Pancreatic Beta Cell Secretion Research Articles

The Regulatory Effect of Vitamin D on Pancreatic Beta Cell Secretion in Patients with Type 2 Diabetes.

Increasing evidence suggests that vitamin D is one of the causes of accelerated development of Insulin Resistance (IR) and islet cell secret dysfunction. Numerous studies have shown that vitamin D can reduce inflammation, activate the transcription of the insulin receptors and related genes, and increase insulin-mediated glucose transport, thereby reducing IR. This article reviews the molecular mechanisms related to vitamin D deficiency and pancreatic β-cell dysfunction in patients with Type 2 Diabetes (T2D).

Metabolic Clearance Rate of Insulin Is Not Saturable within the Physiological Range

The plasma concentration of insulin is determined by pancreatic beta cell secretion and the metabolic clearance of the hormone. It has been suggested that the concentration of insulin determines its metabolic clearance rate. Also, some reports suggest that clearance is saturable and insulin kinetics are non-linear even within physiologic ranges. We assessed the metabolic clearance rate of insulin at different physiologic concentrations to access if clearance changes with concentration. Using the dog model (n=12), insulin was infused peripherally at 3 incremental rates (dose-response) during the euglycemic clamp. Each infusion rate spanned 90mins, and the last 30mins was considered the steady state. The metabolic clearance rate of insulin was calculated as the ratio of the infusion rate to the steady state plasma concentration. The 3 infusion rates, 1.5, 3.0 and 4.5pmol/kg/min yielded steady state plasma insulin concentrations of 92 ± 8, 165 ± 12 and 256 ± 18pM respectively. The metabolic clearance rate of insulin was consistent and independent of dose (17.8 ±1.7, 19.1 ±1.2 and 18.6 ±1.4 ml/kg/min; p = ns) across the different plasma insulin infusion rates. Also, we found a strong linear correlation (r = 0.99) between the infusion rates and steady state insulin concentrations. Insulin kinetics are linear and the metabolic clearance of insulin is not saturable within physiologic ranges in the conscious dog. Though it’s possible that the site of degradation (i.e., liver vs. periphery) may change with dose.These data demonstrate that changing concentrations of plasma insulin within physiologic concentrations does not change the rate of insulin removal from the plasma. Disclosure I. Asare Bediako: None. R.L. Paszkiewicz: None. O.O. Woolcott: None. R.N. Bergman: Advisory Panel; Self; Ingredion, Inc.. Research Support; Self; AstraZeneca. Consultant; Self; GI Dynamics Inc.. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Self; Novo Nordisk A/S.

The Expression Differences of Cyclin Dependent Kinase Inhibitors In Aged and Young Pancreatic Beta Cells

The number of people affected by diabetes is continually rising, affecting over 400 million people worldwide. The insulin secreting pancreatic beta cells are essential to control proper glucose absorption and storage in insulin sensitive peripheral tissue. Both Type 1 and Type 2 diabetes are characterized by decreased functional beta cell mass and, consequently, decreased insulin production. One potential intervention is the use of beta cell transplantation from cadaveric donors. A major impediment to greater application of this treatment is the scarcity of transplant ready beta cells. Increasing the amount of functional beta cells will lead to increased insulin production and better management or a possible treatment strategy for the disease. Various genes have been defined that can induce beta cell replication. A major caveat of these findings, however, is that these factors induce replication in young beta cells and not aged beta cells. Given that the majority of beta cells that will be used for transplant will come from aged donors, it is imperative to understand why aged beta cells are refractory to these proliferative mechanisms. We aimed to determine why aged beta cells do not replicate as well as young beta cells. We hypothesized that one reason for why aged beta cells are refractory to genes that induce proliferation is greater expression of cell cycle inhibitors. The cell cycle is tightly regulated by cyclin‐dependent kinases. Cells also produce proteins known as cyclin‐dependent kinase inhibitors(CDKI's), which bind to cyclin dependent kinases, effectively shutting down cell proliferation. Here we demonstrate the expression of the INK4 and Cip/Kip family of CDKI's by mRNA, protein and histological expression in 5 week old and 5 month old primary rat beta cells. These results begin to define the functional changes that result in the inability of aged beta cells to replicate.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Correlation serum level of 25(OH)D and bone density in type 2 diabetes mellitus patients

Bone density has positive relationship with levels of vitamin D, that reduce the risk of fracture. Some studies shows that vitamin D deficiency is not only related to skletal disease, but also to non-skletal disease such as T2DM. Vitamin D plays an important role in the regulation of blood glucose through the effect of pancreatic beta cell secretion and insulin sensitivity. To investigate correlation between serum level of 25(OH)D and bone density in type 2 diabetes mellitus patients. Observational study with cross sectional design at Internal Medicine Polyclinic Dr. Mohammad Hoesin Palembang Hospital from November 2014 to April 2015, and the result analyzed with statistical correlation. The subjects were taken by consecutive sampling in patients with T2DM who met inclusion criteria. Of 380 people who sought medication, 42 subjects met the inclusion criteria. There were 22 patients with low bone density (19 osteopenia and 3 osteoporosis), and 20 patients with normal bone density. Mean serum level of 25(OH)D in group with normal BMD of lumbar and femur was 19.48±6.75ng/ml, and in group with osteopenia and osteoporosis was 21.54±6.14ng/ml and 17.17±5.66ng/ml respectively. There was no significant correlation of 25(OH)D serum level with lumbar and femur bone density (p<0.05). There is no correlation between levels of 25(OH)D serum and bone density in T2DM patients at Internal Medicine Polyclinic of Mohammad Hoesin Hospital.

Stem cell-derived tissue-associated regulatory T cells suppress autoimmune diabetes

Abstract CD4+ regulatory T cells (Tregs) are essential for normal immune surveillance, and their dysfunction can lead the development of autoimmune diseases, such as type-1 diabetes. Pluripotent stem cells (PSCs) can be utilized to obtain a renewable source of healthy Tregs to treat autoimmune diabetes as they have the ability to produce almost all cell types in the body, including Tregs. However, the right conditions for the development of antigen (Ag)-specific Tregs from PSCs (i.e., PSC-Tregs) have not been fully defined. In this study, we developed a new approach to generate functional Ag-specific Tregs from induced PSC (iPSCs), i.e., iPSC-Tregs, which have the ability to suppress autoimmunity in a murine model of autoimmune diabetes in Ag-associated fashion. We retrovirally transduced murine iPSCs with a DsRed reporter construct containing genes of major histocompatibility complex (MHC) II (I-Ab)-restricted ovalbumin (OVA)-specific T cell receptor (TCR) and the transcriptional factor FoxP3. We in vitro differentiated the DsRed+ iPSC into OVA-specific iPSC-Tregs with an OP9 stromal cell line expressing Notch ligands DL1, DL4 and I-Ab in the presence of recombinant cytokines of rIL-7 and rFlt3L. We visualized the expression of CD3, TCR, CD4, CD25, and CTLA-4 on OVA-specific iPSC-Tregs. Moreover, adoptive transfer of such Tregs dramatically suppressed autoimmunity in a well-established OVA-induced model of autoimmune diabetes (RIP-OVA × OT-I double transgenic mice), including the inflammation and prevents the insulin secreting pancreatic beta cells from destruction. Our results indicate that PSCs can be used to develop Ag-specific Tregs, which have a therapeutic potential for autoimmune diabetes.

Biased Signaling of GPCR Regulates Pancreatic Beta Cell Secretion and Survival

Gastrointestinal hormones which are secreted by enteroendocrine cells play important role in the regulation of pancreatic β cell survival and insulin secretion. Here we demonstrated that cholecystokinin CCK-8s activates a G-protein-coupled receptor, CCKAR, and elevates both IP3 and cAMP levels. Under low-glucose condition, Gq-IP3 signaling contributes to the CCK-8s-induced insulin secretion, while Gs-cAMP signaling increases the CCK-8s-mediated insulin secretion greatly in high glucose conditions. CCK-8s also promotes the CCKAR/β-arrestin-1 formation in pancreatic β cells, and further activates ERK signaling. Using β-arrestin-1 siRNA-mediated knockdown cells and β-arrestin-1 knockout mice, we demonstrated that β-arrestin-1 mediates both CCK-8s-induced insulin secretion and the protective function in pancreatic β cells. The association of β-arrestin-1 and CCKAR mediates cytoplasmic late-phase ERK phosphorylation, then activates the p90RSK-phospho-Bad pathway, which contributes to the anti-apoptotic effect of CCK-8s. Further studies on biased signaling of CCKAR in pancreatic β cells will help developing biased CCKAR ligands.

Glucose-Induced Cyclic-AMP Oscillations: Modeling Incretin Impact on Pancreatic Beta Cell Secretion

Pancreatic beta cells modulate insulin secretion via incretin-induced amplification pathways of cytosolic calcium (Ca2+)-induced exocytosis, which may be help compensate for reduced insulin sensitivity in Type II Diabetes Mellitus. One modulator is cAMP, which is activated by an incretin-triggered Gs protein cascade and sensitive to glucose levels. Interestingly, cAMP is found to be oscillatory, even in cases where Ca2+ is not, providing a possible mechanism for pulstile insulin secretion in the absence of Ca2+ oscillations. When Ca2+ and cAMP both oscillate, the two may be either in-phase or out-of-phase with one another. To understand the cAMP oscillations and their relationship to Ca2+ oscillations we use mathematical modeling. We model the cAMP production sensitivity to glucose metabolism with AMP sensitive adenylyl cyclases and degradation with Ca2+ sensitive phosphodiesterases. These modest additions to the Dual Oscillator Model for beta cells allow us to capture observed relationships between cAMP and Ca2+. This provides further evidence for metabolic oscillations in beta-cells that are affected by, but that do not require, oscillations in Ca2+.

Proinsulin in Healthy Pregnancy, Pregnancy with Gestational Diabetes and after Delivery

Summary The aim of the present study was to evaluate the levels of pro-insulin and pro-insulin/ insulin ratio (PIR) in pregnant with normal glucose tolerance (NGT), pregnant with gestational diabetes mellitus (GDM) and women after delivery with GDM history. Normal pregnancy is characterized by progressive insulin resistance, which is physiologically compensated by an increase in insulin secretion. The higher secretion of the insulin precursor pro-insulin has been associated with β-cell dysfunction. A total of 102 pregnant women between 24-28 gestational weeks (53 GDM pregnant, 49 with NGT) and 22 postpartum with GDM history, as assessed by a 2h oral glucose tolerance test, were included in the study. Fasting plasma insulin and pro-insulin (PI) concentrations at the basal state were measured in all women. The ratio pro-insulin/insulin was calculated. BMI was significantly higher in GDM pregnant compared to NGT weight-matched group (30.56 ± 6.9 vs. 30.56 ± 6.9; p &lt; 0, 011) and compared to the levels after delivery (30.56 ± 6.9vs. 27.9 ± 6, 27; p &lt; 0, 001). Significant differences in the levels of PI between NGT and GDM pregnant (3.94 ± 2.78 vs. 7.59 ± 5.27; p = 0.006), between GDM and postpartum women (7.59 ± 5.27 vs. 4.46 ± 1.14; p = 0.022) were established. No signifi cant difference in the level of PIR between two pregnant groups was observed. Separately NGT and GDM showed signifi cant difference compared to young mothers (0.41 ± 0.14 vs. 0.148 ± 0.031, p &lt; 0.02; 0.46 ± 0.16 vs. 0.148 ± 0.031, p = 0.009). Fasting insulin was statistically higher in GDM pregnant compare to NGT and women after delivery (13.84 ± 8.43 vs. 11.35 ± 7.38, p = 0.02; 13.84 ± 8.43 vs. 10.60 ± 7.53, p &lt; 0.01). The correlation between PIR and BMI in the three groups studied were r = 0.416; r = 0,741; r = 0,556 (with statistical significance p = 0.01 between NGT and GDM pregnancy, p = 0.02 between GDM pregnancy and postpartum, p &lt; 0.0001 between NGT pregnancy and young mother with GDM history). In our study, comparison of PI levels between pregnant with NGT and GDM demonstrated that the OR of developing GDM was 1.194 (95% CI, 1.028-1.329, P = 0.001). Increasing the value of PI with 10 pmol/l increases the risk for development of GDM with 19.4%. According to our results, pregnant with GDM have elevated levels of pro-insulin and PIR which could serve as a markers for this condition. These results support our findings about relationship and influence of BMI on β-cell functions, established in this study with normotolerant, gestational diabetes pregnant and women postpartum with GDM history. These results demonstrate that gestational diabetics have abnormalities in pancreatic beta-cell secretion, which are likely to be important both in the etiology of gestational diabetes and non-insulin dependent diabetes.

The pancreatic islet as a signaling hub

Over the last two decades we have focused on beta cell signal transduction, bringing many new insights, especially in the context of insulin signal transduction, the role of inositol polyphosphates and the regulation of cytoplasmic free Ca(2+) concentration. However, there has been a growing awareness that the beta cell, which is mandatory for insulin secretion, has a unique context within the micro-organ of the pancreatic Islet of Langerhans. In this environment the beta cell both mediates and receives paracrine regulation, critical for the control of blood glucose homeostasis. Failure of an appropriate beta cell function leads to the development of diabetes mellitus. In our quest to understand the molecular events maintaining beta cell function we have faced two key challenges. Firstly, whilst there are many similarities between signal transduction in pancreatic islets between the much used rodent models and humans there are some notable differences. Critical distinctions between rodent and primate can be made in the structure of the islet, including the arrangement of the islet cells, the innervation pattern and the microcirculation. This means that important signaling interactions between islets cells, mediated through for example insulin, glucagon, GABA, glutamate and ATP, will have a unique human framework. The second challenge was to be able to take the discoveries we have made using in vitro systems and examine them in an in vivo context. Advances in in vivo imaging achieved by utilizing the anterior chamber of the eye as a transplantation site for pancreatic islets make it possible for non-invasive, longitudinal studies at single cell resolution in real time of islet cell physiology and pathology. Thus it is becoming possible to study the insulin secreting pancreatic beta cell within the framework of the unique micro-organ, the Islet of Langerhans, for the first time in a physiological context, i.e. when being innervated and connected to the blood supply.

The pancreatic beta cell as a paradigm for advances in inositide research

In a previous review for Advances in Enzyme Research (Berggren and Barker, 2008) we outlined the history of our involvement in discovering important roles for inositides in the insulin secreting pancreatic beta cell. In this current appraisal we bring the work up to date and project how we believe this field will continue to develop in the future. Recently, we have seen an important synergism between the growth in our understanding of inositide function and our knowledge of beta cell stimulus-secretion coupling in both physiological and pathophysiological contexts. Important advances have been made in three areas. 1. The classic regulation of cytoplasmic free Ca(2+) concentration [Ca(2+)](i) by Inositol 1,4,5-trisphosphate (Ins(1,4,5)P(3)) and its receptor, 2. A novel role of the inositol pyrophosphates, especially 5-diphosphoinositol pentakisphosphate (5-PP-InsP(5)), in exocytosis, and 3. The unique signaling roles of PI3K pathways instituted by the engagement of the insulin receptor in an autocrine, positive feed-back loop. We examine each of these in turn and close with an assessment of the likely future directions the research will take.

Pancreas-protective effects of chlorella in STZ-induced diabetic animal model: insights into the mechanism

The aim of this study is to examine the effect of intragastric administration of chlorella (1 g/kg body weight) for a period of 30 days to treat normal and diabetic male Wistar rats. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) (60 mg/kg - 1 body weight). A significant (p < 0.05) reduction of blood glucose level in diabetic chlorella-treated rats was observed compared to diabetic untreated. Chlorella increased the number of glutathione-positive cell in diabetic rats compared to untreated diabetics. Chlorella administration increased the percentage of insulin secreting pancreatic beta cells both in normal and diabetic treated rats. Percentage of glucagon producing alpha cells of the pancreas were reduced both in normal and diabetic chlorella-treated rats. Chlorella-induced regenerative ability on pancreas was mediated by up-regulation of Ki67 and down-regulation of P53 and by its potent anti-oxidant ability. The present results suggest that chlorella may play an important role in improving the overall condition of diabetic patients and delay its complication by restoring the function of pancreatic insulin-secreting cells.

Insights into the critical role of NADPH oxidase(s) in the normal and dysregulated pancreatic beta cell

It is now widely accepted that reactive oxygen species (ROS) contribute to cell and tissue dysfunction and damage in diabetes. The source of ROS in the insulin secreting pancreatic beta cells has traditionally been considered to be the mitochondrial electron transport chain. While this source is undoubtedly important, we fully describe in this article recent information and evidence of NADPH oxidase-dependent generation of ROS in pancreatic beta cells and identify the various isoforms that contribute to O(2)(*-) and H(2)O(2) production in various conditions. While glucose-stimulated ROS generation may be important for acute regulation of insulin secretion, at higher levels ROS may disrupt mitochondrial energy metabolism. However, ROS may alter other cellular processes such as signal transduction, ion fluxes and/or cell proliferation/death. The various beta cell isoforms of NADPH oxidase (described in this review) may, via differences in the kinetics and species of ROS generated, positively and negatively regulate insulin secretion and cell survival.

Pharmacodynamics of glucose regulation by methylprednisolone. I. Adrenalectomized rats

Mechanisms related to the adverse effects of corticosteroids on glucose homeostasis were studied. Five groups of adrenalectomized (ADX) rats were given methylprednisolone (MPL) intravenously at 10 and 50 mg/kg, or a continuous 7 day infusion at rates of 0, 0.1, 0.3 mg/kg/h via subcutaneously implanted Alzet mini-pumps. Plasma concentrations of MPL, glucose and insulin were determined at various time points up to 72 h after injection or 336 h after infusion. The pharmacokinetics of MPL was captured with a two-compartment model. The Adapt II software was used in modeling. Injection of MPL caused a temporary glucose increase over 6 h by stimulating gluconeogenesis. The glucose changes stimulated pancreatic beta-cell secretion yielding a later insulin peak at around 10 h. In turn, insulin can stimulate glucose disposition. However, long-term MPL treatment caused continuous hyperglycemia during and after infusion. Insulin was increased during infusion, and immediately returned to baseline after the infusion was terminated, despite the almost doubled glucose concentration. A disease progression model incorporating the reduced endogenous glucose disposition was included to capture glucose homeostasis under different treatments. The results exemplify the importance of the steroid dosing regimen in mediating pharmacological and adverse metabolic effects. This mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model quantitatively describes the induction of hyperglycemia and provides additional insights into metabolic disorders such as diabetes.

Dipeptidyl peptidase iv inhibitors and diabetes therapy

Current type 2 diabetes therapies are mainly targeted at stimulating pancreatic beta-cell secretion and reducing insulin resistance. A number of alternative therapies are currently being developed to take advantage of the actions of the incretin hormones Glucagon-Like Peptide-1 (GLP-1) and Glucose-dependent Insulinotropic Polypeptide (GIP). These hormones are released from the small intestine in response to nutrient ingestion and stimulate insulin secretion in a glucose-dependent manner. One approach to potentiating their actions is based on inhibiting dipeptidyl peptidase IV (DPP IV), the major enzyme responsible for degrading the incretins in vivo. DPP IV exhibits characteristics that have allowed the development of specific orally administered inhibitors with proven efficacy in improving glucose tolerance in animal models of diabetes. A number of clinical trials have demonstrated that DPP IV inhibitors are effective in improving glucose disposal and reducing hemoglobin A1c levels in type 2 diabetic patients and one inhibitor, sitagliptin, is now in therapeutic use, with others likely to receive FDA approval in the near future. Studies aimed at elucidating the mode of action of the inhibitors are still ongoing. Both enhancement of insulin secretion and reduction in glucagon secretion, resulting from the blockade of incretin degradation, are believed to play important roles in DPP IV inhibitor action. Preclinical studies indicate that increased levels of incretins improve beta-cell secretory function and exert effects on beta-cell mitogenesis and survival that can preserve beta-cell mass. Roles for other hormones, neuropeptides and cytokines in DPP IV inhibitor-medicated responses are also possible.

Cytological and immunocytochemical characterization of the insulin secreting insulinoma cell line RINm5F.

The rat insulinoma cell line RINm5F, an insulin secreting pancreatic beta cell line, has been used as an attractive model for basic studies of the mechanisms of insulin secretion and, more recently, as a model for the development of alternative methods for the treatment of diabetes. To elucidate the cytological properties and expression patterns of hormones of the gastro-entero-pancreatic system, suspensions of RINm5F cells were investigated by various methods including immunocytochemistry on serial semithin sections, quantitative immunocytochemistry, routine electron microscopy, immuno-electron microscopy, in situ hybridization, and TUNEL technique. At the ultrastructural level, several phenotypes of RIm5F cells were characterized by differences in the number, shape, size, and density of their secretory granules. The most common type contained a mixture of round granules varying in size and electron density. A second type predominantly contained relatively large, moderately dense granules. Moreover, a minority of cells was characterized by the occurrence of polymorphous electron dense granules or the complete absence of any secretory granules. The immunohistochemical data showed that, among the established islet hormones, insulin was present in more than 50% of cells, whereas glucagon and somatostatin occurred only sporadically. Though cells positive for pancreatic polypeptide (PP) were not found, PP-related peptides (NPY and PYY) however could be detected in a minority of cells. The great majority of RINm5F cells were immunoreactive for chromogranin B (CgB), followed by insulin, chromogranin A (CgA), and serotonin (5-HT). In addition to intercellular differences in the density of immunostaining, numerous colocalizations of immunoreactivities were found, suggesting that RINm5F cells represent a mixture of subtypes concerning the individual pattern of hormone expression. The present results reveal a wide range of heterogeneity with respect to the morphology and especially the hormone content between individual RINm5F cells.

Influence of Phytostanol Phosphoryl Ascorbate (FM-VP4) on Insulin Resistance, Hyperglycemia, Plasma Lipid Levels, and Gastrointestinal Absorption of Exogenous Cholesterol in Zucker (fa/fa) Fatty and Lean Rats

The purpose of this investigation was to determine the effects of Phytostanol Phosphoryl Ascorbate (FM-VP4) on insulin resistance, hyperglycemia, plasma lipid levels, body weight, and gastrointestinal absorption of exogenous cholesterol in Zucker (fa/fa) fatty and lean rats. A group of 12 age-matched male obese (n = 6) and lean (n = 6) Zucker rats were administered 250 mg/kg twice a day (as 2% FM-VP4 in drinking water) for 30 consecutive days. Fasted blood samples prior to and following treatment were taken from all rats for glucose, lipid, insulin, and leptin determination. An oral glucose tolerance test was also carried out at the end of the treatment protocol. In addition, male obese (n = 7) and lean (n = 8) Zucker rats were coadministered a single oral gavage of [(3)H]cholesterol plus cold cholesterol with or without FM-VP4 (20 mg/kg) dissolved in Intralipid and the plasma concentration of the radiolabel was determined 10 h following the dose. FM-VP4 30-day treatment did not alter body weight, morning glucose, insulin, lipids, and leptin concentrations. There was no alteration in glucose tolerance in the nondiabetic, normoglycemic lean group; however, there was a highly significant improvement in glucose tolerance in the fatty group following FM-VP4 treatment. In addition, the insulin response to oral glucose showed no significant change in nondiabetic lean rats, whereas there was a change in the insulin secretory profile in the fatty group following FM-VP4 treatment. Furthermore, following a single oral gavage of FM-VP4 resulted in a significant decrease in the percentage of radiolabeled cholesterol absorbed. These findings suggest that FM-VP4 treatment to fatty Zucker rats could result in increased glucose responsiveness of the insulin secreting pancreatic beta cells. Furthermore, our findings suggest that FM-VP4 may only be effective presystemically. Systemic administration of FM-VP4 is warranted to determine the therapeutic potential of this effect.

Hyperproinsulinaemia in elderly subjects: evidence for age-related pancreatic β-cell dysfunction

We investigated whether pancreatic beta-cell dysfunction has a role in the pathogenesis of glucose intolerance in the elderly by comparing plasma glucose, immunoreactive insulin, C-peptide and proinsulin concentrations during a 100-g oral glucose load in six healthy older male volunteers [aged 69 (65.9-74.9) years; median (95% confidence limits)] and seven young male controls [aged 24.0 (21.9-26.3) years]. Fasting and integrated concentrations of glucose and C-peptide were similar in the elderly and young. Although fasting, insulin and proinsulin levels were similar, integrated insulin (P=0.05) and proinsulin (P<0.05) concentrations were higher in the elderly than in controls. Insulin resistance, measured as homeostasis model assessment, was greater (P<0.05) in the elderly than in controls. Elderly men had greater molar ratios of integrated insulin:C-peptide (P<0.05) and proinsulin:C-peptide (P<0.01) but their respective fasting molar ratios were similar when compared with controls. Pancreatic beta-cell secretion in older subjects, as assessed by C-peptide concentrations, was inappropriately low in the presence of insulin resistance. Their post-prandial 'hyperinsulinaemia' is probably due to a combination of hyperproinsulinaemia and reduced metabolic clearance of insulin. Older subjects had disproportionately high proinsulin to C-peptide levels, suggesting pancreatic beta-cell dysfunction. These results are consistent with the notion that decreased insulin sensitivity and pancreatic beta-cell dysfunction may predispose the elderly to glucose intolerance.

Post-transplantation hypoglycaemia in type 1 diabetic pancreas allograft recipients

Physiologic replacement of insulin in patients with type 1 (insulin-dependent) diabetes following pancreas allograft transplantation results in normoglycaemia during fasting and postprandial states. However, this is achieved at the expense of peripheral hyperinsulinaemia in the heterotopic pancreas allograft recipients with systemic insulin drainage. In addition, the pancreas allograft is denervated and thus devoid of autonomic nervous regulation of pancreatic beta-cell secretion. Recent reports of hypoglycaemia (symptomatic and asymptomatic), which can be fatal, have raised serious concerns regarding the aetiology of the hypoglycaemic epiphenomenon in type 1 diabetic pancreas allograft recipients. Although the prevalence of significant hypoglycaemia following pancreas transplantation remains unknown, it is important to conduct studies to determine the mechanisms, the natural history, predictors and treatment as well as the long-term prognosis (graft and patient survival rates) of type 1 diabetic patients who develop pancreas-allograft-associated hypoglycaemia. Indeed, predictors of hypoglycaemia following pancreas allograft could significantly impact on the selection of appropriate therapeutic options for pancreas allograft transplantation. Finally, whether postpancreas allograft transplantation-associated hypoglycaemia in type 1 diabetic patients carries greater morbidity and mortality when compared to those without hypoglycaemia deserves to be investigated.

Age-related differences in the pancreatic beta-cell response to hyperglycemia after eccentric exercise.

Eccentric exercise (ECC) causes muscle damage, insulin resistance, and increased pancreatic beta-cell secretion in young individuals. However, the effects of age on the pancreatic beta-cell response to glucose after ECC are unknown. Hyperglycemic clamps (180 min, 10.0 mM) were performed on eight young (age 22 +/- 1 yr) and eight older (age 66 +/- 2 yr) healthy sedentary males without exercise (CONT) and 48 h after ECC. ECC increased (P < 0.02) muscle soreness ratings and plasma creatine kinase concentrations in both groups. Insulin and C-peptide secretions were similar between young and older subjects during CONT clamps. ECC increased (P < 0.05) first-phase (0-10 min) C-peptide area under the curve in young (4.2 +/- 0.4 vs. 3.7 +/- 0.6 nM . min; ECC vs. CONT, respectively) but not in older subjects (3.2 +/- 0.7 vs. 3.5 +/- 0.7 nM . min; ECC vs. CONT), with significant group differences (P < 0.02). Indeed, ECC repressed (P < 0.05) first-phase peak C-peptide concentrations in older subjects (0. 93 +/- 0.16 vs. 1.12 +/- 0.11 nM; ECC vs. CONT). Moreover, first-phase C-peptide-to-insulin molar ratios suggest age-related differences (P < 0.05) in insulin/C-peptide clearance after ECC. Furthermore, the observed C-peptide response after ECC was related to abdominal adiposity [r = -0.62, P < 0.02, and r = -0.66, P < 0. 006, for first and second (10-180 min) phases, respectively]. In conclusion, older individuals did not exhibit the compensatory increase in beta-cell secretion observed among young individuals after ECC. Thus, with increasing age, the pancreatic beta-cell may be less responsive to the physiological stress associated with ECC.

Longitudinal changes in pancreatic beta-cell function and metabolic clearance rate of insulin in pregnant women with normal and abnormal glucose tolerance.

To evaluate basal pancreatic beta-cell secretion and suppression during infused insulin and the metabolic clearance rate of insulin in women with normal and abnormal glucose tolerance prior to conception and during pregnancy. Seven women with normal glucose tolerance and nine women with abnormal glucose tolerance during gestation were evaluated prior to conception, in early (12-14 weeks) and late (34-36 weeks) gestation. Basal insulin and C-peptide were measured after an 11-h fast and during the last 40 min of a 2-h hyperinsulinemic-euglycemic clamp at 40 mU.m-2.m-1. Suppression of basal C-peptide was calculated as the steady-state C-peptide/basal C-peptide. The metabolic clearance rate of insulin was calculated by dividing the insulin infusion rate by the steady-state insulin concentration, which was corrected for residual beta-cell secretion. No significant differences were noted in the following parameters between women with normal and abnormal glucose tolerance with advancing gestation: increase in basal insulin (P = 0.20) and C-peptide (P = 0.12), ability of infused insulin to decrease basal C-peptide concentration (P = 0.22), and metabolic clearance rate of insulin (P = 0.76). There was a significant 65% increase in both basal insulin (P = 0.0005) and C-peptide (P = 0.0002) concentrations in all subjects with advancing gestation. There was a significant (P = 0.0001) decrease in the ability of the infused insulin to decrease basal C-peptide concentration. C-peptide as a percentage of the basal was 64% before conception, 74% in early pregnancy, and 108% in late pregnancy. The metabolic clearance rate of insulin significantly (P = 0.0005) increased with advancing gestation: pregravid 442 ml.m-2.min-1, early pregnancy 514 ml.m-2. min-1, and 526 ml.m-2.min-1 in late pregnancy. Pregnancy is accompanied by progressive alterations in insulin kinetics, which are partly responsible for the hyperinsulinemia of this condition. These alterations are more likely a homeostatic response to the increased physiological insulin resistance of pregnancy.