Pattern Of Insulin Response Research Articles

Hyperinsulinaemia in pregnancy and gestational outcomes: A case series

Background: Pathological insulin resistance in pregnancy is associated with an increased risk for complications such as gestational diabetes mellitus and pre-eclampsia. Individuals with pathological insulin resistance also exhibit hyperinsulinaemia. Currently, there are no diagnostic criteria for pathological hyperinsulinaemia in pregnancy that may be used to indicate risk of adverse outcomes.Aim: This case series aimed to explore the relationship between first trimester insulin response patterns and gestational outcomes.Setting: Auckland, New Zealand.Methods: Participants included four pregnant women with prepregnancy body mass index ≥ 25 kg/m2 and aged 25–35 years. Glucose and insulin response patterns were examined following a 120 min oral glucose tolerance test (OGTT) at 12–15 weeks of gestation using a modified Kraft methodology. Outcomes assessed at 25 and 35 weeks of gestation included gestational weight gain (GWG), blood pressure, fasting capillary blood glucose and foetal growth. Lifestyle and medical information were collected at each trimester. After delivery, total GWG, infant size, delivery method and clinical outcomes were recorded.Results: Kraft pattern IIB hyperinsulinaemia was identified in two cases. Amongst them, Case #1 experienced excessive GWG, induction of labour and surgically assisted delivery. Case #4 delivered by emergency caesarean, and the neonate required intensive care admission for 17 h. No cases developed hyperglycaemia or hypertension. Infant weights were between 3.75 kg and 3.86 kg.Conclusion: Dynamic insulin assay provides a promising template to assess metabolic risk in the first trimester of pregnancy. Diagnosing hyperinsulinaemia early in pregnancy means that lifestyle-based initiatives could be introduced earlier to mitigate excess GWG and potential adverse outcomes.

Improved Insulin Resistance and Glucose Variability by Super-Low Carbohydrate Diet

Background Diabetes mellitus (DM) has been more prevalent. American Diabetes Association (ADA) proposed the Standards of Medical Care in Diabetes-2022. For nutritional therapy, low carbohydrate diet (LCD) has been recognized for its benefits. Authors have continued diabetic research concerning LCD and meal tolerance test (MTT). Case Presentation The case is 61-year-old male with type 2 diabetes mellitus (T2DM) for years. His hemoglobin A1c (HbA1c) increased to 7.8% in autumn 2021, and further evaluation and treatment was conducted including LCD, daily check of meal and carbohydrate amount, 75 g OGTT, glucagon stimulation test (GST) and others. Results He was on super-LCD method including 12% of carbohydrate. His carbohydrate intake amount and 45-minutes post-prandial blood glucose showed significant correlation. The results of 75 g OGTT twice in May 2020 and December 2021 showed that similar pattern of glucose and insulin responses and insulinogenic index (IGI). In contrast, they showed decreased fasting immuno-reactive insulin (IRI) and Homeostasis model assessment insulin resistance (HOMA-R). For GST, C-peptide showed normal response. Discussion and Conclusion Judging from the results of MTT, OGTT, GST and IGI, he seems to show rather decreased insulin resistance by LCD associated with preserved insulin secretion ability to some degree. Further investigation would be required from pathophysiological point of view.

125-LB: Differential Influences of Gastric Bypass and Sleeve Gastrectomy on Glucose-Reducing Effects of DPP-4 Inhibitor

The two most commonly performed bariatric surgical procedures, gastric bypass (GB) and sleeve gastrectomy (SG), induce diabetes remission before any significant weight loss. While the role of entero-insular axis after SG remains unknown, weight-independent glycemic effects of GB have been attributed to larger systemic appearance of glucose and incretin effect. We examined the effect of increasing endogenous incretins 2-3 fold with a DPP-4 inhibitor on glycemic effects of GB and SG. Glucose and islet-cell secretory responses were measured in 4 subjects with a history of GB, 4 with SG and 4 non-surgical controls (CN) during 50-gram oral glucose ingestion with and without 200 mg sitagliptin orally on two separate days. GB, SG, and CN groups were matched for BMI, FFM, HbA1c, age, fasting glucose and insulin levels; GB and SG were matched for weight loss and time postsurgery; none had diabetes. Compared to SG-treated subjects and controls, subjects with prior GB had lower prandial glycemia (AUCGlucose 3hr) (P < 0.001), and higher AUCGlucagon 3hr (P < 0.0001). The expected differences in prandial insulin response pattern to glucose ingestion among surgical and controls was observed; however, AUCInsulin 3hr and AUCC-peptide 3hr were similar between groups. Sitagliptin did not change AUCGlucose 3hr in GB-treated subjects, whereas the prandial glucose response was reduced by 21 ± 13 % in SG-treated and non-surgical controls by sitagliptin. Enhanced endogenous incretins diminished early glucagon (AUCGlucagon 1hr) in all 3 groups (P < 0.05), improved β-cell glucose sensitivity in CN (P < 0.05), but it had no effect on beta-cell function in GB or SG subjects. Sitagliptin had no effect on insulin clearance or insulin sensitivity in fasting or fed states. These findings indicate that glucose metabolism after SG, similar to non-operated controls, is enhanced by incretins, which are at maximum in GB group and thus not influenced by DPP-4 inhibition. Disclosure H. Honka: None. M. S. Rayas: Research Support; Self; National Center for Advancing Translational Sciences. R. A. Defronzo: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk, Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk. A. Gastaldelli: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Consultant; Self; Eli Lilly and Company, Inventiva Pharma, Research Support; Self; Gilead Sciences, Inc., Speaker’s Bureau; Self; Novo Nordisk. M. Salehi: None. Funding National Institutes of Health (TR002646); National Institute of Diabetes and Digestive and Kidney Diseases (DK105379)

The different patterns of insulin response during Oral Glucose Tolerance Test (OGTT) in transfused young patients with β-Thalassemia.

Background and aim:Dysregulation of glucose metabolism is a common complication of transfusions in Transfusion Dependent Thalassemia (TDT) patients. For early diagnosis of glucose disturbances, screening is recommended. The age of starting and the type of screening vary; the more common methods are assessment of RPG, FPG, 2h PG and 2 hours OGTT. The combined assessment of glucose tolerance and insulin response during OGTT is rarely recommended. The main objective of the study is the evaluation of simultaneous assessment of Glucose Tolerance (GT) and Insulin Response (IR) during OGTT in patients with TDT.Methods:43 TDT patients aged 12-28years, without clinical evidence of glucose disturbances, were randomly selected for the study. The 2-hour OGTT in 30 minutes intervals was applied. Plasma glucose and insulin were assessed in all samples using routine laboratory methods.Results:Of 43 patients 31(72%) had Normal GT; of them 9 (29%) had normal insulin response (NIR), 14 (45%) high IR and 8(26%) delayed peak IR. Delayed peak IR was found in 8 of the 9 patients with Impaired GT and in 2 of the 3 with diabetic GT. Deficient IR (hypoinsulinemia) was found in two patients.Conclusions:Simultaneous assessment of GT and IR during OGTT in TDT patients, seems to be a most sensitive and creditable screening test for early diagnosis of glucose disturbances. High IR and delayed peak IR in normoglycemic patients are valuable indices for diagnosis of the pre-diabetic state that precede the development of glucose disturbances in TDT patients and start proper follow and management. (www.actabiomedica.it).

47 Quantitative evaluation of hunger in pregnant sows: metabolic and hormonal responses to feeding frequency under limit-fed regime

Abstract The objectives of the study were to determine the pattern of glucose, insulin, active ghrelin, and total PYY responses and indirectly quantify perceived hunger in pregnant sows under-limit fed conditions. Eighteen sows [(Landrace × Yorkshire); BW 211.86 ± 1.29 kg; parity 3.80 ± 0.16; backfat 13.50 ± 0.25 mm)] were sampled from 180 sows. Sows were blocked by parity and BW and randomly assigned to 1 of 3 treatments in a RCBD. Treatments included sows fed once at [0730 h (Control, T1), twice [half ration at 0730 and 1530 h (T2)], or thrice [one-third portion at 0730, 1130, and 1530 h (T3)]. The daily feed quantity was kept at 1.25× maintenance energy intake (100 × (BW)0.75) kcal ME/d. Sows received corn-soybean meal-based diet which provided 6935 kcal ME/d and SID Lys:ME of 1.71 g/Mcal from d 30 to 60 of gestation. Hunger was quantified using total area under the curve (AUC) of the hormonal responses. Data analysis was done using PROC MIXED and GLIMMIX procedure of SAS. Sow was the experimental unit. Adjustment for multiple comparisons was by Tukey’s method. The control sows had greater 23-h mean glucose concentration than sows fed 3× daily (P = 0.002). Active ghrelin concentration for sows fed 3× daily tended to be lower (P = 0.063) compared with control sows but reduced (P = 0.018) relative to sows fed 2× daily. In conclusion, sows fed 3× daily had 9.0% reduction in 23-h glucose total AUC, 42.5% greater 23-h insulin total AUC, 27.4% reduction in active ghrelin total AUC, and 14.2% greater PYY total AUC compared with pregnant sows fed 1× daily. It is suggested that hunger in pregnant sows occurs at active ghrelin/total PYY ratio of 5.06 ± 0.20 and at a mean plasma glucose concentration of 70.37 ± 1.39 mg/dL and below.

Longitudinal Pattern of First-Phase Insulin Response Is Associated With Genetic Variants Outside the Class II HLA Region in Children With Multiple Autoantibodies.

A declining first-phase insulin response (FPIR) is associated with positivity for multiple islet autoantibodies, irrespective of class II HLA DR-DQ genotype. We examined the associations of FPIR with genetic variants outside the HLA DR-DQ region in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study in children with and without multiple autoantibodies. Association between FPIR and class I alleles A*24 and B*39 and eight single nucleotide polymorphisms outside the HLA region were analyzed in 438 children who had one or more FPIR results available after seroconversion. Hierarchical linear mixed models were used to analyze repeated measurements of FPIR. In children with multiple autoantibodies, the change in FPIR over time was significantly different between those with various PTPN2 (rs45450798), FUT2 (rs601338), CTSH (rs3825932), and IKZF4 (rs1701704) genotypes in at least one of the models. In general, children carrying susceptibility alleles for type 1 diabetes experienced a more rapid decline in insulin secretion compared with children without susceptibility alleles. The presence of the class I HLA A*24 allele was also associated with a steeper decline of FPIR over time in children with multiple autoantibodies. Certain genetic variants outside the class II HLA region may have a significant impact on the longitudinal pattern of FPIR.

Determining a diagnostic algorithm for hyperinsulinaemia

Background: Ascertaining Kraft dynamic insulin response patterns following a 3-h 100 g oral glucose tolerance test seems to be the most reliable method for diagnosing hyperinsulinaemia. However, this test may be too resource-intensive for standard clinical use.Aim: This study aims to see if Kraft patterns can be accurately predicted using fewer blood samples with sensitivity and specificity analyses.Setting: St Joseph Hospital, Chicago, Illinois, United States and Human Potential Centre, Auckland University of technology, Auckland, New Zealand.Method: We analysed the results of 4185 men and women with a normal glucose tolerance, who had a 100 g oral glucose tolerance test with Kraft pattern analysis. Participants were dichotomised into normal–low insulin tolerance (Kraft I or V patterns) or hyperinsulinaemia (Kraft IIA–IV patterns). Sensitivity and specificity analysis was applied to available variables (including age, body mass index, fasting insulin or glucose) both individually and in combination.Results: Out of a maximal combined sensitivity and specificity score of 2.0, 2-h insulin level 45 µU/mL attained the highest score (1.80). Two-hour insulin also attained the highest sensitivity ( 30 µU/mL, 0.98) and the highest specificity ( 50 µU/mL, 0.99) scores. Combining the 2-h insulin with other variables reduced the sensitivity and/or specificity. Dynamic measures had a better combined sensitivity and specificity compared to fasting or anthropological measures.Conclusion: People with a 2-h plasma insulin level 30 µU/mL are unlikely to be hyperinsulinaemic. Given that first-line treatment is lifestyle modification, we recommend that a 2-h plasma insulin level 30 µU/mL following a 100 g oral glucose tolerance test be used to identify the hyperinsulinaemic individual.

The Effects of Mixed Nut Consumption on Satiety, Anxiety, Postprandial Glucose, Insulin Response, and Bowel Movement Patterns in Healthy Adults (P06-008-19)

ObjectivesNuts are a rich source of nutrients, fiber, antioxidants and phytochemicals which may reduce the risk for chronic diseases. Many studies have examined the effects of individual types of nuts only. There is limited research investigating if the beneficial effects extend to the consumption of a nut mixture, which is how people more often choose to consume nuts. Therefore, the purpose of this study was to examine the effects of daily mixed nut consumption on satiety, postprandial glucose, insulin response, anxiety and bowel movement patterns in healthy young adults. MethodsSubjects (N = 20) were randomized into two groups either consuming 42 g (250 Kcal) of mixed nuts (n = 10, 9 females, 1 male, age 24.5 ± 1.2 y, BMI 24.8 ± 1.5 kg/m2) containing cashews, almonds, pecans, peanuts, walnuts, pistachios, brazil and macadamia nuts or 46 g of iso-Kcaloric lightly salted potato chips (n = 10, 8 females, 2 males, age 24.2 ± 1.0 y, BMI 23.3 ± 1.0 kg/m2) every day for three weeks. Measurements for blood pressure (BP) using an automatic BP monitor, waist to hip ratio, satiety using a visual analogue scale, anxiety using the State-Trait Anxiety Inventory Scale and bowel movement patterns using a 7-day bowel movement diary were taken at baseline and wk 3. Plasma glucose and insulin levels were measured at baseline, 45mins postprandial and at wk 3 and analyzed using an ultrasensitive insulin enzyme-linked immunosorbent assay. ResultsBoth types of snack consumption increased satiety while only mixed nut consumption improved postprandial glucose and insulin levels (P < 0.05). Body weight, BMI (body mass index), body fat, systolic and diastolic BP, waist and hip circumferences, waist to hip ratio, and anxiety were not significantly different among groups. Both the potato chip and mixed nut groups significantly reduced straining during bowel movements however only the mixed nut group significantly increased stool amount (P < 0.05). ConclusionsThe consumption of mixed nuts stabilized postprandial glucose and insulin responses and improved bowel movement patterns more than the potato chip group suggesting that the regular consumption of mixed nuts may reduce the risk for developing diabetes as well as improve gut health. Funding SourcesAmerican Heart Association (16GRNT31360007).

Repeatability characteristics of insulin response patterns and measures of insulin resistance

Background: Hyperinsulinaemia is emerging as an independent risk factor for metabolic disease, but diagnostic measures are limited. It is plausible that insulin resistance measures, such as homeostatic model assessment (HOMA) type 2 variants, may model hyperinsulinaemia, but repeatability data are limited. Kraft and Hayashi insulin response patterns may not only add value in diagnosing hyperinsulinaemia, but also lack suitable repeatability data.Aim: The aim of this study was to investigate the repeatability of insulin response patterns, and fasting and dynamic measures of insulin resistance, and to determine whether these latter measures can predict the insulin response pattern.Setting: This study was conducted at Auckland University of Technology Millennium Institute’s sports performance laboratories.Methods: Oral glucose (100 g) tolerance tests were conducted weekly on eight people. Six people completed four tests, while two completed at least two tests. Each test assessed insulin resistance and response patterns. Insulin resistance measures included fasting tests (HOMA2, McAuley Index) and a dynamic test (oral glucose insulin sensitivity [OGIS]). The insulin response patterns were assessed with both Kraft and Hayashi methodologies. Repeatability characteristics of ordinal variables were assessed by Bland and Altman methods, while Fleiss’ κ was applied to categorical variables.Results: Fasting measures of insulin resistance recorded poor repeatability (HOMA2) or poor sensitivity (McAuley Index) compared to the dynamic measure (OGIS). Kraft insulin response patterns were more repeatable compared to Hayashi patterns, based on a combination of Fleiss’ κ (0.290 vs. 0.186,) p-value (0.15 vs. 0.798) and 95% confidence intervals.Conclusions: Both hyperinsulinaemia and insulin resistance should be dynamically assessed with a multi-sampled oral glucose tolerance test. Further investigations are required to confirm a preferred methodology.

Identifying hyperinsulinaemia in the absence of impaired glucose tolerance: An examination of the Kraft database

ObjectiveHyperinsulinaemia is associated with development of chronic metabolic disease and is emerging as a health risk independent to that of insulin resistance. However, little is known to what extent hyperinsulinaemia occurs with normal glucose tolerance in lean subjects. MethodOral glucose tolerance tests with concurrent insulin assay were conducted during the 1970s–1990s. Participants were classified according to glucose tolerance and insulin response pattern. Analysis of variance compared differences in plasma glucose, plasma insulin, and demographic and metabolic risk factors between groups. ResultsParticipants with normal glucose tolerance comprised 54% (n=4185) of the total cohort. Of these, just over half (n=2079) showed hyperinsulinaemia despite normal glucose clearance. Obesity had a modest association with hyperinsulinaemia in people with normal glucose tolerance. Fasting insulin had limited value in diagnosing hyperinsulinaemia. The majority of participants (93%) with impaired glucose tolerance or diabetes had concurrent hyperinsulinaemia. ConclusionHyperinsulinaemia in the absence of impaired glucose tolerance may provide the earliest detection for metabolic disease risk and likely occurs in a substantial proportion of an otherwise healthy population. Dynamic insulin patterning may produce more meaningful and potentially helpful diagnoses. Further research is needed to investigate clinically useful hyperinsulinaemia screening tools.

Glucagon-like peptide-1: The missing link in the metabolic clock?

Circadian expression of clock genes in peripheral tissues is critical to the coordinated regulation of intestinal digestive and absorptive functions, insulin secretion, and peripheral tissue nutrient deposition during periods of nutrient ingestion, thereby preventing metabolic dysregulation. As glucagon‐like peptide‐1 is a key incretin hormone that regulates glucose‐dependent insulin secretion, we hypothesized that this intestinal hormone is a player in the peripheral metabolic clock, linking nutrient ingestion to insulin secretion. We have now established that secretion of glucagon‐like peptide‐1 from the intestinal L cell shows a rhythmic pattern in rats and humans in vivo that is altered by circadian disruptors, such as constant light exposure, consumption of a Western diet and feeding at inappropriate times (i.e., during the light period in rodents). Interestingly, the alterations in the rhythm of the glucagon‐like peptide‐1 secretory responses were found to parallel the changes in the pattern of insulin responses in association with significant impairments in glucose tolerance. Furthermore, we have detected circadian clock gene expression, and showed circadian secretion of glucagon‐like peptide‐1 from both the murine and human L cell in vitro. These findings demonstrate that glucagon‐like peptide‐1 is a functional component of the peripheral metabolic clock, and suggest that altered release of glucagon‐like peptide‐1 might play a role in the metabolic perturbations that result from circadian disruption.

Effect of Different Insulin Response Patterns During Oral Glucose Tolerance Test on Glycemia in Individuals with Normal Glucose Tolerance.

Research is still going on for detecting the earliest glucose homeostasis derangements in individuals, which is crucial for the prevention of glucose intolerance. This cross-sectional study analyzes different insulin response patterns during the oral glucose tolerance test (OGTT) and their implications on glycemia in normoglycemic individuals. The sample frame was the "Offspring of Individuals with Diabetes Study" database. All participants underwent OGTT. Blood samples were collected at 0, 30, 60, and 120 min for measurement of insulin, C-peptide, and proinsulin levels. Normal glucose tolerant individuals were selected for analysis. Four hundred fifty subjects (mean age, 25 years) were included and divided into two groups according to timing of plasma insulin peaking during OGTT: Group 1, peaking at 30 min; and Group 2, peaking at 60 or 120 min. Body mass index (BMI) and insulin resistance were comparable between the groups; however, Group 2 showed a significantly higher 60- and 120-min glucose level and lower disposition index. Based on the magnitude of the insulin levels, Group 1 was subdivided into Group N (normal pattern) and Group E (exaggerated pattern) with a 30-min insulin cutoff of 74 μU/mL (Group E, ≥74 μU/mL). Group 2 was subdivided into Group DL (delayed and limited pattern; 60-min insulin <73.0 μU/mL and 120-min insulin <80.0 μU/mL) and Group DE (delayed and exaggerated pattern; 60-min insulin ≥73.0 μU/mL or 120-min insulin ≥80.0 μU/mL). Group DE showed a significantly higher area under the curve (AUC) of glucose compared with the other groups and had a lower disposition index and high-density lipoprotein levels. Group DL had significantly lower insulin resistance and BMI compared with Group E but showed a similar AUC of glucose. A delayed insulin pattern was associated with higher postprandial glucose levels. Individuals with delayed and exaggerated insulin secretion may have a higher risk for glucose intolerance.

Altered insulin response to an acute bout of exercise in pediatric obesity.

Pediatric obesity typically induces insulin resistance, often later evolving into type 2 diabetes. While exercise, enhancing insulin sensitivity, is broadly used to prevent this transition, it is unknown whether alterations in the exercise insulin response pattern occur in obese children. Therefore, we measured exercise insulin responses in 57 healthy weight (NW), 20 overweight (OW), and 56 obese (Ob) children. Blood samples were drawn before and after 30 min of intermittent (2 min on, 1 min off) cycling at ~80% VO2max. In a smaller group (14 NW, 6 OW, 15 Ob), a high-fat meal was ingested 45 min preexercise. Baseline glycemia was similar and increased slightly and similarly in all groups during exercise. Basal insulin (pmol/L) was significantly higher in Ob vs. other groups; postexercise, insulin increased in NW (+7± 3) and OW (+5 ± 8), but decreased in Ob (-15±5, p < .0167 vs. NW). This insulin drop in Ob was disproportionately more pronounced in the half of Ob children with higher basal insulin (Ob-H). In all groups, high-fat feeding caused a rapid rise in insulin, promptly corrected by exercise. In Ob, however, insulin rose again 30 min postexercise. Our data indicates a distinct pattern of exercise-induced insulin modulation in pediatric obesity, possibly modulated by basal insulin concentrations.

Oreocnide integrifolia (Gaud.) Miq leaf water extract improves metabolic alterations in high fructose fed insulin resistant and hypertensive rats

Aims of the studyThe present study demonstrates the folklore use of Oreocnide integrifolia (Gaud.) Miq (OI) leaf extract used by the people of northeast India and scientifically validates the ethnomedicinal claims against diabetes and hypertension in an experimental rat model. Materials and methodsMale Charles foster rats were fed high fructose diet (60g/100g) for a period of 6 weeks for induction of insulin resistance and hypertension. Animals were divided into five groups (a) control, (b) fructose control, (c) fructose+OI 250, (d) fructose+OI 500 and (e) fructose+Metformin. Plasma levels of glucose, insulin, cholesterol, triglycerides, lipoproteins, free fatty acids along with glucose tolerance and insulin response tests were evaluated. Mean arterial blood pressure was measured at the end of 6-week period and the animals were further challenged with acetylcholine, phenylephrine, isoprenaline or adrenaline to assess the vascular reactivity in vivo. ResultsFructose fed rats exhibited hyperglycemia, hyperinsulinemia, hypertension, elevated lipid profile along with poor glucose tolerance and insulin response pattern. OI extract treated group of animals showed remarkable potential to lower all these manifestations and showed improved vascular response when challenged with different drugs displaying its antihypertensive property. ConclusionThe benefits of using OI extract in a model of metabolic syndrome validate the potential of OI extract as a therapeutant against diabetes associated hypertension.

Determinants of Impaired Fasting Glucose Versus Glucose Intolerance in Polycystic Ovary Syndrome

OBJECTIVETo determine insulin resistance and response in patients with polycystic ovary syndrome (PCOS) and normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance, and combined glucose intolerance (CGI).RESEARCH DESIGN AND METHODSIn this cross-sectional study, 143 patients with PCOS (diagnosed on the basis of National Institutes of Health criteria) underwent oral glucose tolerance testing (OGTT), and 68 patients also had frequently sampled intravenous glucose tolerance tests. Changes in plasma glucose, insulin, cardiovascular risk factors, and androgens were measured.RESULTSCompared with patients with NGT, those with both IFG and CGI were significantly insulin resistant (homeostasis model assessment 3.3 ± 0.2 vs. 6.1 ± 0.9 and 6.4 ± 0.5, P < 0.0001) and hyperinsulinemic (insulin area under the curve for 120 min 973 ± 69 vs. 1,470 ± 197 and 1,461 ± 172 pmol/l, P < 0.0001). Insulin response was delayed in patients with CGI but not in those with IFG (2-h OGTT, insulin 1,001 ± 40 vs. 583 ± 45 pmol/l, P < 0.0001). Compared with the NGT group, the CGI group had a lower disposition index (1,615 ± 236 vs. 987 ± 296, P < 0.0234) and adiponectin level (11.1 ± 1.1 vs. 6.2 ± 0.8 ng/ml, P < 0.0096). Compared with the insulin-resistant tertile of the NGT group, those with IFG had a reduced insulinogenic index (421 ± 130 vs. 268 ± 68, P < 0.05). Compared with the insulin-sensitive tertile of the NGT group, the resistant tertile had higher triglyceride and high-sensitivity C-reactive protein (hs-CRP) and lower HDL cholesterol and sex hormone–binding globulin (SHBG). In the entire population, insulin resistance correlated directly with triglyceride, hs-CRP, and the free androgen index and inversely with SHBG.CONCLUSIONSPatients with PCOS develop IFG and CGI despite having significant hyperinsulinemia. Patients with IFG and CGI exhibit similar insulin resistance but very different insulin response patterns. Increases in cardiac risk factors and free androgen level precede overt glucose intolerance.

Diffusion Characteristics of Microfabricated Silicon Nanopore Membranes as Immunoisolation Membranes for Use in Cellular Therapeutics

Immunoisolating membranes protect transplanted xenogeneic tissue by physically isolating them from the host. However, most are commercial filter membranes that do not possess all the features needed for immunoisolation. Silicon nanopore membranes are thin layers of silicon containing tens of thousands of nanometer-sized channels, which allow passive diffusion of small molecules. They are excellent size-selective barriers, and the objective of this study was to further characterize their immunoprotective properties and make comparisons with commercial filter membranes. Diffusion across membranes was studied using molecules of different sizes, including fluorescein isothiocyanate-dextrans (relative molecular sizes of 4.4 kDa, 20 kDa, and 70 kDa), glucose (0.18 kDa), insulin (6.1 kDa), and immunoglobulin G (IgG) (150 kDa). Protection from complement-mediated lysis was analyzed by a hemolysis assay. Comparative studies were done with filter membranes that have been reported as immunoisolation barriers. To evaluate if silicon nanopore membranes changed insulin response patterns for glucose-stimulated islets, macrocapsules were constructed with nanopore membranes and filled with pancreatic islets, and dynamic perifusion studies were performed. Relative to commercial membranes, silicon nanopore membranes showed high rates of diffusion for glucose and insulin, and acted as efficient barriers to complement proteins and IgG. No other commercial membrane showed comparable diffusion and immunoisolating properties. Islets placed within the macrocapsule exhibited glucose-responsive insulin secretion in perifusion studies. Silicon nanopore membranes possess unique and desirable diffusion properties as immunoisolation membranes and allow rapid response times for the stimulation of islets by glucose. These features are attributed to the physical properties of the membranes, namely, the straight channels, adequate porosity, and the 5 microm thickness.

Sugars, insulin sensitivity, and the postprandial state

Since insulin resistance was first associated with type 2 diabetes and later with cardiovascular disease and hypertension, there has been considerable interest in the role of dietary and environmental factors. Sucrose and fructose have been a particular research focus. Research on animals, particularly rodents, has shown a clear and consistent effect of high-sucrose and high-fructose diets in decreasing insulin sensitivity. Experiments in humans have produced very conflicting results, with limited evidence for a negative effect on insulin sensitivity at higher intakes of fructose or sucrose (generally > 30% of daily energy from sucrose and > 15% of daily energy from fructose). Observation studies in humans have not shown a link between sucrose consumption and insulin sensitivity independent of other dietary factors. This is in contrast with several small studies that showed an improvement in insulin sensitivity after subjects followed dietary advice to lower the glycemic index of their food choices (where sugars were not a target for change). However, the pattern of postprandial glucose and insulin responses elicited by sucrose and fructose differs substantially from that elicited by starches, with lower troughs elicited by sucrose and fructose 2-3 h after eating. These differences in the pattern of postprandial responses offer a potential explanation for the conflicting results on insulin sensitivity, with the possibility that increases in insulin exposure may affect insulin sensitivity through down-regulation of insulin action.

Pharmacological evaluation and chemical stability of 2‐benzylthioether‐5′‐O‐(1‐thiotriphosphate)‐adenosine, a new insulin secretagogue acting through P2Y receptors

AbstractActivation of P2Y receptors on pancreatic β‐cells by extracellular ATP bring about amplification of glucose‐induced insulin secretion, which has been shown to reduce hyperglycemia in vivo. A new P2 receptor ligand, 2‐benzylthio‐ATP‐α‐S, was synthesized based on a combination of modifications of the ATP skeleton, as a potential insulin secretagogue. The two diastereoisomers of this ligand were separated and are designated A and B. The effects of these compounds on insulin secretion and vascular resistance in the rat isolated and perfused pancreas were evaluated in the presence of a slightly stimulating glucose concentration (8.3 mM) and were compared with ATP‐α‐S and ATP. Both isomers of 2‐benzylthio‐ATP‐α‐S (0.015–1.5 μM) induced a concentration‐dependent increase in glucose‐induced insulin release. The potency of isomer A was not significantly different from that of isomer B, and both were approximately 100‐fold more potent than ATP. ATP‐α‐S induced a similar pattern of insulin response; however, it was only approximately 10‐fold more potent than ATP. These compounds also induced vascular effects: ATP‐α‐S induced a vasodilatation and was transiently vasoconstrictor only at a high concentration, whereas the C2‐substituted derivative constantly induced a vasoconstriction. The chemical stability of these ligands was evaluated under physiological conditions and gastric juice pH. Hydrolysis of 2‐benzylthio‐ATP‐α‐S has been studied both in pH 7.4 and pH 1.4 at 37°C using 31P nuclear magnetic resonance (NMR) spectroscopy and high‐performance liquid chromatography. This compound exhibited high chemical stability with respect to hydrolysis of the glycosidic bond and desulfurization of the phosphorothioate moiety. Hydrolysis of the phospho ester bond, which was the only detectable degrading reaction under the investigation conditions (pH 7.4, 37°C), was slow, with a half‐life of 264 h. Moreover, even at gastric juice conditions (pH 1.4, 37°C), hydrolysis of the terminal phosphate was the only detectable reaction, with half‐life of 17.5 h. In conclusion, both isomers of 2‐benzylthio‐ATP‐α‐S are soluble in water and highly chemically stable. These compounds are highly potent and effective insulin secretagogues; however, they increase pancreatic vascular resistance. Drug Dev. Res. 53:33–43, 2001. © 2001 Wiley‐Liss, Inc.

Insulin Response Patterns Contribute to Different Perinatal Risks in Gestational Diabetes

The aim of this study was to evaluate the insulin dynamics of patients with gestational diabetes mellitus (GDM) and to compare perinatal outcomes according to the insulin response patterns. Twenty-two out of 925 consecutive women examined were diagnosed as having GDM. One hundred and ten women who experienced a normal pregnancy were used as controls. Plasma glucose levels and insulin responses were evaluated by a 2-hour 75-gram oral glucose tolerance test (OGTT). Immunoreactive insulin (IRI), the area under the curve (AUC) of glucose (AUCg) and insulin (AUCi), and the insulinogenic index (II = ΔIRI 30 min/ΔBS 30 min) were measured. The GDM patients were divided into three subgroups, consisting of hyper-, normo- and hypoinsulinemic groups, according to the mean ± 2 SD of the AUCi obtained from the controls. Clinical and laboratory findings were compared among the GDM subgroups and controls. The GDM patients showed impaired insulin secretion to glucose stimuli, with low plasma insulin levels (at 30 min) and reduced insulin/glucose ratios (at 30 and 60 min) early in the 75-gram OGTT. The II and AUCi/AUCg values of GDM patients were reduced as compared with those of controls. These reduced insulin responses were remarkable in hypo- and normoinsulinemic GDM patients, but were not detected in hyperinsulinemic GDM patients. The number of babies large for their gestational age in normo- and hypoinsulinemic GDM patients was significantly higher than that in hyperinsulinemic GDM patients or controls. Hyperinsulinemic GDM patients had a high frequency of pregnancy-induced hypertension (40%). The body mass index prior to pregnancy of hyperinsulinemic GDM patients was significantly higher than that of normoinsulinemic GDM patients or controls. It was demonstrated that not only insulin secretion, but also perinatal clinical characteristics, differed among the GDM subgroups. The heterogeneity of the disease was thus confirmed.

Overestimation of minimal model glucose effectiveness in presence of insulin response is due to undermodeling.

Glucose effectiveness is an important determinant of glucose tolerance that can be derived from minimal model analysis of an intravenous glucose tolerance test (IVGTT). However, recent evidence suggests that glucose effectiveness is overestimated by minimal model analysis. Here we compare a new model-independent estimate of glucose effectiveness with the minimal model estimate by reanalyzing published data in which insulin-dependent diabetic subjects were each given IVGTTs under two conditions (Quon, M. J., C. Cochran, S. I. Taylor, and R. C. Eastman. Diabetes 43: 890-896, 1994). In one case, a basal insulin level was maintained (BI-IVGTT). In the second case, a dynamic insulin response was recreated (DI-IVGTT). Our results show that minimal model glucose effectiveness is very similar to the model-independent measurement during a BI-IVGTT but is three times higher during a DI-IVGTT. To investigate the causes of minimal model overestimation in the presence of a dynamic insulin response, Monte Carlo simulation studies on a two-compartment model of glucose kinetics with various insulin response patterns were performed. Results suggest that minimal model overestimation is due to single-compartment representation of glucose kinetics that results in a critical oversimplification in the presence of increasingly dynamic insulin secretion patterns.