Alpha Cell Dysfunction Research Articles

Effect of Frey's procedure on islet cell function in patients with chronic calcific pancreatitis

BackgroundFrey's procedure involves both drainage and resection of the pancreas in subjects with chronic calcific pancreatitis (CCP). The procedure may affect the pancreatic endocrine function after surgery. The present study was to evaluate the effect of Frey's procedure on both beta and alpha cell function in CCP patients. MethodsThirty CCP patients who underwent Frey's procedure were included. According to the glycemic status, patients were divided into the diabetes mellitus (DM), prediabetes, and normal glucose tolerance (NGT) groups. Islet cell function was assessed before and 3 months after surgery. ResultsAt baseline, there was a significant difference in beta cell function among the three groups [NGT group 1.71 (1.64–2.07) vs prediabetes group1.50 (0.83–1.61) vs DM group 0.33 (0.12–0.55), P < 0.0001], but the insulin resistance was not different among them. Post glucose hyperglucagonemia representing alpha-cell dysfunction during oral glucose tolerance test was present in all of them, but showed no significant difference [NGT group 0.15 (0.06–0.31) vs prediabetes group 0.32 (0.05–0.70) vs DM group 0.07 (0.02–0.18), P = 0.20]. Frey's procedure did not change beta cell function and insulin resistance. However, alpha-cell dysfunction deteriorated after surgery [0.10 (0.03–0.27) vs 0.33 (0.09–0.68), P = 0.004]. ConclusionsAlthough Frey's procedure does not affect the beta cell function and insulin resistance in CCP patients, the alpha-cell dysfunction deteriorates after surgery.

The GLP-1 response to glucose does not mediate beta and alpha cell dysfunction in Hispanics with abnormal glucose metabolism

AimsGlucagon-like peptide-1 (GLP-1) contributes to insulin secretion after meals. Though Hispanics have increased risk for type 2 diabetes mellitus, it is unknown if impaired GLP-1 secretion contributes to this risk. We therefore studied plasma GLP-1 secretion and action in Hispanic adults. MethodsHispanic (H; n = 31) and non-Hispanic (nH; n = 15) participants underwent an oral glucose tolerance test (OGTT). All participants were categorized by glucose tolerance into four groups: normal glucose tolerant non-Hispanic (NGT-nH; n = 15), normal glucose tolerant Hispanic (NGT-H; n = 12), impaired glucose tolerant Hispanic (IGT-H; n = 11), or newly diagnosed type 2 diabetes mellitus, Hispanic (T2D-H; n = 8). ResultsGlucose-induced increments in plasma GLP-1 (Δ-GLP-1) were not different in NGT-H and NGT-nH (p = .38), nor amongst Hispanic subgroups with varying degrees of glucose homeostasis (p = .6). In contrast, the insulinogenic index in T2D-H group was lower than the other groups (p = .016). Subjects with abnormal glucose homeostasis (AGH), i.e., T2D-H plus IGT-H, had a diminished glucagon suppression index compared to patients with normal glucose homeostasis (NGT-H plus NGT-nH) (p = .035). ConclusionsGLP-1 responses to glucose were similar in Hispanic and Non-Hispanic NGT. Despite similar glucose-induced Δ-GLP-1, insulin and glucagon responses were abnormal in T2D-H and AGH, respectively. Thus, impaired GLP-1 secretion is unlikely to play a role in islet dysfunction in T2D. Although GLP-1 therapeutics enhance insulin secretion and glucagon suppression, it is likely due to pharmacological amplification of the GLP-1 pathways rather than treatment of hormonal deficiency.

Pancreatic Alpha-Cell Dysfunction Contributes to the Disruption of Glucose Homeostasis and Compensatory Insulin Hypersecretion in Glucocorticoid-Treated Rats

Glucocorticoid (GC)-based therapies can cause insulin resistance (IR), glucose intolerance, hyperglycemia and, occasionally, overt diabetes. Understanding the mechanisms behind these metabolic disorders could improve the management of glucose homeostasis in patients undergoing GC treatment. For this purpose, adult rats were treated with a daily injection of dexamethasone (1 mg/kg b.w., i.p.) (DEX) or saline as a control for 5 consecutive days. The DEX rats developed IR, augmented glycemia, hyperinsulinemia and hyperglucagonemia. Treatment of the DEX rats with a glucagon receptor antagonist normalized their blood glucose level. The characteristic inhibitory effect of glucose on glucagon secretion was impaired in the islets of the DEX rats, while no direct effects were found on α-cells in islets that were incubated with DEX in vitro. A higher proportion of docked secretory granules was found in the DEX α-cells as well as a trend towards increased α-cell mass. Additionally, insulin secretion in the presence of glucagon was augmented in the islets of the DEX rats, which was most likely due to their higher glucagon receptor content. We also found that the enzyme 11βHSD-1, which participates in GC metabolism, contributed to the insulin hypersecretion in the DEX rats under basal glucose conditions. Altogether, we showed that GC treatment induces hyperglucagonemia, which contributes to an imbalance in glucose homeostasis and compensatory β-cell hypersecretion. This hyperglucagonemia may result from altered α-cell function and, likely, α-cell mass. Additionally, blockage of the glucagon receptor seems to be effective in preventing the elevation in blood glucose levels induced by GC administration.

Early insulin therapy prevents beta cell loss in a mouse model for permanent neonatal diabetes (Munich Ins2 C95S)

Heterozygous male Munich Ins2(C95S) mutant mice, a model for permanent neonatal diabetes mellitus, demonstrate a progressive diabetic phenotype with severe loss of functional beta cell mass. The aim of this study was to investigate the influence of early insulin treatment on glucose homeostasis and beta cell destruction in male Munich Ins2(C95S) mutants. One group of male Ins2(C95S) mutants was treated with subcutaneous insulin pellets, as soon as blood glucose levels began to rise; placebo-treated mutants and wild-type mice served as controls. An additional group of mutant mice received a sodium-dependent glucose transporter 2 (SGLT2) inhibitor (AVE2268) via rodent chow. Insulin treatment normalised blood glucose concentrations, improved oral glucose tolerance, preserved insulin sensitivity and inhibited oxidative stress of Munich Ins2(C95S) mutant mice. Pancreatic C-peptide content, as well as total beta cell and isolated beta cell volumes, of insulin-treated mutant mice were higher than those of placebo-treated mutants. In addition, alpha cell dysfunction and hyperplasia of non-beta cells were completely normalised in insulin-treated mutant mice. Treatment with the SGLT2 inhibitor lowered blood glucose, improved glucose tolerance and normalised insulin sensitivity as well as oxidative stress of Ins2(C95S) mutants. The abundance of the endoplasmic reticulum (ER) stress markers binding Ig protein (BiP) and phosphorylated eukaryotic translation initiation factor 2 alpha (P-eIF2α) was significantly increased in the islets of mutants, before onset of hyperglycaemia, vs wild-type mice. We conclude that early insulin treatment protects Munich Ins2(C95S) mutant mice from insulin resistance, alpha cell hyperfunction, beta cell loss and hyperplasia of non-beta cells, some well-known features of human diabetes mellitus. Therefore, insulin treatment may be considered early for human patients harbouring INS mutations.

Multidisciplinary Interventions

More than 20 million people in the United States, or 7% of the population, have diabetes, with health care and work-related costs estimated to be $174 billion in 2007. Obesity constitutes one of the major driving factors behind this epidemic. Most drugs currently used to treat diabetes address the primary metabolic defects in type 2 diabetes mellitus, which are insulin resistance and pancreatic islet dysfunction. Incretin augmentation therapies, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase IV inhibitors, restore glucose homeostasis by addressing some of the unmet needs in diabetes therapies related to alpha-cell dysfunction and chronic beta-cell dysfunction. This new group of drugs offers certain advantages because its use is characterized by a low incidence of hypoglycemia and the absence of weight gain. Moreover, the use of fixed-dose combinations of dipeptidyl peptidase IV inhibitors with other oral antidiabetic agents seems very attractive to patients because of their reduced pill intake and minimized financial burden, which may improve adherence. An efficient strategy to slow down the epidemic of diabetes must include these emerging therapies and regimens, coupled with intensive patient education that includes information on treatment benefits and adverse effects, medication costs, and medication regimen complexity.

Multidisciplinary Interventions: Mapping New Horizons in Diabetes Care

More than 20 million people in the United States, or 7% of the population, have diabetes, with health care and work-related costs estimated to be $174 billion in 2007. Obesity constitutes one of the major driving factors behind this epidemic. Most drugs currently used to treat diabetes address the primary metabolic defects in type 2 diabetes mellitus, which are insulin resistance and pancreatic islet dysfunction. Incretin augmentation therapies, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase IV inhibitors, restore glucose homeostasis by addressing some of the unmet needs in diabetes therapies related to alpha-cell dysfunction and chronic beta-cell dysfunction. This new group of drugs offers certain advantages because its use is characterized by a low incidence of hypoglycemia and the absence of weight gain. Moreover, the use of fixed-dose combinations of dipeptidyl peptidase IV inhibitors with other oral antidiabetic agents seems very attractive to patients because of their reduced pill intake and minimized financial burden, which may improve adherence. An efficient strategy to slow down the epidemic of diabetes must include these emerging therapies and regimens, coupled with intensive patient education that includes information on treatment benefits and adverse effects, medication costs, and medication regimen complexity.

Beta- and Alpha-Cell Dysfunction in Type 2 Diabetes

Insulin resistance is a common pathogenetic feature of type 2 diabetes. However, hyperglycemia would not develop if a concomitant defect in insulin secretion were not present. Impaired insulin secretion results from functional and survival defects of the beta-cell. The functional defects can be demonstrated early in the natural history of diabetes and they are hallmarked by abnormal pulsatility of basal insulin secretion and loss of first-phase insulin release in response to a glucose challenge. Moreover, a significant reduction of the beta-cell mass is apparent at the time of the diagnosis of diabetes. The progressive increase in glucose levels, that seems to characterize the natural history of type 2 diabetes, has been claimed to be largely due to progressive reduction of function and mass of beta-cells. Although a genetic predisposition is likely to account for impaired insulin secretion, chronic exposure to hyperglycemia and high circulating FFA is likely to contribute to both functional and survival defects. The disturbance in the endocrine activity of the pancreas is not limited to insulin, since a concomitant increase in fasting plasma glucagon and impaired suppression after the ingestion of an oral glucose load are often observed. This alteration becomes prominent after the ingestion of a mixed meal, when plasma glucagon remains much higher in the diabetic patient as compared to normal individuals. The disproportionate changes in the plasma concentration of the two pancreatic hormones is clearly evident when the insulin:glucagon molar ratio is considered. It is the latter that mainly affects hepatic glucose production. Because of the reduction of the insulin:glucagon molar ratio basal endogenous glucose concentration will be higher causing fasting hyperglycemia, while the hepatic glucose output will not be efficiently suppressed after the ingestion of a meal, contributing to excessive post-prandial glucose rise. Correcting beta- and alpha-cell dysfunction becomes, therefore, an attractive and rational therapeutic approach, particularly in the light of new treatments that may directly act on these pathogenetic mechanisms of type 2 diabetes.

Chronic exposure to high glucose concentrations increases proglucagon messenger ribonucleic acid levels and glucagon release from InR1G9 cells.

Alpha cell function is impaired in diabetes. In diabetics, plasma levels of glucagon are high despite persistently elevated glucose levels and may even rise paradoxically in response to a glucose load; high plasma glucagon levels are accompanied by increased proglucagon gene expression. We have investigated the effects of high glucose concentrations on InR1G9 cells, a glucagon-producing cell line. We show here that chronically elevated glucose concentrations increase glucagon release by 2.5- to 4-fold, glucagon cell content by 2.5- to 3-fold, and proglucagon messenger RNA levels by 4- to 8-fold, whereas changes for 24 h have no effect on proglucagon messenger RNA levels. Persistently elevated glucose affects proglucagon gene expression at the level of transcription and insulin is capable of preventing this effect. We conclude that chronically elevated glucose may be an important factor in the alpha cell dysfunction that occurs in diabetes and thus that glucose may not only affect the beta cell but also the alpha cell.

Endocrine pancreatic cells of postatal “diabetes” (DB) mice in cell culture

Ultrastructural characteristics as well as secretory and biosynthetic behavior of monolayer pancreatic cell cultures established from 4-day-old C57BL/KsJ misty diabetic (m db/m db) mice have been studied in comparison to normal littermate controls. Hypersecretion of glucagon by alpha-cells from BL/Ks misty diabetic mice after 2 days in vitro was found to precede any hyperfunction of the insulin-secreting beta-cells. The increased level of glucagon-release in BL/Ks cell cultures from diabetic mice was accompanied by a greatly enhanced level of incorporation of [3H]tryptophan into glucagon-like molecules whose specific radioactivity was up to 15-fold higher than that observed in cultures from genetic controls. The finding of an alpha-cell dysfunction in cultures established from preweaning diabetic BL/Ks mice suggests that glucagon could play an early role in shaping the events that culminate in the expression of frank diabetes in this inbred strain.

Glucagon and Catecholamine Secretion During Hypoglycemia in Normal and Diabetic Man

To examine the role of catecholamines in glucopenia-induced glucagon secretion, urinary epinephrine and norepinephrine and plasma immunoreactive glucagon (IRG) were measured during insulin-induced hypoglycemia in normal and insulin-dependent diabetic-man. Despite equivalent levels of hypoglycemia the mean plasma IRG increment in diabetes was only 15% of normals. The increases in epinephrine and norepinephrine were comparable in diabetics and normals; thus, the blunted response in plasma IRG to the stimulus of low blood sugar in diabetics cannot be explained by a generalized defect in catecholamine secretion. It is suggested that an alpha-cell glucoreceptor defect may account for the abnormal response to glucopenia in diabetics. To evaluate the possibility that impaired sensitivity to circulating catecholamines could explain the alpha cell dysfunction in diabetics, exogenous epinephrine was infused in normals and insulin-dependent diabetics. Elevated plasma IRG during epinephrine infusion was observed in only 50% of normals. The diabetics were hyperresponsive; mean increment in plasma IRG 3 times that of normals. The data demonstrate enhanced rather than impaired sensitivity to catecholamines in diabetes mellitus.

Effects of Acute Insulin Withdrawal and Administration on Plasma Glucagon Responses to Intravenous Arginine in Insulin-dependent Diabetic Subjects

To assess further the role of insulin in the abnormal alpha-cell dysfunction found in human diabetes mellitus, the effects of acute insulin withdrawal and administration on plasma glucagon responses to intravenous arginine were studied in eight insulin-dependent diabetic subjects. Arginine infusions (30 gm. over 30 minutes) were performed during and at one and four hours after discontinuation of a 14-hour insulin infusion (1.5 U. per hour), which had rendered the subjects euglycemic, and on another occasion before and one and four hours into a five-hour infusion of insulin (1.5 U. per hour). During the last hour of the 14-hour infusion, glucagon responses to arginine (area under the curve, nanograms per milliliter per minute) were similar to those found in normal subjects (10.3 +/- 0.8 vs. 9.0 +/- 0.8, respectively). After discontinuation of the insulin infusions, glucagon responses increased progressively (p less than 0.01) to values (16.8 +/- 1.2) that exceeded those of normal subjects by four hours (p less than 0.01). These were similar to results found in the same subjects studied when their diabetes was in less than optimal control (14.9 +/- 1.3). Infusion of insulin under these conditions progressively decreased glucagon responses to arginine to values (9.6 +/- 0.8; p less than 0.01) that, at four hours, were similar to those of normal subjects and to values found at the end of the 14-hour infusion of insulin in the same diabetic individuals. These results demonstrate a rapid effect of insulin on glucagon responses to arginine and suggest that the abnormal responses seen in diabetes mellitus are the immediate result of insulin deficiency. Since abnormal glucagon responses to glucose in diabetes are not as readily corrected by insulin, the mechanisms underlying the abnormal responses to these two stimuli may differ.

PANCREATIC ALPHA AND BETA CELL FUNCTION IN CHILDREN WITH CYSTIC FIBROSIS (CF)

Inappropriate plasma glucagon responses to oral glucose have been reported in diabetes (DM), and it has been suggested that alpha cell dysfunction is a characteristic of genetic DM. To further evaluate this hypothesis, plasma glucagon and insulin were measured in children with CF following standard oral glucose (GTT) or intravenous arginine (ATT) tolerance tests. CF patients were classified as being normal (Group A) or variably abnormal (Group B) on the basis of the glucose responses to the GTT. During the GTT plasma glucagon declined by a mean of 64 ± 22 pg/ml in A (p < 0.05) and by 34 ± 7 pg/ml in B (p < 0.01), (A vs. B ns.) while plasma insulins peaked at a mean of 28 ± 5 μU/ml in A and 48 ± 15 μU/ml in B. The ATT resulted in a significantly greater glucagon response at 30 min. in A than B, 622 ± 39 pg/ml vs. 238 ± 74 pg/ml (p < 0.005); while the peak insulin responses were low in both groups, 13 ± 2.6 vs. 21 ± 2.2 μU/ml. These data suggest (1) suppressibility of glucagon to glucose persists despite carbohydrate intolerance in CF patients in contrast to reported non-suppressibility in genetic DM. (2) Insulin responsiveness is obtunded in CF patients in both groups. (3) CF affects pancreatic alpha and beta cell function as well as exocrine function.