Excessive Glucagon Secretion Research Articles

Mechano-sensor Piezo1 inhibits glucagon production in pancreatic α-cells

ObjectiveGlucagon is a critical hormone regulating glucose metabolism. It stimulates the liver to release glucose under low blood sugar conditions, thereby maintaining blood glucose stability. Excessive glucagon secretion and hyperglycemia is observed in individuals with diabetes. Precise modulation of glucagon is significant to maintain glucose homeostasis. Piezo1 is a mechanosensitive ion channel capable of converting extracellular mechanical forces into intracellular signals, thus regulating hormonal synthesis and secretion. This study aims to investigate the role of Piezo1 in regulating glucagon production in α cells. MethodsThe effects of Piezo1 on glucagon production were examined in normal- or high-fat diet fed α cell-specific Piezo1 knockout mice (Gcg-Piezo1−/−), and the murine pancreatic α cell line αTC1–6. Expression of Proglucagon was investigated by real-time PCR and western blotting. Plasma glucagon and insulin were detected by enzyme immunoassay. ResultsUnder both normal- and high-fat diet conditions, Gcg-Piezo1−/− mice exhibited increased pancreatic α cell proportion, hyperglucagonemia, impaired glucose tolerance, and activated pancreatic mTORC1 signaling. Activation of Piezo1 by its agonist Yoda1 or overexpression of Piezo1 led to decreased glucagon synthesis and suppressed mTOR signaling pathway in αTC1–6 cells. Additionally, the levels of glucagon in the medium were also reduced. Conversely, knockdown of Piezo1 produced opposite effects. ConclusionOur study uncovers the regulatory role of the Piezo1 ion channel in α cells. Piezo1 influences glucagon production by affecting mTOR signaling pathway.

PH-temperature Responsive Hydrogel-Mediated Delivery of Exendin-4 Encapsulated Chitosan Nanospheres for Sustained Therapeutic Efficacy in Type 2 Diabetes Mellitus.

Type 2 Diabetes Mellitus (T2D) is a chronic, obesity-related, and inflammatory disorder characterize by insulin resistance, inadequate insulin secretion, hyperglycemia, and excessive glucagon secretion. Exendin-4 (EX), a clinically established antidiabetic medication that acts as a glucagon-like peptide-1 receptor agonist, is effective in lowering glucose levels and stimulating insulin secretion while significantly reducing hunger. However, the requirement for multiple daily injections due to EX's short half-life is a significant limitation in its clinical application, leading to high treatment costs and patient inconvenience. To address this issue, an injectable hydrogel system is developed that can provide sustained EX release at the injection site, reducing the need for daily injections. In this study, the electrospray technique is examine to form EX@CS nanospheres by electrostatic interaction between cationic chitosan (CS) and negatively charged EX. These nanospheres are uniformly dispersed in a pH-temperature responsive pentablock copolymer, which forms micelles and undergoes sol-to-gel transition at physiological conditions. Following injection, the hydrogel gradually degraded, exhibiting excellent biocompatibility. The EX@CS nanospheres are subsequently released, maintaining therapeutic levels for over 72h compared to free EX solution. The findings demonstrate that the pH-temperature responsive hydrogel system containing EX@CS nanospheres can be a promising platform for the treatment of T2D.

Diabetes and associated cardiovascular complications: The role of microRNAs

Diabetes mellitus (DM) refers to a complex cluster of metabolic disorders characterized by hyperglycemia caused by inadequate insulin secretion, insulin resistance, or excessive glucagon secretion. If not correctly treated, the prolonged effects of DM-associated metabolic perturbations lead to systemic vascular complications and cardiovascular disease (CVD), the principal cause of mortality among patients with DM. Given the increase in the global prevalence of diabetes, novel diagnostic and therapeutic procedures are necessary for its effective identification and treatment. Recent findings point to an important role of microRNA (miRNAs) in DM initiation and progression, as well as the occurrence of associated cardiovascular complications. miRNAs are short, highly conserved, single-stranded, non-coding RNAs that contribute to the maintenance of physiological homeostasis through the regulation of crucial processes such as metabolism, cell proliferation, and apoptosis. The increased availability of high-throughput methodologies for identifying and characterizing non-coding RNAs has led to considerable interest in miRNAs as potential biomarkers and therapeutic agents for DM. In this review, we first comprehensively detail the regulatory miRNAs involved in the pathophysiology of DM and diabetic cardiomyopathy (DCMP). Subsequently, we summarize findings regarding the utility of several of these miRNAs as potential prognostic and diagnostic biomarkers for DM and DM-associated CVD. Finally, we evaluate the potential of miRNA-based therapeutic approaches for treating DM and DCMP in the clinical setting.

Implication of sugar, protein and incretins in excessive glucagon secretion in type 2 diabetes after mixed meals

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. 50g 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 15min and lasting over 3h, 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.

Alpha-cells and therapy of diabetes: Inhibition, antagonism or death?

Absolute or relative hyperglucagonaemia is a characteristic of both Type 1 and Type 2 diabetes, resulting in fasting hyperglycaemia due in part to increased hepatic glucose production and lack of postprandial suppression of circulating glucagon concentrations. Consequently, therapeutics that target glucagon secretion or biological action may be effective antidiabetic agents. In this regard, specific glucagon receptor (GCGR) antagonists have been developed that exhibit impressive glucose-lowering actions, but unfortunately may cause off-target adverse effects in humans. Further to this, several currently approved antidiabetic agents, including GLP-1 mimetics, DPP-4 inhibitors, metformin, sulphonylureas and pramlintide likely exert part of their glucose homeostatic actions through direct or indirect inhibition of GCGR signalling. In addition to agents that inhibit the release of glucagon, compounds that enhance the transdifferentiation of glucagon secreting alpha-cells towards an insulin positive beta-cell phenotype could also help curb excess glucagon secretion in diabetes. Use of alpha-cell toxins represents another possible strategy to address hyperglucagonaemia in diabetes. In that respect, research from the 1920 s with diguanides such as synthalin A demonstrated effective glucose-lowering with alpha-cell ablation in both animal models and humans with diabetes. However, further clinical use of synthalin A was curtailed due its adverse effects and the increased availability of insulin. Overall, these observations with therapeutics that directly target alpha-cells, or GCGR signaling, highlight a largely untapped potential for diabetes therapy that merits further detailed consideration.

A Clinical Decision Support System for Diabetes Patients with Deep Learning: Experience of a Taiwan Medical Center.

Background: Diabetes mellitus (DM) is a major public health problem worldwide. It involves dysfunction of blood sugar regulation resulting from insulin resistance, inadequate insulin secretion, or excessive glucagon secretion.Methods: This study collated 971,401 drug usage records of 51,009 DM patients. These data include patient identification code, age, gender, outpatient visiting dates, visiting code, medication features (included items, doses, and frequencies of drugs), HbA1c results, and testing time. We apply a random forest (RF) model for feature selection and implement a regression model with the bidirectional long short-term memory (Bi-LSTM) deep learning architecture. Finally, we use the root mean square error (RMSE) as the evaluation index for the prediction model.Results: After data cleaning, the data included 8,729 male and 9,115 female cases. Metformin was the most important feature suggested by the RF model, followed by glimepiride, acarbose, pioglitazone, glibenclamide, gliclazide, repaglinide, nateglinide, sitagliptin, and vildagliptin. The model performed better with the past two seasons in the training data than with additional seasons. Further, the Bi-LSTM architecture model performed better than support vector machines (SVMs).Discussion & Conclusion: This study found that Bi-LSTM models is a well kernel in a CDSS which help physicians' decision-making, and the increasing the number of seasons will negative impact the performance. In addition, this study found that the most important drug is metformin, which is recommended as first-line treatment OHA in various situations for DM patients.

Pathways of Glucagon Secretion and Trafficking in the Pancreatic Alpha Cell: Novel Pathways, Proteins, and Targets for Hyperglucagonemia.

Patients with diabetes mellitus exhibit hyperglucagonemia, or excess glucagon secretion, which may be the underlying cause of the hyperglycemia of diabetes. Defective alpha cell secretory responses to glucose and paracrine effectors in both Type 1 and Type 2 diabetes may drive the development of hyperglucagonemia. Therefore, uncovering the mechanisms that regulate glucagon secretion from the pancreatic alpha cell is critical for developing improved treatments for diabetes. In this review, we focus on aspects of alpha cell biology for possible mechanisms for alpha cell dysfunction in diabetes: proglucagon processing, intrinsic and paracrine control of glucagon secretion, secretory granule dynamics, and alterations in intracellular trafficking. We explore possible clues gleaned from these studies in how inhibition of glucagon secretion can be targeted as a treatment for diabetes mellitus.

Glucagonoma: “A Diagnostic Challenge”

Abstract Introduction: Glucagonoma is a rare pancreatic α-islet cell tumor accounting for nearly 1% of all the neuroendocrine tumors (NET), with an incidence of 1 in 20 million people. We present here a patient with glucagonoma with uncontrolled diabetes mellitus (DM) for over ten years and necrolytic migratory erythema (NME) for two years. Clinical Case: A 50-year-old Caucasian male was referred to the endocrinology team for uncontrolled DM type 2. The DM was diagnosed over 10 years prior with initial HbA1c of 10.2% and remained uncontrolled with HbA1c >9%, despite compliance with lifestyle modifications and treatment with multiple agents including metformin, glipizide, empagliflozin, and pioglitazone. Given poor glycemic control, the treatment was escalated to glargine and lixisenatide. Over the years, the patient presented with unintentional weight loss of 105 pounds, fatigue, normocytic normochromic anemia, and diffuse erythematous rash with plaques and scaling on the trunk, flexor surfaces of lower and upper extremities, soles of hands and feet. Punch biopsy of the lesions revealed neutrophilic infiltration. He denied diarrhea, deep venous thrombosis, pulmonary embolism, psychiatric symptoms, or family history of neuroendocrine tumor (NET) or MEN 1 syndrome. A CT chest abdomen and pelvis revealed a 5 cm mass on the pancreatic tail along with liver metastasis. The biopsy confirmed a well-differentiated NET. Serum glucagon and chromogranin-A levels were elevated at 2967 pg/mL (N: 50-150 pg/mL) and 263.8 ng/mL (N: 0-101.8 ng/mL) respectively, consistent with pancreatic glucagonoma. Octreoscan revealed diffuse uptake in the liver, omentum, and spleen. He was started on Octreotide injections monthly, followed by distal pancreatectomy, splenectomy, hepatic wedge resection, and excision of the omental implant with the plan to treat the residual liver metastasis with radioembolization. Pathology analysis showed local invasion and metastasis to local lymph nodes with immunostaining positive for AE1/3, synaptophysin, chromogranin, and Ki67 index <2% consistent with Grade I well-differentiated NET. Post-surgery, serum glucagon and chromogranin-A levels dropped to 400 pg/mL and 68.8 ng/mL respectively. Insulin requirements markedly dropped with an improvement in glycemic control and resolution of the rash. Conclusions: Glucagonoma is an uncommon, slow-growing pancreatic neoplasm resulting in excessive glucagon secretion and it is characterized by diabetes mellitus, NME, chronic diarrhea, and deep vein thrombosis. Nearly 50% of glucagonomas are metastatic at the time of diagnosis. Patients without metastasis have a 10-year survival rate of almost 100%, compared with 51.6% of patients with metastasis, emphasizing the importance of early diagnosis and multidisciplinary treatment approach to achieve a better therapeutic outcome.

No association of SNP 313A→G in GSTP1 with nephropathy, hypertension and dyslipidemia in type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycaemia resulting from the combination of resistance to insulin action, excessive or inappropriate glucagon secretion, and inadequate insu...

CARDIOVASCULAR SAFETY OF GLIPTINS. FOCUS ON ALOGLIPTIN

Type 2 diabetes is a chronic progressive disease the prevalence of which is increasing. The development of new strategies for the treatment of diabetes, among which drugs that modulate the “incretin effect” are worth noting, continues. Dipeptidyl peptidase-4 inhibitors (DPP-4, gliptins) are a group of oral antidiabetic incretin drugs that enhance the glucose-induced activity of β-cells and suppress excessive glucagon secretion by pancreatic α-cells. This group of antidiabetic drugs is widespread due to a number of relevant benefits, such as neutral effect on body weight, low risk of hypoglycaemia, convenient administration scheme and good adherence to treatment. Efficacy and safety of treatment demonstrated by global multicenter trials allow for a wide use of gliptins in clinical practice.

Insulin, glucagon and somatostatin stores in the pancreas of subjects with type-2 diabetes and their lean and obese non-diabetic controls

In type-2 diabetes, both insufficient insulin and excessive glucagon secretion contribute to hyperglycemia. We compared insulin, glucagon and somatostatin stores in pancreas obtained at autopsy of 20 lean and 19 obese non-diabetic (ND), and 18 type-2 diabetic (T2D) subjects. From concentrations and pancreas weight, total content of hormones was calculated. Insulin content was 35% lower in T2D than ND subjects (7.4 versus 11.3 mg), whereas glucagon content was similar (0.76 versus 0.81 mg). The higher ratio of glucagon/insulin contents in T2D was thus explained by the decrease in insulin. With increasing BMI of ND subjects, insulin and glucagon contents respectively tended to increase and decrease, resulting in a lower glucagon/insulin ratio in obesity. With aging, insulin and glucagon contents did not significantly change in ND subjects but declined in T2D subjects, without association with the duration of diabetes or type of treatment. The somatostatin content was lower in T2D than ND subjects (0.027 versus 0.038 mg), but ratios somatostatin/insulin and somatostatin/glucagon were not different. In conclusion, insulin stores are about 1/3 lower in T2D than ND subjects, whereas glucagon stores are unchanged. Abnormal secretion of each hormone in type-2 diabetes cannot be attributed to major alterations in their pancreatic reserves.

Selection and characterization of DNA aptamer against glucagon receptor by cell-SELEX

Excessive secretion of glucagon, a functional insulin antagonist, significantly contributes to hyperglycemia. Glucagon exerts its physiological functions through activation of the glucagon receptor (GCGR). Inhibition of GCGR activity represents a potential therapeutic approach for reducing excess glucose production in diabetes mellitus. Aptamers are short DNA or RNA oligonucleotides evolved from systematic evolution of ligands by exponential enrichment (SELEX). Here, we have successfully selected a DNA aptamer against GCGR by cell-SELEX, which can specifically bind membrane protein of CHO-GCGR cells with a Kd of 52.7 ± 5.1 nM. Aptamer-mediated pull-down and gcgr knockdown assay verified that GCGR was the target of aptamer GR-3. Binding analysis revealed that GR-3 could recognize other cells with different affinity according to the level of GCGR protein expressed in these cells. Hepatic tissue imaging suggested that GR-3 could bind the cell membrane of hepatic tissues. With the advantages of small size, high binding affinity, good stability, lack of immunogenicity, and easy synthesis, aptamer GR-3 against GCGR can be a promising tool with the potential to attenuate hyperglycemia in diabetes mellitus.

P10 Effects of Sanseviera liberica methanolic root extract on liver glycogen and serum insulin in streptozotocin-induced diabetic albino rats

The present study was undertaken to examine the effects of Sanseviera liberica methanolic root extract on glycogen level and insulin level in streptozotocin-induced diabetic albino rats. The Sanseviera liberica methanolic root extract has been shown to have a hypoglycaemic effect. Diabetes mellitus is a group of physiological dysfunctions characterized by hyperglycaemia resulting directly from insulin resistance, inadequate insulin secretion, or excessive glucagon secretion. Liver is the major site for glycogen storage. Glycogen content can be significantly altered upon disruption of glucose homeostasis in metabolic syndromes, such as diabetes. Estimation of liver glycogen was carried out by taking liver samples from normal control, diabetic control and extract treated albino rats. Rats weighing 100–160 g were administered a 60 mg/kg body weight dose of streptozotocin intraperitoneally for the induction of diabetes, followed by the oral administration of 200 mg/kg body weight Sanseviera liberica methanolic root extract from day 3 to day 21, half an hour prior to feeding twice daily. The liver glycogen and serum insulin of the animals was then analysed. Results showed a significant ( P Sanseviera liberica methanolic extract. This study has established a possible mechanism of action of roots of Sanseviera liberica methanolic root extract (SME) group by reversing DM induced elevated liver glycogen to near normal levels, which may be due to its activating effect on glucokinase and glycogen synthetase.

Exploring the molecular mechanisms underlying α- and β-cell dysfunction in diabetes.

Pancreatic islet dysfunction, including impaired insulin secretion in β cells and dysregulated glucagon secretion in α cells, is the chief pathology of diabetes. In β cells, oxidative stress, evoked by chronic hyperglycemia, was found to induce dysfunction of a critical transcription factor, PDX1, caused by its nucleocytoplasmic translocation via interactions with the insulin and JNK signaling pathways and another transcription factor, FOXO1. The significance of α-cell insulin signaling in the physiological and pathological regulation of α-cell biology was demonstrated in α-cell-specific insulin receptor knockout mice, which exhibited dysregulated glucagon secretion. Moreover, a high-glucose load directly induced excessive glucagon secretion in a glucagon-secreting cell line and isolated islets, together with impairment of insulin signaling. These findings indicate that disordered insulin signaling is central to the pathophysiology of islet dysfunction in both α and β cells. On the other hand, certain beneficial effects of GLP-1 on dysfunctional α and β cells indicate that it has therapeutic potential for diabetes patients who exhibit insulin resistance in islets. These studies, involving basic medical research approaches, have-at least in part-clarified the molecular mechanisms underlying α- and β-cell dysfunction in diabetes, and offer important clues that should aid the development of future therapeutic approaches to the disease.

Exploiting Delta Cell Paracrine Interactions to Curb Glucagon Hypersecretion in Diabetes

Diabetes is first and foremost a disease of insulin impairment, but is often accompanied by aberrant glucagon secretion. Uncontrolled alpha cell activity leads to further complications such as diabetic hyperglycemia, and we currently lack good options to manage this aspect of the disease. Within healthy pancreatic islets, delta cells exert an inhibitory influence over the alpha and beta cells via somatostatin; thus, they are uniquely positioned as the principal source of local inhibitory control preventing hormone signaling from going awry. Recent studies from our lab and others have identified local signals (such as Urocortin3 from the beta cells) and external factors (such as ghrelin from the GI tract) that act to directly stimulate somatostatin secretion. These observations cast delta cells as central hubs that are essential to maintain homeostatic control of insulin and glucagon. The objective of this study is to test if the negative feedback from pancreatic delta cells can be targeted to restore control over excess glucagon release in diabetes.MethodsWe have combined transcriptomics, chemicogenetics, and functional imaging of alpha, beta and delta cells in intact islets to help showcase the role of the delta cell within the islet.ResultsOur results indicate that Urocortin3 transiently silences alpha cell activity by activating delta cell‐dependent negative feedback.ConclusionBy targeting the delta cells, we can take advantage of the local feedback mechanism and restore inhibition of alpha cells. Our findings suggest that the pancreatic delta cell is a viable target to normalize the excess glucagon secretion that is partially responsible for hyperglycemia in diabetes.Support or Funding InformationGlyn Noguchi is supported by a NIGMS‐funded Pharmacology Training Program (T32GM099608). The Huising Lab is funded by awards from the Juvenile Diabetes Research Foundation (JDRF) and a Hartwell Individual Biomedical Research Award.

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.

Diabetes Mellitus Review

Diabetes mellitus is a group of physiological dysfunctions characterized by hyperglycemia resulting directly from insulin resistance, inadequate insulin secretion, or excessive glucagon secretion. Type 1 diabetes (T1D) is an autoimmune disorder leading to the destruction of pancreatic beta-cells. Type 2 diabetes (T2D), which is much more common, is primarily a problem of progressively impaired glucose regulation due to a combination of dysfunctional pancreatic beta cells and insulin resistance. The purpose of this article is to review the basic science of type 2 diabetes and its complications, and to discuss the most recent treatment guidelines.

Somatostatin expression in the pancreatic cells of smoking and non-smoking chronic pancreatitis patients with or without diabetes.

The aim of the analysis is to determine the location and degree of the hormone immunoreactivity in tissues of patients with chronic pancreatitis and diabetes. The study was performed on 11 non-smoking and 12 smoking patients with chronic pancreatitis (CP) with/without diabetes. The hormone was located in the pancreatic tissues by means of the immunohistochemical method using somatostatin antibodies. The histopathological evaluation of the hormone expression intensity in tissue sections was carried out using the semi-quantitative method and was calculated by means of a digital image analysis. The hormone's strong immunohistochemical reaction and the modified D-cell location may be a result of the pancreatic tissue fibrosis process prevention in patients with CP. Changes in the intensity of SS immunoreactivity and the D-cell distribution in the pancreas of patients with CP and diabetes may possibly result from the additional hormone compensatory effect in the excessive glucagon secretion inhibition. Smoking patients with diabetes showed significantly higher hormone immunostaining in the pancreas compared to non-smoking patients without diabetes and healthy persons. The severity of histopathological changes in smoking CP patients indicates that the cigarette smoke components may further exacerbate the inflammatory reactions. Patients with CP were found to have a strong immunohistochemical reaction to SS and changes in the distribution of D cells when compared to healthy patients. The strongest immunohistochemical SS reaction has been identified in the pancreatic tissue from smoking patients with diabetes.

Mitochondria as a Target for Future Diabetes Treatments

Diabetes mellitus is rapidly becoming the world’s most dangerous serial killer. Type 1 diabetes (T1D) is a currently incurable autoimmune disease marked by progressive, and eventually exhaustive, destruction of the insulin-producing pancreatic beta cells. Type 2 diabetes (T2D) describes the combination of insulin resistance in peripheral tissue, insufficient insulin secretion from the pancreatic beta cells, and excessive glucagon secretion from the pancreatic alpha cells. T1D as well as severe cases of T2D are treated with insulin replacement, which can merely be considered as life support for the acute phases of the disease. Islet replacement of insulin-producing pancreatic beta cells represents a potential treatment method for both insulin-depleted diabetes (T1D) and insulin-resistant diabetes (T2D) and may shift diabetes management from life saving measures to a cure. One of the key challenges in islet transplants is the generation of reactive oxygen species (ROS) and the associated oxidative stress, which restricts graft longevity. A major leak of ROS takes place during oxidative phosphorylation at mitochondrial electron transport chain (ETC). Additionally, hyperglycemia-induced superoxide (O2•-) production has been linked to the development and progression of diabetic complications, both macrovascular and microvascular. Decreasing ROS in diabetic patients may prevent the incidence of long term diabetes complications. This review provides an overview of the role of mitochondria in diabetes, introducing them as a possible target for future treatment of diabetes.

Evidence That in Uncontrolled Diabetes, Hyperglucagonemia Is Required for Ketosis but Not for Increased Hepatic Glucose Production or Hyperglycemia.

Several lines of evidence implicate excess glucagon secretion in the elevated rates of hepatic glucose production (HGP), hyperglycemia, and ketosis characteristic of uncontrolled insulin-deficient diabetes (uDM), but whether hyperglucagonemia is required for hyperglycemia in this setting is unknown. To address this question, adult male Wistar rats received either streptozotocin (STZ) to induce uDM (STZ-DM) or vehicle and remained nondiabetic. Four days later, animals received daily subcutaneous injections of either the synthetic GLP-1 receptor agonist liraglutide in a dose-escalating regimen to reverse hyperglucagonemia or its vehicle for 10 days. As expected, plasma glucagon levels were elevated in STZ-DM rats, and although liraglutide treatment lowered glucagon levels to those of nondiabetic controls, it failed to attenuate diabetic hyperglycemia, elevated rates of glucose appearance (Ra), or increased hepatic gluconeogenic gene expression. In contrast, it markedly reduced levels of both plasma ketone bodies and hepatic expression of the rate-limiting enzyme involved in ketone body production. To independently confirm this finding, in a separate study, treatment of STZ-DM rats with a glucagon-neutralizing antibody was sufficient to potently lower plasma ketone bodies but failed to normalize elevated levels of either blood glucose or Ra. These data suggest that in rats with uDM, hyperglucagonemia is required for ketosis but not for increased HGP or hyperglycemia.