Constant Hyperglycemia Research Articles

Transient but not chronic hyperglycemia accelerates ocular glymphatic transport

Glymphatic transport is vital for the physiological homeostasis of the retina and optic nerve. Pathological alterations of ocular glymphatic fluid transport and enlarged perivascular spaces have been described in glaucomatous mice. It remains to be established how diabetic retinopathy, which impairs vision in about 50% of diabetes patients, impacts ocular glymphatic fluid transport. Here, we examined ocular glymphatic transport in chronic hyperglycemic diabetic mice as well as in healthy mice experiencing a daily transient increase in blood glucose. Mice suffering from severe diabetes for two and four months, induced by streptozotocin, exhibited no alterations in ocular glymphatic fluid transport in the optic nerve compared to age-matched, non-diabetic controls. In contrast, transient increases in blood glucose induced by repeated daily glucose injections in healthy, awake, non-diabetic mice accelerated antero- and retrograde ocular glymphatic transport. Structural analysis showed enlarged perivascular spaces in the optic nerves of glucose-treated mice, which were absent in diabetic mice. Thus, transient repeated hyperglycemic events, but not constant hyperglycemia, ultimately enlarge perivascular spaces in the murine optic nerve. These findings indicate that fluid transport in the mouse eye is vulnerable to fluctuating glycemic levels rather than constant hyperglycemia, suggesting that poor glycemic control drives glymphatic malfunction and perivascular enlargement in the optic nerve.

Chemical Constituents Based Approach for the Management of Diabetes.

A number of complexities in compliance with long-term diabetes have been elicited. It has become a global concern without any convincing medicinal, therapeutical methodology. Both hyperglycaemia and oxidative pressure are major notable parts that play a significant role in the initialization of diabetic inconvenience. Natural medications have gained a lot of attention in recent years as expected restorative specialists in the prevention and treatment of diabetic complications due to their many objectives and less poisonous outcomes. This survey means to evaluate the accessible information on therapeutic spices for constriction and the executives of diabetic complications. Bibliographic investigation was accomplished by checking old-style course books and papers, directing overall bases of logical information (SCOPUS, PUBMED, SCIELO, Google Scholar, NISCAIR,) to recapture accessible distributed writing. For the assessment of plants with the potential in calming diabetic complications, several inclusion models rely on the numerous medicinal spices as well as their crucial mixes. Furthermore, several models, including plants, have been considered, each of which has a suitable impact on increasing oxidative pressure in diabetes. Different therapeutic plants/plant withdrawals containing alkaloids, terpenoids, phenolic compounds, flavonoids, saponins, and phytosterol-type synthetic constituents were uncovered that are profitable in the administration of diabetic complexities. Results may be attributed to the improvement of oxidative pressure, constant hyperglycemia, and twitch of different metabolic pathways related to the pathogenesis of diabetic confusions. An optimistic approach for new medication terminology to treat diabetic confusion is screening compound competitors from homegrown medication. Investigation of the activity of different plant extracts as well as their potency profile and to determine their job in the treatment of diabetic inconveniences must be there. In addition, an ideal rat model which imitates human diabetic complications ought to be created.

KETOSIS MANAGEMENT IN A TYPE 2 DIABETES MELLITUS PATIENT: A NUTRITIONAL APPROACH

Ketosis-inclined type 2 diabetes, an insulin deficiency tends to occur in response to constant hyperglycemia auxiliary to insulin resistance. Hyperglycemia will additionally restrict the secretion of insulin, and a few examinations have even shown a decrease of insulin production at the genetic level by restraining transcription of insulin-producing proteins. Here in this study, we detailed a patient having ketosis in Type 2 Diabetes mellitus and observed all require parameter in dietary management. The patient was found ketone positive in initial days. Due to high level of blood sugar and constipation, he was suggested a diabetic fluid diet and high fiber content meal. Initially Glucose level was 187mg/dl and Hb level- 12.5, after the observation with maintain diet the Hb level- 14.5 and Glucose level was >150mg/dl. Serum proteins and albumin were also found in normal range and the patients found ketone negative in later stage. To date, clinical trials have provided evidence of benefits of Keto diets in terms of clinical outcomes. However, the molecular events responsible for these improvements still remain unclear in spite of the high amount of knowledge on the primary mechanisms of both the diabetes and the metabolic state of ketosis.

Effect of glucose concentration and culture substrate on HUVECs viability in in vitro cultures: A literature review and own results

Some clinical studies reported that glucose variability increased the risk of developing diabetes-related late complications more than constant hyperglycemia, while others claimed that the evidence was not strong enough to support such a conclusion. A few in vitro studies investigated the effect of constantly high or variable glucose levels (VGLs) on endothelial cells (EC). The first aim of this work was to review these studies and demonstrate that most of them support the notion that viability and other metabolic parameters of EC deteriorate faster in cell cultures with VGLs than in cultures with stable normal or high glucose concentration. The second aim was to verify whether the effect of glucose concentration is the same regardless of other culture conditions such as the substrate on which the cells are grown. We cultured Human Umbilical Vein Endothelial Cells (HUVECs) for 7 or 14 days in constant (5 mM or 20 mM) or variable (switching between 5 mM and 20 mM once a day) glucose concentration in culture plates, which were either not-covered with any additional substrate or were covered with fibronectin or gelatin. We assessed the cell viability using a propidium iodide test. The ANOVA revealed that HUVECs viability was affected not only by glucose concentration and duration of the cell culturing but also by the type of substrate and interactions of these three factors. In conclusion, the effect of glucose level on EC viability should not be analyzed in isolation from other culture conditions that may amplify or attenuate this effect.

The Fluctuation of Serum PTH Level of Type 2 Diabetes mellitus’ Patient on Oral Dapagliflozin

Background: Sodium-Glucose co-Transporter 2 (SGLT2) inhibitors, a set of relatively new medicines treating type 2 diabetes showed a great number of merits in control of glycemia and cardiovascular risk factor management, but also attracted attention on bone fracture. One of those major effects on skeleton might be Parathyroid Hormone (PTH). Case Presentation: We present the case of a 68-year-old female patient with type 2 diabetes on insulin injection and oral acarbose therapy who was admitted with constant hyperglycemia to our hospital. In the beginning, she showed a high level of serum PTH. In the process of oral dapagliflozin treatment, PTH concentration firstly increased and then decreased to the normal range. Diagnostic tests are completed to exclude hyperparathyroidism. Conclusions: The use of SGLT2 inhibitors among diabetes and nondiabetic populations is increasing, a great deal of undiscovered influence, such as hormone and ion fluctuation needs further investigation.

Assessment of Diabetes Health Promotion Behaviors for Clients with Type 2 Diabetes Mellitus at Diabetic Center in Al-Diwaniya City

Background: Diabetes mellitus (DM) is a significant worldwide medical issue that causes high human,social, and financial expenses on nations at all pay levels. The constant hyperglycemia of diabetes is relatedto long-term damage, brokenness, and disappointment of different organs, particularly of the eyes, kidneys,nerves, heart, and blood vessels.Method: A descriptive correlational design is used in this study which aims to measure health-relatedexperiences and lifestyle behaviors for clients with type 2 diabetes for the period from (1st October 2019 to27th August 2020). The study included a convenience sample of 358 clients with type 2 diabetes mellituswho were recruited from Al-Diwaniya Teaching Hospital at Diabetes and Endocrine Center.Data were collected using a self-report study instrument that includes the socio-demographic sheet, thehealth profile, and the Type 2 Diabetes and Health Promotion Scale. The data were analyzed using StatisticalPackage for Social Sciences (SPSS) version 26 using the frequency, percent, arithmetic mean, standarddeviation, Pearson correlation, Independent-sample t-test, and one-way analysis of variance (ANOVA).The study results displayed that most of participants reported poor Physical Activity level (n = 266; 74.3%),more than two-fifth reported good Risk Reduction level (n = 148; 41.3%), less than two-fifth reportedgood Stress Management level (n = 134; 37.4%), less than two-fifth reported fair Healthy Diet level (n= 135; 37.7%), more than two-fifth reported good overall behavior (n = 193; 53.9%). Furthermore, thereare statistically significant inverse correlations between participants’ age and their Physical Activity, RiskReduction, Stress Management, Enjoying Life, and overall behavior.Conclusion: The researcher concluded that the younger the clients, the poorer the Physical Activity, RiskReduction, Stress Management, Enjoying Life, and overall behavior; the older the client, the better theHealth Responsibility; the better socioeconomic status, the better the Physical Activity, Risk Reduction,Stress Management, Enjoying Life, and overall behavior.

In Vitro Bioaccessibility of Extractable Compounds from Tannat Grape Skin Possessing Health Promoting Properties with Potential to Reduce the Risk of Diabetes.

Diabetes pathogenesis encompasses oxidative stress, inflammation, insulin malfunctioning and partial or total insulin secretion impairment, which leads to a constant hyperglycemia. Polyphenols are known to possess bioactive properties, being Tannat grape skin a natural and sustainable source of these compounds. The present study aimed to find out the bioaccessibility of health-promoting molecules composing a multifunctional extract from Tannat grape skin obtained under hydro-alcoholic-acid conditions. The identification of phenolic compounds in the samples was performed by ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Subsequently, the samples were in vitro digested mimicking the human oral gastrointestinal conditions and the bioactivity of the digest (antioxidant, anti-inflammatory and modulation of glucose metabolism) was assessed. Effect on glucose metabolism was estimated by measuring carbohydrases activity and the functionality of glucose transporters of small intestine cells in presence and absence of the digested extract. Flavonoids, phenolic acids and phenolic alcohols were the major phenol compounds detected in the extract. The bioaccessible compounds protected the intestinal cells and macrophages against the induced formation of reactive oxygen species (ROS) and nitric oxide (NO). In addition, glucose transporters were inhibited by the digested extract. In conclusion, the bioaccessible compounds of the extract, including phenols, modulated key biochemical events involved in the pathogenesis of diabetes such as oxidative stress, inflammation and glucose absorption. The extract was effective under prevention with co-administration conditions supporting its potential for either reducing the risk or treating this disease.

Antidiabetic treatment on memory and spatial learning: From the pancreas to the neuron.

The detrimental effects of constant hyperglycemia on neural function have been quantitatively and qualitatively evaluated in the setting of diabetes mellitus. Some of the hallmark features of diabetic encephalopathy (DE) are impaired synaptic adaptation and diminished spatial learning capacity. Chronic and progressive cognitive dysfunction, perpetuated by several positive feedback mechanisms in diabetic subjects, facilitates the development of early-onset dementia and Alzheimer’s disease. Despite the numerous clinical manifestations of DE having been described in detail and their pathophysiological substrate having been elucidated in both type 1 and type 2 diabetes mellitus, an effective therapeutic approach is yet to be proposed. Therefore, the aim of this review is to summarize the growing body of evidence concerning the effect of current antidiabetic treatment options on diabetic and non-DE.

Analysis of diabetes mellitus for early prediction using optimal features selection

Diabetes is a chronic disease or group of metabolic disease where a person suffers from an extended level of blood glucose in the body, which is either the insulin production is inadequate, or because the body’s cells do not respond properly to insulin. The constant hyperglycemia of diabetes is related to long-haul harm, brokenness, and failure of various organs, particularly the eyes, kidneys, nerves, heart, and veins. The objective of this research is to make use of significant features, design a prediction algorithm using Machine learning and find the optimal classifier to give the closest result comparing to clinical outcomes. The proposed method aims to focus on selecting the attributes that ail in early detection of Diabetes Miletus using Predictive analysis. The result shows the decision tree algorithm and the Random forest has the highest specificity of 98.20% and 98.00%, respectively holds best for the analysis of diabetic data. Naïve Bayesian outcome states the best accuracy of 82.30%. The research also generalizes the selection of optimal features from dataset to improve the classification accuracy.

Circulating microRNAs as biomarkers for diabetic neuropathy: A novel approach.

Oxidative stress stemming from tissue exposure to constant hyperglycemia is one of the major pathogenetic pathways of diabetic macro- and microvascular complications. Diabetic polyneuropathy, commonly manifesting as distal, symmetrical sensorimotor polyneuropathy, is characterized by progressive severity of symptoms, with rates analogous to the quality of glycemic control achieved by the patients and physicians. Palliative care with analgesics and aggressive glycemic control often improve quality of life in the absence of causative treatment. Currently, there is a growing body of evidence indicating the role of microRNAs in the pathogenesis of diabetic complications, with emphasis on diabetic nephropathy and neuropathy. Therefore, in this review, we aim to explore the role of microRNAs and their polymorphisms in the pathophysiology of diabetic polyneuropathy, as well as, the possibility of novel diagnostic and therapeutic applications by epigenetic profiling and manipulation.

The impact of glycemic variability on diabetic peripheral neuropathy.

Mean glucose values alone cannot explain the patterns of morbidity and mortality due to dysglycemia in diabetes. Development of continuous glucose monitoring systems has improved the analysis and interpretation of glycemic variability. The roles of glycemic components other than constant hyperglycemia in diabetic complications must be investigated because large clinical studies have indicated that risk factors besides the average glucose value of HbA1c are involved in chronic macrocomplications/microcomplications of diabetes. Among these complications, the pathogenesis of diabetic peripheral neuropathy is particularly complex, and several factors related to glucose and nonglucose pathways have been suggested as risk factors. There is little information regarding the effect of glycemic variability on diabetic peripheral neuropathy, unlike other microvascular complications of retinopathy and nephropathy, and whether glycemic variability causes harmful effects is still a matter of debate. In this review, we discuss the relationships between glycemic variability and diabetic peripheral neuropathy, focusing on somatosensory peripheral neuropathies rather than autonomic neuropathies.

Understanding basic carbohydrate counting, glycemic index, and glycemic load for improved glycemic control in Hispanic patients with type 2 diabetes mellitus.

Hispanic patients with type 2 diabetes mellitus generally have poor glycemic control. Constant hyperglycemia in individuals with type 2 diabetes can cause microvascular and macrovascular complications that lead to early morbidity and mortality. Good glycemic control requires a balance between diet, exercise, and medication, but dietary balance is difficult to achieve for many patients. Of the macronutrients, carbohydrates mostly affect blood glucose levels. Basic carbohydrate counting, glycemic index, and glycemic load are important tools for patients to master to control their blood glucose levels.

MORPHOFUNCTIONAL CHANGES OF PITUITARY-NEUROHYPOPHYSIS SYSTEM IN IMMATURE RATS WITH STREPTOZOTOCIN DIABETES MELLITUS

The research is devoted to the study of morphofunctional organization of the pituitary-neurohypophysis system of diabetes type 1. It was found that on the 14 th day after the streptozotocin diabetes simulation in 1-month old animals with hyperglycemia the increasing of functional activity of neurosecretory cells of supraoptic nuclei and increasing of bulk density in their neurosecretory granules are observed. Because of such conditions in the nervous lobe of neurohypophysis increase of bulk density of neurosecretory granules by the diffusing and the residual types are observed. On the 42 th day of the experiment constant high hyperglycemia leads to the stage of depletion of neurosecretory cells of supraoptic and paraventricular nuclei and development of dystrophic-destructive changes in them. In the neurohypophysis the reducing of bulk density of young and mature neurosecretory granules is observed. In the pituicytes of type-2 a large number of different sizes and shapes of lipid drops are observed.

Periodic vs constant high glucose in inducing pro-inflammatory cytokine expression in human coronary artery endothelial cells

Fluctuating hyperglycemia exerts a more deleterious effect than constant hyperglycemia on cardiovascular outcome in diabetic patients. We investigated the inflammatory responses of human coronary artery endothelial cells (HCAECs) to constant and periodic high glucose in vitro. HCAECs were incubated for 72 h continuously either in normal glucose (5.5 mmol/L), constant high glucose (25 mmol/L glucose), periodic high glucose (5.5 and 25 mmol/L glucose alternating every 6 h) or mannitol. Concentrations of interleukin (IL)-6, tumor necrosis factor (TNF)-α and intercellular adhesion molecule (ICAM)-1 in the supernatants of cell culture were measured using ELISA kits. The mRNAs of IL-6, TNF-α and ICAM-1 were evaluated by real-time quantitative PCR. Periodic high glucose caused a more intense inflammatory response than normal glucose and constant high glucose in HCAECs, with a marked increase in IL-6, TNF-α and ICAM-1 in supernatants of cell culture (P < 0.05). The concentrations of the three pro-inflammatory cytokine mRNAs were higher in cells exposed to periodic high glucose than those exposed to constant high glucose and normal glucose (P < 0.05). In cultured HCAECs, periodic high glucose evoked a more intense inflammatory response than constant high glucose.

Hyperglycemia Induces the Variations of 11β-Hydroxysteroid Dehydrogenase Type 1 and Peroxisome Proliferator-Activated Receptor-γExpression in Hippocampus and Hypothalamus of Diabetic Rats

In this paper, we first observed that there were differences in expressions of 11β-HSD1 and PPAR-γ, in hippocampi and hypothalami, among constant hyperglycemia group, control group and the fluctuant glycemia group, using Immunohistochemical analysis. However, whether in expression o f 11β-HSD1 or PPAR-γ, there were no statistic differences between the control group or the fluctuant glycemia group. So, we removed the fluctuant glycemia group, retaining only constant hyperglycemia group and control group, being fed for 8 weeks. After 8 weeks of induction, 11β-HSD1 expression increased and PPAR-γ expression decreased in the constant hyperglycemia group compared with control group, both in hippocampi and hypothalami, by Western Blot. The constant hyperglycemia group also showed impaired cognition in MORRIS watermaze, lower serum corticosterone level, and higher Serum ACTH concentration after 8 weeks. We inferred that the cognition impairment may be related to the abnormal expression of 11β-HSD1 and PPAR-γ in central nerves system. As for 11β-HSD1 is a regulating enzyme, converting the inactive 11-dehydrocorticosterone into the active glucocorticoid corticosterone, thus amplifying GC action in local tissues. It is also well known that high local GC levels can affect the cognitive function. In addition, PPAR-a protective receptor, which is related to cognition.

Differential Effects of Chronic Pulsatile versus Chronic Constant Maternal Hyperglycemia on Fetal Pancreaticβ-Cells

Constant maternal hyperglycemia limits, while pulsatile maternal hyperglycemia may enhance, fetal glucose-stimulated insulin secretion (GSIS) in sheep. However, the impact of such different patterns of hyperglycemia on the development of the fetal β-cell is unknown. We measured the impact of one week of chronic constant hyperglycemia (CHG, n = 6) versus pulsatile hyperglycemia (PHG, n = 5) versus controls (n = 7) on the percentage of the fetal pancreas staining for insulin (β-cell area), mitotic and apoptotic indices and size of fetal β-cells, and fetal insulin secretion in sheep. Baseline insulin concentrations were higher in CHG fetuses (P < 0.05) compared to controls and PHG. GSIS was lower in the CHG group (P < 0.005) compared to controls and PHG. PHG β-cell area was increased 50% (P < 0.05) compared to controls and CHG. CHG β-cell apoptosis was increased over 400% (P < 0.05) compared to controls and PHG. These results indicate that late gestation constant maternal hyperglycemia leads to significant β-cell toxicity (increased apoptosis and decreased GSIS). Furthermore, pulsatile maternal hyperglycemia increases pancreatic β-cell area but did not increase GSIS, indicating decreased β-cell responsiveness. These findings demonstrate differential effects that the pattern of maternal hyperglycemia has on fetal pancreatic β-cell development, which might contribute to later life limitation in insulin secretion.

Progressive Decline in Insulin Levels in Rabson-Mendenhall Syndrome1

Mutations in the insulin receptor gene cause the severe insulin-resistant syndromes leprechaunism and Rabson-Mendenhall syndrome, whose metabolic features include fasting hypoglycemia, post-prandial hyperglycemia, and extremely elevated insulin levels. Patients with Rabson-Mendenhall syndrome have a protracted course and eventually develop ketoacidosis. To determine the mechanism causing this progression and the paradoxical fasting hypoglycemia, we conducted a retrospective study in a patient with Rabson-Mendenhall syndrome, who was a compound heterozygous for two missense mutations affecting the kinase domain of the insulin receptor beta-subunit (I1115T and R1131W). At birth, the patient had fasting hypoglycemia and postprandial hyperglycemia. This was followed at approximately 3 yr of age by constant hyperglycemia and, at 6 yr of age, by constant ketoacidosis. Urinary organic acids during ketoacidosis resembled those of patients with type 1 diabetes. Plasma glucose levels increased (r2 = 0.31; P < 0.01), whereas insulin levels decreased with age (r2 = 0.51; P < 0.01). During periods ofhypoglycemia and hyperglycemia (0-1 yr of age), constant hyperglycemia (3-4 yr of age), and hyperglycemia with ketoacidosis (6-7 yr of age), insulin levels were significantly correlated with plasma glucose levels (P < 0.05). However, the slope of the regression and the predicted insulin level at zero glucose decreased with increasing age. When insulin levels were normalized for the plasma glucose concentrations, an exponential decrease in the insulin/glucose ratio was observed (r2 = 0.92; P < 0.01), with most of the decline occurring before 2 yr of age. These results indicate that the paradoxical fasting hypoglycemia of patients with Rabson-Mendenhall syndrome is associated with severely increased levels of circulating insulin and that the progression of this disease is due to a decline in insulin levels.

Insulin, branched-chain amino acids, and growth failure in uremia.

Insulin and branched-chain amino acid (BCAA) metabolism was studied in 14 adolescents with uremia on hemodialysis. Glucose tolerance was measured by intravenous glucose tolerance tests. Insulin sensitivity was measured by the euglycemia clamp technique. Insulin secretion during constant hyperglycemia was measured by the hyperglycemic clamp technique. Fasting plasma BCAA concentrations were compared with data from 8 adolescent controls, whereas insulin indices were compared with 8 young adults controls and with published normal data in adolescents. The patients could be further sub-divided into two groups with respect to their growth velocity standard deviation score (GVSDS). Group 1 consisted of 7 patients with GVSDS less than -2. This group demonstrated insulin resistance, glucose intolerance, and low insulin secretion. This group also had low plasma valine, leucine, and isoleucine concentrations compared with control values. Group 2 consisted of 7 patients with GVSDS more than -2. This group demonstrated insulin resistance, but normal glucose tolerance and normal insulin secretion. Plasma valine, leucine, and isoleucine concentrations in group 2 were not different from control values. Total plasma BCAA correlated with glucose tolerance index and with insulin secretion, but not with insulin sensitivity. Growth failure in uremia is associated with glucose intolerance, hypoinsulinemia, and low plasma BCAA concentrations. Impaired utilization of conventional energy sources leading to preferential oxidation of BCAA may contribute to reduced anabolism and growth failure in uremia.

Effect of metabolic acidosis on insulin action and secretion in uremia

Metabolic acidosis affects both vitamin D and insulin metabolism. Vitamin D is important in modulation of both insulin secretion and insulin sensitivity in uremia. The present study examines the effect of correction of metabolic acidosis on insulin action and secretion as well as 1,25 vitamin D3 concentrations in uremic patients. Eight patients (age 18 +/- 1 year) on maintenance hemodialysis with metabolic acidosis were studied before and after two weeks of oral sodium bicarbonate (NaHCO3) treatment to correct the acidosis. To control for the effect of additional sodium, they were also studied after two weeks of an equivalent amount of oral sodium chloride (NaCl). Controls consisted of 7 healthy controls (age 19 +/- 1 year). Insulin sensitivity was measured by the hyperinsulinemic euglycemic clamp technique. Insulin secretion was measured by the hyperglycemic clamp technique. Oral NaHCO3 treatment led to significant increases in venous pH and serum bicarbonate concentrations but no significant change in intact parathyroid hormone (PTH) concentrations. Circulating 1,25 dihydroxyvitamin [(OH)2] D3 were significantly lower than control values initially and increased significantly after treatment. Oral NaCl did not change any of the biochemical parameters. Before treatment of acidosis, uremic patients had lower insulin sensitivity (insulin resistance) during constant hyperinsulinemia and lower insulin secretion during constant hyperglycemia compared with controls. Following two weeks of NaHCO3 treatment there were significant increases in insulin sensitivity and insulin secretion, although the values did not normalize. There were no changes in insulin sensitivity or insulin secretion following two weeks of NaCl. Treatment of metabolic acidosis increased both insulin sensitivity and insulin secretion in patients with uremia. This was accompanied by an increase in the circulating levels of 1,25(OH)2D3 but no change in those of parathyroid hormone.

Maturation of Glucose-Stimulated Insulin Secretion in Fetal Sheep

To determine the gestational maturation of fetal insulin response to glucose and arginine and the effects of sustained hyperglycemia on these processes, we measured insulin secretion in different groups of fetal sheep at 75, 100, 122, and 137 days of gestation (50, 67, 81, and 91% of term gestation, respectively). The basal glucose concentration decreased progressively from 1.36 ± 0.16 mM at 75 days to 1.00 ± 0.07 mM at 137 days (p < 0.05). The fetal plasma insulin concentration did not change (54 ± 11 pM at 75 days, 68 ± 8 pM at 137 days), but there was a significant increase in the increment in plasma insulin concentration in response to a hyperglycemic clamp over this same period (ΔI pM/ΔG mM) from 20 ± 3 at 75 days to 105 ± 8 at 137 days (p < 0.001). The ΔI (pM) in response to arginine also increased from 129 ± 17 pM at 75 days to 635 ± 103 pM at 137 days (p < 0.001). Sustained hyperglycemia from 90 to 100 days reduced the ΔI (pM)/ΔG (mM) to glucose (13 ± 2, p < 0.01) and the ΔI pM to arginine (369 ± 86, p < 0.05) to values less than those found in euglycemic animals (ΔI/ΔG = 58 ± 4 to glucose, ΔI = 525 ± 71 to arginine). Thus, glucose and arginine stimulate insulin secretion at midgestation at 20% of the rate near term, and there is a consistently positive developmental pattern of insulin secretion to these secretagogues over the second half of gestation. Furthermore, chronic, high, relatively constant hyperglycemia blunts insulin secretion to glucose and arginine close to midgestation, similar to the effect seen near term. Such developmental and adaptive capacities may account for an important part of the variability in fetal glucose metabolism observed in animal models and human cases of diabetes during pregnancy.