Loss Of First-phase Insulin Secretion Research Articles

Intra-islet glucagon signalling regulates beta-cell connectivity, first-phase insulin secretion and glucose homoeostasis

ObjectiveType 2 diabetes (T2D) is characterised by the loss of first-phase insulin secretion. We studied mice with β-cell selective loss of the glucagon receptor (Gcgrfl/fl X Ins-1Cre), to investigate the role of intra-islet glucagon receptor (GCGR) signalling on pan-islet [Ca2+]I activity and insulin secretion. MethodsMetabolic profiling was conducted on Gcgrβ-cell−/− and littermate controls. Crossing with GCaMP6f (STOP flox) animals further allowed for β-cell specific expression of a fluorescent calcium indicator. These islets were functionally imaged in vitro and in vivo. Wild-type mice were transplanted with islets expressing GCaMP6f in β-cells into the anterior eye chamber and placed on a high fat diet. Part of the cohort received a glucagon analogue (GCG-analogue) for 40 days and the control group were fed to achieve weight matching. Calcium imaging was performed regularly during the development of hyperglycaemia and in response to GCG-analogue treatment. ResultsGcgrβ-cell−/− mice exhibited higher glucose levels following intraperitoneal glucose challenge (control 12.7 mmol/L ± 0.6 vs. Gcgrβ-cell−/− 15.4 mmol/L ± 0.0 at 15 min, p = 0.002); fasting glycaemia was not different to controls. In vitro, Gcgrβ-cell−/− islets showed profound loss of pan-islet [Ca2+]I waves in response to glucose which was only partially rescued in vivo. Diet induced obesity and hyperglycaemia also resulted in a loss of co-ordinated [Ca2+]I waves in transplanted islets. This was reversed with GCG-analogue treatment, independently of weight-loss (n = 8). ConclusionThese data provide novel evidence for the role of intra-islet GCGR signalling in sustaining synchronised [Ca2+]I waves and support a possible therapeutic role for glucagonergic agents to restore the insulin secretory capacity lost in T2D.

187-OR: Declines in ß-Cell Glucose Responsiveness Correlate with Loss of Glucose Metabolism during T1D Pathogenesis

Features of type 1 diabetes (T1D) include loss of first-phase insulin secretion in response to glucose, declining c-peptide, and glucose intolerance; indicating β cell dysfunction. Here, we investigate the mechanisms of this dysfunction with the hypothesis that immune dysregulation during the early stages of T1D development impacts β cell dysfunction in pathways affecting glucose metabolism. The live pancreas tissue slice (LPTS) model is ideal for the study of T1D pathogenesis due to its preservation of the pancreatic environment. LPTS were generated from organ donors without diabetes or autoantibodies (ND, n=9) , donors positive for one or more autoantibodies without a diagnosis of T1D (AAb+, n=6) , and donors with T1D (T1D, n=4) . Imaging studies were conducted to assess the impact of T cell infiltration on β cell function through Ca2+ imaging and slice perifusion. Islets from ND and AAb+ donors had no insulitis and exhibited Ca2+ responses to both high glucose (HG) and potassium chloride (KCl) . A majority of β cell+ islets in tissue from donors with T1D had infiltrating T cells with several having insulitis. Islet HG response from donors with T1D was heterogenous (∼50% failed to respond) while all T1D islets exhibited responses to KCl. Insulin secretion was significantly higher in LPTS from ND donors than in donors with T1D (p=0.0079) . To determine the basis for this loss of function, we assessed transcriptomics of islets within these cohorts. When comparing gene expression levels in islets from ND versus T1D, significant differences were observed in genes involved in glycolysis (GAPDH, p=3.27x10-21) , the citric acid cycle components (OGDH, p=1.88x10-18) , and the electric transport chain (F1FoATP synthase, p=2.69x10-13) . The decreased expression of glucose metabolism genes during T1D development along with the loss of β cell function in LPTS demonstrates β cell dysfunction before their demise and may be a contributory mechanism towards the pathogenesis of disease. Disclosure M.Huber: None. M.Slak rupnik: None. D.M.Drotar: None. H.Hiller: None. M.Beery: None. I.Kusmartseva: None. M.A.Atkinson: None. E.Phelps: Research Support; Immunocore, Ltd. C.E.Mathews: None. Funding National Institutes of Health (5T32DK108736-03) National Institutes of Health (PO1 AI42288)

Dysfunction of Persisting β Cells Is a Key Feature of Early Type 2 Diabetes Pathogenesis

Type 2 diabetes is characterized by peripheral insulin resistance and insufficient insulin release from pancreatic islet β cells. However, the role and sequence of β cell dysfunction and mass loss for reduced insulin levels in type 2 diabetes pathogenesis are unclear. Here, we exploit freshly explanted pancreas specimens from metabolically phenotyped surgical patients using an in situ tissue slice technology. This approach allows assessment of β cell volume and function within pancreas samples of metabolically stratified individuals. We show that, in tissue of pre-diabetic, impaired glucose-tolerant subjects, β cell volume is unchanged, but function significantly deteriorates, exhibiting increased basal release and loss of first-phase insulin secretion. In individuals with type 2 diabetes, function within the sustained β cell volume further declines. These results indicate that dysfunction of persisting β cells is a key factor in the early development and progression of type 2 diabetes, representing a major target for diabetes prevention and therapy.

Ca2+ channel clustering with insulin-containing granules is disturbed in type 2 diabetes.

Loss of first-phase insulin secretion is an early sign of developing type 2 diabetes (T2D). Ca2+ entry through voltage-gated L-type Ca2+ channels triggers exocytosis of insulin-containing granules in pancreatic β cells and is required for the postprandial spike in insulin secretion. Using high-resolution microscopy, we have identified a subset of docked insulin granules in human β cells and rat-derived clonal insulin 1 (INS1) cells for which localized Ca2+ influx triggers exocytosis with high probability and minimal latency. This immediately releasable pool (IRP) of granules, identified both structurally and functionally, was absent in β cells from human T2D donors and in INS1 cells cultured in fatty acids that mimic the diabetic state. Upon arrival at the plasma membrane, IRP granules slowly associated with 15 to 20 L-type channels. We determined that recruitment depended on a direct interaction with the synaptic protein Munc13, because expression of the II–III loop of the channel, the C2 domain of Munc13-1, or of Munc13-1 with a mutated C2 domain all disrupted L-type channel clustering at granules and ablated fast exocytosis. Thus, rapid insulin secretion requires Munc13-mediated recruitment of L-type Ca2+ channels in close proximity to insulin granules. Loss of this organization underlies disturbed insulin secretion kinetics in T2D.

GGPPS-mediated Rab27A geranylgeranylation regulates β cell dysfunction during type 2 diabetes development by affecting insulin granule docked pool formation.

Loss of first-phase insulin secretion associated with β cell dysfunction is an independent predictor of type 2 diabetes mellitus (T2DM) onset. Here we found that a critical enzyme involved in protein prenylation, geranylgeranyl pyrophosphate synthase (GGPPS), is required to maintain first-phase insulin secretion. GGPPS shows a biphasic expression pattern in islets of db/db mice during the progression of T2DM: GGPPS is increased during the insulin compensatory period, followed by a decrease during β cell dysfunction. Ggpps deletion in β cells results in typical T2DM β cell dysfunction, with blunted glucose-stimulated insulin secretion and consequent insulin secretion insufficiency. However, the number and size of islets and insulin biosynthesis are unaltered. Transmission electron microscopy shows a reduced number of insulin granules adjacent to the cellular membrane, suggesting a defect in docked granule pool formation, while the reserve pool is unaffected. Ggpps ablation depletes GGPP and impairs Rab27A geranylgeranylation, which is responsible for the docked pool deficiency in Ggpps-null mice. Moreover, GGPPS re-expression or GGPP administration restore glucose-stimulated insulin secretion in Ggpps-null islets. These results suggest that GGPPS-controlled protein geranylgeranylation, which regulates formation of the insulin granule docked pool, is critical for β cell function and insulin release during the development of T2DM.

Insulin resistance, β-cell dysfunction and differences in curves of plasma glucose and insulin in the intermediate points of the standard glucose tolerance test in adults with cystic fibrosis

Abstract Background Diabetes has become a co-morbidity with a negative impact on nutritional status, lung function and survival in cystic fibrosis. Objective To identify any changes in intermediate points after a 2-h oral glucose tolerance test (OGTT), pancreatic β-cell dysfunction, and insulin resistance in cystic fibrosis-related diabetes. Methods It was carried out a retrospective analysis in a cohort of 64 patients affected of cystic fibrosis, older than 14 years, using the first pathological OGTT. Peripheral insulin resistance was measured using the homeostasis model assessment for insulin resistance (HOMA-IR), and pancreatic β-cell function was calculated according to Wareham. Time to maximum plasma insulin and glucose levels and area under the curve (AUC0–120) were also measured. Results Twenty-eight women and 36 men with a mean age of 26.8 years were enrolled, of whom 26.7% had normal glucose tolerance (NGT), 18.3% cystic fibrosis-related diabetes without fasting hyperglycemia (CFRD w/o FPG), 10% indeterminate (INDET), and 45% impaired glucose tolerance (IGT). HOMA-IR values were not significantly different between the diagnostic categories. Patients with any pathological change had worse β-cell function, with a significant delay in insulin secretion, although there were no differences in total insulin production (AUC0–120). Time to maximum glucose levels was significantly shorter in NGT patients as compared to other categories, with glucose AUC0–120 being higher in the different diagnostic categories as compared to NGT. Conclusions In over half the cases, peak blood glucose levels during a standard OGTT are reached in the intermediate time points, rather than at the usual time of 120 min. Patients with cystic fibrosis and impaired glucose metabolism have a delayed insulin secretion during the standard OGTT due to loss of first-phase insulin secretion, with no differences in total insulin production. Absence of significant changes in HOMA-IR suggests that β-cell dysfunction is the main pathogenetic mechanism.

Resistencia insulínica, disfunción de la célula β pancreática y diferencias en los puntos intermedios de las curvas de glucemia e insulina tras una sobrecarga oral estándar de glucosa en adultos con fibrosis quística

Backgrounddiabetes has become a co-morbidity with a negative impact on nutritional status, lung function and survival in cystic fibrosis. ObjectiveTo identify any changes in intermediate points after a 2-hour oral glucose tolerance test (OGTT), pancreatic β-cell dysfunction, and insulin resistance in cystic fibrosis-related diabetes. MethodsIt was carried out a retrospective analysis in a cohort of 64 patients affected of cystic fibrosis, older than 14 years, using the first pathological OGTT. Peripheral insulin resistance was measured using the homeostasis model assessment for insulin resistance (HOMA- IR), and pancreatic β-cell function was calculated according to Wareham. Time to maximum plasma insulin and glucose levels and area under the curve (AUC0-120) were also measured. ResultsTwenty-eight women and 36 men with a mean age of 26.8 years were enrolled, of whom 26.7% had normal glucose tolerance (NGT), 18.3% cystic fibrosis-related diabetes without fasting hyperglycemia (CFRD w/o FPG), 10% indeterminate (INDET), and 45% impaired glucose tolerance (IGT). HOMA-IR values were not significantly different between the diagnostic categories. Patients with any pathological change had worse β cell function, with a significant delay in insulin secretion, although there were no differences in total insulin production (AUC0-120). Time to maximum glucose levels was significantly shorter in NGT patients as compared to other categories, with glucose AUC0-120 being higher in the different diagnostic categories as compared to NGT. ConclusionsIn over half the cases, peak blood glucose levels during a standard OGTT are reached in the intermediate time points, rather than at the usual time of 120minutes. Patients with cystic fibrosis and impaired glucose metabolism have a delayed insulin secretion during the standard OGTT due to loss of first-phase insulin secretion, with no differences in total insulin production. Absence of significant changes in HOMA-IR suggests that β-cell dysfunction is the main pathogenetic mechanism.

Distinct Classes of Central GLUT2-Dependent Sensors Control Counterregulation and Feeding

The pancreatic β-cell paradigm for glucose sensing has been proposed to apply to brain glucose sensors controlling counterregulation to hypoglycemia and feeding behavior. Over recent years, we tested this model in mice by first showing that inactivation of the GLUT2 gene suppressed glucose sensing and correctly regulated insulin secretion by pancreatic β-cells. Then, we restored the function of the β-cell in GLUT2-null mice by transgenic expression of a glucose transporter under the control of the rat insulin promoter. Using these rescued mice, we showed that GLUT2-dependent sensors are present in several anatomical sites, including the hepatoportal vein and the central nervous system. When these extrapancreatic glucose sensors are inactivated, the mice display loss of first-phase insulin secretion and hyperglucagonemia in the fed state, and they eat more than control mice—defects characteristic of developing obesity/diabetes. By gene complementation experiments, we further showed that glucose sensors controlling glucagon secretion require GLUT2 expression in glial cells. However, transgenic expression of GLUT2 in astrocytes or neurons failed to restore the normal control of feeding, indicating that different classes of glucose sensors control the response to hypoglycemia and food intake.

Exenatide Augments First- and Second-Phase Insulin Secretion in Response to Intravenous Glucose in Subjects with Type 2 Diabetes

First-phase insulin secretion (within 10 min after a sudden rise in plasma glucose) is reduced in type 2 diabetes mellitus (DM2). The incretin mimetic exenatide has glucoregulatory activities in DM2, including glucose-dependent enhancement of insulin secretion. The objective of the study was to determine whether exenatide can restore a more normal pattern of insulin secretion in subjects with DM2. Fasted subjects received iv insulin infusion to reach plasma glucose 4.4-5.6 mmol/liter. Subjects received iv exenatide (DM2) or saline (DM2 and healthy volunteers), followed by iv glucose challenge. Thirteen evaluable DM2 subjects were included in the study: 11 males, two females; age, 56 +/- 7 yr; body mass index, 31.7 +/- 2.4 kg/m2; hemoglobin A1c, 6.6 +/- 0.7% (mean +/- sd) treated with diet/exercise (n = 1), metformin (n = 10), or acarbose (n = 2). Controls included 12 healthy, weight-matched subjects with normal glucose tolerance: nine males, three females; age, 57 +/- 9 yr; and body mass index, 32.0 +/- 3.0 kg/m2. The study was conducted at an academic hospital. Plasma insulin, plasma C-peptide, insulin secretion rate (derived by deconvolution), and plasma glucagon were the main outcome measures. DM2 subjects administered saline had diminished first-phase insulin secretion, compared with healthy control subjects. Exenatide-treated DM2 subjects had an insulin secretory pattern similar to healthy subjects in both first (0-10 min) and second (10-180 min) phases after glucose challenge, in contrast to saline-treated DM2 subjects. In exenatide-treated DM2 subjects, the most common adverse event was moderate nausea (two of 13 subjects). Short-term exposure to exenatide can restore the insulin secretory pattern in response to acute rises in glucose concentrations in DM2 patients who, in the absence of exenatide, do not display a first phase of insulin secretion. Loss of first-phase insulin secretion in DM2 patients may be restored by treatment with exenatide.

Review: The importance of effective early phase insulin secretion

Low insulin sensitivity and a selective loss of acute insulin release identify those individuals at the highest risk of developing type 2 diabetes. Normally, the rapid release of insulin after the ingestion of a meal is critical for post-prandial glucose regulation as first-phase insulin modulates suppression of endogenous glucose production and, therefore, limits meal-related plasma glucose excursions. The loss of first-phase insulin secretion contributes to the development of glucose intolerance. Indeed, postprandial hyperglycaemia represents the first and more evident perturbation of glucose homeostasis in about 60% of newly diagnosed type 2 diabetic patients. In these individuals, restoration of first-phase insulin secretion may result in more efficient inhibition of hepatic glucose production and improved glucose tolerance. In the light of these considerations, therapeutic intervention either alone or in combination with improvement of insulin resistance should be considered early in the course of the disease to prevent excessively rapid deterioration of glycaemic control.

Impaired insulin secretion and glucose tolerance in beta cell-selective Ca(v)1.2 Ca2+ channel null mice.

Insulin is secreted from pancreatic beta cells in response to an elevation of cytoplasmic Ca(2+) resulting from enhanced Ca(2+) influx through voltage-gated Ca(2+) channels. Mouse beta cells express several types of Ca(2+) channel (L-, R- and possibly P/Q-type). beta cell-selective ablation of the gene encoding the L-type Ca(2+) channel subtype Ca(v)1.2 (betaCa(v)1.2(-/-) mouse) decreased the whole-cell Ca(2+) current by only approximately 45%, but almost abolished first-phase insulin secretion and resulted in systemic glucose intolerance. These effects did not correlate with any major effects on intracellular Ca(2+) handling and glucose-induced electrical activity. However, high-resolution capacitance measurements of exocytosis in single beta cells revealed that the loss of first-phase insulin secretion in the betaCa(v)1.2(-/-) mouse was associated with the disappearance of a rapid component of exocytosis reflecting fusion of secretory granules physically attached to the Ca(v)1.2 channel. Thus, the conduit of Ca(2+) entry determines the ability of the cation to elicit secretion.

Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance.

Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance.

Restoration of early rise in plasma insulin levels improves the glucose tolerance of type 2 diabetic patients.

The loss of first-phase insulin secretion is a characteristic feature of type 2 diabetic patients. The fast-acting insulin analog lispro provides a therapeutic tool for assessing the metabolic outcome of restoration of an early rise in plasma insulin levels after the ingestion of an oral glucose load. We studied eight type 2 diabetic patients on two different occasions when they received an oral glucose load (50 g) preceded by either human regular insulin or insulin analog lispro (both 0.075 U/kg lean body mass). Tritiated glucose was infused throughout the studies, and the oral glucose was labeled with [13C6]glucose for monitoring systemic and oral glucose kinetics, respectively. Basal plasma glucose (8.2 +/- 0.9 vs. 7.5 +/- 0.8 mmol/l), insulin (224 +/- 21 vs. 203 +/- 21 pmol/l), and endogenous glucose production (10.4 +/- 1.0 vs. 11.1 +/- 1.1 micromol x kg(-1) x min(-1)) were similar on both occasions. In spite of comparable incremental areas under the curve, the time course of plasma insulin concentration was much different. After injection of regular insulin, plasma insulin peaked at 120 min (368 +/- 42 pmol/l), while with lispro, the peak occurred at 60 min (481 +/- 42 pmol/l). Plasma insulin concentration during the last 3 h of the study, however, was lower with lispro compared with regular insulin. The incremental area under the curve of plasma C-peptide was lower with lispro (0.05 +/- 0.01 vs. 0.13 +/- 0.04 micromol/300 min; P < 0.01). After the ingestion of the oral glucose load, plasma glucose concentration increased by 78% at 80-100 min with regular insulin and by 62% with lispro (P < 0.05) and remained lower for the ensuing 3 h. The incremental area under the curve was 46% lower with lispro (715 +/- 109 vs. 389 +/- 109 pmol/300 min; P < 0.01). There was no difference in the two studies in the rate of appearance of the ingested glucose and in the overall rate of glucose disposal. During the initial 90 min, however, the rate of endogenous glucose production was suppressed in a prompter and more profound manner when lispro was administered (1.39 +/- 0.10 vs. 5.00 +/- 1.22 micromol x kg(-1) x min(-1); P < 0.05), while there was no difference in the late prandial phase. These results show that an early rise in plasma insulin levels after the ingestion of a glucose load is associated with a significant improvement in glucose tolerance due to a prompter, though short-lived, suppression of endogenous glucose production. This amelioration in plasma glucose profile prevents late hyperglycemia and hyperinsulinemia. Therefore, restoration of a more physiologic profile of prandial plasma insulin profile represents a rational approach for treatment of type 2 diabetic patients.

What therapy do our NIDDM patients need? Insulin releasers

NIDDM is the result of concomitant defects in both insulin secretion and insulin action. Although plasma insulin concentration in NIDDM patients may be normal or even increased as compared to normal individuals, insulin secretion is always impaired when related to ambient hyperglycemia. Moreover, the loss of first-phase insulin secretion is always present and it occurs at the very early stage of the disease. The defect in the early release of insulin may have quite an impact in post-prandial glucose homeostasis, due to inadequate suppression of hepatic glucose production. Therefore, insulin releasers should be able; 1. to increase total insulin secretory capacity, and 2. to restore physiologic profile of insulin secretion. However, this is rarely achieved with the current therapeutical tools. Sulfonylureas may exert some suppressive action on the liver and may maintain a portal-peripheral venous insulin gradient. Metformin may improve insulin sensitivity but has no effect on the β-cell. Exogenous insulin exerts an inhibitory effect on hepatic glucose production but it does not maintain the physiologic gradient, neither can it mimic first-phase insulin secretion. Therefore, more appropriate tools must be sought. Prompt stimulation of insulin secretion can be elicited by alpha 2-adrenoreceptor antagonists, but their clinical use is still under evaluation. New sulfonylureas are under development, though some of them may exert a better peripheral action than more potent stimulation of the β-cell. Special interest has been focused on incretin peptides. Infusion of glucagon-like peptide 1 (GLP-1) in NIDDM patients improves glucose tolerance through enhancement of acute release of insulin, suppression of glucagon secretion, and improvement of peripheral glucose utilization. Finally, the possibility should be considered to reproduce rather than stimulate first-phase insulin secretion by s.c. injection of fast-acting insulin analogs. Whatever the mean will be used, restoration of first-phase insulin secretion may be expected to improve post-prandial glucose profile as a consequence of better modulation of hepatic glucose production. The reduced rise in post-prandial plasma glucose level is likely to relieve the challenge on the β-cell so that a smoother second phase insulin secretion is obtained. In the long run, this may translate in an overall amelioration of glucose control while avoiding chronic hyperinsulinemia.

Pathogenesis of NIDDM. A balanced overview.

Non-insulin-dependent diabetes mellitus (NIDDM) results from an imbalance between insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional studies have demonstrated that the earliest detectable abnormality in NIDDM is an impairment in the body's ability to respond to insulin. Because the pancreas is able to appropriately augment its secretion of insulin to offset the insulin resistance, glucose tolerance remains normal. With time, however, the beta-cell fails to maintain its high rate of insulin secretion and the relative insulinopenia (i.e., relative to the degree of insulin resistance) leads to the development of impaired glucose tolerance and eventually overt diabetes mellitus. The cause of pancreatic "exhaustion" remains unknown but may be related to the effect of glucose toxicity in a genetically predisposed beta-cell. Information concerning the loss of first-phase insulin secretion, altered pulsatility of insulin release, and enhanced proinsulin-insulin secretory ratio is discussed as it pertains to altered beta-cell function in NIDDM. Insulin resistance in NIDDM involves both hepatic and peripheral, muscle, tissues. In the postabsorptive state hepatic glucose output is normal or increased, despite the presence of fasting hyperinsulinemia, whereas the efficiency of tissue glucose uptake is reduced. In response to both endogenously secreted or exogenously administered insulin, hepatic glucose production fails to suppress normally and muscle glucose uptake is diminished. The accelerated rate of hepatic glucose output is due entirely to augmented gluconeogenesis. In muscle many cellular defects in insulin action have been described including impaired insulin-receptor tyrosine kinase activity, diminished glucose transport, and reduced glycogen synthase and pyruvate dehydrogenase. The abnormalities account for disturbances in the two major intracellular pathways of glucose disposal, glycogen synthesis, and glucose oxidation. In the earliest stages of NIDDM, the major defect involves the inability of insulin to promote glucose uptake and storage as glycogen. Other potential mechanisms that have been put forward to explain the insulin resistance, include increased lipid oxidation, altered skeletal muscle capillary density/fiber type/blood flow, impaired insulin transport across the vascular endothelium, increased amylin, calcitonin gene-related peptide levels, and glucose toxicity.

Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans.

To examine the importance of first-phase insulin secretion on total body glucose homeostasis, six normal subjects (age, 24 +/- 1 yr; ideal body wt, 100 +/- 1%) received three hyperglycemic (+75 mg/100 ml) clamp studies in combination with [3-3H]glucose: study I, 150 min hyperglycemic clamp; study II, hyperglycemic clamp plus somatostatin (6 micrograms/min) plus basal glucagon replacement (0.4 ng.kg-1.min-1) plus an insulin infusion designed to mimic only the second phase of insulin secretion; and study III, hyperglycemic clamp plus somatostatin plus basal glucagon plus an insulin infusion designed to mimic both the first and second phase of insulin secretion. Basal plasma C-peptide concentrations averaged 0.21 +/- 0.01 pmol/ml in the three study protocols. In study I the plasma C-peptide response demonstrated an early burst within the first 10 min followed by a gradually increasing phase of C-peptide secretion that lasted until the end of the study. In studies II and III plasma C-peptide declined within the first 10 min after somatostatin was started and averaged 0.06 +/- 0.01 and 0.05 +/- 0.01 pmol/min, respectively. Basal hepatic glucose production (2.3 +/- 0.2 mg.kg-1.min-1) was suppressed by 90% at 20 min and remained suppressed thereafter in studies I and III. In contrast, in study II hepatic glucose production was inhibited by only 50% (1.1 +/- 0.2 mg.kg-1.min-1) at 60 min (P less than 0.01 vs. studies I and III) and remained incompletely suppressed even after 150 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Artificial endocrine pancreas (closed-loop-system for blood sugar control in diabetes mellitus): introduction to the subject.

Clearly, continuous blood glucose monitoring by portable instruments is the only and absolute prerequisite for unprejudiced evaluation of the various strategies for substitution of insulin deficiency in any form of diabetes mellitus. Continuous blood or tissue glucose monitoring remain the prerequisite for reestablishing a satisfactory feedback control mechanism between insulin secretion and blood glucose concentration in any nondiabetic patient. Loss of first-phase insulin secretion produces defects in regulation of carbohydrate metabolism, as in type II diabetic human subjects. All efforts to solve this important problem are justified.