin and somatostatin, and juxtacrine signals between EphA4/7 on α-cells and ephrins on β-cells. Although these signals modulate different pathways, both appear to be required for proper inhibition of glucagon secretion in response to glucose. This improved understanding of the modulation of glucagon secretion can provide novel therapeutic routes for the treatment of some individuals with diabetes.

Protein kinase C-δ signaling regulates glucagon secretion from pancreatic islets.

Accumulating evidence supports the "glucagonocentric hypothesis", in which antecedent α-cell failure and inhibition of glucagon secretion are responsible for diabetes progression. Protein kinase C (PKC) is involved in glucagon secretion from α-cells, although which PKC isozyme is involved and the mechanism underlying this PKC-regulated glucagon secretion remains unknown. Here, the involvement of PKCδ in the onset and progression of diabetes was elucidated. Immunofluorescence studies revealed that PKCδ was expressed and activated in α-cells of STZ-induced diabetic model mice. Phorbol 12-myristate 13-acetate (PMA) stimulation significantly augmented glucagon secretion from isolated islets. Pre-treatment with quercetin and rottlerin, PKCδ signaling inhibitors, significantly suppressed the PMA-induced elevation of glucagon secretion. While Go6976, a Ca2+-dependent PKC selective inhibitor did not suppress glucagon secretion. Quercetin suppressed PMA-induced phosphorylation of Tyr311 of PKCδ in isolated islets. However, quercetin itself had no effect on either glucagon secretion or glucagon mRNA expression. Our data suggest that PKCδ signaling inhibitors suppressed glucagon secretion. Elucidation of detailed signaling pathways causing PKCδ activation in the onset and progression of diabetes followed by the augmentation of glucagon secretion could lead to the identification of novel therapeutic target molecules and the development of novel therapeutic drugs for diabetes. J. Med. Invest. 64: 122-128, February, 2017.

Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells

In the pancreatic islet, serotonin is an autocrine signal increasing beta cell mass during metabolic challenges such as those associated with pregnancy or high-fat diet. It is still unclear whether serotonin is relevant for regular islet physiology and hormone secretion. Here, we show that human beta cells produce and secrete serotonin when stimulated with increases in glucose concentration. Serotonin secretion from beta cells decreases cyclic AMP (cAMP) levels in neighboring alpha cells via 5-HT1F receptors and inhibits glucagon secretion. Without serotonergic input, alpha cells lose their ability to regulate glucagon secretion in response to changes in glucose concentration, suggesting that diminished serotonergic control of alpha cells can cause glucose blindness and the uncontrolled glucagon secretion associated with diabetes. Supporting this model, pharmacological activation of 5-HT1F receptors reduces glucagon secretion and has hypoglycemic effects in diabetic mice. Thus, modulation of serotonin signaling in the islet represents a drug intervention opportunity.

A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion

SummaryThe counterregulatory response to hypoglycemia, which restores normal blood glucose levels to ensure sufficient provision of glucose to the brain, is critical for survival. To discover underlying brain regulatory systems, we performed a genetic screen in recombinant inbred mice for quantitative trait loci (QTL) controlling glucagon secretion in response to neuroglucopenia. We identified a QTL on the distal part of chromosome 7 and combined this genetic information with transcriptomic analysis of hypothalami. This revealed Fgf15 as the strongest candidate to control the glucagon response. Fgf15 was expressed by neurons of the dorsomedial hypothalamus and the perifornical area. Intracerebroventricular injection of FGF19, the human ortholog of Fgf15, reduced activation by neuroglucopenia of dorsal vagal complex neurons, of the parasympathetic nerve, and lowered glucagon secretion. In contrast, silencing Fgf15 in the dorsomedial hypothalamus increased neuroglucopenia-induced glucagon secretion. These data identify hypothalamic Fgf15 as a regulator of glucagon secretion.

Dapagliflozin stimulates glucagon secretion at high glucose: experiments and mathematical simulations of human A-cells.

Glucagon is one of the main regulators of blood glucose levels and dysfunctional stimulus secretion coupling in pancreatic A-cells is believed to be an important factor during development of diabetes. However, regulation of glucagon secretion is poorly understood. Recently it has been shown that Na+/glucose co-transporter (SGLT) inhibitors used for the treatment of diabetes increase glucagon levels in man. Here, we show experimentally that the SGLT2 inhibitor dapagliflozin increases glucagon secretion at high glucose levels both in human and mouse islets, but has little effect at low glucose concentrations. Because glucagon secretion is regulated by electrical activity we developed a mathematical model of A-cell electrical activity based on published data from human A-cells. With operating SGLT2, simulated glucose application leads to cell depolarization and inactivation of the voltage-gated ion channels carrying the action potential, and hence to reduce action potential height. According to our model, inhibition of SGLT2 reduces glucose-induced depolarization via electrical mechanisms. We suggest that blocking SGLTs partly relieves glucose suppression of glucagon secretion by allowing full-scale action potentials to develop. Based on our simulations we propose that SGLT2 is a glucose sensor and actively contributes to regulation of glucagon levels in humans which has clinical implications.

Diabetes and obesity treatment based on dual incretin receptor activation: 'twincretins'.

The gut incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion and regulate glucagon secretion. GLP-1 also slows gastric emptying and suppresses appetite, whereas GIP seems to affect lipid metabolism. The introduction of selective GLP-1 receptor (GLP-1R) agonists for the treatment of type 2 diabetes and obesity has increased the scientific and clinical interest in incretins. Combining the body weight-lowering and glucose-lowering effects of GLP-1 with a more potent improvement of β cell function through additional GIP action could potentially offer a more effective treatment of diabetes and obesity, with fewer adverse effects than selective GLP-1R agonists; therefore, new drugs designed to co-activate both the GIP receptor (GIPR) and the GLP-1R simultaneously are under development. In the present review, we address advances in the field of GIPR and GLP-1R co-agonism and review in vitro studies, animal studies and human trials involving co-administration of the two incretins, as well as results from a recently developed GIPR/GLP-1R co-agonist, and highlight promising areas and challenges within the field of incretin dual agonists.

Effect of Cell Adhesion Molecule 1 Expression on Intracellular Granule Movement in Pancreatic α Cells.

Although glucagon secreted from pancreatic α cells plays a role in increasing glucose concentrations in serum, the mechanism regulating glucagon secretion from α cells remains unclear. Cell adhesion molecule 1 (CADM1), identified as an adhesion molecule in α cells, has been reported not only to communicate among α cells and between nerve fibers, but also to prevent excessive glucagon secretion from α cells. Here, we investigated the effect of CADM1 expression on the movement of intracellular secretory granules in α cells because the granule transport is an important step in secretion. Spinning disk microscopic analysis showed that granules moved at a mean velocity of 0.236±0.010μm/s in the mouse α cell line αTC6 that expressed CADM1 endogenously. The mean velocity was significantly decreased in CADM1-knockdown (KD) cells (mean velocity: 0.190±0.016μm/s). The velocity of granule movement decreased greatly in αTC6 cells treated with the microtubule-depolymerizing reagent nocodazole, but not in αTC6 cells treated with the actin-depolymerizing reagent cytochalasin D. No difference in the mean velocity was observed between αTC6 and CADM1-KD cells treated with nocodazole. These results suggest that intracellular granules in pancreatic α cells move along the microtubule network, and that CADM1 influences their velocity.

Paracrine regulation of glucagon secretion: the β/α/δ model.

The regulation of glucagon secretion in the pancreatic α-cell is not well understood. It has been proposed that glucose suppresses glucagon secretion either directly through an intrinsic mechanism within the α-cell or indirectly through an extrinsic mechanism. Previously, we described a mathematical model for isolated pancreatic α-cells and used it to investigate possible intrinsic mechanisms of regulating glucagon secretion. We demonstrated that glucose can suppress glucagon secretion through both ATP-dependent potassium channels (KATP) and a store-operated current (SOC). We have now developed an islet model that combines previously published mathematical models of α- and β-cells with a new model of δ-cells and use it to explore the effects of insulin and somatostatin on glucagon secretion. We show that the model can reproduce experimental observations that the inhibitory effect of glucose remains even when paracrine modulators are no longer acting on the α-cell. We demonstrate how paracrine interactions can either synchronize α- and δ-cells to produce pulsatile oscillations in glucagon and somatostatin secretion or fail to do so. The model can also account for the paradoxical observation that glucagon can be out of phase with insulin, whereas α-cell calcium is in phase with insulin. We conclude that both paracrine interactions and the α-cell's intrinsic mechanisms are needed to explain the response of glucagon secretion to glucose.

Glucagon secretion is increased in patients with Type 2 diabetic nephropathy

AimsCurrently little is known about the relationship between renal function, albuminuria and glucagon; we analyzed the secretion of glucagon (GLA) and C-peptide in Type 2 diabetic patients with different degrees of nephropathy. Methods357 patients with Type 2 diabetes including 119 cases without nephropathy and 238 cases with nephropathy were divided into four groups according to the stages of diabetic nephropathy. Patients with diabetic nephropathy were further classified according to the level of estimated glomerular filtration rate (eGFR). OGTT and insulin, C-peptide, glucagon releasing tests were performed in all patients. Characteristics of glucagon and C-peptide secretion in different groups were compared. Glucagon/glucose ratio (GLA/GLU) and glucagon/insulin ratio (GLA/INS) were used to represent the inhibition of glucose or insulin on glucagon secretion, respectively. ResultsWith the progress of diabetic nephropathy, glucagon level increased significantly; the glucagon peak after glucose load delayed from 60min to 120min, whereas C-peptide level decreased significantly. Related factors analysis suggested that glucagon was independently correlated with eGFR. Further analysis showed that glucagon level was higher in group with eGFR<60ml/min compared with that in group with eGFR≥60ml/min. In addition, both GLA/INS and GLA/GLU were higher in group with eGFR<60ml/min compared with those in group with eGFR≥60ml/min. ConclusionsPatients with Type 2 diabetic nephropathy have worsened islet alpha and beta cell function. Therefore medications based on the regulation of glucagon secretion may improve glycemic control and also be beneficial for delaying the progress of diabetic nephropathy.

EphA4 Receptor Forward Signaling Inhibits Glucagon Secretion From α-Cells.

The loss of inhibition of glucagon secretion exacerbates hyperglycemia in type 1 and 2 diabetes. However, the molecular mechanisms that regulate glucagon secretion in unaffected and diabetic states remain relatively unexplained. We present evidence supporting a new model of juxtacrine-mediated regulation of glucagon secretion where neighboring islet cells negatively regulate glucagon secretion through tonic stimulation of α-cell EphA receptors. Primarily through EphA4 receptors, this stimulation correlates with maintenance of a dense F-actin network. In islets, additional stimulation and inhibition of endogenous EphA forward signaling result in inhibition and enhancement, respectively, of glucagon secretion, accompanied by an increase and decrease, respectively, in α-cell F-actin density. Sorted α-cells lack endogenous stimulation of EphA forward signaling from neighboring cells, resulting in enhanced basal glucagon secretion as compared with islets and the elimination of glucose inhibition of glucagon secretion. Restoration of EphA forward signaling in sorted α-cells recapitulates both normal basal glucagon secretion and glucose inhibition of glucagon secretion. Additionally, α-cell–specific EphA4−/− mice exhibit abnormal glucagon dynamics, and EphA4−/− α-cells contain less dense F-actin networks than EphA4+/+ α-cells. This juxtacrine-mediated model provides insight into the functional and dysfunctional regulation of glucagon secretion and opens up new therapeutic strategies for the clinical management of diabetes.

Olfactory receptor Olfr544 responding to azelaic acid regulates glucagon secretion in α-cells of mouse pancreatic islets

Olfactory receptors (ORs) are extensively expressed in olfactory as well as non-olfactory tissues. Although many OR transcripts are expressed in non-olfactory tissues, only a few studies demonstrate the functional role of ORs. Here, we verified that mouse pancreatic α-cells express potential OR-mediated downstream effectors. Moreover, high levels of mRNA for the olfactory receptors Olfr543, Olfr544, Olfr545, and Olfr1349 were expressed in α-cells as assessed using RNA-sequencing, microarray, and quantitative real-time RT-PCR analyses. Treatment with dicarboxylic acids (azelaic acid and sebacic acid) increased intracellular Ca2+ mobilization in pancreatic α-cells. The azelaic acid-induced Ca2+ response as well as glucagon secretion was concentration- and time-dependent manner. Olfr544 was expressed in α-cells, and the EC50 value of azelaic acid to Olfr544 was 19.97 μM, whereas Olfr545 did not respond to azelaic acid. Our findings demonstrate that Olfr544 responds to azelaic acid to regulate glucagon secretion through Ca2+ mobilization in α-cells of the mouse pancreatic islets, suggesting that Olfr544 may be an important therapeutic target for metabolic diseases.

Glucagon and type 2 diabetes: the return of the alpha cell.

In normal physiology, glucagon from pancreatic alpha cells plays an important role in maintaining glucose homeostasis via its regulatory effect on hepatic glucose production. Patients with type 2 diabetes suffer from fasting and postprandial hyperglucagonemia, which stimulate hepatic glucose production and, thus, contribute to the hyperglycemia characterizing these patients. Although this has been known for years, research focusing on alpha cell (patho)physiology has historically been dwarfed by research on beta cells and insulin. Today the mechanisms behind type 2 diabetic hyperglucagonemia are still poorly understood. Preclinical and clinical studies have shown that the gastrointestinal hormone glucose-dependent insulinotropic polypeptide (GIP) might play an important role in this pathophysiological phenomenon. Furthermore, it has become apparent that suppression of glucagon secretion or antagonization of the glucagon receptor constitutes potentially effective treatment strategies for patients with type 2 diabetes. In this review, we focus on the regulation of glucagon secretion by the incretin hormones glucagon-like peptide-1 (GLP-1) and GIP. Furthermore, potential advantages and limitations of suppressing glucagon secretion or antagonizing the glucagon receptor, respectively, in the treatment of patients with type 2 diabetes will be discussed.

Neural regulation of pancreatic islet cell mass and function.

Intracellular glucose signalling pathways control the secretion of glucagon and insulin by pancreatic islet α- and β-cells, respectively. However, glucose also indirectly controls the secretion of these hormones through regulation of the autonomic nervous system that richly innervates this endocrine organ. Both parasympathetic and sympathetic nervous systems also impact endocrine pancreas postnatal development and plasticity in adult animals. Defects in these autonomic regulations impair β-cell mass expansion during the weaning period and β-cell mass adaptation in adult life. Both branches of the autonomic nervous system also regulate glucagon secretion. In type 2 diabetes, impaired glucose-dependent autonomic activity causes the loss of cephalic and first phases of insulin secretion, and impaired suppression of glucagon secretion in the postabsorptive phase; in diabetic patients treated with insulin, it causes a progressive failure of hypoglycaemia to trigger the secretion of glucagon and other counterregulatory hormones. Therefore, identification of the glucose-sensing cells that control the autonomic innervation of the endocrine pancreatic and insulin and glucagon secretion is an important goal of research. This is required for a better understanding of the physiological control of glucose homeostasis and its deregulation in diabetes. This review will discuss recent advances in this field of investigation.

PTEN deletion in pancreatic α-cells protects against high-fat diet-induced hyperglucagonemia and insulin resistance.

An aberrant increase in circulating catabolic hormone glucagon contributes to type 2 diabetes pathogenesis. However, mechanisms regulating glucagon secretion and α-cell mass are not well understood. In this study, we aimed to demonstrate that phosphatidylinositol 3-kinase (PI3K) signaling is an important regulator of α-cell function. Mice with deletion of PTEN, a negative regulator of this pathway, in α-cells show reduced circulating glucagon levels and attenuated l-arginine-stimulated glucagon secretion both in vivo and in vitro. This hypoglucagonemic state is maintained after high-fat-diet feeding, leading to reduced expression of hepatic glycogenolytic and gluconeogenic genes. These beneficial effects protected high-fat diet-fed mice against hyperglycemia and insulin resistance. The data demonstrate an inhibitory role of PI3K signaling on α-cell function and provide experimental evidence for enhancing α-cell PI3K signaling for diabetes treatment.

Regulation of glucagon secretion by incretin-like hormone family in the patients at risk of developing type 2 diabetes mellitus

The study included 127 patients with type 2 diabetes (T2D) risk factors, who underwent oral glucose tolerance test (75 g glucose) with pancreatic and incretin hormones estimated in fasting state, at 30 and 120 minutes after glucose load. According to the test results the population was divided into 3 groups: group with normal glucose tolerance (NGT), group with high risk of diabetes developing (impaired glucose tolerance (IGT) and impaired fasting glycemia (IFG)) and newly-diagnosed T2D. The stimulated glucagon secretion was suppressed in NGT group, whereas in T2D patients there was an increase in glucagon levels at 30 min after the glucose load. Within high risk group the area under curve (AUC) of glucagon secretion was significantly elevated in IFG patients comparing to IGT (0,52 vs 0,07 ng·ml-1·min-1, р=0,0005). AUC of glucagon secretion was positively related only to fasting glucagon-like peptide 2 (GLP-2) level (r=0,61, р=0,0001), that suggests glucagonotropic properties for GLP-2. We conclude that glucagon stimulation by GLP-2 may play a role in decreased glucagon suppression in T2D patients and IFG state development.

Modeling the Pancreatic α-Cell: Dual Mechanisms of Glucose Suppression of Glucagon Secretion

The mechanism by which glucose induces insulin secretion in β-cells is fairly well understood. Despite years of research, however, the mechanism of glucagon secretion in α-cells is still not well established. It has been proposed that glucose regulates glucagon secretion by decreasing the conductance of either outward ATP-dependent potassium channels (K(ATP)) or an inward store-operated current (SOC). We have developed a mathematical model based on mouse data to test these hypotheses and found that both mechanisms are possible. Glucose metabolism closes K(ATP) channels, which depolarizes the cell but paradoxically reduces calcium influx by inactivating voltage-dependent calcium and sodium channels and decreases secretion. Glucose metabolism also activates SERCA pumps, which fills the endoplasmic reticulum and hyperpolarizes the cells by reducing the inward current through SOC channels and again suppresses glucagon secretion. We find further that the two mechanisms can combine to account for the nonmonotonic dependence of secretion on glucose observed in some studies, an effect that cannot be obtained with either mechanism alone.

Increasing glucagon secretion could antagonize the action of exogenous insulin for glycemic control in streptozocin-induced diabetic rhesus monkeys

Although intraislet insulin signaling is known to play a critical role in regulating glucagon secretion, it is unknown whether abnormal glucagon secretion influences the hypoglycemic effect of exogenous insulin with intraislet insulin deletion. We performed a longitudinal study using 16 streptozocin (STZ)-induced diabetic rhesus monkeys to explore α-cell function under the absence β-cells and to assess whether increasing glucagon secretion antagonizes the action of exogenous insulin for glycemic control. We found that although the α-cells were impaired and the basal secretion levels of glucagon decreased rapidly after STZ (80-90 mg/kg) administration, as based on long-term observation post-STZ injection, glucagon secretion and the number of α-cells were increased. Glycemic control was increasingly difficult, the insulin resistance (HOMA-IR) index was significantly higher, and the triglycerides (TG) levels were gradually decreased. Moreover, a significant correlation between the levels of glucagon and HOMA-IR was found. Under the long-term absence of β-cells, the inhibitory effect on α-cell activity is profoundly attenuated, leading to an increase in glucagon secretion and the amount of α-cells and even α-cell dysfunction. Increased glucagon levels have a serious impact on the insulin sensitivity in vivo and result in an antagonization of the hypoglycemic effect of exogenous insulin.